Rheumatology, 2-Volume Set [8 ed.] 0702081337, 9780702081330, 9780323930604, 9780323930611

Table of contents :
Cover
Rheumatology
Copyright
Dedication
Contributors
Preface​
Acknowledgments​
Contents
Volume I
01
1 The synovium
Definitions
Embryology
Structure
Cell Types Found in the Synovium as Revealed by Single-Cell Analysis
Intimal Cells
Synovial Macrophages
Synovial Fibroblasts and the Stroma
Intimal Matrix
Vascular Network
Cell Origins and Recruitment
Function
Maintenance of the Tissue Surface
Lubrication
Chondrocyte Health and Nutrition
Synovium as a Target for Immune-Mediated Disease
Summary
Acknowledgment
References
02
2
The articular cartilage
Overall Tissue Organization
Aggrecan
Collagen Fibrillar Networks
Fibers With Collagen Type II as the Main Constituent
Collagen type XI
Collagen type IX
Molecules Regulating Collagen Fiber Assembly
Cartilage oligomeric matrix protein
Decorin
Fibromodulin and lumican
Other leucine-rich repeat proteins
Heparin and heparan sulfate proteoglycans
Fibers and Networks With Collagen Type VI as the Main Constituent
Collagen type VI
Biglycan and decorin
Matrilins
A module cross-linking to other matrix constituents
Molecules Interacting at the Cell Surface and Modulating Chondrocyte Behavior
Integrin-Binding Proteins
Chondroadherin
Fibronectin
Discoidin Domain 2–Containing Receptor
Hyaluronan
Ligands for Heparin Sulfate/Syndecans
Other Molecular Functions
Binding and Sequestering Growth Factors in the Extracellular Matrix
Transforming growth factor-β
Fibroblast growth factor
Other Molecules in the Extracellular Matrix
Matrix Protein Fragments as Indicators of Disease
Repair and Regeneration of Cartilage
Replacing Cartilage
Microfracture
Implanted Cell-Based Therapies
Autologous Chondrocyte Implantation
Stem/Progenitor Cells of Other Tissues
Progenitor Cells of Articular Cartilage
Tissue-Engineered Cartilage
Acknowledgment
References
03
3
Bone structure and function
Introduction
Organization of Bone
Macroscopic (Organ) Level
Microscopic (Tissue) Level
Composition of Bone
Proteoglycans
Osteocalcin
Osteopontin
Osteonectin
Alkaline Phosphatases and Ectonucleotide Pyrophosphatase and Phosphodiesterases
Thrombospondins 1 and 2
Proteins Involved in Mineralization
Fibroblast growth factor 23
PHEX
Dentin matrix protein-1
Matrix extracellular phosphoglycoprotein
Growth Factors
Insulin-like growth factors
Bone morphogenetic protein family
Fibroblast growth factors
Transforming growth factor-β
Platelet-derived growth factor and vascular endothelial growth factor
Bone Cells
Osteoclasts
Osteoclast morphology and function
Osteoclast formation and differentiation
Osteoclast apoptosis
Regulation of osteoclast generation and survival
Osteoblasts
Osteoblast function
Osteoblast formation and differentiation
Osteoblast apoptosis
Regulation of osteoblast generation and apoptosis
OSTEOCYTES
Osteocyte apoptosis: Consequences and regulation
Preservation of osteocyte viability by mechanical stimuli
Osteocyte apoptosis and aging
Hormonal regulation of osteocyte life span
Regulation of bone formation by osteocytes: Sclerostin
Osteocytes as mediators of the anabolic actions of canonical Wnt signaling in bone
Regulation of bone resorption by osteocytes: RANKL and osteoprotegerin
Osteocytes and the bone-remodeling compartment
Growth, Modeling, Remodeling, and Repair
Growth
Modeling
Remodeling
Repair
References
04
4 Tendons and ligaments
Introduction
Classification of Disease Affecting Tendons and Ligaments
Etiology of Tendinopathy, Enthesopathy, and Desmopathy
Pathophysiology of Tendon and Ligaments
Inflammation Activation Pathways Show Plasticity in Tendon Disease
Fibroblast Activation in Tendon Disease
Diseased Tendons Show Dysregulated Resolution Responses
Pain and Neuropeptides
Extracellular Matrix Turnover in Health and Disease
Treatment of Tendon and Ligament Pathology
Medical Treatments
Surgical Treatments
Recent Evidence from Randomized Controlled Trials of Tendon Therapies
Conclusions
References
05
5
Biomechanics of peripheral joints and spine
Introduction
Biomechanics of Whole Joints and Spine
Whole-Joint Movement
Mechanical Function of the Spine
Spinal Movements
Statics and Dynamics
Example of static analysis
Limitations of static analysis
Joint Lubrication
Modes of lubrication
Lubrication in diarthrodial joints
Biomechanics of Tissues
Structural and Material Properties
Stress and Strain
Viscoelasticity
Forces Acting on the Spine
Muscle Forces
Intraabdominal Pressure
Diurnal Variation
Measurement of Spinal Loading in Vivo
Intervertebral Disk Mechanics
Resistance to Compression, Shear, Torsion, and Bending
Acknowledgment
References
06
6
Scientific basis of pain
Nociception and Pain
Types of Pain
The Peripheral Basis of Pain
Structure and Dual Function of Peripheral Nociceptors
Sensory Function of Nociceptors
Sensitization of Nociceptors (Peripheral Sensitization)
Molecular Mechanisms of Peripheral Stimulus Transduction and Peripheral Sensitization
Peripheral Mechanisms of Neuropathic Pain
The Central Basis of Pain
Nociceptive Spinal Cord Neurons
Generation of the Conscious Pain Response in the Thalamocortical System
Central Sensitization (Especially Spinal Sensitization)
Neuroplasticity at the Thalamocortical Level
Reduction of Endogenous Descending Pain Inhibition
Integrative View of Pain
Local Pathological Processes in the Tissue
Systemic/General Factors
Conclusions
References
07
7
Principles of innate immunity
Introduction
Sensing by Innate Immunity
Signaling Sensors
Toll-like receptors
Cytosolic signaling sensors
Internalizing Sensors
Lectin
Soluble Sensors
Complement system
Phylogenetic Comparison of the Recognition System
Critical Functions of Innate Immunity
Induction of Inflammation
Activation of Adaptive Immunity on Infection
Antiviral Responses
Molecular Mechanism of Sensor Signaling
Sensors and Diseases
Toll-Like Receptors and Autoimmunity
Type I Interferonopathies
Toll-Like Receptors and Metabolic Diseases
NOD-Like Receptors and Inflammation
Conclusion
Acknowledgments
References
08
8 Principles of adaptive immunity
Introduction
The Adaptive Immune System
Clonal Selection and Expansion of Lymphocytes
Antigen Receptors of Lymphocytes
Generation of Diversity of Antigen Receptors
B Cells and Humoral Immunity
Development of B Cells
B-Cell Activation and Functions
T Cells and Cell-Mediated Immunity
Recognition of Antigens by T Cells
Processing of Antigens for Presentation to T Cells
T-Cell Development
T-Cell Activation
T-Cell Function
Immunologic Tolerance and Autoimmunity
Conclusion
References
09
9
Signal transduction in immune cells
Introduction
Membrane-Permeable Ligands That Bind Intracellular Receptors
Steroid Hormone Receptors With Ligand-Binding, Dna-Binding, and Transactivation Domains
Receptors With Intrinsic Enzymatic Activity
Receptors That Associate With Enzymes
Type I/II Cytokine Receptors
Antigen Receptors and FC Receptors: The Multichain Immune Recognition Receptor Family
Tumor Necrosis Factor Receptor Superfamily
Innate Recognition of Pathogens
G Protein–Coupled Receptors
Summary
References
10
10
Cytokines
Introduction
Interleukin-1 Receptor Family
Ligand and Receptor Structure
Family Members and their Action
Interleukin-1α and interleukin-1β
Negative regulation of interleukin-1α and interleukin-1β
Interleukin-18
Interleukin-33
Interleukin-36 members and interleukin-36 receptor antagonist
Interleukin-37 and interleukin-38
Signal Transduction
Tumor Necrosis Factor Receptor Superfamily
Ligand and Receptor Structure
Tumor Necrosis Factor–Family Receptor Signaling
Tumor Necrosis Factor Receptor Family Members and their Actions
Type I and II Cytokine Receptors: Hematopoietin and Interferon Receptors
Cytokines that use Glycoprotein 130: Interleukin-6 as a Prototype
Cytokine Receptors Using the β Chain: Interleukin-3, Interleukin-5, and Granulocyte-Macrophage Colony-Stimulating Factor
Cytokine Receptors Using the γ Chain: Interleukin-2, Interleukin-4, Interleukin-7, Interleukin-9, Interleukin-15, and Inter ...
Homodimeric Receptors
Heterodimeric Cytokines
Interferons
Interleukin-10 Family
Signaling by Type I/II Cytokine Receptors
Interleukin-17 Receptors
Transforming Growth Factor-β Receptor Family Cytokines
Signaling
Receptor Tyrosine Kinases
Other Cytokines
Chemokines
Ligand and receptor organization
Family Members and their Actions
Chemokines and immune cell development
Chemokines in lymphoid organs
Sphingosine 1 phosphate
Chemokines in inflammation and HIV infection
Signaling
References
11
11
Inflammation and its chemical mediators
Introduction
The Cells of Inflammation
Endothelial Cell Activation and Leukocyte Adhesion
Granulocytes
Neutrophils
Neutrophil extracellular traps
Eosinophils and basophils
Mast cells
Macrophages
Inflammasomes
Platelets
Regulation and Modulation of Inflammatory Cells
Metabolic Regulation of Inflammation
Trained Immunity, or Innate Immune Memory
Inflammatory Mediators
The Complement System
Lipid Mediators of Inflammation
Arachidonic acid derivatives
Cyclooxygenase products
Lipoxygenase products
Platelet-activating factor
Vasoactive amines
Histamine
Serotonin
Reactive oxygen species and nitric oxide
Reactive oxygen species
Nitric oxide
The Nervous System in Inflammation
Autonomic Influence on Inflammation
The parasympathetic nervous system: a largely antiinflammatory pathway
The sympathetic nervous system
Neuroendocrine mechanisms
Neuropeptides
Substance P
Calcitonin gene-related protein
Neuropeptide Y
Vasoactive intestinal peptide
The Resolution of Inflammation
Elimination Of The Inciting Stimulus And Proinflammatory Signals
Removal of Inflammatory Cells
Lipoxins, Resolvins, and Other Antiinflammatory Mediators
Immune Activity After Resolution of Inflammation
The Aging Inflammatory System: Immunosenescence and Inflammaging
Acknowledgments
References
12
12
The complement system
Classical Pathway
Mannose-Binding Lectin Pathway
Alternative Pathway
Anaphylatoxins
Regulation of the Complement System
Complement in Disease
Complement in Autoimmunity
Complement in Inflammatory Diseases
Strategies for Therapeutically Targeting Complement
Conclusions
References
13
13
Osteoimmunology
Introduction
Current Concepts in Osteoimmunology
Osteoclasts as Triggers of Arthritic Bone Erosions
Molecular and Cellular Mechanisms of Inflammatory Bone Erosion
Intraarticular and Systemic Bone Loss in Rheumatic Disease
Osteoimmunologic Aspects of Bone Formation in Rheumatic Disease
Bone Marrow as a Niche for B-Cell Differentiation and Autoantibody Formation
Conclusion
References
14
14
Joint tissue destruction and proteolysis
Introduction
Proteolytic Pathways of Connective Tissue Breakdown
Extracellular Proteolysis
Matrix Metalloproteinases
MMP regulation—from transcription to inhibition
Regulation of MMP transcription
Epigenetic regulation
Regulation by activation
Regulation by inhibition
Endocytic regulation
Regulation of MMPs and Their Inhibitors by the ECM
Other Proteinases Involved in Pathological Joint Destruction
ADAM and ADAMTS proteinase families
Serine Proteinases
Intracellular Pathways
Osteoclastic Bone Resorption
Model Systems of Joint Destruction
Proteinase Deficiency in Murine Models of Arthritis
Therapeutic Inhibition of Proteinases
Repair of Connective Tissue Matrix
Acknowledgments
References
15
15
Principles of tissue engineering and cell- and gene-based therapy
Introduction
Tissue Engineering
Autologous Chondrocyte Implantation
Mesenchymal Stem Cells
Intraarticular Injection of Mesenchymal Stem Cells
Cell Concentrates
Bone marrow aspirate concentrate
Stromal vascular fraction
Matrix-Guided Application of Mesenchymal Stem Cells
Synthetic scaffolds
Natural scaffolds
Fabrication methods
Trophic and Immunosuppressive Effects of Mesenchymal Stem Cells
Gene Transfer Strategies
Rheumatoid Arthritis
Osteoarthritis
References
16
16 Big Data analysis
What Is Big Data?
Sources of Big Data in Rheumatology
Clinical Data
Challenges and Considerations in the Analysis of Big Clinical and Health Data
Traditional analytical approaches to Big Data
Machine learning approaches to Big Data
Supervised machine learning
Unsupervised machine learning
“Garbage in, garbage out”
Data heterogeneity and integration
Biological Data
Challenges of generation and storage of big biological data
Application and the Future of Big Data
Ethics
References
17
17
Principles and techniques in molecular biology
Introduction
The Human Genome Sequence and Biomedical Research
Basic Manipulation of DNA: Cloning Vectors and Cutting and Pasting DNA Using Enzymes
Polymerase Chain Reaction
DNA Sequencing
Gene Transcription
Gene Expression Profiling
DNA Chip Microarrays
Massively Parallel Sequencing of RNA
Single Cell RNA Sequencing
Regulation of Gene Expression and Protein–DNA Interactions
Analysis of Gene Function
Genetic Manipulation of Mice
Transgenic Mice
Knockout Mice
Mice with cre/lox-Directed Targeted Disruption
CRISPR-Cas9 and Genome Editing
Analysis of Proteins
Proteomics
Molecular Biology: The New Pathology for Practicing Rheumatologists?
References
18
18
Proteomics
Proteomics—A Powerful New Tool for Personalized Medicine
How Does a Mass Spectrometer Work?
Main Proteomics Technologies
Expression Proteomics
Interaction Proteomics
Thermal Shift Proteomics
Post-translational Modification Proteomics
Yeast Two-Hybrid Assay
Mammalian-Membrane Two-Hybrid Assay
How Can Proteomics Help Rheumatology?
Nucleic Acid Programmable Protein Arrays
Recent Advances in Data Acquisition of Mass Spectra
Outlook
References
19
19
Metabolomics
We Are What We Eat: Metabolism Has Driven Our Development
Metabolism Underpins Musculoskeletal Function
Inflammation Perturbs Metabolism
Metabolism and Immune Inflammation
Metabolism in Rheumatology
Metabolomics
Acquiring Metabolomics Data
Making Sense of the Data
Applications of Metabolomics in Rheumatology
Osteoarthritis
Rheumatoid Arthritis
Metabolomics and Other Rheumatic Diseases
Systemic Metabolic Effects
Responses to Therapy
Conclusions
References
20
20
Epigenetics
What Is Epigenetics?
Transcriptional Control Through Epigenetic Mechanisms
Molecular Epigenetics—The Basic Mechanisms
Histone Modifications
Histone acetylation
Histone methylation and citrullination
Histone SUMOylation
DNA Modifications
Epigenetics in Disease
The Origin of Epigenetic Alterations
Rheumatic Diseases and Epigenetic Changes
Systemic lupus erythematosus
Rheumatoid arthritis
Other rheumatic diseases
References
21
21
Precision medicine and pharmacogenomics in rheumatology
Pharmacogenomics
Experimental Approaches and Considerations Regarding Study Design and Data Interpretation
Synthetic Disease-Modifying Antirheumatic Drugs
Methotrexate
Azathioprine
Sulfasalazine
Biologic Disease-Modifying Antirheumatic Drugs
Conclusion
Acknowledgments
References
22
22
The microbiome in rheumatic diseases
Introduction
The Microbiome
Mucosal Barriers and Host-Immune Interactions
Physiologic intestinal inflammation and homeostasis in health
Dysbiosis as a trigger for autoimmunity
Research Methods for Study of the Human Microbiome
The Microbiome in Animal Models of Inflammatory Arthritis
The Microbiome in Human Inflammatory Arthritis
Spondyloarthritis
Inflammatory bowel disease–related arthropathy
Psoriatic arthritis and psoriasis
Rheumatoid Arthritis
The intestinal microbiome in rheumatoid arthritis
The oral microbiome in rheumatoid arthritis
The Microbiome in Systemic Lupus Erythematosus
Pharmacomicrobiomics
Manipulating the Microbiome to Modulate Autoimmune Disease
Conclusion
References
23
23
Principles of epidemiology
Introduction
What Is Epidemiology?
What Can Epidemiologic Methods Accomplish?
What Will Be Covered in This Chapter?
How to Study and Define Populations
Defining the Pieces of an Epidemiologic Study
Defining Exposure
Defining Outcome
Descriptive Epidemiology
Analytic Epidemiology
Traditional Study Designs
Other Study Designs
Measures
Some Notes About Measures and Modeling
Types of Bias
Confounding
Selection Bias
Immortal Time
Misclassification
Generalizability
Summary
References
24
24
Principles of clinical outcome assessment
Introduction
Purpose of Measuring a Clinical Outcome
Sensibility
Validity
Reliability
Responsiveness
Quality assessment of methods in studies of measurement properties and its statistics
Variations in outcome measurement
Interpretability
Examples of Clinical Outcome Assessement
Global assessments
Multidimensional Health Status Instruments
Assessment of Adverse Reactions
Measurement in Clinical Trials
References
25
25
Principles of health economics
Introduction
Concepts of Health Economic Analysis
Types of Costs
Perspectives
Types of Economic Analyses
Cost analysis
Cost–benefit analysis
Cost-effectiveness analysis
Cost–utility analysis
Quality of Life
Time Horizon and Discounting
Reference Case
Health Technology Assessment
Decision Analysis Modeling
Cost-Effectiveness Thresholds
Budgets
Economic Applications in Rheumatic Diseases
Rheumatoid Arthritis
Multiple Technology Analysis
Biosimilar Drugs
Resource Impact
Recommendation
Conclusion
References
26
26
Principles of genetic epidemiology
Introduction
Complex Rheumatic Diseases
Rationale for Investigating the Genetic Basis of Rheumatic Diseases
Approaches for Identifying Disease Genes
Association Studies
Selection of cases and control participants
Power and effect sizes
Selection of genetic markers
Analysis and interpretation of results
Successful Examples of Candidate Association Studies
Protein Tyrosine Phosphatase N22
Whole-Genome Association Studies of Rheumatologic Conditions
New Horizons
References
27
27
Interpreting the medical literature for the rheumatologist
Introduction
Levels of Evidence
Randomized Controlled Trials or Observational Studies?
Critical Appraisal I: Issues Pertaining to Randomized Controlled Trials
Internal Validity and External Validity
Efficacy vs Effectiveness
Superiority Trials and Noninferiority Trials
Statistical Power
Intention-to-Treat Analysis
Subgroup Analyses
Critical Appraisal II: Issues Pertaining to Observational Studies
Types of Cohorts
Healthy cohorts
Clinical cohorts
Use of registries
Selection Bias
Left-censorship bias
Right-censorship bias
Confounding by indication
Critical Appraisal III: Issues Pertaining to Randomized Controlled Trials and Observational Studies
Generalizability
Missing Data
Data Interpretation
The Statistical Test
Conflict of interests
Conclusion
References
28
28
Ethics in clinical trials
Introduction
“Ethical Guardrails” in Clinical Research
Key Principles for Ethical Clinical Trials
Selected Challenges in Clinical Trial Ethics
Conclusion
Acknowledgment
References
29
29
History and physical examination
Introduction
Screening Assessment
Screening History
Screening Examination
Assessing a Musculoskeletal Problem
Aims and Key Principles
The Consultation to Assess a Musculoskeletal Problem: Key Components
History
What are the symptoms?
Pain
What are the site and distribution of the pain?
What are its characteristics?
What precipitates, worsens, or improves the pain?
Stiffness
Swelling and deformity
Weakness and instability
Loss of movement or function
Fatigue and malaise
Anxiety and depression
What are the mode of onset, pattern, and chronology of the various symptoms?
Associated symptoms, preceding factors, red flags, and other clues
Previous health interventions and symptom response
What is its impact?
Social history and occupation
General examination
Regional examination of the musculoskeletal system
Posture
Gait
Identifying and characterizing any abnormalities
Inflammation
Damage
Deformity
Biomechanical abnormalities
What other features are of diagnostic importance?
Examination
Method of examination
Look
Attitude and spontaneous movement
Swelling and deformities
Skin
Wasting
Feel
Warmth
Tenderness
Swelling
Move
Stress
Documentation
Joint problems
Regional pain problems
Generalized pain problems
Neck or back problems
Muscle problems
Bone disorders
Systemic problems with musculoskeletal symptoms
Communicating the findings
Interpretation
References
30
30
Laboratory tests in rheumatic disorders
Introduction
Laboratory Tests in Rheumatic Diseases
Blood Cell Counts
White blood cells
Platelets
Red blood cells
Biochemical Testing
Liver Function Tests
Alkaline Phosphatase
Kidney Function Tests and Urinalysis
Uric acid
Calcium and vitamin D
Acute-phase reactants
Serologic Testing
Autoantibodies
Rheumatoid factor
Antibodies to citrullinated protein and peptide antigens
Antinuclear antibodies
Anti-double-stranded DNA antibodies
Anti-Sm and anti-U1 ribonucleoprotein antibodies
Anti-Ro (SS-A) and anti-La (SS-B) antibodies
Anticentromere and anti-Scl-70 antibodies
Autoantibodies in idiopathic inflammatory myopathies
Antiphospholipid antibodies
Antineutrophil cytoplasmic antibodies
Complement
Conclusion
References
31
31
Aspiration and injection of joints and periarticular tissue and intralesional therapy
Indications for Aspirating or Injecting Musculoskeletal Tissues
Aspiration of Fluid or Diagnostic or Therapeutic Purposes
Key Practice Issues
Procedure
External landmark-guided aspiration
Ultrasound-guided aspiration and injection
Aftercare
Contraindications
Corticosteroid Injections
Complications of corticosteroid injections23
Other Therapeutic Injections
Viscosupplementation
Synoviorthesis
Other Injections
Wrist and Hand
Finger and Metacarpophalangeal Joints
First Carpometacarpal Joint
Wrist (Radiocarpal and Midcarpal Joints, Distal Radioulnar Joint)
Trigger Finger and Trigger Thumb
Digital Flexor Tenosynovitis
Carpal Tunnel Syndrome57
De Quervain Tenosynovitis59
Wrist Extensor Tenosynovitis
Ganglia
Elbow Region
Elbow (Joint)
Olecranon Bursa
Lateral Epicondylar Syndrome, or Tennis Elbow, and Medial Epicondylar Syndrome, or Golfer’s Elbow61,62
Shoulder Region
Shoulder (Glenohumeral Joint)
Acromioclavicular Joint
Subacromial Bursa
Rotator Cuff Calcific Tendinopathy
Long Head of The Biceps Brachii Tendon
HIP Region
HIP joint66
Iliopsoas Bursa
Trochanteric Syndrome
Knee Region
Knee (Joint)
Baker Cyst
Medial Knee Pain and Pes Anserinus Syndrome
Ankle and Foot
Ankle (Joint)
Subtalar Joint
Metatarsophalangeal Joints
Retrocalcaneal Bursa
Posterior Tibialis Tendon (Ptt), Peroneal Tendon, Extensor and Flexor Tendon Sheath
Plantar Fascia Calcaneal Enthesis73,74
Intermetatarsal Bursae
Morton Neuroma76
Intralesional Corticosteroid Treatment
Acknowledgments
References
32
32
Synovial fluid analysis
Macroscopic Characterization
Microscopic Analysis
Wet-Preparation Microscopy
Cell Counts
Crystal Detection
MSU Crystals
CPP Crystals
BCP Crystals
Lipids
Glucocorticoid Crystals
Other Crystalline Contents Of Sf
Noncrystalline Particulate Matter
Ragocytes
Cytocentrifuge Preparation
Bacterial and Septic Arthritis
Nonbacterial Infections
Synovial Fluid Cytology
Summary
References
33
33
Minimally invasive procedures
Introduction
Arthrocentesis
Biopsies
Skin and Subcutaneous Tissue
Abdominal Fat Pad Fine-Needle Aspiration
Temporal Artery
Muscle and Fascia
Salivary Glands
Synovium
Blind (or closed) needle biopsy
Arthroscopic biopsy and joint lavage
Ultrasound-guided synovial biopsy
Acknowledgment
References
34
34
The skin in rheumatic disease
Introduction
Approach to the Patient
Major Systemic Connective Tissue Disorders
Systemic Lupus Erythematosus
Dermatomyositis
Systemic Sclerosis
Sjögren Syndrome (Sicca Syndrome)
Other Systemic Rheumatic Diseases
Rheumatoid Arthritis
Juvenile Idiopathic Arthritis
Relapsing Polychondritis (Atrophic Polychondritis, Systemic Chondromalacia, Polychondropathia)
Psoriatic Arthritis
References
35
35
Ocular manifestations of rheumatic diseases
Introduction
UVEITIS
Management
Scleral Disease
Management
Retinal Vascular Disease
Optic Nerve Disease
Orbital Disease
Corneal Disease
Keratoconjunctivitis Sicca
References
36
36
The cardiovascular system in rheumatic disease
Introduction and Overview
Coronary Artery Disease
Prevention of Coronary Events in Rheumatologic Conditions
Atypical Coronary Disease in SARDs
Coronary Arteritis
Functional Coronary Artery Disorders
Hypertension
Heart Failure and Direct Myocardial Involvement
Valvular Heart Disease
Pericarditis
Arrhythmias
Pulmonary Hypertension
Medication and the Heart
Conclusion
References
37
37
The lungs in rheumatic disease
Introduction
Interstitial Lung Disease
Pathologic and Radiologic Features in Interstitial Lung Disease
Evaluation of Patients With Interstitial Lung Disease in the Rheumatic Diseases
Radiographic Studies
Pulmonary Function Testing
Bronchoscopy
Surgical Lung Biopsy
Ancillary Studies
Lung Involvement in Rheumatic Diseases
Systemic Sclerosis
Rheumatoid Arthritis
Dermatomyositis and Polymyositis
Systemic Lupus Erythematosus
Sjögren Syndrome
Interstitial Pneumonia With Autoimmune Features
Drug-Induced Lung Injury
Lung and Vasculitic Syndromes
Treatment of Interstitial Lung Disease Associated With the Rheumatic Diseases
Conclusion
References
38
38
The gastrointestinal tract in rheumatic disease
Introduction
Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative Colitis
Extraintestinal Manifestations of Inflammatory Bowel Disease
Peripheral Arthritis and Arthralgia Associated With Inflammatory Bowel Disease
Axial Arthritis Associated With Inflammatory Bowel Disease
Bacterial Enteritis
Celiac Disease
Whipple’s Disease
Polyarteritis Nodosa
Henoch-Schönlein Purpura
Behçet Disease
Microscopic Colitis
Conclusion
Acknowledgments
References
39
39
The kidneys in rheumatic diseases
Introduction
Approach to the Patient with Rheumatologic Disease and Suspected Kidney Disease
Acute Versus Chronic Kidney Disease
Glomerular Disease: Nephrotic Versus Nephritic
Diagnostic Tools for Identification of Kidney Disease
Glomerular Filtration Rate
Serum Creatinine
Proteinuria: Urinary Albumin or Protein Excretion Rate
Hematuria
Leukocyturia, Eosinophiluria, and Urinary Casts
Electrolytes and Acid–Base Status
Plasma Complement Levels
Imaging Studies
Kidney Biopsy
Kidney Involvement In Rheumatologic Diseases (Table 39.3)
Rheumatoid Arthritis
Infection-Related Rheumatic Diseases
Infectious arthritis (bacterial, viral, mycobacterial, fungal, parasitic, tickborne)
Acute rheumatic fever
Reactive arthritis
Spondyloarthritis and Psoriatic Arthritis
Axial spondyloarthritis/ankylosing spondylitis
Psoriatic arthritis
Systemic Lupus Erythematosus and Related Diseases
Systemic lupus erythematosus
Sjögren syndrome
Mixed connective tissue disease
Antiphospholipid syndrome
Thrombotic microangiopathy
Systemic Sclerosis/Scleroderma
Systemic sclerosis/scleroderma
Inflammatory Muscle Disease
Polymyositis and dermatomyositis
Vasculitides
Polyarteritis nodosa
Antineutrophil cytoplasmic autoantibody-associated vasculitis
Takayasu arteritis
Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA)
Behçet disease
Kawasaki disease
Immunoglobulin A vasculitis and Henoch-Schönlein purpura
Cryoglobulinemia
Other Systemic Illnesses
Adult-onset Still’s disease
Sarcoidosis
Relapsing polychondritis
Amyloidosis
Immunoglobulin G4-related disease
Nephrogenic systemic fibrosis
Osteoarthritis
Crystal-Related Arthropathies
Gout
Pseudogout
Nephrotoxicity of Antirheumatologic Pharmacologic Therapy
Nonsteroidal Antiinflammatory Drugs
Functional effects
Interstitial nephritis and nephrotic syndrome
Analgesic nephropathy and papillary necrosis
Calcineurin Inhibitors: Cyclosporine and Tacrolimus
Acute kidney injury
Systemic arterial hypertension
Chronic kidney disease
Hemolytic-uremic syndrome
Disease-Modifying Antirheumatic Drugs and Biologic Agents
Rheumatologic Complications of Kidney Disease
Etiologic Factors Specific to Kidney Failure and Their Associated Rheumatic Syndromes
β2-microglobulin amyloidosis
CKD-mineral and bone disorder (CKD-MBD): calcium, phosphorus, vitamin D, fibroblast growth factor 23 (FGF23), and parathyro ...
Oxalate deposition
Hydroxyapatite arthropathy
Clinical Features of CKD-MBD: Bone Disorder and Turnover
Renal osteodystrophy
Other arthropathies in dialysis patients
Rheumatologic-Associated Issues Postkidney Transplantation
Metabolic bone disease
Calcineurin-induced pain syndrome
Renal replacement therapy with transplantation
Acknowledgment
References
40
40
The nervous system in rheumatic disease
Introduction
Peripheral Nervous System
Distal Neuropathy
Cranial Neuropathy
Optic Neuropathy
Trigeminal Neuropathy
Facial Palsy
Multiple Mononeuropathies
Non-Length-Dependent Neuropathy
Central Nervous System
Meningitis
Encephalitis
Myelitis
Conclusion
References
41
41
The muscles in rheumatic disease
Introduction
Skeletal Muscle Anatomy and Architecture
Normal Muscle Contractile Function
Muscle Involvement in Rheumatologic Conditions
Idiopathic Inflammatory Myopathies
Metabolic Myopathies
Cachexia Associated With Rheumatological Diseases
Drug-Induced Myopathy
Generalized Myalgia
Clinical Assessment of Skeletal Muscle
Neurophysiology
Muscle Biopsy
Magnetic Resonance Imaging
Manual Muscle Testing
Acknowledgment
References
42
42
Multimorbidity
Introducing The Concept of Multimorbidity
Assessment and Screening of Multimorbidity
Impact of Multimorbidity
Health Economic Implications
Mortality
Disease-Related Outcomes
Prevalence of Multimorbidity
Impact of Distinct Morbid Conditions
Cardiovascular Disease
Cancer
Depression
Respiratory Diseases
Venous Thromboembolic Disease
Other Important Morbid Conditions
Conclusion
References
43
43
Conventional radiography and computed tomography
Conventional Radiography
Uses
Projection views
Hand and wrist
Sacroiliac joints
Knees
Choice of Joints
Techniques and Physics
Magnification radiography
Digital radiography
Computerized x-ray image analysis methods—Computer-aided detection
Interventional techniques
Computed Tomography
Multidetector Computed Tomography
Applications in Rheumatology
Bone
Peripheral and axial joints
Soft tissues and vessels
Dual-Energy Computed Tomography
References
44
44
Magnetic resonance imaging
Introduction
Basic Principles
T2 Relaxation
T1 Relaxation
Magnetic Resonance Imaging Contrast
Image Quality
Conventional Magnetic Resonance Imaging Methods
Two-Dimensional Fast Spin-Echo Imaging
Three-Dimensional Gradient-Echo Techniques
Advanced Magnetic Resonance Imaging Techniques
Double-Echo Steady-State Imaging
Parallel Imaging
Balanced Steady-State Free Precession Imaging
Three-Dimensional Fast Spin-Echo Imaging
High-Field Magnetic Resonance Imaging
Cartilage Thickness and Volume Mapping
Magnetic Resonance Imaging to Demonstrate Physiologic Activity
Contrast-enhanced imaging
T2 relaxation time mapping
T1rho mapping
Delayed contrast-enhanced imaging
Sodium magnetic resonance imaging
Positron Emission tomography and Magnetic Resonance Imaging
Artificial Intelligence, Machine Learning, and Super-Resolution
Conclusion
Acknowledgments
References
45
45
Functional magnetic resonance imaging
fMRI in Understanding the Mechanism of Pain
fMRI in evaluation of experimental or acute pain
Sensory–discriminative aspect of pain
Affective and cognitive aspects of pain
fMRI in understanding chronic pain
Task-based fMRI
Resting-state fMRI
fMRI in Patient Evaluation and Pain Management
fMRI in therapeutic evaluation
prediction of response to treatment and placebo
Future of fMRI in Clinical Application
Summary
References
46
46
Musculoskeletal ultrasonography
Introduction
Musculoskeletal Ultrasound Imaging
Basic Principles of Ultrasonography
Ultrasound Equipment
Education and Training
Standard Views and Artifacts
Anisotropy
Refractile shadowing and edge artifact
Acoustic shadowing
Acoustic enhancement
Reverberation
Power Doppler scanning technique artifacts
Doppler imaging artifacts
Musculoskeletal Ultrasonography in Rheumatology
Synovial Tissue and the Synovial Joint
Tendon and Enthesis
Dactylitis
Muscle
Bone Erosion and Osteophyte
Cartilage
Soft Tissue Calcification and Crystal-Induced Arthritis
Noninflammatory Soft Tissue Disorders
Spine and Sacroiliac Joint
Intervention
Nonmusculoskeletal Tissue Ultrasonography in Rheumatology
Peripheral Nerves
Vasculitis
Parotid and Salivary Glands
Skin
Conclusion
References
47
47
Bone scintigraphy and positron emission tomography
Introduction
Bone Scintigraphy
Principles
Single-photon emission computed tomography
Uses
Positron Emission Tomography
Background
Uses
Positron Emission Tomography/Computed Tomography
Applications of 18F-Fluorodeoxyglucose Positron Emission Tomography in Inflammatory Diseases
Large-vessel vasculitis
Systemic lupus erythematosus
Sarcoidosis
Arthritis
Fever of unknown origin
IgG4-related disease
Practical Issues
References
48
48
Dual x-ray absorptiometry and measurement of bone
Introduction
Diagnosis of Osteoporosis
Skeletal Sites to Measure
Using Non-Dual X-ray Absorptiometry Technologies for Osteoporosis Diagnosis
Technical Aspects of DXa
Indications for Bone Mineral Density Testing
Vertebral Fracture Assessment
Fracture Risk Assessment
Bone Mineral Density
Clinical Risk Factors and Fracture Risk Assessment Tool (10-Year Fracture Risk Tool)
Bone Turnover Markers
Other Modalities for Fracture Risk Assessment
Quantitative ultrasonography
Quantitative computed tomography
Recent emerging technologies for fracture risk assessment
Monitoring of Therapy
Quantitative Computed Tomography and Peripheral Computed Tomography
Quantitative Ultrasonography
Biochemical Bone Turnover Markers
Bone Turnover Markers After Discontinuing Therapy
Evaluation of Cortical and Trabecular Bone
High-Resolution Peripheral Quantitative Computed Tomography
Finite Element Analysis
High-Resolution Magnetic Resonance Imaging
Bone Material Strength as Measured by Microindentation
Bone Biopsy
Conclusions
References
49
49
Use of imaging as an outcome measure in clinical trials
Introduction
General Aspects for Clinical Trials
Different Phases of Drug Development
Readers
Assessment of Reader Agreement
Grouping of Films—Read Sessions
Blinding Time Sequence
Presentation of Data
Statistical Handling of Missing Data
Statistical Analyses
Minimum Duration of Trial
Placebo Versus Active Comparator
Rheumatoid Arthritis
Conventional Radiography
Films of hands and feet
Scoring Methods
Sharp’s method
Genant’s modification of Sharp’s method
van der Heijde’s modification of Sharp’s method
Magnetic Resonance Imaging and Ultrasonography
Magnetic resonance imaging sum scores
Ultrasonography
HR-pQCT
Psoriatic Arthritis
Conventional Radiography
Typical lesions and site of lesions
Scoring Methods
Psoriatic arthritis scoring method based on the Sharp scoring method for rheumatoid arthritis
Sharp–van der Heijde modified scoring method for psoriatic arthritis
Magnetic Resonance Imaging and Ultrasonography
Axial Spondyloarthritis
Conventional Radiography
Scoring methods
Assessment of the spine
Modified Stoke Ankylosing Spondylitis Spine Score
Low-dose CT
Magnetic Resonance Imaging and Ultrasonography
Scoring methods
Sacroiliac joints
Spine
References
50
50
The patient perspective
Key Points
Introduction
Patients’ Perception of Remission and Flares
Patient-Centered Care
Holistic Approach
Patient-Reported Outcomes
Shared Decision Making
Self-Management
Multidisciplinary Team Care
Organization of Care
Patient Education
Conclusion
References
51
51
Treatment recommendations and “treat to target”
General Treatment Approaches to Rheumatic Diseases
Taking an Integrated Chronic Disease Management Approach (Icdm)
Definition of chronic disease management
Multidisciplinary team-based care
Treating the whole patient: assessing and addressing comorbidities
Incorporating Patient Preferences Through Shared Decision Making (SDM)
Treat-to-Target Concept
Treat-to-Target For Rheumatoid Arthritis
Imaging as the target in treat-to-target strategies
Adherence to treat-to-target strategies in rheumatoid arthritis
Treat-to-Target for Psoriatic Arthritis
Treat-to-Target for Axial Spondyloarthritis
Treat-to-Target for Systemic Lupus Erythematosus
Treat-to-Target for Osteoarthritis
Treat-to-Target for Gout
References
52
52
Arthritis patient education, self-management, and health promotion
Introduction
Patient Education During the Clinical Encounter
Factors Affecting Patient Adherence to Treatments
Designing Patient Education Self-Management Programs
Structure and Content of Arthritis Education and Self-Management Programs
Health Literacy and Cultural Considerations in Patient Education
Evidence for the Effectiveness of Self-Management Education Programs
Team Care, Team Roles, and Approaches to Management
Public Health Approaches to Patient Education In Arthritis
Technology and the Future of Arthritis Patient Education
References
53
53
Principles of rehabilitation: physical and occupational therapy
Rehabilitation and its Role in People with Disability Caused by Rheumatic Diseases
Rehabilitation Adopts A Biopsychosocial Approach To Patients And Their Needs
Patient-Centered Care is a Central Tenet of Rehabilitation
Education of Patients and Caregivers is Important to Facilitate Self-Management and Adherence to Treatment Recommendations
Adherence to an Individualized Structured Exercise Program is Fundamental to Self-Management
Patients Should be Encouraged and Supported to Maintain or Increase Their General Physical Activity Levels
Aids, Adaptive Devices, and Environmental Modifications Can Maximize Functional Independence
Joint Protection and Energy Conservation are Important to Minimize Symptoms
Occupational Rehabilitation is Important for Patients of Working Age
Regular Monitoring and Follow-Up are Important
References
54
54
Multidisciplinary approaches to managing chronic pain in arthritis
Introduction
Prevalence of Pain in Musculoskeletal and Rheumatologic Conditions
Measurement of Pain
Psychological Factors and Pain
Psychological Factors Associated with Outcome
Interventions
Physical Activity for the Relief and Self-Management of Pain
Lifestyle Management of Rheumatologic Pain
Joint Protection Programs
Arthritis Self-Management Programs
Splinting for the Painful Hand
Sleep
Activity Pacing
Relaxation
Work
Patient Education and E-Health
Novel Interventions for Pain Relief
Graded Motor Imagery (GMI) Programme
Visual Illusions
Conclusion
Acknowledgment
References
55
55
Placebo, nocebo, caring, and healing in rheumatology
Introduction
Definition
Biological Mechanisms
Conclusions
References
56
56
Complementary and alternative medicine
Overview
Who Seeks Complementary and Alternative Medicine and Why
Widely Used Complementary and Alternative Medicine Systems and Their Therapies
Traditional Chinese Medicine and Acupuncture
Philosophy and history
Treatment
Evidence
Herbal Medicine
Philosophy and history
Treatment
Evidence
Topical capsaicin
Curcumin
Ginger
Devil’s claw
Boswellia serrata
Nutraceuticals and Dietary Supplements
Glucosamine and chondroitin
S-adenosylmethionine
Avocado/soybean unsaponifiables
Omega-3 and omega-6 fatty acids
Homeopathy
Referral and Professional Practice
References
57
57
Outcomes and perioperative management of patients with inflammatory arthritis and systemic lupus erythematosus undergoi ...
Key Points
Introduction
Outcomes and Adverse Events
Rheumatoid Arthritis
Spondyloarthritis
SLE
Perioperative Management
Anesthesia in Patients With Rheumatic Disease
Perioperative Management of Comorbid Medical Conditions
Cardiovascular Disease
Venous Thromboembolism
Antiphospholipid Syndrome
Pulmonary Disease
Management of Antirheumatic Therapy
Chronic Glucocorticoid Therapy
Prevention of Postoperative Infection
Conclusion
References
58
58
Indications for and long-term complications of total hip and knee arthroplasty
Introduction
Indications
Osteoarthritis Is the Most Common Indication for TJA
Clinical Presentation
Contraindications for TJA
Age and TJA
BMI and TJA
Outcomes
Complications
Nonorthopedic Complications
Orthopedic Complications
Impact Of BMI On Complications
Impact of Age on Complications
Conclusion
References
59
59
Medication management during preconception, pregnancy, and lactation
Introduction
Pregnancy
Rheumatic Diseases And Pregnancy
Aspirin And Other Nonsteroidal Antiinflammatory Drugs
Glucocorticoids
Antimalarials
Sulfasalazine
Immunosuppressive Agents
Azathioprine
Cyclosporine
Mycophenolate Mofetil
Tacrolimus
Methotrexate
Leflunomide
Cyclophosphamide
Intravenous Immunoglobulin
Tumor Necrosis Factor-α Blockade And Inhibitors
Rituximab, Other Biologic Agents, And Small Molecules
Inadvertent Teratogenic Medication Exposure
Paternal Medications Pre- And Postconception
Conclusion
References
60
60
Principles of pharmacologic pain management
Introduction
Opioid Mechanisms
The Evidence
Patient Selection and Medication Management
Risk Assessment
Prescription Drug Monitoring Plans
Informed Consent
Dosing
Drug Monitoring
Adverse Drug Effects
Driving and Opioids
Older Adults and Chronically Ill Patients
Acute-on-Chronic Pain
Dual-Action Opioids
Alternative Medications for Chronic Musculoskeletal Pain
Tricyclic Antidepressants, Selective Serotonin Reuptake Inhibitors, and Calcium Channel Blockers (Gabapentinoids)
Topical Analgesics
Cannabinoids
References
61
61
Nonsteroidal antiinflammatory drugs
Introduction
Mechanism of Action
Cyclooxygenase Isozyme Selectivity
Pharmacokinetics and Drug Interactions
Clinical Efficacy
Adverse Effects
Gastrointestinal
Cardiovascular
Renal
Respiratory
Hepatic
Rational Selection of Nonsteroidal Antiinflammatory Drug Therapy
References
62
62
Systemic glucocorticoids in rheumatology
Nomenclature and Pharmacology
Preparations and Structure
Dosing
Bioequivalence and Bioavailability
Metabolism and Drug Interactions
Clearance and Dose Timing
Mechanisms of Glucocorticoid Action
Efficacy
Efficacy in Rheumatoid Arthritis
Efficacy in Systemic Connective Tissue Disorders and Vasculitis
Efficacy in Polymyalgia Rheumatica and Large-Vessel Vasculitis
Adverse Effects
Bone and Muscle
Cardiovascular
Dermatologic and Appearance
Gastrointestinal
Infectious Diseases
Metabolic and Endocrine
Neuropsychiatric
Ophthalmologic
Use in Pregnancy
Practical Recommendations
Evidence-Based Treatment Guidelines
Perioperative and Stress-Dose Considerations
Glucocorticoids in Children
Glucocorticoid Withdrawal Regimens and Alternate-Day Therapy
References
63
63
Methotrexate
Introduction
Pharmacology
Mechanism of Action
Efficacy in Rheumatoid Arthritis
Initial Use
Efficacy Compared With Other Disease-Modifying Antirheumatic Drugs
Efficacy in Combination With Other Disease-Modifying Antirheumatic Drugs
Effect of Methotrexate on Structural Damage
Long-Term Studies
Predictors of Response to Methotrexate
Effect on Mortality
Adverse Effects
Common Adverse Effects
Hepatic Toxicity
Pulmonary Toxicity
Vaccination
Other Adverse Effects
Teratogenicity
Folic Acid Supplementation
Methotrexate Use in Rheumatoid Arthritis: Recommendations
Methotrexate in Other Rheumatic Diseases (Table 63.3)
Psoriatic Arthritis
Juvenile Idiopathic Arthritis
Other Rheumatic Diseases
Conclusions
Acknowledgment
References
64
64
Synthetic disease-modifying antirheumatic drugs and leflunomide
Introduction
Parenteral Gold
Introduction
Pharmacology
Mode of Action
Efficacy
Toxicity
Dosage and Monitoring
Bucillamine
Introduction
Pharmacology
Mode of Action
Efficacy
Adverse Effects
Dosage and Monitoring
Sulfasalazine
Introduction
Pharmacology
Mode of Action
Efficacy
Toxicity
Dosage and Monitoring
Hydroxychloroquine
Introduction
Pharmacology
Mode of Action
Efficacy
Rheumatoid arthritis
Systemic lupus erythematosus
Metabolic effects
Toxicity
Dosing of hydroxychloroquine
Leflunomide
Introduction
Pharmacology
Mode of Action
Efficacy in Rheumatoid Arthritis
Monotherapy
Combination therapy
Combination therapy with biologic agents
Efficacy in Other Rheumatologic Conditions
Safety and Tolerability
Tetracycline Derivatives: Minocycline and Doxycycline
Introduction
Randomized controlled trials of minocycline
Randomized controlled trials (RCTs) of doxycycline in RA and OA
Metaanalysis of minocycline and doxycycline for rheumatoid arthritis
Doxycycline for the Treatment of Osteoarthritis
References
65
65
Immunosuppressive agents: cyclosporine, cyclophosphamide, azathioprine, mycophenolate mofetil, and tacrolimus
Introduction
Mechanisms of Action
Azathioprine
Cyclophosphamide
Cyclosporine
Mycophenolate Mofetil
Tacrolimus
Pharmacokinetics
Azathioprine
Cyclophosphamide
Cyclosporine
Mycophenolate Mofetil
Tacrolimus
Efficacy, Toxicity, and Therapeutic Use
Azathioprine
Efficacy
Toxicity
Therapeutic use
Cyclophosphamide
Efficacy
Toxicity
Therapeutic use
Cyclosporine
Efficacy
Toxicity
Therapeutic use
Mycophenolate Mofetil
Efficacy
Toxicity
Therapeutic use
Tacrolimus
Efficacy
Toxicity
Therapeutic use
Acknowledgment
References
66
66
Kinase inhibitors and other synthetic agents
Introduction
Tyrosine Kinases
Tyrosine Kinase Inhibitors
JAK Inhibitors for Rheumatoid Arthritis
Tofacitinib
Baricitinib
Safety and tolerability of the approved JAK inhibitors
Position of JAK inhibitors in the treatment of RA
JAK Inhibitors for Other Rheumatological Indications
Psoriatic arthritis
Systemic lupus erythematosus and other connective tissue diseases
Other JAK inhibitors
Other Kinase Inhibitors
References
67
67
Overview of biologic agents
Introduction
Antibodies and the Humoral Immune Response
Antibody Structure
Structural Characterization of Approved Antibody Therapeutics
Mechanisms of Action
Placental Transfer of Biological Drugs
Immunogenicity
Specific MoA of Biological Drugs: Relating Structure to Function
Targeting Cytokines: TNF-α as an Example
Cell Depletion: B Cells as an Example
Targeting Cell–Cell Interactions
Future Directions
Alternative Structures
Using Multiple Antibodies and Bispecific Molecules
References
68
68
Interleukin-1 inhibitors
Interleukin-1 Family
Ligands and Receptors
Interleukin-1 Plays a Critical Role in Inflammation
Regulation of Interleukin-1β Maturation by the Inflammasome
Therapeutic Inhibitors of Interleukin-1 in Rheumatic Diseases
Rheumatoid Arthritis
Recombinant interleukin-1 receptor antagonist (anakinra, Kineret)
Soluble interleukin-1 receptors
Monoclonal antibodies
Inhibition of interleukin-1β production
Ankylosing Spondylitis
Psoriatic Arthritis
Systemic Lupus Erythematosus
Osteoarthritis
Crystal-Induced Arthritis
Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still’s Disease
Interleukin-1 Inhibition for Periodic Fever Syndromes
Other Autoinflammatory Disorders
General Comments on Available Interleukin-1 Inhibitors
References
69
69
Interleukin-6 inhibitors
Tocilizumab
Mechanism of Action
Use, Recommended Dose, and Dose Adjustment
Intravenous administration
Subcutaneous administration
Pharmacokinetics
Intravenous administration
Subcutaneous administration
Use in Specific Populations
Pregnancy and nursing
Use in older adults
Hepatic or renal impairment
Clinical Trial Results in Rheumatoid Arthritis
Safety
Infections
Gastrointestinal perforation
Malignancies
Cardiovascular events
Infusion reactions
Hematology
Transaminase elevations
Lipids
Use in Other Rheumatoid Diseases
Large-vessel vasculitis (Takayasu and giant cell arteritis)
Juvenile idiopathic arthritis
Adult-onset Still disease
Systemic lupus erythematosus
Scleroderma
Spondyloarthritis
Upcoming Agents
Sarilumab
Olokizumab
Clazakizumab
Sirukumab
Acknowledgment
References
70
70
Tumor necrosis factor inhibitors
Introduction
Mechanism of Action
Biologic Effects
Approved Indications and Practical Use
Adalimumab (Humira)
Pharmacology
Indications and Use
Adalimumab in Rheumatoid Arthritis Pivotal Trials
Etanercept (Enbrel)
Pharmacology
Indications and Use
Etanercept in Rheumatoid Arthritis Pivotal Trials
Infliximab (Remicade)
Pharmacology
Indications and Dosing
Clinical Efficacy of Infliximab in Rheumatoid Arthritis
Certolizumab Pegol (Cimzia)
Pharmacology
Indications and Dosing
Clinical Efficacy of Certolizumab Pegol in Rheumatoid Arthritis
Golimumab (Simponi)
Pharmacology
Indications and Dosing
Clinical Efficacy of Golimumab in Rheumatoid Arthritis
Dose Reduction or Withdrawal of Anti–Tumor Necrosis Factor Therapy
Immunogenicity
Switching Between Anti–Tumor Necrosis Factor Agents
Expanded Indications
Ankylosing Spondylitis
Psoriatic Arthritis
Other Orphan Disorders
Granulomatous Disease
Antineutrophil Cytoplasmic Antibody–Associated Granulomatous Vasculitis
Giant Cell Arteritis
Polymyalgia Rheumatica
Sarcoidosis
Pyoderma Gangrenosum
Hidradenitis Suppurativa
Takayasu Arteritis
Inflammatory Eye Disease or Uveitis
Behçet Syndrome
Baseless Use of Tumor Necrosis Factor Inhibitors
Tumor Necrosis Factor Inhibitors in Early Rheumatoid Arthritis
Tumor Necrosis Factor Inhibitors in Children
Tumor Necrosis Factor Inhibitors in Older Adults
Pregnancy and Lactation
Safety of Anti–Tumor Necrosis Factor Therapy
Infusion Reactions
Injection Site Reactions
Infectious Risk
Tuberculosis
Other Opportunist Infections
Malignancy
Autoimmune Responses
Demyelinating Syndromes
Congestive Heart Failure
Interstitial Lung Disease
Cytopenias
Hepatotoxicity
Cutaneous Reactions
Unusual Toxicities
Vaccinations
Monitoring
Conclusion
References
71
71
Interleukin-17, interleukin-12, and interleukin-23 inhibitors
Potential Cytokine Targets in Rheumatic Diseases
Interleukin-17
Description, Receptor, and Function
Interleukin-17 in Rheumatic Disease
Clinical Trials
Interleukin-23
Description, Receptor, and Function
Interleukin-12 and Interleukin-23 in Rheumatic Diseases
Clinical Trials
Significant Points
Conclusion
References
72
72
Inhibitors of T-cell costimulation
Rationale for Targeting T Cells in Rheumatoid Arthritis
Costimulatory Signal in T-Cell Activation
Abatacept
Clinical Efficacy
Intravenous abatacept
Comparison with tumor necrosis factor inhibitors
Treatment of early rheumatoid arthritis
Subcutaneous abatacept
Combination with methotrexate
Comparison with tumor necrosis factor inhibitors
Drug-free remission
Safety
Infusion-related reaction
Infection
Tuberculosis
Vaccination
Malignancy
Subcutaneous abatacept
Safety of Abatacept in Routine Clinical Practice
Immunogenicity
Real-World Effectiveness And Safety
Biologic Effects
Summary of the Efficacy and Safety of Abatacept
New Costimulatory Inhibitors
Conclusions
References
73
73
Inhibitors of B cells
Introduction
Roles of B Cells in Rheumatic and Musculoskeletal Diseases
Targeting CD20
Rituximab
Rituximab Biosimilars
Other Type 1 and 2 Anti-Cd20 Molecules
Efficacy for Rheumatoid Arthritis
Radiographic Outcomes
Outcome of Repeat Cycles
Effect Of Rituximab Dose
Retreatment Of Nonresponse
Concomitant Conventional Synthetic Disease Modifying Antirheumatic Drugs
Antibody status
Type 1 interferon
Interleukin-33
Peripheral blood B-cell studies
Genetic studies
Factors Predicting Response to Rituximab
Rituximab: Use in Connective Tissue Diseases
Anca-Associated Vasculitis (AAV)
Systemic Lupus Erythematosus
Primary Sjögren Syndrome
Safety of Rituximab
Screening Before Therapy
Infusion Reactions
Infections
Low Immunoglobulin Levels Before And After Rituximab
Vaccination Responses And Immunization Following Rituximab
Progressive Multifocal LEUKOENCEPHALOPATHY (Pml)
Immunogenicity
Rituximab In Chronic Lung Disease
Malignancy
Inhibition of B-Cell Survival Factors
Efficacy of Belimumab in Systemic Lupus Erythematosus
Summary
References
74
74
Emerging therapeutic targets
Introduction
Anti-cytokines (Table 74.1)
Granulocyte–Macrophage Colony-Stimulating Factor
Interferon-Alpha
Interleukin-17 AXIS
BAFF/TACI/APRIL
IL-4/IL-13
T CELLS (Table 74.2)
VIB4920
Signaling Pathways (Table 74.3)
Bruton Tyrosine Kinase Inhibition
Other Signaling Pathways
Adhesion
E6011
Asp5094
Glucocorticoid Analogues (Table 74.6)
AZD-9567
ABBV-3373
AP1189
Immunoregulation
Cells as Therapies (Table 74.4)
Vagal Nerve Stimulation
Microbiome Manipulation
Targeting Stroma
RO7123520/RG6125 (Secara)
R-Roscovitine (Seliciclib)
Miscellaneous Interventions (Table 74.6)
ABX464
MBS2320
CF101
CR6086
Complement C5a
Autotaxin
Proteasome Inhibitors
Cannabinoid Receptors
References
75
75
Biosimilars in rheumatology
Definitions
Biosimilars
Biomimics
“Second-Generation” Biopharmaceuticals
Development of Biosimilars
Demonstration of Biosimilarity
Biosimilars for Inflammatory Diseases
Approved Biosimilars
Biosimilars in Development
Immunogenicity
Extrapolation of Indications
Interchangeability
Nomenclature
Cost
References
76
76
Infections in rheumatoid arthritis: biologic therapy and JAK inhibitors
Rheumatoid Arthritis and Burden of Infection
Prednisone
Biologic Therapies and Risk for Infection
Tumor Necrosis Factor Antagonists and Risk for Infection
Opportunistic Infections with Anti–Tumor Necrosis Factor Therapy
Abatacept, Rituximab, Tocilizumab, and Anakinra
Risk for Serious Bacterial and Opportunistic Infections
JAK Inhibitors
Prevention of Infection in Patients Treated with Biologics or Jak Inhibitors: Screening and Vaccination
Intracellular Pathogens
Conclusion
Acknowledgment
References
77
77
Neck pain
Introduction
Epidemiology
Incidence and Prevalence
Risk Factors
Pathogenesis of Neck Pain
Clinical Assessment
History
Clinical Examination
Onset of pain
Quality of pain
Frequency and duration of episodes of pain
Site, radiation, and source of pain
Associated features
Neurologic abnormalities
Clinical Examination
General Examination
Neurologic Examination
Neck Movement
Cervical Nerve Root Compression
Clinical Features
Clinical Examination
Investigations
Imaging
Radiographs
Computed tomography
Magnetic resonance imaging
Isotope scans
Blood Tests
Investigations Targeting Pain
Zygapophyseal joint blocks
Other anesthetic blocks
Provocation diskography
Treatment of Neck Pain
Nonspecific Treatments
Analgesics
Exercises
Physical therapy
Manual therapy or manipulation
Pillows and posture correction
Specific Treatments
Zygapophyseal joints
Intervertebral disks
Treatment—Cervical Nerve Root Compression
Natural History
Treatment Modalities
Corticosteroid injections
Surgery
Whiplash
Biomechanics
Pathology
Imaging
Natural History
Treatment of Acute Whiplash Injury
Treatment of Chronic Whiplash
Conclusion
References
78
78
Low back pain
Epidemiology
Occurrence
Impact
Risk Factors
Clinical Evaluation
Introduction
History
Site of pain
Aggravating and relieving factors
Physical Examination
General examination
Spinal examination
Lumbar range of motion
Manual muscle testing
Neurologic examination
Sensory examination
Deep tendon reflexes
Provocative maneuvers
Root tension signs
Gait analysis
Nonorganic physical signs
Investigations
Imaging
Plain radiographs
Radionuclide bone scintigraphy
Computed tomography
Magnetic resonance imaging
Correlation between magnetic resonance imaging and clinical findings
Comparison between magnetic resonance imaging and other modalities
Other imaging techniques
Clinical Laboratory Tests
Electrodiagnostic Studies
Concerning Causes of Low Back Pain (Box 78.3)
Cauda Equina Compression
Abdominal Aortic Aneurysm
Infections
Vertebral osteomyelitis
Disk infection
Pyogenic sacroiliitis
Herpetic Neuralgia
Neoplasms
Osteoid osteoma
Other primary spinal tumors
Multiple myeloma
Skeletal metastases
Rheumatologic Causes
Primary Bone Disorders
Referred Pain
Pain referred from other visceral organs
Pain referred from the hip joint
Centrally mediated pain
Mechanical Causes of Low Back Pain
Spondylolysis and Spondylolisthesis
Intervertebral Disk Disorder and Vertebrogenic Low Back Pain
Mechanisms of pain
Clinical features
Investigations
Treatment
Zygapophyseal (Facet) Joint Syndrome
Lumbar Spinal Stenosis
Etiology and pathogenesis
Clinical features
Investigations
Differential diagnosis
Management of Lumbar Spine Disorders
Conservative Approaches
Physical modalities
Exercise
Oral Drug Therapy
Analgesics
Nonsteroidal antiinflammatory drugs
Muscle relaxants
Neuropathic pain agents
Injection Therapy
Epidural injections
Facet joint injection
Complementary/Integrative Therapies
Surgical Treatment
Neuromodulation
References
79
79
The shoulder
Functional Anatomy
The Glenohumeral Joint
The glenohumeral ligaments
Coracohumeral and coracoacromial ligaments
Rotator cuff and long head of biceps tendon
Acromioclavicular Joint
Scapulothoracic Joint
Sternoclavicular Joint
Bursae
Nerve and Blood Supply
History and Physical Examination
History
Examination
Inspection
Palpation
Movements
Special tests
Hypermobility
Glenohumeral joint instability
Differential Diagnoses
Rotator Cuff Tears, Tendinopathy, and Impingement
Pathology
Clinical Features
Investigations
Management
Calcific Tendonitis
Pathology
Clinical Features
Investigations
Management
Biceps Pathology and SLAP Tears
Pathology
Clinical Features
Investigations
Management
Frozen Shoulder
Pathology
Clinical Features
Investigations
Management
Glenohumeral Joint Instability
Pathology
Clinical Features
Investigations
Management
Glenohumeral Arthritis
Pathology
Clinical Features
Investigations
Management
Acromioclavicular Joint Instability
Pathology
Clinical Features
Investigations
Management
Acromioclavicular Arthritis
Pathology
Clinical Features
Investigations
Management
Lateral Clavicular Osteolysis
Scapular Winging
Scapulothoracic Crepitus
Sternoclavicular Disorders
References
80
80
The elbow
Anatomy of the Elbow
Clinical Evaluation
Investigations
Elbow Disorders
Soft Tissue Elbow Conditions
Bone And Joint Conditions
References
81
81
The wrist and hand
Introduction
Clinical Evaluation
History
Physical Examination
Resting Posture
Swelling And Deformity
Differential Diagnosis of Joint Swelling
Other hand findings
Range of motion
Differential Diagnosis of Wrist and Hand Pain
Specific Disorders of the Wrist and Hand
Tenosynovitis
De Quervain Syndrome
Intersection Syndrome
Trigger Finger or Thumb (Stenosing Digital Tenosynovitis)
Ganglions of the Wrist and Hand
Carpal Tunnel Syndrome
Dupuytren Disease
References
82
82
The hip
Functional Anatomy
Bony Structures
Joint Capsule
Hip Musculature
Bursae
Blood Supply
Clinical Evaluation
History
Physical Examination
Gait examination
General inspection
Palpation
Range of motion
Special tests
Patrick (FABER) test
Thomas test
Stinchfield test
Apprehension tests
McCarthy test
Leg length measurement
Radiographic Evaluation
Plain Radiographs
Other Imaging
Role Of Imaging In Clinical Practice
Specific Hip Disorders
Hip Dysplasia
Femoroacetabular Impingement
Clinical features
Imaging
Treatment
Periarticular Soft Tissue Problems
Bursitis
Trochanteric bursitis
Iliopsoas bursitis
Ischiogluteal bursitis
Abductor tendon tears
Acknowledgment
References
83
83
The knee
Structure of the Knee Joint
Skeletal Anatomy
Distal femur
Proximal tibia
Patella
Soft Tissue Anatomy
Superficial Musculature
Extensor mechanism
Deep structures
Ligaments
Medial collateral ligament
Lateral collateral ligament
Anterior and posterior cruciate ligaments
Posterior structures
Neurovascular Supply
Menisci
Clinical Evaluation of a Patient With Knee Symptoms
History
Examination
Observation
Palpation
Range of motion
Ligamentous stability
Patellofemoral joint stability
Imaging
Specific Disorders of the Knee
Early Childhood
Referred hip pain
Infection
Septic arthritis
Osteomyelitis
Discoid meniscus
Malignancy and hematologic conditions
Inflammatory disease of the knee
Adolescence
Osgood-Schlatter disease
Sinding-Larsen-Johansson disease
Osteochondritis dissecans
Anterior cruciate ligament rupture
ADULTS
Anterior knee pain
Chondromalacia patellae
Patellofemoral maltracking, subluxation, and dislocation
Traumatic ligamentous injuries
Anterior cruciate ligament injuries
Posterior cruciate ligament injuries
Medial collateral ligament injuries
Lateral collateral ligament injuries
Bursitis
Patellar tendonitis
Iliotibial band syndrome
Disorders Occurring Across the Age Spectrum from Adolescence
Popliteal cysts
Synovial chondromatosis
Pigmented villonodular synovitis
Meniscal injuries
Extensor mechanism injuries
Isolated cartilage defects
Osteoarthritis
References
84
84
The ankle and foot
Introduction
Epidemiology of Foot and Ankle Problems
Anatomy of the Ankle and Foot
Ankle
Foot
Examination of the Foot and Ankle
Imaging
OTHER ASSESSMENTS
Local Ankle and Foot Problems
Ankle Sprains
Impingement Syndromes
Achilles Tendinopathy
Tibialis Posterior Tendon Dysfunction and Acquired Adult Flatfoot
Flatfeet (Pes Planus) and High-Arched Feet (Pes Cavus)
Nerve Entrapments
Morton neuroma
Tarsal tunnel syndrome
Heel Pain
Midfoot Pain
Forefoot Pain
Foot Problems Secondary to Systemic Conditions
Rheumatoid Arthritis
Psoriatic Arthritis and Seronegative Diseases
Juvenile Idiopathic Arthritis
Osteoarthritis
Connective Tissue Diseases
Crystal Arthropathies
Hypermobility Syndrome
Acknowledgments
References
85
85
The temporomandibular joint
Epidemiology, Etiology, and Classification
Functional Anatomy
Clinical Features
Management
Nonsurgical Management
Surgical Management
Relationship to Other Chronic Pain Disorders
References
86
86
Entrapment neuropathies and compartment syndromes
Introduction
Upper Extremity
Thoracic Outlet Syndrome
Anatomy
Etiology
Clinical features
Diagnosis
Treatment
Ulnar Nerve Compression Syndromes
Cubital Tunnel Syndrome
Anatomy
Etiology
Clinical features
Diagnosis
Treatment
Ulnar Tunnel Syndrome
Anatomy
Etiology
Clinical features
Diagnosis
Treatment
Median Nerve Compression Syndromes (Forearm Entrapment)
Anterior Interosseous Nerve Syndrome
Pronator Teres Syndrome
Carpal Tunnel Syndrome
Anatomy
Etiology
Clinical Features
Tests
Diagnosis
Treatment
Splinting
Local injection of corticosteroid
Nonsteroidal antiinflammatory drugs and other agents
Surgery
Radial Nerve Compression Syndrome
Posterior Interosseous Nerve Syndrome
Anatomy
Etiology
Clinical features
Diagnosis
Treatment
Lower Extremity
Piriformis Syndrome
Anatomy
Etiology
Clinical features
Diagnosis
Treatment
Meralgia Paresthetica
Anatomy
Etiology
Clinical Features
Diagnosis
Treatment
Peroneal Nerve Entrapment
Anatomy
Etiology and Clinical Features
Diagnosis
Treatment
Tarsal Tunnel Syndrome
Anatomy
Etiology
Clinical Features
Diagnosis
Treatment
Morton Metatarsalgia (Morton Neuroma, Interdigital Neuritis)
Anatomy
Etiology
Clinical Features
Diagnosis
Treatment
Compartment Syndromes
Acute Compartment Syndrome
Chronic Compartment Syndrome
Acknowledgments
References
87
87
Complex regional pain syndrome
Introduction
History of CRPS
The establishment of pain as a “5th vital sign”
Triggers
Pathogenesis
Inflammation
Autoimmunity
Neurological System Abnormalities
A Psychological Component to Crps
Biomarkers
Criteria for the Diagnosis of CRPS
The Orlando Criteria
Component factor analysis and the creation of symptom groups
Attempts to validate the Orlando criteria
The Budapest Criteria
Validation of the Budapest criteria
Incidence of CRPS Based on Evolving Criteria
Confusion with Other Diagnoses
CRPS in Children
Treatment of CRPS
Nonpharmaceutical, Nonsurgical Approaches to Crps
Physiotherapy
Psychotherapy
Medications
Nonsteroidal antiinflammatory agents
Calcitonin
Bisphosphonates
Free radical scavengers
Corticosteroids
Isosorbide dinitrate
Antidepressants
Anticonvulsants
Ketamine
Sympathetic blocking agents
Opioids
Surgical Intervention
Sympathetic blockade
Amputation
Integrative Medicine (IM) and Complementary and Alternative Medicine (CAMS)
Acupuncture
Peripheral Nerve Stimulation
Controversial or Potentially Dangerous Therapies
Electroconvulsive therapy
Hyperbaric oxygen therapy
CRPS in the Courtroom
Parallels with the Opioid Epidemic
Conclusions
References
88
88
Fibromyalgia and related syndromes
Introduction
Pathophysiology and Pathogenesis
Risk Factors
Clinical Features
Differential Diagnosis
The Continuum of Fibromyalgia to Fibromyalgianess
Treatment
General Approach
Pharmacologic therapies
Nonpharmacologic therapies
Natural History
References
89
89
Classification and epidemiology of rheumatoid arthritis
Classification of Rheumatoid Arthritis
Disease Occurrence
Incidence
Prevalence
Geographic Variation
Time Trends
Environmental Factors
Lifestyle Factors
Nutrition
Medications
Infectious Agents
Socioeconomic Status and Occupation
Urban and Industrialized Environments
Host Factors
Reproductive and Endocrine Factors
Birth Weight
References
90
90
Clinical features of rheumatoid arthritis
Introduction
Clinical Evaluation
History
Examination and Clinical Features of Specific Joints
Diagnosis
Natural History
Disease Onset
Patterns Of Onset
Gradual onset
Slow, monoarticular onset
Abrupt, acute polyarthritis
Acute monoarthritis
Palindromic rheumatism
Remitting seronegative symmetrical synovitis with pitting edema
Local extraarticular features
Systemic extraarticular features
Patterns of Progression
Clinical Course—Morbidity and Mortality
Acute-onset pattern
Gradual-onset pattern
Assessment of disease activity
Prognosis
References
91
91
Extraarticular features of rheumatoid arthritis
Introduction
Skin Disease
Hematologic Abnormalities
Felty Syndrome
Hepatic Abnormalities
Pulmonary Involvement
Cardiac Disease
Ocular Involvement
Neurologic Impairment
Muscular Involvement
Renal Abnormalities
Amyloidosis
Rheumatoid Vasculitis
Acknowledgment
References
92
92
Common comorbidities in rheumatoid arthritis
Introduction
Measurement of Comorbidity
Cardiovascular Disease and Cardiovascular Risk Factors
Venous Thromboembolism
Malignancy
Metabolic Disease
Osteoporosis and Osteopenia
Mental Health
Fibromyalgia and Central Pain Sensitization
Frequent Infections
Gastrointestinal Disease
Chronic Obstructive Pulmonary Disease
Chronic Kidney Disease
Screening and Management of Comorbidities in Patients with RA
Conclusion
References
93
93
Imaging of rheumatoid arthritis
Introduction
Approach to Imaging and General Imaging Features
Imaging Modalities
Conventional Radiography
Hands and wrists
Feet and ankles
Large joints
Pelvis and hips
Knees
Shoulders
Elbows
Cervical spine
Arthrography
Ultrasonography
Computed Tomography
Magnetic Resonance Imaging
Emerging Imaging Modalities
Final Points
Acknowledgment
References
94
94
Genetics of rheumatoid arthritis
Introduction
Strength of Genetic Contribution
Role of Major Histocompatibility Complex Genes
History
Refining the Amino Acid Sites Driving RA Susceptibility
Biologic Function of HLA-DRB1 Risk Alleles
Genetic Association Between Human Leukocyte Antigen Alleles and Anti–Cyclic Citrullinated Peptide–Positive and–Negative Rhe ...
Major Histocompatibility Complex: Disease Susceptibility or Severity?
Role of Non–Major Histocompatibility Complex Genes
Candidate Gene Association Studies in Rheumatoid Arthritis
PTPN22
PADI4
CTLA4
STAT4
Genome-Wide Association Studies in Rheumatoid Arthritis
Ethnic Differences in Rheumatoid Arthritis Susceptibility
Insight into the Pathogenesis of Rheumatoid Arthritis from Non–Major Histocompatibility Complex Genetic Studies
Gene and Environment Interactions
Conclusion
Summary
References
95
95
Animal models of rheumatoid arthritis
Introduction
Mechanisms of Induction of Experimental Arthritis
Immunization With Cartilage Components
Response to Nonspecific Immunologic Stimuli
Adjuvant- and pristane-induced arthritis
Components of Infectious Agents
Streptococcal cell wall arthritis
Antigen-induced arthritis
Flares of arthritis
Immune Complex–Induced Arthritis
K/BxN and serum transfer models
Anticitrullinated Protein Antibodies and Arthritis Models
Gene Manipulation and Transgenic Models
The 3 R’s
Conclusions
References
96
96
Autoantibodies in rheumatoid arthritis
Introduction
Rheumatoid Factors
Role as Diagnostic and Prognostic Markers
Pathogenetic Involvement
Anticitrullinated Protein/Peptide Antibodies
Citrullinated Autoantigens
Role of ACPA as Diagnostic and Prognostic Markers
Role in Disease Etiology and Pathogenesis
Antibodies to Carbamylated (Homocitrullinated) Antigens
Anti-RA33 Antibodies
Anticollagen Antibodies
Antibodies to Other Posttranslational Modifications
Additional Antibodies
The Impact of Immunoglobulin Glycosylation on Arthritis
Autoantibodies and Disease Pathogenesis
References
97
97
Pathogenesis and pathology of rheumatoid arthritis
Introduction
Normal Synovium
Synovium in Rheumatoid Arthritis
Pannus
Histologic Subtypes of RA Synovium
Mechanisms of Chronic Synovitis in Rheumatoid Arthritis
Cellular Immunology of Rheumatoid Arthritis
New Technologies in the Study of Rheumatoid Arthritis
Cells of Rheumatoid Synovium
Macrophages
Synovial Fibroblasts
T Cells
B Cells
Neutrophils
Other Leukocytes: Dendritic Cells, Mast Cells, NK Cells, and Other Innate Cell Types
Chondrocytes
Molecular Mediators in Rheumatoid Synovium
Tumor Necrosis Factor
Tumor Necrosis Factor Superfamily
Interleukin-1
Interleukin-6
Interleukin-18 and Other IL-1 Family Members
Interferon-γ and Canonical T-Cell–Derived Cytokines: Interleukin-2, -4, -5
Interleukin-10
Interleukin-17
Interleukin-21 and Interleukin-22
Interleukin-12 and Interleukin-23
Interleukin-15
Transforming Growth Factor-β
Granulocyte-Monocyte Colony-Stimulating Factor
Other Secreted Proteins
Chemokines
Arachidonic Acid Metabolites
Ligands for Toll-Like Receptors
Complement and Immune Complexes
Angiogenesis in Rheumatoid Arthritis
Vasculogenesis
Regulatory Networks in Synovial Angiogenesis
Angiostatic Compounds
Perspectives on Targeting Angiogenesis
Joint Destruction
Matrix Metalloproteinases
Collagenases
Stromelysins
Other Matrix Metalloproteinases and Related Enzymes
Role of Matrix Metalloproteinases in Inflammation
Protease Inhibitors
Cysteine and Serine Proteases
Bone Destruction
New Horizons in RA Pathogenesis Research
Genetics and Autoimmunity
Seronegative Rheumatoid Arthritis
T Cells in the Initiation and Propagation of Rheumatoid Arthritis
Cell–Cell and Cytokine Interactions in the Perpetuation of Inflammation in Rheumatoid Arthritis
Unifying Hypothesis
Conclusion
Acknowledgment
References
98
98
Preclinical rheumatoid arthritis
Introduction and Overview of Rheumatoid Arthritis Development
The Pathophysiology of Rheumatoid Arthritis Development Before Clinically Apparent Inflammatory Arthritis
Autoantibody Abnormalities Precede Clinically Apparent Inflammatory Arthritis
Epitope Spreading Occurs in pre-RA
Other Autoantibody Changes in Preclinical Rheumatoid Arthritis
Systemic Inflammation in Pre-RA
Other Immune Features in pre-RA
Genes and Environment in pre-RA
Putting It All Together: When, Where, and How Does RA-Related Autoimmunity Develop?
Caveats to the Model of RA Development
“Autoimmune-Opathy” Preceding Inflammatory Arthritis In RA
Nomenclature
Prediction of Future Rheumatoid Arthritis
Prevention of Rheumatoid Arthritis
Conclusion
Acknowledgment
References
99
99
Assessment of the patient with rheumatoid arthritis and the measurement of outcomes
Introduction
2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis
Disease Process (“Disease Activity”) and Its Consequence (“Disease Outcome”)
Evaluation Versus Prognostication
Individual Measures Versus Composite Indices
Definition and Evaluation of Treatment Targets in Clinical Practice
Assessment Strategies in Clinical Trials
Instruments for Assessing Disease Activity
Core Sets of Disease Activity Variables
Swollen and tender joint counts
Pain
Patient and evaluator assessment of global disease activity
Acute-phase reactants
Composite Indices of Disease Activity
Improvement Criteria
Remission Criteria
Instruments for Assessing Physical Function
Instruments for Assessing Structural Progression
Scoring of Radiographs
Other Imaging Modalities
Other Instruments: Fatigue, Work Productivity, and Comorbidity
Conclusion
References
100
100
Management of rheumatoid arthritis in csDMARD-naïve patients
Introduction
Early Diagnosis and Treatment
Treating to Target
DISEASE MODIFYING ANTIRHEUMATIC DRUG (DMARD) THERAPY
Conventional Synthetic DMARDs
Glucocorticoids
csdmard Strategies—Initial Monotherapy vs Combination Therapy
Biologic/Targeted Synthetic DMARD Induction Strategies
Biologic Dmard Induction Followed by Tapering
Treatment Stratification in Early RA
Non-Dmard and Non-pharmacological Management
References
101
101
Management of rheumatoid arthritis in patients with prior exposure to conventional synthetic disease-modifying antirhe ...
Introduction
Therapeutic Overview
Guiding Principles of Treatment
Adjusting Therapy to Achieve Targets
Comparative Efficacy of Targeted DMARDs (tDMARDs)
Treatment Withdrawal
General Safety Monitoring of DMARD Therapies
Non-class-Specific Adverse Events With Targeted Therapies
Infections and immunizations
Malignancies
Other non-class-specific adverse events with targeted therapies
Potential Class-Specific Adverse Events With tDMARDs
Fertility and Pregnancy
Comorbid Disease
Cardiovascular Disease
Interstitial Lung Disease
Conclusions
References
102
102
Multidisciplinary nonpharmacologic approach to rheumatoid arthritis
Introduction
Coping—Balancing Needs and Resources
Patient Education and Counseling
Exercise Therapy
Hands-on Techniques and Physical Modalities
Orthoses, Insoles, and Shoes
Assistive Technology
Nutrition
Interventions Preventing Job Loss and Work Disability
Multidisciplinary Team Care
Digital Health Interventions
Acknowledgment
References
Volume II
103
103
Evaluation of children with rheumatologic complaints
History Taking for the Musculoskeletal System in Children
General Approach
Constitutional Features
Joint Pain
Joint Swelling And Stiffness
Examination of the Musculoskeletal System
General Examination
Joint Assessment
Cervical spine and temporomandibular joints
Elbows and shoulders
Hands and wrists
Hips
Knees
Feet and ankles
Spine and gait
Differential Diagnosis
Septic Arthritis
Reactive or Postinfectious Arthritis
Musculoskeletal Syndromes and Benign Limb Pains
Regional Syndromes: Hip
Transient (Toxic) Synovitis (Irritable Hip)
Legg-Calvé-Perthes Disease
Imaging
Pathophysiology
Treatment
Prognosis
Long-term follow-up
Slipped Capital Femoral Epiphyses
Clinical findings
Imaging
Treatment
Idiopathic Chondrolysis
Imaging
Treatment and prognosis
Acetabular Dysplasia, Impingement, And Developmental Dysplasia Of The Hip
Clinical findings
Imaging
Treatments
Regional Syndromes: Knee
Patellofemoral Dysfunction
Chondromalacia Patellae
Bone Lesions That Mimic Mechanical Knee Disease
Osgood-Schlatter Disease
Other Knee Disorders
Regional Syndromes: Foot
Acknowledgments
References
104
104
Classification and epidemiology of juvenile idiopathic arthritis
Classification of Childhood Arthritis
History of Childhood Arthritis Classification
Role of the International League of Associations for Rheumatology Classification
Validity of the International League of Associations for Rheumatology Criteria
Descriptive Epidemiology
Incidence and Prevalence
Geographic and Ethnic Variation
Time Trends
Descriptive Epidemiology of the Different Disease Categories
Risk Factors
Genetic Factors
Familial risk
Role of HLA
Role of non–human leukocyte antigen genes
Environmental factors
Summary
Course and Prognosis
Mortality
Outcome
References
105
105
Clinical features of juvenile idiopathic arthritis
Introduction
General Clinical Features
Laboratory Investigations
Imaging
Clinical Features of Different Categories of Juvenile Idiopathic Arthritis (Table 105.3)
Systemic Arthritis
Oligoarthritis, Persistent and Extended
Polyarthritis
Rheumatoid factor–negative polyarticular juvenile idiopathic arthritis
Rheumatoid factor–positive polyarticular juvenile idiopathic arthritis
Psoriatic Arthritis
Enthesitis-Related Arthritis
Undifferentiated Arthritis
Special Problems of Arthritis in Children
Multidimensional Outcome
Mortality, Cancer, and Severe Morbidity
Continuous Activity, Inactivity, and Remission
Risk Factors for Continuous Activity and Damage
Articular and Skeletal Damage
Joint destruction
Local growth disturbances
Knee
Ankle
Wrist and hand
Hip
Cervical spine
Temporomandibular joint
Bone health and osteopenia
General growth disturbance
Pubertal delay
Endocrine Damage
Ophthalmologic Complications and Damage
Physical Disability
Quality of Life
Pain
Fatigue and sleep disturbance
Psychosocial health
Participation
Transition of Care
References
106
106
Etiology and pathogenesis of juvenile idiopathic arthritis
Introduction
Etiology
Genetic Factors
Human leukocyte antigen region
Non–human leukocyte antigen genes
Environmental Factors
Microbes
Pathogenesis
Pathology
Pathogenesis of Oligo- and Poly-Juvenile Idiopathic Arthritis
Enthesitis-Related Arthritis
Systemic Juvenile Idiopathic Arthritis
Conclusion
Acknowledgment
References
107
107 Management of juvenile idiopathic arthritis
Surgical Management
Other Issues of Management
Introduction
Treatment Recommendations for Juvenile Idiopathic Arthritis (Table 107.3)
Oligoarthritis
Polyarthritis Course (Regardless of Onset)
Systemic Arthritis
Macrophage Activation Syndrome
Enthesitis-Related Arthritis
Active Sacroiliac Arthritis
Psoriatic Arthritis
Uveitis
Nonsteroidal Antiinflammatory Drugs
Corticosteroids
Methotrexate
Other Disease-Modifying Antirheumatic Drugs and Immunosuppressive Medications (Table 107.4)
Biologic-Modifying Medications
Tumor Necrosis Factor Inhibitors
Abatacept
Anti–Interleukin (IL)-1 Medications
Anti–Interleukin (IL)-6
Intravenous Immunoglobulin
Rituximab
Janus Kinase (JAK) Inhibitors
Secukinumab
Stem Cell Transplantation
Studies of Disease-Modifying Antirheumatic Drug vs Biologic Combination Therapy for Juvenile Idiopathic Arthritis
Management of Pain
Rehabilitation
Management of Growth Retardation
Complementary and Alternative Therapies
Surgical Interventions
Synovectomy
Arthroplasty
Adjunct Nonsurgical and Surgical Treatment of Temporomandibular Joint Deformities
Conclusion
References
108
108
The juvenile-onset spondyloarthropathies
Classification and Epidemiology
Clinical Manifestations
Genetics
Pathophysiology
Evaluation of Disease Phenotype and Disease Activity
Treatment Considerations
Outcomes
Conclusions
References
109
109
Systemic autoimmune rheumatic diseases in children
Introduction
Juvenile-Onset Systemic Lupus Erythematosus
Epidemiology
Etiopathogenesis
Clinical Presentation
Assessment Of Disease Severity And Monitoring Of Outcome
Management
Management And Prevention Of Comorbidities
Clinical Severity And Outcome
Neonatal Lupus Syndrome
The Pediatric Inflammatory Myopathies: Juvenile Dermatomyositis
Epidemiology
Etiopathogenesis
Clinical Presentation
Assessment And Monitoring
Treatment And Outcome
Sjögren Disease In Children
Epidemiology
Etiopathogenesis
Clinical Presentation And Features
Making The Diagnosis
Management
Prognosis And Outcomes—More Questions Than Answers
Scleroderma
Epidemiology
Etiopathogenesis
Clinical Presentation
Localized scleroderma
Systemic sclerosis
Diagnosis And Management
Treatment And Outcome
Localized scleroderma treatment and outcome
Systemic sclerosis treatment and outcome
Prognosis
References
110
110
Rehabilitation and psychosocial issues in juvenile idiopathic arthritis
Key Points
Introduction
Impacts
Pain
Structural Damage
Hand and Wrist
Lower Extremities
Bone Mineralization
Limitations in Daily Living
Psychosocial Implications
Childhood
Adolescence
Adulthood
Evaluation
Pain Scales
Range of Motion and Muscle Strength
Function, Quality of Life, and Health Status
Goals of Treatment: Evidence-Based Treatment and Outcome
Conclusion
References
111
111
Bacterial native joint arthritis
Introduction
Epidemiology, Origins of Arthritis, and Related Microbiology
Clinical Presentation, Patients’ History, and Diagnosis
Laboratory Diagnoses
Management of Bacterial Arthritis
Degree of Emergency for Lavage/Drainage
Combined surgical and medical therapy
Techniques for lavage/drainage
Resection, Arthrodesis, or Amputation
Antibiotic Treatment
Total Duration of Antibiotic Therapy and of Its Parenteral Part
Supportive Therapy and Research for the Future
Outcomes of Therapy
Acknowledgment
References
112
112
Mycobacterial, brucellar, fungal, and parasitic arthritis
Introduction
Tuberculous Arthritis
Epidemiology
Pathophysiology
Musculoskeletal Manifestations
Spondylitis (Pott’s Disease)
Peripheral Arthritis
Osteomyelitis
Reactive Arthritis (ReA) (Poncet Disease)
Soft Tissue Abscess And Panniculitis
Diagnosis
Imaging
Spondylitis
Peripheral arthritis
Osteomyelitis
Treatment
Prevention
Leprosy and Other Mycobacterial Infections
Epidemiology
Microbiology
Clinical Characteristics
Diagnosis
Treament
Brucellosis
Epidemiology
Microbiology
Clinical Manifestations
Diagnosis
Treatment
Prevention
Fungal Musculoskeletal Infections
Histoplasmosis
Clinical manifestations
Treatment
Blastomycosis
Clinical manifestations
Treatment
Paracoccidioidomycosis
Clinical manifestations
Treatment
Coccidioidomycosis
Clinical manifestations
Treatment
Cryptococcosis
Clinical manifestations
Treatment
Aspergillosis
Clinical manifestations
Therapy
Candidiasis
Clinical manifestations
Treatment
Sporotrichosis
Clinical manifestations
Treatment
Parasitic Arthritis
Protozoans
Diagnosis
Helminths
Cestodes
Diagnosis
Nematodes
Diagnosis
Trematodes
Diagnosis
Treatment
References
113
113
Viral infections
Other Viruses
Introduction
Human Immunodeficiency Virus
Principles of Management of Inflammatory Diseases in the Setting of HIV
Special Situations in Evaluating and Treating Patients With HIV and Rheumatic Disorders
Osteoporosis
Immune reconstitution syndrome
Avascular necrosis
Parvovirus B19
Virology
Clinical Manifestations
Laboratory Investigation
Treatment
Hepatitis B Virus
Virology
Clinical Manifestations
Hepatitis C Virus
Clinical Manifestations
Coexistent arthropathy
Hepatitis C virus–associated arthritis
Arthritis in hepatitis C virus–associated cryoglobulinemic vasculitis
Chikungunya and Other Alphaviruses
Clinical Manifestations
Acute phase (10 days–3 months)
Chronic phase (>3 months)
Laboratory Investigation
Treatment
Human T-Cell Lymphotropic Virus Type I
Other Viruses
References
114
114
Lyme and other tickborne diseases
History
Epidemiology
Etiologic Agent
Pathogenesis
Clinical Manifestations
Skin
Nervous System
Cardiac System
Joints
Diagnosis
Other Tickborne Diseases
Differential Diagnosis
Treatment
Post–Lyme Disease Symptoms
Prevention
References
115
115
Acute rheumatic fever
Introduction
Epidemiology
Rheumatic Fever Risk Factors
Streptococcus Factors
Environmental Factors
Host Factors
HLA class II antigens
B-cell alloantigen
Gene polymorphisms
Pathophysiology
Relationship Between Gabhs And Rheumatic Fever
Molecular Mimicry and Epitope Spreading
Humoral Immune Response
Cellular Immune Response
Cytokine balance
Pathology
Myocarditis
Endocarditis
Pericarditis
Arthritis
Chorea
Clinical Manifestations
Major Manifestation
Arthritis
Carditis
Transition from acute to chronic heart disease
Subclinical carditis
Chronic rheumatic heart disease
Sydenham Chorea
Erythema Marginatum
Subcutaneous Nodules
Other Clinical Features
Minor Manifestation
Investigations
Throat Cultures
Rapid Antigen Detection Test
Streptococcal Antibody Tests
Acute-Phase Reactants
Other Laboratory Findings
Echocardiography
Diagnosis
Treatment
Primary Prevention: Gas Vaccine
Primary Prevention (Pharyngitis Treatment)
Acute Rheumatic Fever
Streptococcus eradication
Arthritis, fever, and rash
Acute carditis
Sydenham Chorea
Secondary Prevention
Endocarditis Prophylaxis
Emergency Valve Procedure
References
116
116
Reactive arthritis
Introduction
Innate Immunity and Reactive Arthritis
Too much immunity or too little?
Self–Nonself Complexities
Chlamydia-Induced Reactive Arthritis
Reactive Arthritis: The Noncanonical Septic Arthritis
Chlamydial persistence: pathogenicity or symbiosis?
Mediators of Susceptibility to Chlamydia-Induced Reactive Arthritis
Importance of Innate Immunity in Chlamydia-Induced Reactive Arthritis
Macrophages as Key Players in Chlamydia-Induced Reactive Arthritis
Classification Criteria
Genetic Factors
Epidemiology
Clinical Features
Arthritis
Extraarticular features
Atypical Aspects of Reactive Arthritis
Sapho
Clostridium Difficile and Giardia Lamblia
Streptococcal Infections
Human Immunodeficiency Virus and Reactive Arthritis
Investigations
Laboratory Testing
Radiology
Treatment
Triggering Infection
Acute Arthritis
Extraarticular Symptoms
Skin and Mucosal Lesions
Chlamydia-Induced Reactive Arthritis
Disease-Modifying Antirheumatic Drugs
Biologic Agents in the Treatment of Reactive Arthritis
Prophylaxis
Prognosis and Natural History
Summary: Key Elements of the Clinical Approach to Reactive Arthritis182 (Box 116.4)
References
117
117
Classification and epidemiology of spondyloarthritis
The Historical Concept of Spondyloarthritis
The Evolution of Axial Spondyloarthritis
Diagnosis and Classification of Axial Spondyloarthritis
Classification of Peripheral Spondyloarthritis
Prevalence of Spondyloarthritis
Impact of Gender
Conclusion
References
118
118
Enthesopathies
Introduction
History
Anatomy and Pathology
Anatomy
Fibrocartilage
Related structures
Histopathologic Features and Cellular Basis for Enthesitis
Enthesitis and the Pathogenesis of Spondyloarthritis
A Universal Hallmark of Spondyloarthritis
Enthesitis and Osteitis
Enthesitis and Anatomically Similar Structures
An Enthesitis-Based Model
Sites of Enthesitis
Symptoms and Signs
Differential Diagnosis
Imaging
Magnetic Resonance Imaging
Conventional Radiography
Ultrasonography
Clinical Scores for Enthesitis Assessment
Management
First-Line Therapy
Disease-Modifying Therapy for Enthesitis
References
119
119
Inflammatory back pain
Introduction
Inflammatory Back Pain Criteria
Inflammatory Back Pain in the Population
Patient Referral Strategies
Inflammatory Back Pain in Diagnosis
Acknowledgment
References
120
120
Clinical features of axial spondyloarthritis
Introduction
Clinical Features
Chronic Back Pain
Arthritis
Enthesitis
Dactylitis
Extra-musculoskeletal manifestations
Uveitis
Inflammatory bowel disease
Psoriasis
Other
Cardiac manifestations
Pulmonary manifestations
Renal manifestations
Neurologic manifestations
Psychosocial manifestations
Constitutional symptoms
Osteoporosis and spinal fractures
Fibromyalgia
Structural damage
Physical Examination Findings
Laboratory and Imaging Investigations
Diagnosis and Classification
Clinical Assessment of axspa
Burden of Disease and Prognosis
Acknowledgments
References
121
121
Pathogenesis and pathophysiology of axial spondyloarthritis
Introduction
Axial Spondyloarthritis: A Polygenic Disease with a Predominant Autoinflammatory Nature
Key Inflammatory Mediators in Spondyloarthritis
Histopathology and New Bone Formation
References
122
122
Genetics of axial spondyloarthritis
Genetic Epidemiology of Ankylosing Spondylitis
Major Histocompatibility Complex Genes
HLA-B27 and B27 Subtypes
Other Major Histocompatibility Complex Genes
Non–Major Histocompatibility Complex Genes
Genetics of Acute Anterior Uveitis
Ankylosing Spondylitis in East Asians
Ankylosing Spondylitis in Africans
Summary and Conclusions
Acknowledgment
References
123
123
Animal models of spondyloarthritis
Introduction
HLA-B27 Transgenic Animals
HLA-B27 Transgenic Mice
HLA-B27 Transgenic rats
TNF Overexpression Models
Human TNF-Transgenic Mice
TNFΔARE MICE
tmTNF Transgenic Mice
IL-23/IL-17 Pathway
Beta-Glucan Induced Disease In Skg Mice
Mechanical Loading
Selective A20 Deficiency
Microbiome
Conclusion
References
124
124
Imaging in spondyloarthritis
Introduction
Technical Aspects Of Imaging In Axial Spondyloarthritis
Importance Of Imaging Of The Sacroiliac Joints In Axial Spondyloarthritis
Conventional Radiology
Computed Tomography
Scintigraphy
Magnetic Resonance Imaging
Technical aspects of MRI
Definition of a positive magnetic resonance imaging of the sacroiliac joint in axial spondyloarthritis
Differential Diagnoses For Involvement Of The Sacroiliac Joint
Imaging Of The Spine In Axial Spondyloarthritis
Conventional Radiographs
Magnetic Resonance Imaging
Definition Of A Positive Magnetic Resonance Imaging Of The Spine In Axial Spondyloarthritis
Differential Diagnoses For Involvement Of The Spine
Cauda Equina Syndrome
Extravertebral Manifestations Of Axial Spondyloarthritis
Future Directions
References
125
125
Management of axial spondyloarthritis
Historical Perspective
Current Perspectives
Assessment Of Efficacy Of Treatment Of Axial Spondyloarthritis
Pooled Indices
Assessment of SpondyloArthritis international Society instruments
Bath indices
Specific Clinical And Laboratory Markers
Laboratory tests
Spinal mobility
Imaging
Physical Therapy
Nonbiologic Pharmacologic Therapy
Nonsteroidal Antiinflammatory Drugs
Nonsteroidal antiinflammatory drugs as disease modifiers
Corticosteroids
Systemic corticosteroids
Intraarticular corticosteroids
Conventional Synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs)
Sulfasalazine
Methotrexate
Other csDMARDs
Targeted Synthetic Disease-Modifying Antirheumatic Drugs (tsDMARDs)
Biologic DMARDs (Table 125.4)
Tumor Necrosis Factor-α–Blocking Agents
Biologic basis
Treatment of early axial spondyloarthritis with tumor necrosis factor blockers
Can a good response to tumor necrosis factor blockers be predicted?
Treatment targeting the interleukin-23–interleukin-17 pathway
bDMARDs for peripheral arthritis and enthesitis
Switching after failure of the first biologic
Management Of Extraarticular Manifestations
Anterior Uveitis
Psoriasis and inflammatory bowel disease in patients with ankylosing spondylitis
Tumor necrosis factor blockers for the treatment of juvenile spondyloarthritis
Adverse events associated with biologic therapy
Osteoporosis
Surgical Intervention In Ankylosing Spondylitis
Hip Replacement
Spinal Surgery
Acknowledgment
References
126
126
Classification and epidemiology of psoriatic arthritis
Introduction
Diagnosis
Epidemiology of Psoriatic Arthritis
Prevalence and Incidence of Psoriatic Arthritis Among Patients in the General Population
Prevalence and Incidence of Psoriatic Arthritis Among Patients with Psoriasis
Risk Factors for PsA Among Patients with Psoriasis
Classification
Classification Versus Diagnosis
Comorbidities Among Patients with PsA
Conclusions
References
127
127
Clinical features of psoriatic arthritis
Introduction
History, Epidemiology, and Criteria
Epidemiology
Principles of the Diagnosis of PsA
Classification Criteria Used in PsA Trials
Key Clinical Features: Skin and Joints
Skin Psoriasis
Nail involvement
Peripheral Joint Involvement
Other Musculoskeletal Features
Dactylitis
Enthesitis
Axial Involvement
Other Extraarticular Features
Rare Forms of PsA
Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome
Psoriatic onychopachydermoperiostitis
Evaluation and Follow-Up
Prognosis
Natural History
Comorbidities
Investigations
Laboratory Investigations
Imaging Investigations
Peripheral joint structural changes as seen on radiographs
Other Imaging Modalities of the Peripheral Joints
Entheseal imaging
Spinal imaging
Acknowledgment
References
128
128
Extraarticular manifestations and comorbidities in psoriatic arthritis
Introduction
Extraarticular Manifestations
Psoriasis
Prevalence and incidence
Classification and clinical manifestations of psoriasis
Psoriasis risk factors for PsA transition
Pathologic mechanisms proposed
Screening and management recommendations
Inflammatory Bowel Disease
Prevalence, incidence, and clinical implications
Pathologic mechanisms proposed
Screening and management recommendations
Ocular Manifestations
Prevalence, incidence, and clinical implications
Pathologic mechanisms proposed
Management recommendations
Comorbidities
Cardiovascular Disease
Prevalence, incidence, and clinical implications
Pathologic mechanisms proposed
Screening and management
Cardiovascular Risk Factors: Metabolic Syndrome, Obesity, Diabetes Mellitus, Dyslipidemia, and Hypertension
Prevalence, incidence, and clinical implications
Pathologic mechanisms proposed
Screening and management recommendations
Malignancy
Prevalence, incidence, and clinical implications
Screening and management recommendations
Liver Disease
Prevalence, incidence, and clinical implications
Pathologic mechanisms proposed
Liver disease and PsA medications
Screening and management recommendations
KIDNEY DISEASE
Prevalence, incidence, and clinical implications
Kidney disease and PsA medications
Infections
Prevalence, incidence, and clinical implications
Infections and PsA medications
Osteoporosis
FIBROMYALGIA
Depression AND ANXIETY
Gout
References
129
129
Etiology and pathogenesis of psoriatic arthritis
Introduction
Genetic Factors
Epigenetics
Environmental Factors
Infection
Trauma, Severity of Psoriasis, Obesity, and Diet
Cells, Cytokines, and Pathways Involved in Skin and Joint Tissue Inflammation
Immunopathology
Psoriatic Plaque
Nail Disease
Synovium
Enthesis
Dactylitis
Links Between Skin and Musculoskeletal Inflammation
Pathologic Cartilage Resorption and Altered Bone Remodeling
Cartilage Resorption
Altered Bone Remodeling
Conclusion
References
130
130
Animal models of psoriatic arthritis
Animal Model Strategies and Concept
Challenges in the Development of Animal Models for Psoriatic Disease
Animal Models of Psoriatic Arthritis
Spontaneous Models of Psoriatic Arthritis
Transgenic Approaches Towards Psoriatic Arthritis Models
Induced Models of Psoriatic Arthritis
Lessons Learned and Future Perspectives
References
131
131
Management of psoriatic arthritis
Introduction
Is Psoriatic Arthritis an Important Pathology?
Assessment of Disease Activity and Outcome of Psoriatic Arthritis
Is there a need for novel treatments in psoriatic arthritis?
Nonsteroidal Antiiinflammatory Drugs and Glucocorticoids
Conventional Synthetic Disease-Modifying Antirheumatic Drugs
Methotrexate
Sulfasalazine
Leflunomide
Cyclosporine
Biologic Disease-Modifying Antirheumatic Drugs
Tumor Necrosis Factor Inhibitors
Etanercept
Infliximab
Adalimumab
Golimumab
Certolizumab
Health Benefits of Tumor Necrosis Factor Inhibitors in Psoriatic Arthritis
Other Biologic Disease-Modifying Antirheumatic Drugs
Costimulatory Blockade Agents
Anti–Interleukin-12 and -23 Agents
Anti–Interleukin-17
Small-Molecule Inhibitors
Treatment Recommendations
Conclusion
Acknowledgments
References
132
132
Epidemiology and classification of systemic lupus erythematosus
Introduction
Classification of Systemic Lupus Erythematosus for Clinical Studies and Trials
Systemic Lupus Erythematosus Heterogeneity and Subtypes
Descriptive Epidemiology of Systemic Lupus Erythematosus
Prevalence and Incidence in the United States
Ethnicity and Geography
Sex
Age
Risk Factors for Systemic Lupus Erythematosus
Hormonal/Reproductive Factors
Cigarette Smoking, Alcohol Consumption, and Obesity
Environmental Contaminants
Nutritional Factors and Ultraviolet Light
Psychosocial Stressors
Infections and Immunizations
Epidemiology of Major Adverse Outcomes Among Patients with Systemic Lupus Erythematosus
Conclusions
Acknowledgment
References
133
133
Preclinical features of systemic lupus erythematosus
Introduction
Importance of Understanding and Identifying Preclinical Lupus
Healthy Individuals with Antinuclear Autoantibodies
Clinical and Serologic Features of Healthy Individuals who Transition to Systemic Lupus Erythematosus
Risk Factors for Transition in Relatives of Patients with Systemic Lupus Erythematosus
Environmental Exposures and Life Experiences in the Preclinical Period which Associate with Future SLE Development
Clinical Manifestations and Transition of Patients with Incomplete, Potential, or Latent Lupus
Transition of Patients with Undifferentiated Connective Tissue Disease to Systemic Lupus Erythematosus
Development of Systemic Lupus Erythematosus in Patients with Another Systemic Autoimmune Disease
Conclusions
Acknowledgments
References
134
134
Clinical features of systemic lupus erythematosus
Introduction
Clinical Features
General Manifestations
Cutaneous Manifestations
Musculoskeletal Features
Renal Manifestations
Neuropsychiatric Manifestations
Gastrointestinal Involvement
Lymphatic And Hematologic Involvement
Pulmonary Involvement
Cardiac Manifestations Of Systemic Lupus Erythematosus
Accelerated Atherosclerosis
Endocrine
Eye, Ear, Nose, Throat
Malignancies
Infections
Acknowledgment
References
135
135
Genetics of systemic lupus erythematosus
Introduction
Female Dominance of Lupus
Rare Presentations of Lupus
TREX1
Early Complement Components
Genetic Association
Genomic Mechanisms
Risk Loci Identified in Cohort Association Studies
Human Leukocyte Antigen Locus at 6p21
HLA-DRB1 and HLA-DQB1
TNFAIP3
ITGAM
ETS1
IRF5 (AND TNPO3)
STAT4 (and STAT1)
CD44
TLR7
IRAK1 (and MECP2)
The Promise of Genetics
References
136
136
Immunopathology of systemic lupus erythematosus
Introduction
Pathology
Characteristic Lesions
Hematoxylin bodies
Libman-Sacks endocarditis
Cutaneous Immunopathology
Vascular Immunopathology
Immunopathology of Lymphoid Organs
Renal Immunopathology
Approach to classification
Prognostic features
Pathogenetic mechanisms
Central Nervous System Immunopathology
Cardiac Immunopathology
Pulmonary Immunopathology
Properties of Immune Complexes
Antibodies and Antigens
Critical Properties of Immune Complexes
Pathogenic Mechanisms
Biology of Immune Complex Handling
Role of Complement in Immune Complex Handling
Receptors for the Fc Region of Immunoglobulin G
Structure and function
Fcγ receptors and systemic lupus erythematosus
Complement and Fcγ Receptor Function: Targets for Treatment
References
137
137
Animal models of systemic lupus erythematosus
Introduction
Spontaneous Mouse Models
New Zealand Black
(NZB × NZW)F1
New Zealand Mixed Strains
SNF1
MRL/LPR AND GLD
BXSB
Induced Models
Pristane-Induced Lupus
Engineered Mouse Models
References
138
138
Autoantibodies in systemic lupus erythematosus
Introduction
Antinuclear Antibodies
Fluorescent ANA Assay
Techniques for Detecting ANA Specificity
Antinuclear and Anticytoplasmic Autoantibodies
“Antiphospholipid” Autoantibodies
Cell Membrane Antigens
Autoantibodies as the Initial Manifestation of Autoimmunity
Mechanisms of Autoantibody Production in Lupus
How are lupus autoantigens selected?
How do autoantibodies cause disease?
References
139
139
Pathogenesis of systemic lupus erythematosus
Genetic Susceptibility and Gender and Environmental Triggering Factors
Innate Immune Responses
Type I Interferons and other Cytokines
Neutrophils and Neutrophil Extracellular Traps (Nets)
Dendritic Cells and other Antigen-Presenting Cells
Adaptive Immune Responses
B Cells and the Production of Autoantibodies
T Cells and Regulation of the Immune Response
Local Factors Involved in Lupus Pathogenesis
Concluding Remarks
References
140
140
Drug-induced lupus
Introduction
Etiology
Drugs Implicated
Genetic Contributions to Idiopathic and Drug-Induced Lupus
Age and Gender Contributions to Drug-Induced and Idiopathic Lupus
Summary
Pathogenesis
Epigenetics and Gene Expression
Epigenetics, chromatin structure, and gene expression
Histone modifications
DNA methylation
ROLE OF DNA METHYLATION IN T CELLS
T cells, DNA methylation, and idiopathic lupus
T cells, DNA methylation, and the environment
Recombinant Biologic Agents
Interferon-αα
Tumor necrosis factor inhibitors
Summary
Clinical Aspects
Idiopathic Lupus in Younger Versus Older Adults
Gender aspects
Clinical and serologic features
Drug-Induced Lupus Versus Idiopathic Lupus
Patient characteristics
Clinical Features
Autoantibodies
Summary
References
141
141 Assessing disease activity and outcome in systemic lupus erythematosus
Introduction
Global Disease Activity Indices
Systemic Lupus Erythematosus Disease Activity Index (Sledai)
Systemic Lupus Activity Measure
SLE Disease Activity Score (SLE-DAS)
Organ-Specific Indices
British Isles Lupus Assessment Group Disease Activity Index (Bilag)
Renal Outcome Measures
Cutaneous Outcome Measures
Measures of Change in Disease Activity
Composite Responder Indices
Measurement of Low Disease Activity State
Measurement of Flare
Measurement of Damage
Health-Related Quality of Life
Generic Questionnaires
Disease-Specific Hrqol Questionnaires
Fatigue Measures
Miscellaneous
Patient and Physician Global Assessment of SLE Activity
Glucocorticoid Background Therapy
Critique of SLE Outcomes and Trial Designs
Conclusion
References
142
142
Management of nonrenal and non–central nervous system lupus
Introduction
Recommended Assessment and Monitoring of SLE Patients with Nonrenal/Non–Central Nervous System Manifestations
Management of Musculoskeletal Manifestations
Arthritis
Avascular Necrosis
Myositis
Management of Cutaneous Manifestations
General Nonpharmacologic Measures
Topical Treatment
Systemic Therapy
Biologic Therapies and Experimental Drugs
Hematologic Involvement
Management of Cardiopulmonary Manifestations
Management of other Nonrenal/Non-CNS Manifestations
Future Perspectives: Treat to Target in Systemic Lupus Erythematosus
References
143
143
Management of central nervous system lupus
Etiology of Neuropsychiatric Systemic Lupus Erythematosus
Clinical Manifestations of Selected Neuropsychiatric Events
Headache
Psychosis, Mood Disorders, and Anxiety
Cerebrovascular Disease
Seizures
Demyelination, Transverse Myelopathy, and Chorea
Peripheral Nervous System Disease
Acute Confusional State
Neurocognitive Disorders
Diagnosis of Neuropsychiatric Systemic Lupus Erythematosus
Neuroimaging in Neuropsychiatric Systemic Lupus Erythematosus
Treatment of Neuropsychiatric Events in Patients with Systemic Lupus Erythematosus
Ischemic-Mediated Injury
Inflammation-Mediated Injury
Pharmacologic Treatment and Rehabilitation of Neurocognitive Disorders
References
144
144
Management of renal lupus
Introduction
Therapeutic Agents in Lupus Nephritis
Cyclophosphamide (High- and Low-Dose Regimens)
Mycophenolate Mofetil/Mycophenolic Acid
Calcineurin Inhibitors
Biologic Agents
Rituximab
Belimumab
Treatment Options and Recommendations
Proliferative Lupus Nephritis
Initial (“induction”) treatment
Mild-moderate disease
Severe disease
Subsequent (“maintenance”) treatment
Class V Lupus Nephropathy
Monitoring and Targets of Therapy
Renal response and nonresponding/refractory disease
Renal relapses
Adjunct Treatment
End-Stage Renal Disease and Kidney Replacement Modalities
References
145
145 Systemic lupus erythematosus in pregnant patients and neonatal lupus
Introduction
Prepregnancy Evaluation and Counseling
Medication Use in Pregnancy
Maternal and Fetal Complications During Pregnancy
Distinguishing Changes of Normal Pregnancy From Lupus Flares
Lupus Nephritis and Preeclampsia
Antiphospholipid Antibodies
Neonatal Lupus
Pregnancy and Systemic Lupus Erythematosus Management
Monitoring
Labor and Delivery
Lactation
References
146
146
Sjögren syndrome
History
Epidemiology
Glandular Pathology
Clinical Features
Glandular Involvement
Ocular manifestations
Oral manifestations
Extraglandular Manifestations
Overview
Primary versus secondary disease
Constitutional symptoms
Cutaneous involvement
Musculoskeletal involvement
Pulmonary involvement
Gastrointestinal and hepatic involvement
Renal involvement
Gynecologic involvement
Neurologic involvement
Endocrine involvement
Systemic vasculitis
Hematologic abnormalities
Systemic Autoimmunity
Association with other Autoimmune Diseases
Lymphoproliferative Disease
Natural History
Classification Criteria
Diagnostic Evaluation
Ophthalmologic Examination
Major Salivary Glands
Labial Gland Biopsy
Assessment of Disease Activity
Differential Diagnosis
Pathogenesis
Genetic Susceptibility
Environmental Factors
Role of the target tissue
Immune Pathways
Interferons and TLR activation
T cells
B cells and B cell–activating factor
Lymphomagenesis
Management
Glandular Manifestations
Extraglandular Manifestations
Lymphoma
References
147
147
Antiphospholipid syndrome: pathogenesis, diagnosis, and management
Antiphospholipid Syndrome: Definition and History
Epidemiology
Pathogenesis
Mechanisms of Thrombosis
Mechanisms of Pregnancy Loss
Clinical Features
Overview
Venous Thrombosis
Arterial Thrombosis
Pregnancy Complications
Nervous System Abnormalities
Cardiac Valve Abnormalities
Skin Manifestations
Thrombocytopenia and Hemolytic Anemia
Renal Manifestations
Catastrophic Antiphospholipid Syndrome
Laboratory Diagnosis
Serologic Assays Used in the Diagnosis of Antiphospholipid Syndrome
Anticardiolipin test
Lupus anticoagulant test
Anti β2-GPI test
Novel Serologic Assays for Antiphospholipid Syndrome
Seronegative APS
Importance of Scoring Systems in APS
Thrombotic risk assessment
Irreversible damage assessment
Management
Management of Thrombosis
Secondary thromboprophylaxis
Non-VKA oral anticoagulants (NOACs)
Primary thromboprophylaxis
Pregnancy Management
General Pregnancy Care in Women With Obstetric Antiphospholipid Syndrome (Oaps)
Pharmacologic Management of Antiphospholipid Syndrome During Pregnancy
Recurrent Early (Preembryonic or Embryonic) Miscarriage
Fetal Death or Prior Early Delivery Due to Severe Preeclampsia or Placental Insufficiency
Antiphospholipid Syndrome With Thrombosis
Postpartum Period
Management of Other Manifestations of Antiphospholipid Syndrome
Alternative Therapies for Refractory and Difficult Cases
Hydroxychloroquine
Statins
Rituximab
Complement Inhibition
Future Treatments
References
148
148
Classification and epidemiology of systemic sclerosis
Introduction
Disease Classification
Very Early Disease Subset
Epidemiology
Prevalence and Incidence
Disease Risk Factors
Influence of Age, Gender, Ethnicity
Age
Gender
Ethnicity
Sur vival
Survival Prognosis Factors
Summary and Conclusion
References
149
149
Clinical and serologic features of systemic sclerosis
Introduction
Diagnosis and Classification
Clinical Features
Skin
Musculoskeletal
Gastrointestinal Tract
Heart
Arrhythmias and conduction defects
Myocarditis
Cardiac fibrosis
Valvular heart disease
Systolic and diastolic dysfunction
Lungs
Upper airways
Parenchymal lung disease
Pleural and pericardial disease
Pulmonary vascular disease
Renal Scleroderma
Digital Vasculopathy
Neurologic Manifestations of Systemic Sclerosis
Calcinosis
Sexual Dysfunction
Psychological and Social Impact of Systemic Sclerosis
Serologic Features of Systemic Sclerosis
Autoimmune Serology
Other Serologic Markers in Systemic Sclerosis
Risk Stratification
Conclusions
References
150
150
Etiology and pathogenesis of systemic sclerosis
Introduction
Etiology
Genetic Studies in Systemic Sclerosis
Functional SNP activity
Whole-exome and whole-genome sequencing
Epigenetic changes in systemic sclerosis
Analysis of gene expression patterns in systemic sclerosis: distinct molecular subsets
Noncoding RNAs in SSc
Single Cell Analyses are Revealing the Complexity of Cell Phenotypes in SSc
Infectious Etiologic Agents in Systemic Sclerosis
Environmental Exposure, Drugs, and Radiation
Pathology
Vascular Pathology
Tissue Fibrosis
Organ-Specific Pathology
Skin
Lungs
Cardiac disease
Gastrointestinal tract
Kidneys
Pathologic features of SSc in other organs
Pathogenesis: Immunity, Vascular Injury, and Fibrosis
Inflammation and Immunity
The immune response in systemic sclerosis
Innate immunity in systemic sclerosis
Monocyte and macrophage activation in fibrosis
Toll-like and nucleic acid receptor in systemic sclerosis
The inflammasome in systemic sclerosis
Oxidative stress
Endoplasmic reticulum stress, autophagy, and the unfolded protein response
Cellular senescence
Humoral immunity in the pathogenesis of systemic sclerosis
Autoantibodies associated with nucleic acids in systemic sclerosis
Neoantigens as autoimmune targets in systemic sclerosis
Autoantibodies implicated in tissue damage in systemic sclerosis
Toll-like receptor activation and autoreactive B cells
Cellular immunity in systemic sclerosis
Adaptive T-cell responses in fibrotic disease
Type 2 helper T-cell immune skewing and fibrosis
Innate lymphoid cells in systemic sclerosis
Proinflammatory mediators in SSc (Table 150.2)
Interferon
Interleukin-4 and interleukin-13
Interleukin-6
Adenosine
Tumor necrosis factor-α
Chemokines
Vascular Injury and Vasculopathy in Systemic Sclerosis
Endothelial cell injury and apoptosis
Cytotoxic factors in endothelial apoptosis
Vascular spasm, reactive oxygen species, and hypoxia
Endothelium-dependent relaxation and nitric oxide
Endothelin-1
Intimal hyperplasia
Endothelial–mesenchymal transformation
Circulating endothelial cells and vascular progenitor cells
Platelet activation and coagulation
Tissue Fibrosis
Pathogenesis of fibrosis: cellular and molecular determinants
Cellular determinants of fibrosis
Fibroblasts
Myofibroblasts
Pericytes
Cellular fate transitions in systemic sclerosis
Bone marrow–derived mesenchymal progenitor cells in SSc
Molecular determinants of fibrosis
Regulation of collagen production
Cell-autonomous regulation of collagen synthesis
Peroxisome proliferator–activated-γ: the interface between adipogenesis and fibrosis
Biomechanical signaling
Fibrogenic Growth Factors and Chemokines
Transforming growth factor-β is a master regulator of connective tissue remodeling
Connective tissue growth factor or CCN2
Platelet-derived growth factors
Wnt–β-catenin signaling
Paracrine mediators with antifibrotic activity
Cultured systemic sclerosis fibroblasts show cell-autonomous persistent activation ex vivo
Animal Models of Systemic Sclerosis
Heritable Animal Models of Scleroderma
Tight skin 1 mouse
Tight skin 2 mice
Constitutive transforming growth factor-β receptor 1 signaling
Inducible Animal Models of Scleroderma
Bleomycin-induced scleroderma in the mouse
Immunologically Induced Mouse Models of Systemic Sclerosis
Topoisomerase I immunization-induced scleroderma in mice
Type V collagen immunization-induced scleroderma in rabbits
Sclerodermatous chronic graft-versus-host disease
References
151
151
Outcomes measures in systemic sclerosis
Introduction
Measuring Disease Activity, Damage, and Severity in Scleroderma
Disease Activity in Scleroderma
Assessment of Disease Damage
Assessment of Disease Severity
Outcome Measures in Scleroderma
Measuring Skin Disease in Scleroderma
Measuring Musculoskeletal Involvement in Scleroderma
Measuring Cardiopulmonary Disease in Scleroderma
The 6-minute walk test—an outcome measure for pulmonary arterial hypertension
Composite outcome endpoints
Dyspnea indices
Measuring Gastrointestinal Tract Disease in Scleroderma
Measuring Vascular Disease in Scleroderma: Raynaud Phenomenon and Digital Ulcers
Measuring ischemic digital ulcers in scleroderma
Measuring Physical Function and Health-Related Quality of Life
Patient-Reported Outcomes Measurement Information System®
COMPOSITE ENDPOINTS
American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous System ...
Biomarkers for Scleroderma
Conclusion
Acknowledgments
References
152
152
Management of systemic sclerosis
Introduction
Principles of Effective Management
Clinical Trials in Systemic Sclerosis
Disease-Modifying Therapies for Systemic Sclerosis
Organ-Based Assessment and Treatments
Raynaud Phenomenon
Critical digital ischemia and ulceration
Musculoskeletal Complications
Skin Thickening
Other Skin Manifestations
Gastrointestinal Complications
Lung Disease
Pulmonary fibrosis
Pulmonary vascular disease
Pulmonary arterial hypertension
Macrovascular Disease
Cardiac Disease
Renal Scleroderma
Summary
References
153
153
Emerging therapies for systemic sclerosis
Introduction
Skin Fibrosis as Outcome for Clinical Trials
Change in Clinical Trial Design for Emerging Therapies in SSc
Development of Targeted Therapies for SSc
Randomized Clinical Trials From 2018–2021 To Identify Emerging Therapies In Ssc
Ild As The Primary Outcome
Skin As The Primary Outcome
Composite Response Index Criss As The Primary Outcome
Pulmonary Hypertension As The Primary Outcome
Gastrointestinal Symptoms As The Primary Outcome
Translation of The Emerging Therapies Into Clinical Use
Summary
References
154
154
Raynaud phenomenon
History
Nomenclature
Epidemiology And Etiology
Pathophysiology
Neural Abnormalities And Mechanisms
Vascular Abnormalities And Mechanisms
Intravascular Abnormalities And Mechanisms
Clinical Features
Investigations
Confirming RP
Investigations For Secondary Causes
Management
General Measures
Drug Treatment
Calcium channel blockers
Other vasodilators
Prostaglandin treatment
Other medical therapies
Surgery
Conclusion
Acknowledgment
References
155
155
Localized scleroderma and scleroderma-like syndromes
Localized Forms of Scleroderma
Morphea
Deep morphea or morphea profunda
Generalized or diffuse morphea
Linear Scleroderma
Conditions that Mimic Scleroderma
Scleromyxedema
Nephrogenic Systemic Fibrosis
Scleredema
Eosinophilic Fasciitis
Chronic Graft-Versus-Host Disease
References
156
156
Clinical features, classification, and epidemiology of inflammatory muscle disease
Epidemiology
Classification Criteria
Incidence and Prevalence by Age, Race, and Sex
Environmental Factors
Genetic Factors
Clinical Features
Constitutional
Skeletal Muscle
Skin
Calcinosis
Joints
Lung
Heart
Gastrointestinal Tract
Peripheral Vascular System
Kidney
Differential Diagnosis
Noninflammatory Myopathies
Other Inflammatory Myopathies
Malignancy and Myositis
Investigations
General Concepts
Serum Muscle Enzymes
Electromyography
Muscle Biopsy
Magnetic Resonance Imaging
Skin
Serum Autoantibodies
Overview of the Natural History and Disease Prognosis
Prognostic Considerations
Survival
Disability
References
157
157
Etiology and pathogenesis of inflammatory muscle disease (myositis)
Introduction
Muscle Biology and Physiology
Muscle Development and Regeneration
Etiology
Genetic Factors
Environmental Factors
Infections
Ultraviolet Light and Vitamin D Deficiency
Drugs
Smoking
Malignancy
Pathogenesis
Muscle Histopathologic Features
Immunopathologic Features
Cytokines and Chemokines
Immune Mechanisms and Muscle Function
Mechanisms of cell damage
Indirect effects of molecules from the immune system (cytokines and others) on muscle metabolism and function
Involvement of the microvasculature in inflammatory myopathies
Humoral Mechanisms
Inclusion Body Myositis
Conclusion
References
158
158
Clinical significance of autoantibodies in inflammatory muscle disease
Introduction
Myositis-Associated Autoantibodies
Anti–PM-SCL
Anti-RO/SSA And Anti-LA/SSB
Anti-KU
Anti–U1-SNRNP
Anti-PUF60
Myositis-Specific Autoantibodies
ANTI-ARS
Dermatomyositis-Specific Autoantibodies
Anti–MI-2
Anti-MDA5
Anti–TIF-1γ
Anti-SAE
Anti-NXP2
Inclusion Body Myositis–Associated Antibody
Anti-MUP44
Immune-Mediated Necrotizing Myopathy–Associated Antibodies
Anti-SRP
Anti-HMGCR/ANTI-200/100
Conclusion
References
159
159
Management of inflammatory muscle disease
General Principles
Assessing Disease Activity and Damage
Drug Therapies
Corticosteroids
Adrenocorticotropic Hormone Gel
Methotrexate
Azathioprine
Intravenous Immunoglobulin
Mycophenolate Mofetil
Cyclosporine and Tacrolimus
Cyclophosphamide
Antimalarials
Rituximab
Anti–Tumor Necrosis Factor Agents
Anakinra
Janus Kinase Inhibitors
Other Therapies
Nonpharmacologic Treatments
Patient and Family Education
Rehabilitation
Management of Extramuscular Manifestations
Interstitial Lung Disease
Cardiac Involvement
Gastrointestinal Involvement
Skin Involvement
Calcinosis
Inclusion Body Myositis
Statin-Associated Necrotizing Myopathy
Future Directions
Acknowledgments
References
160
160
Metabolic, drug-induced, and other noninflammatory myopathies
Key Points
Metabolic Myopathies
Glycogen and glucose metabolism (Fig. 160.1)
Defects of glucose and glycogen metabolism
Myophosphorylase deficiency (McArdle disease, glycogenosis type V)
Phosphofructokinase deficiency (glycogen storage disease type VII, Tarui disease)
Debrancher deficiency (Cori-Forbes disease, glycogenosis type III)
Acid maltase deficiency (glycogenosis type II, Pompe disease)
Lipid metabolism
Fatty acid oxidation disorders
Carnitine palmitoyltransferase II deficiency
Very-long-chain acyl-CoA dehydrogenase deficiency
Long-chain acyl-CoA dehydrogenase deficiency and trifunctional protein deficiency
Mitochondrial myopathies
Myoadenylate deaminase deficiency
Drug- and Toxin-Induced Myopathies
Statins
Colchicine
Hydroxychloroquine
Glucocorticoids
Alcohol
Endocrine Myopathies
Thyroid disorders
Cushing syndrome
Diabetes
Muscular Dystrophies
Duchenne muscular dystrophy
Becker muscular dystrophy
Emery-dreifuss muscular dystrophy
Limb-girdle muscular dystrophies
Myotonic dystrophy
Proximal myotonic myopathy
Infectious Myopathies
Pyomyositis
Gas gangrene
Psoas abscess
Influenza
Human immunodeficiency virus
Parasites
References
161
161
Classification and epidemiology of vasculitis
Introduction
Classification, Definitions, and Diagnostic Criteria for Vasculitis
Historical Background
American College of Rheumatology 1990 Classification Criteria
Chapel Hill Consensus Conferences
European Medicines Agency Algorithm
ACR/EULAR Criteria
Criteria for Childhood Vasculitis
Large-Vessel Vasculitis
Medium-Vessel Vasculitis
Polyarteritis Nodosa
Kawasaki Disease
Small-Vessel Vasculitis
ANCA Vasculitis
Immune Complex Vasculitis
Cryoglobulinemic vasculitis
Immunoglobulin A vasculitis (Henoch–Schönlein purpura)
Hypocomplementemic urticarial vasculitis
Other Types of Vasculitides
Behçet disease
Diagnostic Criteria for Vasculitis
Current Position
Epidemiology of Vasculitis
Vasculitides Predominantly Affecting Large Vessels
Giant Cell Arteritis
Takayasu Arteritis
Vasculitides Predominantly Affecting Medium-Sized Vessels
Polyarteritis Nodosa
Kawasaki Disease
Vasculitides Predominantly Affecting Small Vessels
ANCA-Associated Vasculitis
Incidence
Prevalence
Influence of race and ethnicity
Genetic influences
Other environmental factors
Immunoglobulin A Vasculitis (Henoch–Schönlein Purpura)
Anti–Glomerular Basement Membrane Disease (Goodpasture Syndrome)
Hypocomplementemic Urticarial Vasculitis
Behçet Disease
Secondary Vasculitides
Current Status
References
162
162
Biology and immunopathogenesis of vasculitis
Introduction
The Endothelium
Endothelial Cell Activation
Leukocyte–Endothelial Cell Interaction
Role Of Aging In Leukocyte–Endothelial Cell Interaction
Endothelium, Coagulation, And Inflammation
Damage And Repair: Angiogenesis
Immunopathogenesis Of Small-Vessel Vasculitis
Immune Complex–Mediated Small-Vessel Vasculitides
Immunoglobulin A vasculitis (Henoch Schönlein purpura)
Anti–glomerular basement membrane disease
Cryoglobulinemic vasculitis
Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis)
Antineutrophil Cytoplasmic Antibody–Associated Vasculitides
Immunopathogenesis Of Major Small-Vessel Vasculitides
Granulomatosis with polyangiitis
Microscopic polyangiitis
Eosinophilic granulomatosis with polyangiitis
Immunopathogenesis of Vasculitides of Medium- and Small-Sized Arteries
Polyarteritis Nodosa
Kawasaki Disease
Immunopathogenesis of Large-Vessel Vasculitides
Giant Cell Arteritis
Takayasu Arteritis
Conclusion
References
163
163
Polyarteritis nodosa and Cogan syndrome
Key Points
Introduction
Polyarteritis Nodosa
Definition
Classification
Epidemiology
Environmental factors
Genetics
Clinical Features
Cutaneous lesions
Musculoskeletal features
Neurologic features
Renal involvement
Gastrointestinal involvement
Cardiac involvement
Orchitis
Other features
Secondary polyarteritis nodosa
Limited forms of polyarteritis
Pathology
Investigations
Differential Diagnosis
Management
Prognosis
Cogan Syndrome
Definition
Classification
Typical and atypical Cogan syndrome
Epidemiology
Environmental factors
Pathogenesis
Clinical Features
Ocular
Vestibuloauditory
Vasculitis
Other systemic features
Associations with other diseases
Assessment Of Disease Activity And Investigations
Blood and cerebrospinal fluid
Assessment of organ involvement
Ocular
Vestibuloauditory
Cardiovascular
Neurologic
Differential Diagnosis
Management
Main principles
Ocular disease
Vestibuloauditory disease
Systemic vasculitis
Prognosis
Conclusion
References
164
164
Antineutrophil cytoplasm antibody–associated vasculitis
Definition
Etiology and Pathogenesis
Epidemiology
Classification and Definitions
Clinical Features
Investigations and Differential Diagnosis Of Antineutrophil Cytoplasm Antibody–Associated Vasculitis
Pathology
Clinical Assessment of Vasculitis
Disease Activity
Damage in Vasculitis
Other Scores
Assessing Function
Therapies
Treatments
No Treatment
Topical And Other Treatment Of Upper And Lower Airways
Systemic Glucocorticoid Therapy
Immunosuppressive Agents
Rituximab
Other Immunosuppressive Agents
Outcomes
References
165
165
Takayasu arteritis
History
Epidemiology
Clinical Features
Investigations
Diagnosis And Monitoring Of Disease Activity
Laboratory Investigations
Radiographic Studies
Differential Diagnosis
Pathology And Pathogenesis
Management
General Principles
Immunosuppressive Therapy
Glucocorticoids
Methotrexate
Azathioprine
Cyclophosphamide
Other conventional immunosuppressive agents
Biologic Therapies
Antiplatelet Therapy
Nonmedical Interventions
Management of Comorbid Features
Outcome
Pregnancy
References
166
166
Polymyalgia rheumatica and giant cell arteritis
Introduction
Epidemiology and Diagnosis
Relationship Between Polymyalgia Rheumatica And Giant Cell Arteritis
Pathology
Pathogenesis
Role of Infectious Agents
Immunogenetics
Innate And Adaptive Immune Mechanisms
Clinical Findings
Giant Cell Arteritis
Cranial Symptoms
Visual symptoms
Cerebrovascular ischemic events
Constitutional symptoms
Large-vessel vasculitis
Musculoskeletal symptoms and polymyalgia
Other less frequent manifestations
Polymyalgia Rheumatica
Laboratory Findings
Imaging
Polymyalgia Rheumatica
Giant Cell Arteritis
Ultrasonography
Computed tomography and computed tomography angiography
Magnetic resonance imaging and magnetic resonance angiography
Digital subtraction angiography
18F-Fluorodeoxyglucose positron emission tomography
Differential Diagnosis
Treatment
Giant Cell Arteritis
Polymyalgia Rheumatica
References
167
167
Behçet disease
Introduction
Epidemiology
Pathogenesis
Clinical Features
Mucocutaneous Features
Eye Involvement
Musculoskeletal Features
Cardiovascular Involvement
Neurologic Involvement
Gastrointestinal Involvement
Lung Involvement
Others
Laboratory Features
Disease Course and Prognosis
Differential Diagnosis
Management
References
168
168
Kawasaki disease
History
Epidemiology
Clinical Features
Laboratory Assessments
Pathologic Features
Etiology And Pathogenesis
Treatment And Management
References
169
169
IgA vasculitis (Henoch–Schönlein purpura)
Definition
Epidemiology
Classification
Etiology and Pathogenesis
Environmental Factors
Immunologic Factors
Genetic Background
Clinical Findings
Cutaneous Involvement
Joint Involvement
Gastrointestinal Involvement
Renal Involvement
Genitourinary Involvement
Neurologic Involvement
Pulmonary Involvement
Malignancy
Pregnancy
Diagnosis
Differential Diagnosis
TreatmeNt
Treatment of Henoch–Schönlein Purpura–Associated Nephritis
Moderate nephritis
Rapidly progressive glomerulonephritis
Renal transplantation
Outcome and Prognosis
References
170
170
Cutaneous vasculitis and panniculitis
Classification
Vasculitis
Panniculitis
Pathologic, Clinical, and Systemic Features
Cutaneous Vasculitides
Histopathologic features
Palpable purpura
Urticarial lesions
Other cutaneous lesions
Systemic manifestations
Vasculitic syndromes with prominent cutaneous disease
Acute hemorrhagic edema of infancy
Hypocomplementemic urticarial vasculitis
Vasculitis associated with paraproteinemia
Paraneoplastic vasculitis
Cutaneous polyarteritis nodosa
Erythema elevatum diutinum
Cutaneous vasculitis in patients with rheumatic diseases
Cocaine- or levamisole-associated vasculitis and vasculopathy syndrome
Panniculitides
Erythema nodosum
Idiopathic neutrophilic lobular panniculitis
α1-Antitrypsin deficiency–associated panniculitis
Pancreatic panniculitis
Calcifying panniculitis of renal failure
Poststeroid panniculitis
Lipoatrophic panniculitis
Histiocytic cytophagic panniculitis or subcutaneous panniculitis–like T-cell lymphoma
Lupus erythematosus panniculitis (lupus profundus)
Sclerosing panniculitis (lipodermatosclerosis)
Factitial panniculitis
Investigations
Cutaneous Vasculitis
Panniculitis
Differential Diagnosis
Cutaneous Vasculitis
Panniculitis
Management
Cutaneous Vasculitis
Panniculitis
Conclusion
References
171
171
Cryoglobulinemia
Epidemiology
Clinical Manifestations
Skin Manifestations
Joint Manifestations and Weakness
Renal Manifestations
Nervous Manifestations
Liver Manifestations
Lymphoproliferation
Other Manifestations
Outcome
Diagnosis and Classification
Pathogenesis
Therapy
References
172
172
Primary angiitis of the central nervous system
History
Case Definition and Criteria
Clinical Syndromes of Cerebral Vasculitis
Clinical Findings
Pathogenesis
Pathology
Laboratory Investigations
Brain Imaging
Biopsy Findings
Differential Diagnosis
Reversible Cerebral Vasoconstriction Syndromes
Cerebral Amyloid Angiitis
Paraneoplastic Angiitis
Diagnostic Approach
Treatment and Outcome
References
173
173
Adult-onset Still disease
Introduction
Epidemiology
Pathogenesis
Genetic Predisposition
Environmental Factors
Immune Dysregulation
Clinical Presentation
Fever
Arthritis
Rash
Other Frequent Findings
Infrequent Findings
Laboratory Findings
Classification and Diagnosis
Management
First-Line Treatment: Nonsteroidal Antiinflammatory Drugs and Glucocorticoids
Second-Line Therapy: Immunosuppressants
Third-Line Therapy: Biologic Agents
Tumor necrosis factor inhibitors
Anakinra
Tocilizumab
Other biologic agents
Special Issues Regarding Treatment
Pregnancy
Macrophage activation syndrome
AA amyloidosis
Prognosis and Functional Outcome
References
174
174
Monogenic autoinflammatory diseases
Key Points
Introduction
The Hereditary Episodic Fever Syndromes
Familial Mediterranean Fever
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Laboratory investigations
Treatment
Mevalonate Kinase Deficiency (Previously Hyperimmunoglobulinemia D with Periodic Fever Syndrome)
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Clinical findings
Laboratory investigations
Treatment
TNF-Receptor–Associated Periodic Syndrome
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Laboratory investigations
Treatment
Neutrophilic Urticaria (The Cryopyrin-Associated Periodic Syndrome, Familial Cold Autoinflammatory Syndrome, Muckle-Wells S ...
Background
Genetics and Pathophysiology
The NLRP3 Inflammasome and IL-1β Activation and Secretion
Clinical Features And Laboratory Findings
Familial Cold Autoinflammatory Syndrome
Muckle-Wells Syndrome
Neonatal-Onset Multisystem Inflammatory Disease or Chronic Infantile Neurologic Cutaneous And Arthritis Syndrome
Laboratory investigations of cryopyrin-associated periodic syndromes
Treatment of cryopyrin-associated periodic syndromes
Variable Rashes, High Serum Interleukin-18, and Variable Predisposition to Macrophage Activation Syndrome
NLRC4-Related Autoinflammatory Syndromes
Background
Genetics and pathophysiology
Clinical features and laboratory findings
CDC42-mediated autoinflammatory disease
IL-18PAP-MAS
Treatment of high IL-18 states
NLRP1-Associated Autoinflammation with Arthritis and Dyskeratosis
Background
Genetics and Pathophysiology
Clinical features and laboratory findings
Treatment
Pustular Skin Rashes and Episodic Fevers
Interleukin-1–Mediated Pyogenic Disorders with Sterile Osteomyelitis
Deficiency of the IL-1-receptor antagonist
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Majeed syndrome
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Partially Interleukin-1–Mediated Pyogenic Disorders
Pyogenic Sterile Arthritis, Pyoderma Gangrenosum, and Acne Syndrome
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
HA20: Haploinsufficiency of A20 (Monogenic Form of Behçet’s Disease)
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Pyogenic Disorders Caused by Non–Interleukin-1 Cytokine Dysregulation
Deficiency of Interleukin 36 Receptor Antagonist
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
CARD14-Mediated Psoriasis
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
AP1S3-Mediated Pustular Psoriasis
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Early-Onset Inflammatory Bowel Disease
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Vasculopathy and Panniculitis/Lipoatrophy Syndromes
Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome Or Proteasome-Associated Auto ...
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Otulin-Related Autoinflammatory Syndrome
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Nemo Deleted Exon 5-Autoinflammatory Syndrome (NEMO-NDAS) and SAMD9L-Associated Autoinflammatory Disease (SAMD9L-SAAD)
Vasculopathy and/or Vasculitis with Livedo Reticularis Syndromes
Without Significant Central Nervous System Disease
Sting-associated vasculopathy with onset in infancy
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
With Severe Central Nervous System Disease
Deficiency of adenosine deaminase 2
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Aicardi-Goutières syndromes
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Spondyloenchondrodysplasia with immune dysregulation
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Autoinflammatory Disorders with Granulomatous Skin Diseases
Without Significant Immunodeficiency
Blau syndrome/early onset sarcoidosis (pediatric granulomatous arthritis)
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Laboratory investigations
Complications of untreated disease
Treatment
With Variable Features of Immunodeficiency
PLCG2-associated antibody deficiency and immune dysregulation
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Other Autoinflammatory Syndromes
LACC1-Mediated Monogenic Still Disease
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Familial Cold-Induced Autoinflammatory Syndrome 2 (FCAS2)
Background
Genetics and pathophysiology
Clinical features and laboratory findings
Treatment
Syndromes Presenting with a Wider Clinical Phenotype
Sideroblastic Anemia, B-Cell Immunodeficiency, Periodic Fevers, and Developmental Delay Syndrome
Background
Genetics and pathophysiology
Clinical features and laboratory findings
RIPK1 Deficiency (Cleavage-Resistant RIPK1-Induced Autoinflammatory Syndrome)
Cherubism
Autoinflammation and Immunodeficiency
Acknowledgment
References
175
175
Sarcoidosis
History
Epidemiology
Prevalence and Incidence
Risk Factors
Immunopathogenesis
Step 1: Lymphocytic Alveolitis
Step 2: Granuloma Formation
Step 3: Granuloma Resolution
Diagnostic Investigations
Laboratory Tests
Imaging
Biopsy
Additional Tests
Differential Diagnosis
Clinical Features
Respiratory Involvement
Ophthalmologic Involvement
Cutaneous Involvement
Cardiac Involvement
Nervous System Involvement
Musculoskeletal Involvement
Articular
Osseous
Muscular
Other Organ System Involvement
Childhood Sarcoidosis
Sarcoidosis Associations
Natural History and Prognosis
Management
Monitoring of Therapy
Acknowledgment
References
176
176
Relapsing polychondritis
HISTORY
Epidemiology
Clinical Features
Otorhinolaryngeal Disease
Respiratory Disease
Musculoskeletal Symptoms
Cardiovascular Disease
Ocular Symptoms
Renal Disease
Dermatologic Disease
Neurologic Disease
Miscellaneous Features
Diagnosis And Investigations
Differential Diagnosis
Pathogenesis
Management
Acknowledgments
References
177
177
The systemic amyloidoses
Introduction
Amyloidogenesis In Vivo
Aggregation
Tissue Deposition
Tissue Compromise
Host Responses
Clinical Epidemiology
AA Amyloid
Clinical Features
Diagnosis
Treatment
Aβ2-Microglobulin Amyloidosis (Aβ2m) (Dialysis Related Amyloidosis, DRA)
Clinical Features
Diagnosis
Treatment
AL (Immunoglobulin L-Chain Amyloidosis)
Epidemiology
Clinical Features
Diagnosis
Treatment
The Transthyretin Amyloidoses (ATTR)
Epidemiology
Hereditary autosomal dominant ATTR
ATTR pV50M
ATTR pV142I
ATTRwt (senile systemic amyloidosis)
Clinical Features
ATTR hereditary polyneuropathy
ATTR hereditary and sporadic cardiomyopathy
Diagnosis
Treatment
Attacking the Deposits
References
178
178
IgG4-related disease
History and Overview
Epidemiology
Clinical Features
IgG4-related type 1 autoimmune pancreatitis and sclerosing cholangitis
IgG4-related ophthalmic disease and sialoadenitis
IgG4-related kidney disease
IgG4-related lung disease
IgG4-related retroperitoneal fibrosis (RPF) and periaortitis
Other Organ Manifestations
Laboratory and Image Findings
Blood Test Findings
Histopathologic Findings
Radiologic Imaging
Pathogenesis45
Autoantigens
Innate Immunity
T-Cell Populations
B Cells
Diagnosis
The 2020 Revised Comprehensive Diagnostic (RCD) Criteria for IgG4-RD61
The 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification Criteria For IgG4 ...
Differential Diagnosis
Management
References
179
179
Immune-mediated complications of checkpoint inhibitors
Introduction
Mechanism of Action/Review of T-Cell Activation
Normal T-Cell Activation Background Data
Ctla-4 Antagonist
Pd-1 Inhibition
Immune-Related Adverse Events
Overview of IrAE Toxicity Grades
Endocrine
Gastrointestinal
Hepatic
Pulmonary
Neurologic
Dermatologic
Rheumatic IrAEs (fig. 179.3)
Sicca syndrome
Vasculitis
SLE/nephritis
Inflammatory arthritis
Polymyalgia rheumatica
Pathophysiology
Treatment of Rheumatic IrAEs
Guidelines
Targeted therapies
Anti-Tumor Necrosis Factor Directed Therapies
Anti-Interleukin-6 Directed Therapies
Anti-B-Cell Directed Therapies
Anti-T-Cell Directed Therapies
Other Targeted Therapies
Potential Adverse Effects From Glucocorticoids
Use of Checkpoint Inhibitors In Patients With Preexisting Autoimmune Disease
Conclusion
References
180
180
The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease
Introduction
Rheumatic Diseases and Risk of Covid-19 and Related Outcomes
Risk of Covid-19
Covid-19-Related Outcomes
Use of Antirheumatic Medications for the Management of Covid-19
Antimalarials
Glucocorticoids
Interleukin-6 Inhibitors
Interleukin-1 Inhibitors
Tumor Necrosis Factor Inhibitors
Colchicine
Janus Kinase (Jak) Inhibitors
Autoimmune/Inflammatory Manifestations of Covid-19
Multisystem Inflammatory Syndrome In Children and Adults
Thrombotic Events
New Onset Arthritis In Covid-19
Post-Covid Syndrome
Impact of the Covid-19 Pandemic On People With Rheumatic Disease
References
181
181
Epidemiology and classification of osteoarthritis
Introduction
Definitions of Osteoarthritis
Radiographic Osteoarthritis: Definitions
Prevalence of radiographic osteoarthritis
Prevalence of radiographic hip osteoarthritis
Prevalence of radiographic knee osteoarthritis
Prevalence of radiographic hand osteoarthritis
Prevalence of radiographic osteoarthritis in other sites
Incidence and progression of radiographic osteoarthritis
Incidence and progression of radiographic hip osteoarthritis
Incidence and progression of radiographic knee osteoarthritis
Symptomatic Osteoarthritis: Definitions
Prevalence of symptomatic knee/hip osteoarthritis
Prevalence of symptomatic hip osteoarthritis
Prevalence of symptomatic knee osteoarthritis
Prevalence of symptomatic hand osteoarthritis
Prevalence of symptomatic osteoarthritis in other sites
Incidence and progression of symptomatic osteoarthritis
Incidence of joint replacement
Mortality Rate In Osteoarthritis
Conclusion
References
182
182
Local and systemic risk factors for incidence and progression of osteoarthritis
Introduction
Systemic Risk Factors For Knee Osteoarthritis
Age
Sex
Body Weight
Race/Ethnicity
Bone Mineral Density
Occupational Activity
Nonoccupational Physical Activity
Nutritional And Dietary Factors
Smoking
Local Risk Factors For Knee Osteoarthritis
Injury
Knee Tissue Abnormalities
Local Neuromuscular And Mechanical Factors
Hip Osteoarthritis
Developmental Abnormalities
Hand Osteoarthritis
Hand Osteoarthritis Progression
Risk Factors For Pain In Osteoarthritis
Radiographic Disease
Tissue Lesions Detected By Mri
Psychological Factors
Body Weight
Risk Factors For Function Limitation And Disability In Osteoarthritis
Pain, Strength, Self-Efficacy, Depression, And Physical Activity
Knee Confidence, Instability, And Falls
Body Weight
References
183
183
Clinical features of osteoarthritis
Introduction
Definition
Symptoms (Box 183.1)
Pain
The joint as a driver of osteoarthritis pain
Biopsychosocial aspects of osteoarthritis pain
Joint Deformity and Swelling
Stiffness
Mechanical Symptoms
Signs (BOX 183.1)
Crepitus
Joint Swelling
Observable Deformity
Gait
Somatosensory Alterations
Clinical Presentations
Knees
HIPS
Hands
Shoulders
Feet
Spine
Other Sites
Miscellaneous Osteoarthritis Syndromes
Generalized osteoarthritis
Erosive osteoarthritis
Diffuse idiopathic skeletal hyperostosis
Evaluation
Patient-Reported Outcome Measures
Mortality
Conclusion
References
184
184
Animal models of osteoarthritis
Introduction
Why do we need osteoarthritis models?
How do we Model Osteoarthritis in Animals?
What components of disease are being modeled?
Osteoarthritis Models: A Historical Perspective
How Good are the Osteoarthritis Models as Models of Human Disease?
Current Rodent Osteoarthritis Models
Spontaneous Osteoarthritis
Chemical Induction of Osteoarthritis
Surgical Induction of Osteoarthritis
Meniscectomy
Anterior cruciate ligament transection
Destabilization of the medial meniscus
Genetic Modification
Generation of Genetically Modified Mice
How to ensure maximum value from in vivo studies
Animal Model Limitations
Conclusion
References
185
185
Pathogenesis and pathology of osteoarthritis
Introduction
The Normal Joint: Anatomy, Physiology, and Function
Joint Pathology in Osteoarthritis
Cartilage Pathology
Bone Pathology
Synovial Pathology
Meniscal Pathology
Staging and Grading of Cartilage and Bone Pathology in Osteoarthritis
Grading of Synovial Membrane Alterations in Osteoarthritis
Imaging of Joint Pathology in Osteoarthritis
Pathogenetic Concepts in Osteoarthritis
Animal Models of Osteoarthritis
Cartilage Matrix Degradation
Chondrocyte Activation, Differentiation, and Loss
Disease Risk Factors Inform Pathogenesis
Aging
Oxidative stress and mitochondrial dysfunction
Cellular senescence and the senescence-associated secretory phenotype
Autophagy
Biomechanics and Loading
Mechanoreceptors
The pericellular matrix
Neuromuscular function and proprioception
Obesity and Metabolic Disease
Load
Metabolic derangement and inflammation
Other metabolic/associated conditions
Genetics and Epigenetics
Genetics
Epigenetics
Integration of “omics”
Synovial and Bone Response in OA
Synovial membrane and synovitis in OA
Synovial inflammation and pain sensitization in OA
Bone remodeling and pain in OA
Conclusion
Acknowledgment
References
186
186
Genetics and epigenetics of osteoarthritis
Introduction
Early Heritability Studies
Traits and Outcomes Studied in the Genetics Of Osteoarthritis
Twin and Family Studies
Twin Studies
Familial Aggregation Studies
Familial Disorders Associated with Osteoarthritis
Candidate Gene Studies in Osteoarthritis
Genome-Wide Association Studies in Osteoarthritis
Epigenetics of Osteoarthritis
Introduction to Epigenetics
Candidate Gene Dna Methylation Studies in Osteoarthritis
Genome-Wide Epigenetic Studies in Osteoarthritis
Epigenetics as a Modulator of Genetic Risk
Conclusions
Acknowledgments
References
187
187
Imaging of osteoarthritis
Introduction
Conventional Radiography
Radiographic Procedures
What Pathologic Features can Conventional Radiography Assess in Osteoarthritis?
Osteophytes
Subchondral sclerosis, erosions, and cysts
Joint space narrowing
Bone remodeling and attrition
Subchondral trabecular bone analysis
Joint morphology
Conventional radiography and osteoarthritis symptoms
Conventional radiography and early osteoarthritis
Conventional radiography in advanced osteoarthritis
Conventional radiography: quantification and scoring methods
Hip conventional radiography
Hand conventional radiography
Knee conventional radiography
Magnetic Resonance Imaging
What Pathologic Features can Magnetic Resonance Imaging Assess in Osteoarthritis?
Cartilage abnormalities
Synovitis and joint effusion
Fibrocartilage and ligament abnormalities
Subchondral bone marrow lesions and cysts
Bone attrition
Osteophytes
Bone erosion
Three-dimensional bone shape
Muscle
Magnetic Resonance Imaging: Quantification and Scoring Methods
MRI semiquantitative evaluation: knee
MRI semiquantitative evaluation: hand
MRI semiquantitative evaluation: hip
MRI semiquantitative evaluation: foot
Quantitative MRI Analysis
Ultrasound
What Pathologic Features can Ultrasound Assess in Osteoarthritis?
Synovitis
Cartilage
Osteophytes
Menisci
Ultrasound: Quantification and Scoring Methods
Other Imaging Modalities
Scintigraphy
Computed Tomography and Computed Tomographic Arthrography
Positron Emission Tomography
Considerations for Osteoarthritis Imaging in Clinical Practice
Considerations for Future Research in Osteoarthritis Imaging
Summary
References
188
188
Assessment of the patient with osteoarthritis and measurement of outcomes
Introduction
Biomedical Versus Biopsychosocial Perspective in Assessment of Patients with Osteoarthritis
Fundamental Differences between Patient Assessment in Clinical Research Versus Routine Clinical Practice
The World Health Organization’s International Classification Of Functioning, Disability, And Health
Selection of Measures for Evaluation of Patients with Osteoarthritis
Assessment of Impairments in Osteoarthritis
Examination of physical signs of osteoarthritis
Symptom reporting using standardized questionnaires
Assessment of pain
Assessment of fatigue
Assessment of sleep
Assessment of mood
Assessment of Activity Limitations and Participation Restrictions in Osteoarthritis
Measurement of activity limitations using standardized questionnaires
Performance-Based Assessment of Impairments and Activity Limitations
Assessment of Participation Restrictions
Evaluation of Key Contextual Factors
Responsiveness and Interpretation of Change in Patient Status
Responsiveness of Measure Scores
Interpretation of Changes in Measure Scores
Conclusion
Acknowledgment
References
189
189
Preclinical and early osteoarthritis
Definition of Preclinical and Early Osteoarthritis
Evidence for Preclinical and Early Osteoarthritis
Detection of Preclinical and Early Osteoarthritis
Progression of Osteoarthritis
Triggering Mechanisms
Treatment Paradigms
Potential Benefits to an Early Diagnosis of Osteoarthritis
Summary
References
190
190
Management of osteoarthritis
Introduction
Core Principles in Osteoarthritis Management
Education
Exercise
Individualized Treatment
Multidisciplinary Approach
Behavioral, Psychosocial, and Physical Interventions
Weight Loss
Orthoses, Braces, and Assistive Devices
Other Behavioral, Psychosocial, and Physical Interventions
Pharmacologic Treatments
Topical Agents
Oral Agents
Nonsteroidal antiinflammatory drugs
Other Oral Agents
Acetaminophen
Duloxetine
Glucosamine sulfate and chondroitin sulfate
Opioids
Intraarticular Therapy
Glucocorticoids
Hyaluronate Preparations
Surgical Interventions
Issues Specific to the Management of Hand Osteoarthritis
Core Principles of Hand Osteoarthritis Management
Pharmacologic Treatments
Surgical Interventions
Acknowledgment
References
191
191
Emerging treatments for osteoarthritis
Emerging Symptomatic Treatments (Fig. 191.1)
Drugs Targeting the Nerve Growth Factor Pathway
Anti-NGF antibodies
Tanezumab
Fasinumab
TrkA inhibitors
LEVI-O4
MEDI-7352
Botulinum Toxin
Capsaicin
LMWF5
Resiniferatoxin
Emerging Dmoads (Fig. 191.1 and Table 191.1)
Cartilage as the Target
Cartilage catabolism as the main target
ADAMTS-5 inhibitor
Cartilage anabolism as the main target
Sprifermin or rhFGF18
Inhibition of the Wnt pathway
OP-1/BMP-7
TPX100
Engedi1000
SB-061
LNA043
LRX712
KA34
Bone
Systemically
Cathepsin K inhibitor (MIV711)
Bisphosphonates
Denosumab
Inflammation and Immunomodulators
Anti-IL-1
Anti-TNF
Anti-IL-6
Anti-granulocyte-macrophage colony-stimulating factor (GM-CSF)
APPA
IκB kinase inhibitor
Drugs Targeting Cellular Senescence
UBX101 (unity technology)
Cell and Cell-Derived Therapies
Mesenchymal Stem Cells
Cell-Derived Concentrate
Platelet rich plasma (PRP)
nSTRIDE Autologous Protein Solution (APS) Kit
Research Avenues in Therapeutics
References
192
192
Epidemiology and classification of gout
Historical Perspective
Westernization And Gout Trends
Case Definitions And Classification Criteria
Prevalence of Gout
Incidence of Gout
Risk Factors for Hyperuricemia and Gout
Nonmodifiable Factors: Demographics: Sex, Age, Ethnicity/Race, and Genetics
Modifiable Factors: Obesity, Insulin Resistance, Lifestyle, and Others
Obesity, insulin resistance, and cardiovascular comorbidities
Dietary factors
Alcoholic beverages
Sugar-sweetened beverages
Coffee, teas, and caffeine
Medications and supplements
Environmental and Ambient Exposure
Key Mediating Mechanisms Of Lifestyle Factors: Purine And Insulin Resistance
Cardiovascular-Metabolic Conditions and Other Disorders
References
193
193
Etiology and pathogenesis of gout
Urate Physiology
Forms of Urate
Urate Production and Excretion
Urate Balance
Purine Metabolism and Urate Production
Urate Excretion
Extrarenal urate excretion
Renal urate excretion
Urate transporters
Glucose transporter 9
Urate transporter 1
Other urate transporters
Hyperuricemia
Conditioning Factors
Classification of Hyperuricemia
Monosodium Urate Crystal Formation
Proteins Binding to Monosodium Urate Crystals
The Gout Flare
NLRP3 Inflammasome Activation
Priming signal
Assembly signal
Other Inflammatory Mediators
Neutrophil Activation
Termination of the Gout Flare
Advanced Gout
Tophus Formation
Joint Damage
The Genetics of Gout
Transporter Genes
Metabolic Genes
Genes Influencing Crystal Formation and Crystal-Triggered Inflammation
Rare Genetic Disorders
Purine metabolism syndromes
Autosomal dominant kidney diseases caused by UMOD pathogenic variants (ADTKD-UMOD)
Summary
Acknowledgment
References
194
194
Clinical features of gout
Asymptomatic Hyperuricemia
Acute Gout Flares
Intervals Between Gout Flares
Advanced Tophaceous Gout
References
195
195
Management of gout and hyperuricemia
Treatment of Arthritis and Hyperuricemia in Gout
Therapeutic Targets For Acute Gouty Arthritis
Primary Treatment Objectives
Choice of Drug and Treatment Regimens
Nonsteroidal antiinflammatory drugs
Corticosteroids and adrenocorticotropic hormone (Acth)
Colchicine
Clinical pharmacology of colchicine and drug–drug interactions
Mechanism of action
Evidence basis and colchicine dosing for treatment of acute gout
Side effects
Colchicine And Other Antiinflammatory Drugs For Prophylaxis Of Acute Gout
Interleukin-1 Inhibition for Treatment And Prophylaxis of Gouty Arthritis
Treatment of Hyperuricemia in Gout
Nonpharmacologic Measures
Indications For Pharmacologic Oral Urate-Lowering Therapy For Gout And Drug Choices
The Advantages Of The “Treat To Target” Ult Strategy For Outcomes In Gout
Treating Hyperuricemia In Severe Gout Refractory To First- And Second-Line Therapy
Allopurinol
Clinical pharmacology and mechanism of action
Side Effects
Severe allopurinol hypersensitivity reaction: clinical features and risk management
Allopurinol dosing and factors influencing response to allopurinol, including in chronic kidney disease
Febuxostat
Probenecid
Mechanism of action
Dosing recommendations and side effects
Pegloticase For Refractory Hyperuricemia In Severe, Chronic Gout
Recent developments
Acknowledgments
References
196
196
Calcium pyrophosphate deposition disease (pseudogout)
Introduction
Nomenclature
Epidemiology
Clinical Presentation
Asymptomatic Chondrocalcinosis
Acute Calcium Pyrophosphate Crystal Arthritis (Pseudogout)
Osteoarthritis with Acute Attacks
Osteoarthritis Without Acute Attacks
Polyarticular Inflammatory Arthritis
Neuropathic Arthritis
Other Forms of Calcium Pyrophosphate Deposition Disease
Spinal Involvement
Crowned Dens Syndrome
Extraarticular Calcium Pyrophosphate Deposition Disease Deposits (Tophaceous Calcium Pyrophosphate Deposition Disease)
Involvement of other Mineralized Tissues
Triggers of Acute Attacks of Calcium Pyrophosphate Crystal Arthritis
Intraarticular Hyaluronic Acid Administration
Bisphosphonates
The Postoperative State
Other Triggers
Associated Diseases
Hyperparathyroidism
Hemochromatosis
Hypomagnesemia
Hypophosphatasia
Gout
Rheumatoid Arthritis
Familial Forms of Calcium Pyrophosphate Deposition Disease
Diagnostic Strategies
Synovial Fluid Analysis
Imaging
Conventional radiography
Computed tomography
Magnetic resonance imaging
Diagnostic ultrasonography
Advanced imaging techniques
Pathology
Pathogenesis
Step 1: crystal formation
Step 2: crystal effects
Mechanical consequences
Treatment
Acute Calcium Pyrophosphate Crystal Arthritis (Box 196.4)
Conclusions
Acknowledgments
References
197
197
Basic calcium phosphate crystal deposition disease
History
Calcific Periarthritis
Intraarticular Basic Calcium Phosphate Crystal Deposition
Epidemiology
Calcific Periarthritis
Articular Calcification
Clinical Features
Calcific Periarthritis
Large-joint destructive arthropathies
Additional clinical manifestations
Investigations
Imaging
Biochemical
Synovial or Bursal Fluid
Identification and Characterization of Basic Calcium Phosphate Crystals
Differential Diagnosis
Structure and Function
Nature of the Crystals
Etiology
Pathogenesis
Calcific Periarthritis
Tumoral Calcinosis
Basic Calcium Phosphate Crystals and Osteoarthritis
Management
Calcific Periarthritis
Tumoral Calcinosis
Articular Basic Calcium Phosphate Crystals
Conclusion
References
198
198
Epidemiology and classification of osteoporosis
Key Points
Introduction
History
Definition of Osteoporosis
Classification of Osteoporosis
Assessment of Fracture Risk
Prevalence and Incidence
Risk Factors
Impact of Osteoporotic Fracture
Mortality
Morbidity
Bone Mineral Density and Fracture
Fracture Epidemiology
Hip Fracture
Secular trends in hip fracture
Vertebral Fracture
Distal Forearm Fracture
Prior Fracture and the Risk of Subsequent Fracture
Economic Burden of Fracture
Implications for Prevention
Secondary Prevention: Treating Those Who Have Already Had a Fracture
Primary Prevention: Starting Treatment in Individuals at High Fracture Risk
Future Projections
Conclusion
References
199
199
Clinical evaluation and clinical features of osteoporosis
Key Points
Osteoporosis: Definition And Diagnosis
Clinical Evaluation
Bone Health Optimization Prior to Elective Orthopedic Surgery
History
History of a Patient on Therapy
Physical Examination
Investigations
Bone Mineral Density Testing
Vertebral Fracture Assessment
Trabecular Bone Score
Plain Radiography
Repeat Dual-Energy X-Ray Absorptiometry
Risk Algorithms
Bone Turnover Markers
Laboratory Studies
Diagnosis
Differential Diagnosis
Natural History
Morbidity And Mortality
Osteoporosis In Men
Conclusion
Acknowledgment
References
200
200
Pathophysiology of osteoporosis
Introduction
Determinants of Peak Bone Mass
Genetic Factors Affecting Bone Mass
Monogenic osteoporosis
Ethnic differences
Nutrition Effects on Bone Mass
Exercise Effects on Bone Mass
Gonadal Function Effects on Peak Bone Mass
Determinants of Bone Loss
Nutrition: Calcium and Vitamin D Effects on Bone Loss
Nutrition: other dietary factors
Alcohol and Smoking Effects on Bone Loss
Physical Activity Effects on Bone Loss
Chronic Diseases and Medications
Pathogenesis of Bone Loss
Bone Remodeling
Osteoclast Activation and Resorption
Osteoblast-Mediated Bone Formation and Osteocytes
Gender and other Influences on Remodeling
Effects of Remodeling on Cancellous Bone
Effects of Remodeling on Cortical Bone
References
201
201 Biochemical markers of bone turnover in postmenopausal osteoporosis
Introduction
Bone Turnover
Bone Remodeling
Bone Turnover Assessment
Bone Cells
Practical Aspects
Choice of Bone Turnover Markers
Variability
Overview
Age and sex
Reference BTM intervals
Weight
Circadian
Day to day
Exercise
Immobilization
Nutrition
Surgical menopause
Diseases And Drugs
Osteoporosis
Prediction of Bone Loss
Prediction of Fractures
Diagnosis of Osteoporosis
Treatment of Osteoporosis
Treatment response to drugs given for osteoporosis
Bisphosphonates
Denosumab
Selective estrogen receptor modulators
Anabolic treatment
Selection of therapy
Harm caused by therapy
Offset monitoring
Bone Turnover Markers in Men
Conclusion
References
202
202
Management of osteoporosis
Key Points
Introduction
Recommendations For Treatment
Evaluation for Secondary Osteoporosis
Treatment
Nonpharmacologic Approaches
Physical therapy and balance training
Calcium and Vitamin D Supplementation
Other Lifestyle Modifications
Prevention of Falls
Hip Pads and Other Assistive Devices
Pharmacologic Interventions
Hormone Replacement Therapy
Mechanism of action
Fracture prevention
Side effects
Estrogen Agonist-Antagonists
Mechanism of action
Fracture reduction
Side effects
Newer Estrogen Agonist-Antagonists
Calcitonin
Bisphosphonates
Mechanism of action
Pharmacologic properties
Fracture reduction in clinical trials
Etidronate
Alendronate
Risedronate
Ibandronate
Zoledronate
Denosumab
Mechanism of action
Fracture reduction
Side Effects of Antiresorptive Agents
Parathyroid Hormone
Mechanism of action
Fracture reduction
Teriparatide (Anabolic Therapy) Vs Antiresorptive Therapy
Abaloparatide (PTHrP 1-34)
Mechanism of action
Fracture reduction
Side effects
Romosozumab
Strontium Ranelate
Mechanism of action
Fracture reduction
Side effects
Summary
Mangement of Vertebral Fractures
Operative Management
References
203
203
Glucocorticoid-induced osteoporosis
Key Points
Introduction
Pathophysiology of Glucocorticoid Bone Loss
Epidemiology
Investigations
Bone Mineral Density
Trabecular Bone Score
Advanced Imaging
Biochemical Markers
Management
Risk Stratification
Current Recommendations
Calcium And Vitamin D
Calcitonin
Bisphosphonates
Risedronate
Parathyroid Hormone
Rankl Inhibition: Denosumab
Sclerostin Inhibitor: Romosozumab
Care Gap in the Screening, Prevention, and Treatment of Glucocorticoid-Induced Osteoporosis
Conclusion
References
204
204
Osteomalacia, rickets, and renal osteodystrophy
Introduction
Calcium, Phosphorous, and Vitamin D Metabolism
Effect of Vitamin D on Bone Metabolism
Causes of Osteomalacia and Rickets
Consequences of Vitamin D Deficiency on Bone Mineralization, Mineral Ion Homeostasis, and Growth
Definition of vitamin D deficiency and insufficiency
Calcium Deficiency
Phosphate Deficiency: Heritable and Acquired Disorders
Fanconi Syndrome and Renal Tubular Acidosis
Aluminum, Fluoride, And Heavy Metal Toxicity
Drugs
Clinical Evaluation of Osteomalacia and Rickets
Imaging
Biochemistry
Clinical Findings
Strategies for the Treatment and Prevention of Osteomalacia
Renal Osteodystrophy
Altered Calcium, Phosphate, and Vitamin D Metabolism in Ckd-Mbd
The Skeletal Defects of Renal Osteodystrophy
Strategies for the Treatment of Ckd-Mbd
Acknowledgment
References
205
205
Paget disease of bone
Key Points
Introduction
History
Epidemiology
Pathogenesis
Genetic Factors
Environmental Factors
Histopathology
Clinical Features
Signs And Symptoms
Skeletal Sites
Imaging
Laboratory Findings
Differential Diagnosis
Complications and Natural History
Treatment
Bisphosphonates
Other Drugs
Supportive Therapy
Surgery
Follow-Up and Retreatment
Conclusion
Acknowledgment
References
206
206
Diffuse idiopathic skeletal hyperostosis
History
Epidemiology
Criteria and Characteristic Description
Criteria
Characteristic bone changes
Spectrum of bone changes
General Findings
Clinical Features
Investigations
Differential Diagnosis
Etiology and Pathogenesis
Pathology
Metabolic Factors
Diabetes and obesity
Bone growth factors
Other metabolic factors
Management
Primary Prevention
Specific Interventions
References
207
207
Neuropathic arthropathy
History
Etiology
Diabetes Mellitus
Syringomyelia
Tabes Dorsalis
Leprosy
Congenital Indifference To Pain
Meningomyelocele (Spinal Dysraphism)
Drug-Induced Neuropathic Arthropathy
Other
Clinical Features
Imaging
Plain Radiography
Other Imaging Techniques
Laboratory Investigations and Histologic Analysis
Differential Diagnosis
Pathogenesis
Management
Acute Neuropathic Arthritis
Reduction of weight bearing
Bisphosphonates
Chronic Neuropathic Arthropathy
Conclusion
References
208
208
Osteonecrosis
Introduction
Epidemiology
Glucocorticoids
Alcohol
Systemic Lupus Erythematosus
Coagulopathies and Hemoglobinopathies
Medication-Induced Osteonecrosis of the Jaw
Pathologic Features
Pathogenesis
Altered fat metabolism
Intravascular coagulation
Elevated intraosseous pressure
Intramedullary hemorrhage
Osteocytotoxicity
Other participatory processes
Clinical Features
Imaging
Radiography
Radionuclide Bone Scans
Computed Tomography
Magnetic Resonance Imaging
Staging Systems
Diagnosis
Differential Diagnosis
Specific Variants Of Osteonecrosis
Bone infarct
Subchondral insufficiency fracture
Osteonecrosis during pregnancy
Idiopathic transient osteoporosis of the hip
Management
Role of Conservative Management
Core Decompression
Other Orthopedic Interventions for Osteonecrosis
Arthroplasty
Experimental and Empirical Therapies
References
209
209
Rheumatoid manifestations of endocrine and metabolic diseases and treatments
Acromegaly
Clinical Features
Diabetes Mellitus
Thyroid Disease
Hyperparathyroidism
Adrenal Disorders
Ochronosis
Lipid Disorders
Statin Drug–Associated Muscle Syndromes
Other Drug-Associated Musculoskeletal Manifestations
Aromatase Inhibitors—Musculoskeletal Manifestations
Acknowledgments
References
210
210
Hemophilia-associated arthritis
Hemophilia
History
Epidemiology
Classification
Etiology
Von Willebrand Disease
Hemophilic Arthritis
Clinical Features
Acute hemarthrosis
Differential diagnosis of acute hemarthroses
Subacute arthritis
Chronic arthritis
Non–Joint-Related Disorders
Muscle hemorrhage
Hemophilic pseudotumors
Diagnosis
Imaging
Pathogenesis of Hemophilic Arthritis
Management
Primary Prevention
Management of Arthritis
Acute hemarthroses
Subacute hemophilic arthritis
Chronic arthritis
Complications of Hemophilic Arthritis
Osteoporosis
Chronic pain
Management of Joint Bleeding at Specific Sites
Orthopedic surgery
Knee
Ankle
Elbow
Hip
Exercise and sports
Current Issues in Treatment of Hemophilia
Blood Product–Transmitted Infections
Coagulation Factor Inhibitors
Future Treatment Options
Summary
References
211
211
Rheumatologic manifestations of hemoglobinopathies
Introduction
Sickle Cell Disease
Diagnosis
Clinical
Acute painful crisis
Dactylitis
Osteonecrosis
Soft tissue
Orofacial pain
Infections
Sequelae of chronic hemolysis
Association with rheumatic diseases
Imaging
Treatment
Thalassemia
Clinical
Osteopenia and osteoporosis
Growth
Autoimmune disease
Treatment-induced complications
Imaging
Treatment
References
212
212
Hemochromatosis
Introduction
The Hemochromatosis Arthropathy
Chondrocalcinosis
Spinal Involvement
Radiologic Appearance
Pathophysiology
Osteoporosis
Diagnosis
Treatment
Iron Depletion
General Management
Acknowledgment
References
213
213
Gaucher disease
Epidemiology
Etiology
Biochemistry
Molecular Biology And Genetics
Pathogenesis
Clinical Features
Hematologic Manifestations And Other Extraskeletal Disorders
Skeletal Involvement
Investigations
Biochemical Studies
Imaging
Differential Diagnosis
Management
Enzyme Replacement Therapy
Substrate Reduction Therapy
Symptomatic Treatments
Bone remodeling–targeted treatments and vitamin D
Splenectomy
Orthopedic treatments
Experimental Therapies
References
214
214
Digital clubbing and hypertrophic osteoarthropathy
History
Epidemiology
Classification
Clinical Features
Symptoms
Physical Findings
The Primary Form
Investigations
Differential Diagnosis
Clinical Significance
Pathology
Etiology And Pathogenesis
Prostaglandins And Primary Hypertrophic Osteoarthropathy
Management
References
215
215
Miscellaneous arthropathies
Key Points
Cancer-Related Musculoskeletal Syndromes
Associations of Rheumatologic Diseases with Cancer
Musculoskeletal Manifestations of Cancer
Synovial sarcoma
Cartilaginous tumors
Metastatic disease
Paraneoplastic syndromes
Inflammatory manifestations associated with myelodysplastic syndromes
Carcinomatous polyarthritis
Hypertrophic osteoarthropathy
Palmar fasciitis and polyarthritis syndrome
Oncogenic osteomalacia
Neoplastic Conditions That Mimic Rheumatologic Disease
Acute lymphoblastic leukemia
Hairy cell leukemia
Angioimmunoblastic T-cell lymphoma
Multiple myeloma
Musculoskeletal Side Effects of Oncologic Drugs
Aromatase inhibitors
Immune checkpoint inhibitors
Other Systemic Syndromes With Rheumatologic Features
Multicentric Reticulohistiocytosis
Castleman Disease
Poems Syndrome
Whipple Disease
Syndromes With Predominantly Musculoskeletal Involvement
Bypass arthritis
Intermittent hydrarthrosis
Palindromic Rheumatism
Fibroblastic Rheumatism
SAPHO Syndrome
Diabetic Muscle Infarction
Retroperitoneal Fibrosis
Foreign Body Synovitis
Silicone Synovitis
Pigmented Villonodular Synovitis and Tenosynovitis
Primary Synovial Osteochondromatosis
Synovial Hemangioma
Lipoma Arborescens
Musculoskeletal Syndromes Associated With Chronic Kidney Disease
Arthritis And Periarthritis
β2-Microglobulin Amyloidosis
Gadolinium-Induced Fibrosis (Nephrogenic Systemic Fibrosis)
Use Of Antirheumatic Drugs In Patients Receiving Dialysis
References
216
216
Heritable connective tissue disorders
Key Points
Introduction to Genetic Disorders of the Skeleton and Associated Soft Tissues
Disorders of Bone Density
Skeletal Dysplasias
Marfan Syndrome (MIM154700) and Related Conditions
Clinical Features of Marfan Syndrome
Cardiovascular disease
Ocular disease
Skeletal involvement
Respiratory system
Diagnosis of Marfan Syndrome
Ehlers-Danlos Syndrome
Disorders of Bone Density
Osteopetrosis
Osteoscleroses
Skeletal Dysplasias and Related Conditions
Osteogenesis Imperfecta (Brittle Bone Syndrome)
Diagnosis of osteogenesis imperfecta
Treatment
Chondrodysplasias
Fibroblast growth factor receptor 3–related disorders
Achondroplasia (MIM100800)
Hypochondroplasia (MIM146000)
Thanatophoric dwarfism (MIM187600)
Type 2 Collagenopathies
Multiple epiphyseal dysplasias
Other forms of chondrodysplasia
Dysostoses
Craniosynostoses
Other Miscellaneous Conditions
Fibrodysplasia Ossificans Progressiva (MIM135100)
Abnormalities in the G Protein Signaling System
Activating Mutations IN GNAS1
Enzyme Defects and the Skeleton
Hypophosphatasia
Alkaptonuria (MIM203500)
Mucopolysaccharidoses
References
217
217
Hypermobility syndrome
Introduction
Epidemiology And Genetics
Diagnostic Criteria For Conditions Presenting To Rheumatology With Associated Hypermobility
Diagnosing Generalized Hypermobility
Classification Of The Ehlers-Danlos Syndromes
Hypermobile Ehlers-Danlos Syndrome (hEDS)
Marfan Syndrome
Clinical Musculoskeltal Associations With Joint Laxity (Known And Postulated)
Musculoskeletal Pain
Reduced Proprioception And Muscle Weakness
Pes Planus
Genu Recurvatum
Dislocations And Subluxations
Recurrent Patellar Dislocation
Osteoarthritis
Extraarticular Associations
Fatigue
Gastrointestinal
Autonomic Dysfunction
Postural Orthostatic Tachycardia Syndrome
Hernias
Varicose veins
Uterine prolapse and voiding dysfunction
Psychological Problems
Differentiating Between Chronic Widespread Pain Conditions (Including Fibromyalgia) And Hypermobile Joints With Associated ...
Rehabilitation
Musculoskeletal Rehabilitation
Pain Management
Summary
References
218
218
Bone tumors
Introduction
Metastatic Tumors
Hematologic Malignancies In Bone
Primary Bone Tumors
Metastatic Carcinoma To Bone
Radiographic Appearance
Histologic Appearance
Hematologic Malignancies
Multiple Myeloma
Investigations
Treatment
Malignant Lymphoma
Histologic appearance
Treatment and prognosis
Primary Bone Tumors
Bone Cysts
Aneurysmal bone cyst
Simple bone cysts
Bone-Forming Neoplasms
Incidental bone islands
Osteoid osteoma
Osteoblastoma
Osteosarcoma
Parosteal osteosarcoma
Cartilage Neoplasms
Chondroblastoma
Chondromyxoid Fibroma
Enchondroma
Osteochondroma
Periosteal Chondroma
Chondrosarcoma
Fibrous-Like Neoplasms
Nonossifying fibroma
Fibrous Dysplasia
Undifferentiated High-Grade Pleomorphic Sarcoma
Giant Cell Tumor
Ewing Sarcoma
Osteofibrous Dysplasia And Adamantinoma
Vascular Neoplasms
Hemangiomas
Epithelioid hemangioendotheliomas
Angiosarcomas
Chordoma
References
Appendix:
Classification and Diagnostic Criteria
Classification And Diagnostic Criteria
Acute Rheumatic Fever
Adult-Onset Still Disease
Antiphospholipid Syndrome
Complex Regional Pain Syndrome
Diffuse Idiopathic Skeletal Hyperostosis
Fibromyalgia
Gout
Hypermobility
Igg4-Related Disease
Inflammatory Muscle Disease
Idiopathic Inflammatory Myopathies
Inclusion Body Myositis
Polymyositis And Dermatomyositis
Juvenile Idiopathic Arthritis
Kashin-Beck Disease
Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis
Osteoarthritis
Psoriatic Arthritis
Reactive Arthritis
Relapsing Polychondritis
Rheumatoid Arthritis
Sjögren Syndrome
Spondyloarthritis
Axial
Peripheral
Systemic Lupus Erythematosus
Systemic Sclerosis And Scleroderma
Vasculitis
Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
Granulomatosis with polyangiitis
Childhood Wegener granulomatosis
Polyarteritis Nodosa
Childhood polyarteritis nodosa
Behçet Disease
Cryoglobulinemia
Henoch-Schönlein Purpura And Immunoglobulin A Vasculitis
Childhood Henoch-Schönlein purpura
Hypersensitivity Vasculitis
Kawasaki Disease
Polymyalgia Rheumatica And Giant Cell Arteritis
Polymyalgia rheumatica
Giant cell arteritis
Takayasu Arteritis
Childhood Takayasu arteritis
Primary Angiitis Of The Central Nervous System
Periodic Fever Syndromes
Familial Mediterranean Fever
References

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Rheumatology

Eighth Edition​

Rheumatology​ Marc C. Hochberg, MD, MPH, MACP, MACR​ Professor of Medicine and Epidemiology and Public Health​ Head​ Division of Rheumatology and Clinical Immunology​ Vice Chair​ Department of Medicine​ University of Maryland School of Medicine​ Director​ Medical Care Clinical Center​ Veterans Affairs Maryland Health Care System​ Baltimore, Maryland​

Ellen M. Gravallese, MD​ Theodore Bevier Bayles Professor of Medicine​ Harvard Medical School​ Chief​ Division of Rheumatology, Inflammation and Immunity​ Department of Medicine​ Brigham and Women’s Hospital​ Boston, Massachusetts​

Josef S. Smolen, MD​ Emeritus Professor Division of Rheumatology Department of Medicine 3 Medical University of Vienna Vienna, Austria

Désirée van der Heijde, MD, PhD​ Professor of Rheumatology​ Rheumatology​ Leiden University Medical Center​ Leiden, The Netherlands​

Michael E. Weinblatt, MD​ John R. and Eileen K. Riedman Professor of Medicine​ Harvard Medical School​ Division of Rheumatology, Inflammation and Immunity​ Brigham and Women’s Hospital​ Boston, Massachusetts​

Michael H. Weisman, MD​

Adjunct Professor of Medicine Division of Immunology and Rheumatology Stanford University Professor of Medicine, Emeritus Division of Rheumatology Cedars-Sinai Medical Center Distinguished Professor of Medicine, Emeritus David Geffen School of Medicine at University of California, Los Angeles Los Angeles, California

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To our parents (living or of blessed memory) and our spouses, children, and grandchildren Susan Hochberg, Francine, Jeffrey, and Eleanor (Nora) Zoe Giuffrida, and Jennifer Hochberg M. Timothy Hresko, Andrew (Drew) and Angela Hresko and Gregory Hresko Alice Smolen, Eva, Daniel, Sami, and Ilona Hruschka, Nina Smolen-Wilson, Etienne, Anna, and James Jandi Wilson, Daniel Smolen, and Alexander Smolen and Meeri Parikka Robert Landewé, Féline Kroon and Lennart and Daan van der Burg, Maxime Kroon and Raoul Buijs, Marcel and Anny van der Heijde-Quaedvlieg Barbara Weinblatt, Hillary, Sidney Allen and Annika Gray Chapman, and Courtney and Michael Fasciano Betsy Weisman, Greg, Nicole, Mia, and Joseph Weisman, Lisa, Andrew, David, and Thomas Cope, and Annie, Bill, Caroline, and Dorothy Macomber

Contributors Abby G. Abelson, MD Clinical Assistant Professor of Medicine Chair Department of Rheumatic and Immunologic Diseases Cleveland Clinic Lerner College of Medicine at Case Western Reserve University Cleveland, Ohio Chapter 202, Management of osteoporosis

Mary Abraham, MD, MBA Assistant Professor Rheumatology Department of Internal Medicine NYU Langone Manhattan, New York Chapter 21, Precision medicine and pharmacogenomics in rheumatology

Steven B. Abramson, MD Professor of Internal Medicine Department of Medicine Professor Department of Pathology Chair of the Department of Medicine Vice Dean for Education Faculty and Academic Affairs NYU Grossman School of Medicine New York, New York Chapter 22, The microbiome in rheumatic diseases

Jonathan D. Adachi, BSc, MD, FRCPC Actavis Chair in Rheumatology for Better Bone Health Professor Department of Medicine McMaster University Michael G. DeGroote School of Medicine Hamilton, Ontario, Canada Chapter 203, Glucocorticoid-induced osteoporosis

Rohit Aggarwal, MD Professor of Medicine University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Chapter 156, Clinical features, classification, and epidemiology of inflammatory muscle disease

Amjid Ashraf Ali, MB ChB, FRCS(Trauma & Orthopaedics) Consultants Shoulder and Elbow Surgeon Trauma and Orthopaedics Sheffield Teaching Hospitals Sheffield, United Kingdom Chapter 80, The elbow

Kavitta B. Allem, MD Physician Division of Rheumatology Scripps Clinic/Scripps Green Hospital La Jolla, California Chapter 65, Immunosuppressive agents: cyclosporine, cyclophosphamide, azathioprine, mycophenolate mofetil, and tacrolimus

Mohammed Almehthel, MD, FRCPC, ABIM Clinical Associate Professor Medicine University of British Columbia Vancouver, British Columbia, Canada Chapter 48, Dual x-ray absorptiometry and measurement of bone

Mohammed Almohaya, MD, MHSc Endocrinologist Obesity, Endocrine and Metabolism Center King Fahad Medical City Riyadh, Saudi Arabia Chapter 48, Dual x-ray absorptiometry and measurement of bone

Elena Riera Alonso, MD Rheumatologyst Division of Rheumatology Hospital Mútua Terrassa Barcelona, Spain Chapter 173, Adult-onset Still disease

Mary-Carmen Amigo, MD, FACP, MACR, M Bioeth Professor Rheumatology Service American British Cowdray (ABC) Medical Center Mexico City, Mexico Chapter 147, Antiphospholipid syndrome: pathogenesis, diagnosis, and management

Dana P. Ascherman, MD Professor of Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Chapter 156, Clinical features, classification, and epidemiology of inflammatory muscle disease

Sergei P. Atamas, MD, PhD Executive Director, Research Discovery and Preclinical Development Corbus Pharmaceuticals, Inc. Norwood, Massachusetts Chapter 8, Principles of adaptive immunity

Timothy J. Atkinson, PharmD Clinical Pharmacy Specialist Pain Management Pharmacy Service VA Tennessee Valley Healthcare System Murfreesboro, Tennessee Chapter 60, Principles of pharmacologic pain management

Maha A. Azeez, MB BCh BAO, BSc, MD, MRCPI Consultant Rheumatologist Oxford University Hospitals NHS Foundation Trust Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford, United Kingdom Chapter 70, Tumor necrosis factor inhibitors

Alan N. Baer, MD, FACP, MACR Professor of Medicine Division of Rheumatology Johns Hopkins University Director Jerome L. Greene Sjögren’s Syndrome Center Baltimore, Maryland Chapter 146, Sjögren syndrome

Xenofon Baraliakos, MD, PhD Professor Rheumatology Rheumazentrum Ruhrgebiet Herne Ruhr-University Bochum Bochum, Germany Chapter 124, Imaging in spondyloarthritis

Shizuo Akira, MD, PhD

Martin Aringer, MD

Thomas Bardin, MD

Professor Laboratory of Host Defense WPI Immunology Frontier Research Center Osaka University Osaka, Japan

Professor of Medicine (Rheumatology) Department of Medicine III Division of Rheumatology University Medical Center and Faculty of Medicine Carl Gustav Carus at the TU Dresden Dresden, Germany

Emeritus Professor of Rheumatology Université de Paris Paris, France

Chapter 7, Principles of innate immunity

Daniel Aletaha, MD, MSc, MBA Professor and Head Division of Rheumatology Medical University of Vienna Vienna, Austria Chapter 99, Assessment of the patient with rheumatoid arthritis and the measurement of outcomes

Chapter 9, Signal transduction in immune cells

Elizabeth V. Arkema, ScM, ScD Associate Professor Department of Medicine Solna Karolinska Institutet Stockholm, Sweden Chapter 23, Principles of epidemiology Chapter 175, Sarcoidosis

Chapter 215, Miscellaneous arthropathies

Leslie Barnsley, B.Med.Hons, Grad.Dip.Epi., PhD, FRACP, FAFRM(RACP) Senior Staff Specialist Department of Rheumatology Concord Hospital Associate Professor Medicine Sydney University Sydney, New South Wales, Australia Chapter 77, Neck pain

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CONTRIBUTORS

Andrew J. Barr, MBBS, PhD, MRCP

Francis Berenbaum, MD, PhD

Markus Böhm, MD

Consultant Rheumatologist Leeds Teaching Hospitals NHS Trust Leeds, United Kingdom

Professor of Rheumatology AP-HP Saint-Antoine Hospital Sorbonne Université—INSERM Paris, France

Professor Dermatology University of Münster Münster, Germany

Chapter 187, Imaging of osteoarthritis

Joan M. Bathon, MD Professor of Medicine Chief Division of Rheumatology Columbia University Irving Medical Center/ New York Presbyterian Hospital New York, New York Chapter 101, Management of rheumatoid arthritis in patients with prior exposure to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)

Jill J.F. Belch, MBChB, MD (Hons), FRCP, FRS Professor of Vascular Medicine Division of Clinical and Molecular Medicine Ninewells Hospital and Medical School Dundee, United Kingdom Chapter 154, Raynaud phenomenon

Teresita Bellido, PhD Professor and Chair Department of Physiology and Cell Biology Professor Department of Internal Medicine Division of Endocrinology Department of Orthopedic Surgery University of Arkansas for Medical Sciences Little Rock, Arkansas Chapter 3, Bone structure and function

Ami Ben-Artzi, MD Division of Rheumatology Cedars-Sinai Medical Center Los Angeles, California Chapter 93, Imaging of rheumatoid arthritis

Fabrizio Benedetti, MD Professor Department of Neuroscience University of Turin Medical School Turin, Italy Director Medicine & Physiology of Hypoxia Plateau Rosà, Switzerland Chapter 55, Placebo, nocebo, caring, and healing in rheumatology

Kim L. Bennell, BAppSci(physio), PhD Professor of Physiotherapy Director Centre for Health, Exercise & Sports Medicine University of Melbourne Melbourne, Australia Chapter 53, Principles of rehabilitation: physical and occupational therapy

Sarah E. Bennett, PhD, MSc, BSc Research Associate Faculty of Health and Applied Sciences University of the West of England Bristol, United Kingdom Chapter 54, Multidisciplinary approaches to managing chronic pain in arthritis

Roberta A. Berard, MD, FRCPC, MSc Associate Professor Pediatrics Western University London, Ontario, Canada Chapter 107, Management of juvenile idiopathic arthritis

Chapter 191, Emerging treatments for osteoarthritis

Brian Berman, MD Professor Emeritus of Family and Community Medicine University of Maryland School of Medicine Baltimore Maryland Chapter 56, Complementary and alternative medicine

Bonnie L. Bermas, MD Professor of Medicine Division of Rheumatic Diseases UT Southwestern Medical Center Dallas, Texas Chapter 59, Medication management during preconception, pregnancy, and lactation

Alice Elizabeth Berry, PhD, MSc, BSc Research Fellow Faculty of Health and Applied Sciences University of the West of England Bristol, United Kingdom Chapter 54, Multidisciplinary approaches to managing chronic pain in arthritis

George Bertsias, MD, PhD Associate Professor of Rheumatology and Clinical Immunology Medical School University of Crete Herakleio, Greece Chapter 144, Management of renal lupus

Suleman Bhana, MD, FACR Senior Medical Director, Rheumatology Inflammation & Immunology, North America Medical Affairs Pfizer, Inc. New York, New York Chapter 180, The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease

Shamik Bhattacharyya, MD, MS Physician Neurology Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Chapter 40, The nervous system in rheumatic disease

Yelda Bilginer, MD Hacettepe University Ankara, Turkey Chapter 169, IgA vasculitis (Henoch–Schönlein purpura)

Jane F. Bleasel, MBBS, PhD, MHPE, FRACP Professor Sydney Medical School University of Sydney Sydney, Australia Chapter 210, Hemophilia-associated arthritis

Joel A. Block, MD The Willard L Wood MD Professor and Director Division of Rheumatology Rush University Medical Center Chicago, Illinois Chapter 183, Clinical features of osteoarthritis

Chapter 34, The skin in rheumatic disease

Michael Bonelli, Assoc. Prof, Priv. Doz, Dr. Division of Rheumatology Department of Internal Medicine III Medical University of Vienna Vienna, Austria Chapter 9, Signal transduction in immune cells

Dimitrios T. Boumpas, MD, FACP Professor of Medicine 4th Department of Internal Medicine Attikon University Hospital and Joint Academic Rheumatology Program National and Kapodistrian University of Athens Medical School Affiliated Investigator Immunobiology Biomedical Research Foundation of the Academy of Athens Athens, Greece Chapter 144, Management of renal lupus

Aline Bozec, PhD Professor of Rheumatology and Immunology Department of Internal Medicine 3 Friedrich Alexander University (FAU) Erlangen, Germany Chapter 13, Osteoimmunology

Richard D. Brasington, Jr., MD Emeritus Professor of Medicine and Ophthalmology and Visual Sciences Division of Rheumatology Washington University School of Medicine in St. Louis St. Louis, Missouri Chapter 90, Clinical features of rheumatoid arthritis

Jürgen Braun, Prof.Dr. Elisabethgruppe Rheumazentrum Ruhrgebiet Ruhr-University Bochum Herne, NRW, Germany Chapter 124, Imaging in spondyloarthritis

Elisabeth Brouwer, MD, PhD Professor Department of Rheumatology and Clinical Immunology University Medical Center Groningen University of Groningen Groningen, The Netherlands Chapter 162, Biology and immunopathogenesis of vasculitis

Jacques P. Brown, MD, FRCPC Clinical Professor of Medicine Medicine Université Laval Senior Clinical Researcher Rheumatology CHU de Québec-Université Laval Quebec City, Quebec, Canada Chapter 205, Paget disease of bone

Matthew A. Brown, MBBS, MD, FRACP, FAHMS, FAA Chief Scientific Officer Genomics England Professor of Medicine King’s College London London, United Kingdom Chapter 122, Genetics of axial spondyloarthritis

CONTRIBUTORS Matthew L. Brown, MD

Joel N. Buxbaum, MD

Ricard Cervera, MD, PhD, FRCP

Cooper University Hospital Camden, New Jersey

Professor Molecular Medicine Emeritus The Scripps Research Institute La Jolla, California

Head of the Department of Autoimmune Diseases Hospital Clínic Professor of Medicine University of Barcelona Barcelona, Catalonia, Spain

Chapter 82, The hip

Maya H. Buch, MBChB, FRCP, PhD Professor of Rheumatology Centre for Musculoskeletal Research Division of Musculoskeletal and Dermatological Sciences School of Biological Sciences Faculty of Biology Medicine & Health The University of Manchester Manchester, United Kingdom Honorary Professor of Rheumatology Leeds Institute of Rheumatic & Musculoskeletal Medicine Faculty of Medicine & Health University of Leeds Leeds, United Kingdom Chapter 100, Management of rheumatoid arthritis in csDMARD-naïve patients

Christopher D. Buckley, MBBS, DPhil Kennedy Professor of Translational Rheumatology Kennedy Institute of Rheumatology University of Oxford Roosevelt Drive Headington Oxford Chapter 1, The synovium

William D. Bugbee, MD Attending Physician Department of Orthopaedic Surgery Scripps Clinic La Jolla, California Chapter 82, The hip

Gerd-Rüdiger Burmester, MD Professor of Medicine Department of Rheumatology and Clinical Immunology Charité-Universitätsmedizin Berlin Berlin, Germany Chapter 30, Laboratory tests in rheumatic disorders

Jane C. Burns, MD Professor of Pediatrics Director Kawasaki Disease Research Center University of California San Diego School of Medicine La Jolla, California Director Kawasaki Disease Clinic Rady Children’s Hospital-San Diego San Diego, California Chapter 168, Kawasaki disease

David B. Burr, PhD Distinguished Professor Emeritus Anatomy, Cell Biology and Physiology Indiana University School of Medicine Distinguished Professor Emeritus Biomedical Engineering Indiana University-Purdue University, Indianapolis (IUPUI) Indianapolis, Indiana Chapter 3, Bone structure and function

Frank Buttgereit, MD Professor of Rheumatology Charité University Medicine Berlin Department of Rheumatology and Clinical Immunology Berlin, Germany Chapter 62, Systemic glucocorticoids in rheumatology

Chapter 177, The systemic amyloidoses

Vivian P. Bykerk, MD Professor of Medicine Weill Cornell Medical College Cornell University Rheumatologist Hospital for Special Surgery New York, New York Chapter 64, Synthetic disease-modifying antirheumatic drugs and leflunomide

Cassandra Calabrese, DO Physician Rheumatologic and Immunologic Diseases Physician Infectious Disease Cleveland Clinic Foundation Cleveland, Ohio Chapter 179, Immune-mediated complications of checkpoint inhibitors

Leonard H. Calabrese, DO Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Vice Chairman Department of Rheumatic and Immunological Diseases R.J. Fasenmyer Chair of Clinical Immunology Theodore F. Classen DO Chair of Osteopathic Research and Education Cleveland Clinic Foundation Cleveland, Ohio Chapter 113, Viral infections

Jeffrey P. Callen, MD Professor of Medicine (Dermatology) Chief Division of Dermatology University of Louisville School of Medicine Louisville, Kentucky Chapter 170, Cutaneous vasculitis and panniculitis

Andrew J. Carr, DSc, MA, ChM, FRCS Nuffield Professor of Orthopaedic Surgery Head Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences University of Oxford Oxford, United Kingdom Chapter 4, Tendons and ligaments

John A. Carrino, MD, MPH Professor Radiology Weil Cornell Medicine Vice-Chairman Radiology & Imaging Hospital for Special Surgery New York, New York Chapter 208, Osteonecrosis

Sabrina Cavallo, BSc (OT), MSc, PhD Assistant Professor Occupational Therapy Program Université de Montréal Researcher Centre for Interdisciplinary Research in Rehabilitation of Greater Montreal Institut Universitaire sur la Réadaptation en Déficience Physique de Montréal Montréal, Québec, Canada Chapter 110, Rehabilitation and psychosocial issues in juvenile idiopathic arthritis

ix

Chapter 142, Management of nonrenal and non–central nervous system lupus

Christopher Chang, MD, PhD, MBA Professor of Medicine Division of Rheumatology, Allergy and Clinical Immunology University of California, Davis Davis, California Medical Director Division of Pediatric Immunology and Allergy Joe DiMaggio Children’s Hospital Hollywood, Florida Professor of Pediatrics Pediatrics Florida Atlantic University Boca Raton, Florida Professor of Pediatrics Pediatrics Florida International University Miami, Florida Chapter 87, Complex regional pain syndrome

Joyce C. Chang, MD, MSCE Assistant Professor of Pediatrics Division of Immunology Boston Children’s Hospital and Harvard Medical School Boston, Massachusetts Chapter 109, Systemic autoimmune rheumatic diseases in children

Benjamin C. Chaon, MD Assistant Professor Uveitis and Ocular Immunology Johns Hopkins University Wilmer Eye Institute Baltimore, Maryland Chapter 35, Ocular manifestations of rheumatic diseases

Prateek Chaudhary, DO Colorado Center for Arthritis and Osteoporosis LLC Longmont, Colorado Chapter 145, Systemic lupus erythematosus in pregnant patients and neonatal lupus

Hyon K. Choi, MD, DrPH Professor of Medicine Division of Rheumatology, Allergy and Immunology Harvard Medical School Professor of Medicine Department of Medicine Director Gout and Crystal Arthropathy Center Director Clinical Epidemiology and Health Outcomes Massachusetts General Hospital Boston, Massachusetts Chapter 192, Epidemiology and classification of gout

Ernest H.S. Choy, MD, FRCP Professor of Rheumatology CREATE Centre Section of Rheumatology School of Medicine Cardiff University Cardiff, United Kingdom Chapter 72, Inhibitors of T-cell costimulation

x

CONTRIBUTORS

Lisa Christopher-Stine, MD, MPH Associate Professor of Medicine (Rheumatology) and Neurology Director Johns Hopkins Myositis Center Johns Hopkins University School of Medicine Baltimore, Maryland Chapter 160, Metabolic, drug-induced, and other noninflammatory myopathies

Lorinda Chung, MD, MS Professor of Medicine and Dermatology Division of Immunology and Rheumatology Stanford University School of Medicine Palo Alto, California Chapter 158, Clinical significance of autoantibodies in inflammatory muscle disease

Francesco Ciccia, MD, PhD Full Professor Department of Precision Medicine Rheumatology Unit University of the studies of Campania “Luigi Vanvitelli” Naples, Italy Chapter 166, Polymyalgia rheumatica and giant cell arteritis

Daniel J. Clauw, MD Professor of Anesthesiology Medicine (Rheumatology) and Psychiatry Director Chronic Pain and Fatigue Research Center University of Michigan Medical School Ann Arbor, Michigan Chapter 88, Fibromyalgia and related syndromes

Jacqui Clinch, MBBS, MRCP, FRCPCH Consultant in Paediatric Rheumatology Paediatric Rheumatology Bristol Royal Hospital for Children Bristol, United Kingdom Consultant in Paediatric Pain Bath Centre for Pain Services Royal National Hospital for Rheumatic Diseases Bath, United Kingdom Chapter 217, Hypermobility syndrome

Megan E.B. Clowse, MD, MPH Associate Professor of Medicine Division of Rheumatology and Immunology Duke University Medical Center Durham, North Carolina Chapter 145, Systemic lupus erythematosus in pregnant patients and neonatal lupus

John (Gerry) Coghlan, MD, FRCP Consultant Cardiologist Cardiology Royal Free Hospital London, United Kingdom Chapter 36, The cardiovascular system in rheumatic disease

Robert A. Colbert, MD, PhD Senior Investigator National Institute of Arthritis, Musculoskeletal and Skin Diseases National Institutes of Health Bethesda, Maryland Chapter 106, Etiology and pathogenesis of juvenile idiopathic arthritis

Philip G. Conaghan, MBBS, PhD, FRACP, FRCP Director & Professor of Musculoskeletal Medicine Leeds Institute of Rheumatic and Musculoskeletal Medicine University of Leeds

Deputy Director National Institute for Health Research Leeds Biomedical Research Centre Leeds, United Kingdom Chapter 187, Imaging of osteoarthritis

Cyrus Cooper, FMedSci Professor and Director MRC Lifecourse Epidemiology Unit University of Southampton Southampton, United Kingdom Chapter 198, Epidemiology and classification of osteoporosis

Wendy Costello Irish Children’s Arthritis Network (iCAN) Chapter 180, The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease

Karen H. Costenbader, MD, MPH Lupus Program Director Division of Rheumatology, Immunology and Allergy Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts Chapter 132, Epidemiology and classification of systemic lupus erythematosus

George L.D. Cox, BMedSci, BMBS, MD, FRCS(T&O) Consultant Department of Trauma & Orthopaedics University Hospital Southampton Southampton, United Kingdom Chapter 79, The shoulder

Paul Creamer, MD, FRCP Consultant and Senior Clinical Lecturer Department of Rheumatology North Bristol Trust Bristol, United Kingdom Chapter 207, Neuropathic arthropathy

Bruce N. Cronstein, MD Paul R. Esserman Professor of Medicine Division of Rheumatology New York University School of Medicine New York, New York Chapter 21, Precision medicine and pharmacogenomics in rheumatology

Raymond K. Cross, MD, MS Professor of Medicine Medicine University of Maryland School of Medicine Baltimore, Maryland Chapter 38, The gastrointestinal tract in rheumatic disease

Jeffrey R. Curtis, MD, MS, MPH Harbert-Ball Professor of Medicine Division of Clinical Immunology & Rheumatology University of Alabama at Birmingham Birmingham, Alabama Chapter 92, Common comorbidities in rheumatoid arthritis

Chris D’Adamo, PhD Director Center for Integrative Medicine Assistant Professor Department of Family and Community Medicine Assistant Professor of Epidemiology and Public Health University of Maryland School of Medicine Baltimore, Maryland Chapter 56, Complementary and alternative medicine

Vivette D. D’Agati, MD Professor of Pathology Columbia University College of Physicians and Surgeons Director Renal Pathology Laboratory Columbia University Medical Center New York, New York Chapter 136, Immunopathology of systemic lupus erythematosus

David I. Daikh, MD, PhD Professor of Medicine Division of Arthritis and Rheumatic Diseases Oregon Health and Science University Attending PhysicianDivision of Hospital and Specialty Medicine Portland VA Health Care System Portland, Oregon Chapter 137, Animal models of systemic lupus erythematosus

Stephanie G. Dakin, PhD, BVetMed, MRCVS Associate Professor of Musculoskeletal Sciences Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences University of Oxford Oxford, United Kingdom Chapter 4, Tendons and ligaments

Nicola Dalbeth, MBChB, MD, FRACP Professor and Rheumatologist Department of Medicine University of Auckland Auckland, New Zealand Chapter 193, Etiology and pathogenesis of gout

Aileen M. Davis, PhD Professor Institute of Health Policy, Management and EvaluationProfessor Department of Physical Therapy University of Toronto Toronto, Ontario, Canada Chapter 188, Assessment of the patient with osteoarthritis and measurement of outcomes

David P. D’Cruz, MD, FRCP Consultant Rheumatologist The Louise Coote Lupus Unit Guy’s Hospital London, United Kingdom Chapter 36, The cardiovascular system in rheumatic disease

Carlos Eduardo de Barros Branco, MD Researcher Valvular Heart Disease Unit Heart Institute—University of São Paulo Medical School São Paulo, Brazil Chapter 115, Acute rheumatic fever

Berber de Boer, MD Resident Rheumatology LUMC Leiden, The Netherlands Chapter 69, Interleukin-6 inhibitors

Ann-Sophie De Craemer, MD Faculty of Medicine and Health Sciences Department of Internal Medicine and Pediatrics Ghent University Department of Rheumatology Ghent University Hospital Molecular Immunology and Inflammation Unit VIB Center for Inflammation Research Ghent, Belgium Chapter 121, Pathogenesis and pathophysiology of axial spondyloarthritis

CONTRIBUTORS Adriana A. de Jesus, MD, PhD

Edward F. DiCarlo, MD

Paul Emery, MD, MA, FMedSci, FRCP

Staff Scientist Translational Autoinflammatory Diseases Section NIAID, NIH Bethesda, Maryland

Attending Pathologist Department of Pathology and Laboratory Medicine Hospital for Special Surgery Professor of Clinical Pathology and Laboratory Medicine Cornell University Medical College New York, New York

Versus Arthritis Professor of Rheumatology Leeds Institute of Rheumatic and Musculoskeletal Medicine University of Leeds Director NIHR Leeds Biomedical Research Centre Leeds Teaching Hospital NHS Trust Leeds, United Kingdom

Chapter 174, Monogenic autoinflammatory diseases

Salvatore De Vita, MD Professor of Rheumatology Department of Medicine University of Udine Chief Rheumatology Clinic Hospital S. Maria della Misericordia Udine, Italy Chapter 171, Cryoglobulinemia

Maarten de Wit, PhD Independent Patient Researcher Centre for Patient Education Stichting Tools Amsterdam, The Netherlands Chapter 50, The patient perspective

Chad L. Deal, MD Associate Professor of Medicine Cleveland Clinic Lerner College of Medicine at Case Western Reserve University Head Center for Osteoporosis and Metabolic Bone Disease Rheumatology Cleveland Clinic Cleveland, Ohio Chapter 202, Management of osteoporosis

Kevin D. Deane, MD, PhD Professor of Medicine Division of Rheumatology University of Colorado School of Medicine Aurora, Colorado Chapter 98, Preclinical rheumatoid arthritis

Paul F. Dellaripa, MD Associate Professor of Medicine Harvard Medical School Division of Rheumatology Brigham and Women’s Hospital Boston, Massachusetts Chapter 37, The lungs in rheumatic disease

Elaine Dennison, MB, BChir, MSc, FRCP, PhD Professor of Musculoskeletal Epidemiology MRC Lifecourse Epidemiology Unit Southampton University Southampton, United Kingdom Professor of Clinical Research School of Biological Sciences Victoria University Wellington, New Zealand Chapter 198, Epidemiology and classification of osteoporosis

Christopher P. Denton, PhD, FRCP Professor of Experimental Rheumatology, Consultant Rheumatologist Centre for Rheumatology University College London (UCL) Royal Free Hospital London, United Kingdom Chapter 149, Clinical and serologic features of systemic sclerosis †

Deceased.

Chapter 185, Pathogenesis and pathology of osteoarthritis

Oliver Distler, Prof., Dr. University Hospital Zurich Department of Rheumatology University of Zurich Zurich, Switzerland Chapter 153, Emerging therapies for systemic sclerosis

Pamela Donlan, PT, DPT, EdD, CLT-LANA Assistant Clinical Professor Bouve College of Health Sciences Department of Physical Therapy, Movement and Rehabilitation Sciences Northeastern University Boston, Massachusetts Chapter 52, Arthritis patient education, self-management, and health promotion

Tracy J. Doyle, MD, MPH Division of Pulmonary and Critical Care Medicine Brigham and Women’s Hospital Boston, Massachusetts Chapter 37, The lungs in rheumatic disease

Hannah du Preez, BA (Hons), MA (Cantab.), BM Department of Radiology St Bartholomew’s Hospital Barts Health NHS Trust London, United Kingdom Chapter 211, Rheumatologic manifestations of hemoglobinopathies

George S.M. Dyer, MD Associate Professor of Orthopaedic Surgery Department of Orthopaedic Surgery Brigham and Women’s Hospital Harvard Medical School Cambridge Massachusetts Orthopedic Surgeon Brigham and Women’s Hospital Boston, Massachusetts Chapter 81, The wrist and hand

Chapter 73, Inhibitors of B cells

Max R. Emmerling, MD, DDS Attending in Oral & Maxillofacial Surgery Cook County Health Chicago, Illinois Chapter 85, The temporomandibular joint

Gerard Espinosa, MD, PhD Department of Autoimmune Diseases Hospital Clínic Associate Professor of Medicine University of Barcelona Barcelona, Catalonia, Spain Chapter 142, Management of nonrenal and non–central nervous system lupus

Luis R. Espinoza†, MD Professor and Chief Rheumatology Section LSU Health Science Center Louisiana State University New Orleans, Louisiana Chapter 112, Mycobacterial, brucellar, fungal, and parasitic arthritis

Stephen Eyre, PhD Professor Division of Musculoskeletal and Dermatological Sciences The University of Manchester Manchester, United Kingdom Chapter 26, Principles of genetic epidemiology

Antonis Fanouriakis, MD Assistant Professor of Internal Medicine-Rheumatology Medical School National and Kapodistrian University of Athens and Joint Academic Rheumatology Program Athens, Greece Chapter 144, Management of renal lupus

Richard Eastell, MD, FRCP, FRCPath, FMedSci

Joshua Farber, MD

Professor of Bone Metabolism Department of Oncology and Metabolism University of Sheffield Sheffield, South Yorkshire, United Kingdom

Senior Investigator Laboratory of Molecular Immunology, DIR National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland

Chapter 201, Biochemical markers of bone turnover in postmenopausal osteoporosis

Jan Ehrchen, Priv. Doz. Dr. med. Dr. rer. nat. Department of Dermatology University Hospital of Münster Münster, Germany Chapter 34, The skin in rheumatic disease

Dirk Elewaut, MD, PhD Professor of Rheumatology and Immunology Ghent University Chair of the Department of Rheumatology Ghent University Hospital Group Leader Molecular Immunology and Inflammation Unit VIB Center for Inflammation Research Ghent, Belgium Chapter 121, Pathogenesis and pathophysiology of axial spondyloarthritis

xi

Chapter 10, Cytokines

Anders Fasth, MD, PhD Professor Department of Pediatrics University of Gothenburg Department of Pediatric Immunology Senior Consultant Department of Pediatrics Queen Silvia Children’s Hospital Gothenburg, Sweden Senior Consultant Servicio de Inmunología y Reumatología Pediátrica Hospital Nacional de Niños “Dr. Carlos Sáenz Herrera” San José, Costa Rica Chapter 105, Clinical features of juvenile idiopathic arthritis

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CONTRIBUTORS

Eugen Feist, MD

Lindsy Forbess, MD, MSc

Nophar Geifman, PhD, MSc

Professor Rheumatology Helios-Clinic Gommern, Germany

Assistant Professor of Medicine Division of Rheumatology Cedars-Sinai Medical Center Los Angeles, California

Professor School of Health Sciences Faculty of Health and Medical Sciences University of Surrey Guildford, United Kingdom

Chapter 30, Laboratory tests in rheumatic disorders

Candace H. Feldman, MD, MPH, ScD Division of Rheumatology, Inflammation and Immunity Associate Physician Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts Chapter 132, Epidemiology and classification of systemic lupus erythematosus

Ruth Fernandez-Ruiz, MD, MS Post-doctoral Fellow Division of Rheumatology Department of Medicine NYU Grossman School of Medicine New York, New York Chapter 11, Inflammation and its chemical mediators

Chapter 93, Imaging of rheumatoid arthritis Chapter 163, Polyarteritis nodosa and Cogan syndrome

David A. Fox, MD Professor of Medicine Division of Rheumatology University of Michigan Medical School Ann Arbor, Michigan Chapter 71, Interleukin-17, interleukin-12, and interleukin-23 inhibitors

Tracy M. Frech, MD, MS Internal Medicine Vanderbilt University Medical Center Nashville Tennessee Adjunct University of Utah Salt Lake City, Utah Chapter 152, Management of systemic sclerosis

Andrew Filer, MBChB, PhD

Elisa Frisaldi, PhD

Reader, Institute of Inflammation and Ageing The University of Birmingham Honorary Consultant Rheumatologist Department of Rheumatology University Hospitals Birmingham NHS Foundation Trust Birmingham, United Kingdom

Research Fellow in Neurophysiology Neuroscience Department University of Turin Medical School Turin, Italy

Chapter 1, The synovium

David F. Fiorentino, MD, PhD Professor Dermatology Stanford University School of Medicine Redwood City, California Chapter 158, Clinical significance of autoantibodies in inflammatory muscle disease

Benjamin A. Fisher, MD(res), MBBS Senior Clinical Lecturer Rheumatology Research Group Institute of Inflammation and Ageing University of Birmingham Honorary Consultant Rheumatologist Department of Rheumatology University Hospitals Birmingham NHS Trust Birmingham, The United Kingdom Chapter 67, Overview of biologic agents

John D. Fisk, PhD Psychologist Seniors Health Nova Scotia Health Authority Associate Professor Psychiatry Assistant Professor Medicine Adjunct Professor Psychology & Neuroscience Dalhousie University Halifax, Nova Scotia, Canada Chapter 143, Management of central nervous system lupus

Martin F. Flajnik, PhD Professor Microbiology and Immunology University of Maryland Baltimore Baltimore, Maryland Chapter 8, Principles of adaptive immunity

Chapter 55, Placebo, nocebo, caring, and healing in rheumatology

Cem Gabay, MD Professor of Medicine Head Division of Rheumatology University Hospitals of Geneva Geneva, Switzerland Chapter 68, Interleukin-1 inhibitors

Massimo Gadina, PhD Chief Translational Immunology Section National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health Bethesda, Maryland Chapter 10, Cytokines

Saviana Gandolfo, MD Clinic of Rheumatology Department of Medicine Udine University Hospital S. Maria della Misericordia Udine, Italy Chapter 171, Cryoglobulinemia

Daniela Garelick, MBBS, BSc Dr Rheumatology Sheba Medical Center Ramat Gan, Israel Chapter 211, Rheumatologic manifestations of hemoglobinopathies

Steffen Gay, MD Professor Emeritus of Experimental Rheumatology Senior Consultant Center of Experimental Rheumatology Department of Rheumatology University Hospital of Zurich University of Zurich Zurich, Switzerland Chapter 20, Epigenetics

Chapter 16, Big Data analysis

Michael D. George, MD, MSCE Assistant Professor Medicine University of Pennsylvania Assistant Professor Biostatistics Epidemiology and Informatics University of Pennsylvania Philadelphia, Pennsylvania Chapter 92, Common comorbidities in rheumatoid arthritis

M. Eric Gershwin, MD Chief Division of Rheumatology, Allergy and Clinical Immunology Internal Medicine University of California Davis, California Chapter 87, Complex regional pain syndrome

Jay Ghadiali, MD Fellow Rheumatology University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania Chapter 185, Pathogenesis and pathology of osteoarthritis

Elisabeth Gilis, PhD Faculty of Medicine and Health Sciences Department of Internal Medicine and Pediatrics Ghent University Department of Rheumatology, Molecular Immunology and Inflammation Unit VIB Center for Inflammation Research Ghent, Belgium Chapter 121, Pathogenesis and pathophysiology of axial spondyloarthritis

Deborah T. Gold, MEd, PhD Professor Emerita of Medical Sociology Psychiatry & Behavioral Sciences Sociology Duke University Medical Center Durham, North Carolina Chapter 199, Clinical evaluation and clinical features of osteoporosis

Garry E. Gold, MD Professor of Radiology Radiology Stanford School of Medicine Stanford, California Chapter 44, Magnetic resonance imaging

Raphaela Goldbach-Mansky, MD, MHS Senior Investigator Translational Autoinflammatory Diseases Section NIH Bethesda, Maryland Chapter 174, Monogenic autoinflammatory diseases

José A. Gómez-Puerta, MD, PhD, MPH Head of the Department of Rheumatology Hospital Clínic Associate Professor of Medicine University of Barcelona Barcelona, Catalonia, Spain Chapter 142, Management of nonrenal and non–central nervous system lupus

CONTRIBUTORS Susan M. Goodman, MD

Ahmet Gül, MD

Philip J. Hashkes, MD, MSc

Attending Physician Division of Rheumatology Hospital for Special Surgery Professor of Medicine Department of Medicine Weill Cornell Medical School New York, New York

Professor of Medicine Department of Internal Medicine Division of Rheumatology Istanbul University Istanbul Faculty of Medicine Istanbul, Turkey

Head Pediatric Rheumatology Unit Department of Pediatrics Shaare Zedek Medical Center Associate Professor of Pediatrics Hebrew University Hadassah School of Medicine Jerusalem, Israel

Chapter 57, Outcomes and perioperative management of patients with inflammatory arthritis and systemic lupus erythematosus undergoing total joint arthroplasty

Caroline Gordon, MD, MA, FRCP Emeritus Professor of Rheumatology Rheumatology Research Group Institute of Inflammation and Ageing University of Birmingham Birmingham, United Kingdom Chapter 67, Overview of biologic agents

Sharon Gordon, DDS, MPH, PhD Associate Dean for Academic Affairs and Research Kansas City University College of Dental Medicine Kansas City, Missouri Chapter 85, The temporomandibular joint

Laure Gossec, MD, PhD Professor Rheumatology Sorbonne Université INSERM Institut Pierre Louis d’Epidémiologie et de Santé Publique Paris France AP-HP Pitié-Salpêtrière Hospital Rheumatology Department Paris, France Chapter 127, Clinical features of psoriatic arthritis

Andrew J. Grainger, BM, BS, FRCR, FRCP Consultant Radiologist Cambridge University Hospitals NHS Foundation Trust Cambridge, United Kingdom Chapter 187, Imaging of osteoarthritis

Rebecca Grainger, MBChB, BmedSci, PhD University of Otago Wellington, New Zealand Chapter 180, The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease

Ellen M. Gravallese, MD Theodore Bevier Bayles Professor of Medicine Harvard Medical School Chief Division of Rheumatology, Inflammation and Immunity Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts Chapter 97, Pathogenesis and pathology of rheumatoid arthritis

Jeffrey D. Greenberg, MD, MPH Assistant Professor of Medicine Division of Rheumatology New York University School of Medicine New York, New York Chapter 21, Precision medicine and pharmacogenomics in rheumatology

Luiza Guilherme Guglielmi, PhD Professor of Immunology Heart Institute—InCor University of São Paulo School of Medicine Institute for Immunology Investigation National Institute for Science and Technology São Paulo, Brazil Chapter 115, Acute rheumatic fever

Chapter 167, Behçet disease

Rao P. Gullapalli, PhD Professor and Associate Vice Chair for Research Department of Diagnostic Radiology & Nuclear Medicine University of Maryland School of Medicine Baltimore, Maryland Chapter 45, Functional magnetic resonance imaging

Monica Guma, MD, PhD Associate Professor Medicine UCSD La Jolla, California Chapter 129, Etiology and pathogenesis of psoriatic arthritis

Sarthak Gupta, MD Assistant Research Physician Lupus Clinical Trials Unit National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health Bethesda, Maryland Chapter 139, Pathogenesis of systemic lupus erythematosus

Shuhong Han, PhD Division of Rheumatology, Allergy, & Clinical Immunology University of Florida College of Medicine Gainesville, Florida Chapter 138, Autoantibodies in systemic lupus erythematosus

John G. Hanly, MD, FRCP(C) Professor of Medicine and Pathology Dalhousie University and Queen Elizabeth II Health Sciences Center Halifax, Nova Scotia, Canada Chapter 143, Management of central nervous system lupus

Eric P. Hanson, MD Associate Professor Pediatrics, Microbiology and Immunology and Medical and Molecular Genetics Indiana University School of Medicine Indianapolis, Indiana Chapter 9, Signal transduction in immune cells

Boulos Haraoui, MD, FRCPC Associate Professor of Medicine Université de Montréal Montreal, Quebec, Canada Chapter 64, Synthetic disease-modifying antirheumatic drugs and leflunomide

John B. Harley, MD, PhD Principal Investigator Research Service US Department of Veterans Affairs (USDVA) Medical Center and Cincinnati Education and Research for Veterans Foundation Cincinnati, Ohio Chapter 135, Genetics of systemic lupus erythematosus

Tayseer G. Haroun Northern Virginia Center for Arthritis Reston, Virginia Chapter 145, Systemic lupus erythematosus in pregnant patients and neonatal lupus

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Chapter 107, Management of juvenile idiopathic arthritis

Sarfaraz A. Hasni, MD, MSc Director Lupus Clinical Research National Institute of Arthritis, Musculoskeletal, and Skin Diseases National Institutes of Health Bethesda, Maryland Chapter 41, The muscles in rheumatic disease

Andrew Bassim Hassan, DPhil, FRCP Head Sarcoma and TYA Oncology Unit NHS Department of Oncology Oxford Haematology and Cancer Centre Oxford University Hospitals Trust Professor of Medical Oncology Sir William Dunn School of Pathology University of Oxford Oxford, United Kingdom Chapter 218, Bone tumors

Lukas Haupt, MD Department of Rheumatology Hietzing Hospital Vienna, Austria Appendix: Classification and diagnostic criteria

Jonathan S. Hausmann, MD Program in Rheumatology Boston Children’s Hospital Division of Rheumatology and Clinical Immunology Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts Chapter 180, The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease

Gillian A. Hawker, MD, MSc Professor of Medicine Division of Rheumatology University of Toronto Chair of Medicine University of Toronto Toronto, Ontario, Canada Chapter 188, Assessment of the patient with osteoarthritis and measurement of outcomes

Turid Heiberg, PhD Regional Research Support Oslo University Hospital Oslo, Norway Chapter 102, Multidisciplinary nonpharmacologic approach to rheumatoid arthritis

Simon M. Helfgott, MD, CM Associate Professor of Medicine Medicine Harvard Medical School Director of Education & Fellowship Training Division of Rheumatology Brigham and Women’s Hospital Boston, Massachusetts Chapter 209, Rheumatoid manifestations of endocrine and metabolic diseases and treatments

.

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CONTRIBUTORS

Rana S. Hinman, BPhysio, PhD

Robert D. Inman, MD

Douglas A. Jabs, MD, MBA

Professor of Physiotherapy Centre for Health Exercise & Sports Medicine University of Melbourne Melbourne, Australia

Professor of Medicine and Immunology University of Toronto Faculty of Medicine Schroeder Arthritis Institute University Health Network Professor of Medicine Medicine University of Toronto Toronto, Ontario, Canada

Director Center for Clinical Trials and Evidence Synthesis Professor of Epidemiology The Johns Hopkins Bloomberg School of Public Health Professor of Ophthalmology The Wilmer Eye Institute The Johns Hopkins University School of Medicine Baltimore, Maryland

Chapter 53, Principles of rehabilitation: physical and occupational therapy

Anna-Maria Hoffmann-Vold, MD, PhD Department of Rheumatology Oslo University Hospital Oslo, Norway Chapter 153, Emerging therapies for systemic sclerosis

Christopher R. Holroyd, BM, FRCP, PhD Consultant Rheumatologist MRC Lifecourse Epidemiology Unit University of Southampton Southampton, United Kingdom Chapter 198, Epidemiology and classification of osteoporosis

Cathy Holt, BEng, PhD Professor of Biomechanics and Orthopaedic Engineering School of Engineering Cardiff University Cardiff, Wales Chapter 5, Biomechanics of peripheral joints and spine

Audra Horomanski, MD Assistant Professor Division of Immunology & RheumatologyStanford University Stanford, California Chapter 158, Clinical significance of autoantibodies in inflammatory muscle disease

Thomas W.J. Huizinga, MD, PhD Professor of Rheumatology Leiden University Medical Center Leiden, The Netherlands Chapter 69, Interleukin-6 inhibitors

Frances Humby, PhD, MBBS, MRCP Centre for Experimental Medicine and Rheumatology William Harvey Research Institute Queen Mary University of London London, United Kingdom Chapter 33, Minimally invasive procedures

M. Elaine Husni, MD, MPH Staff Physician Orthopedic and Rheumatologic Institute Vice Chair Department of Rheumatic and Immunologic Diseases Cleveland Clinic Director Arthritis and Musculoskeletal Center Department of Rheumatic and Immunologic Diseases Cleveland, Ohio Chapter 126, Classification and epidemiology of psoriatic arthritis

Jonathan Hwang, MD Michael G. DeGroote School of Medicine McMaster University Hamilton, Ontario, Canada Chapter 203, Glucocorticoid-induced osteoporosis

Kimme Hyrich, MD, PhD Professor Centre for Musculoskeletal Research University of Manchester Manchester, United Kingdom Chapter 16, Big Data analysis

Chapter 116, Reactive arthritis

Dai Inoue, MD, PhD Assistant Professor Department of Radiology Kanazawa University Hospital Ishikawa, Japan Chapter 178, IgG4-related disease

Zacharia Isaac, MD Division Chief Pain and Spine Care Department of Physical Medicine and Rehabilitation Harvard Medical School Associate Chairman Physical Medicine and Rehabilitation Brigham and Women’s Hospital Boston, Massachusetts Chapter 78, Low back pain

John D. Isaacs, BSc (Hon), MB BS, PhD Professor of Clinical Rheumatology Translational and Clinical Research Institute Newcastle University Consultant Rheumatologist Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle Upon Tyne, United Kingdom Chapter 74, Emerging therapeutic targets

David Isenberg, MD, FRCP, FAMS Professor The Centre for Rheumatology Research Department of Medicine Professor Rheumatology/Medicine University College London London, United Kingdom Chapter 211, Rheumatologic manifestations of hemoglobinopathies

Maura D. Iversen, BSc, MPH, DPT, SD Professor and Dean College of Health Professions Sacred Heart University Fairfield, Connecticut Senior Instructor in Medicine Harvard Medical School Behavioral Scientist Section of Clinical Sciences Division of Rheumatology, Inflammation & Immunity Brigham & Women’s Hospital Boston, Massachusetts Professor Emeritus Bouve College of Health Sciences Department of Physical Therapy, Movement and Rehabilitation Sciences Northeastern University Boston, Massachusetts Chapter 52, Arthritis patient education, self-management, and health promotion

Chapter 35, Ocular manifestations of rheumatic diseases

Judith A. James, MD, PhD Vice President of Clinical Affairs Oklahoma Medical Research Foundation Oklahoma City, Oklahoma Associate Vice Provost for Clinical and Translational Science Oklahoma University Health Sciences Center Oklahoma City, Oklahoma Chapter 133, Preclinical features of systemic lupus erythematosus

Bochra Jandali, MD Assistant Professor Department of Internal Medicine University of Texas Houston, Texas Chapter 148, Classification and epidemiology of systemic sclerosis

M. Kassim Javaid, MBBS, BMedSCI, PhD, FRCP Associate Professor in Metabolic Bone Disease Botnar Institute of Musculoskeletal Sciences University of Oxford Oxford, United Kingdom Chapter 216, Heritable connective tissue disorders

Rose-Marie Javier, MD Senior Lecturer Rheumatology Medical University Louis Pasteur Senior Attending Physician Rheumatology Unit University Hospital Hautepierre Strasbourg, France Chapter 213, Gaucher disease

Roy Jefferis, BSc, PhD, FRSC, CChem, MRCP, FRCPath, DSc Professor Emeritus Institute of Immunology & Immunotherapy University of Birmingham Birmingham, The United Kingdom Chapter 67, Overview of biologic agents

Matlock A. Jeffries, MD, FACP, FACR Associate Member Oklahoma Medical Research Foundation Arthritis and Clinical Immunology Program Interim Section Chief of Rheumatology Clinical Associate Professor of Medicine Adjunct Clinical Associate Professor of Microbiology and Immunology University of Oklahoma Health Sciences Center Department of Medicine, Division of Rheumatology, Immunology, and Allergy Oklahoma City, Oklahoma Chapter 186, Genetics and epigenetics of osteoarthritis

CONTRIBUTORS Sindhu R. Johnson, MD, PhD

Mariana J. Kaplan, MD

Jennifer A. Kelly, MPH

Director Toronto Scleroderma Program Rheumatology University Health Network Associate Professor of Medicine Associate Director Clinical Epidemiology & Health Care Research Program Institute of Health Policy, Management & Evaluation University of Toronto Toronto, Ontario, Canada

Senior Investigator and Chief Systemic Autoimmunity Branch Deputy Scientific DirectorIntramural Research Program National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health Bethesda, Maryland

Research Program Director Genes and Human Disease Program Oklahoma Medical Research Foundation Oklahoma City, Oklahoma

Chapter 24, Principles of clinical outcome assessment

Brian Johnstone, PhD Professor Orthopaedics and Rehabilitation Oregon Health & Science University Portland, Oregon Chapter 2, The articular cartilage

Anna Helena Jonsson, MD, PhD Associate Physician Division of Rheumatology, Inflammation, and Immunity Department of Medicine Brigham and Women’s Hospital Instructor in Medicine Harvard Medical School Boston, Massachusetts Chapter 97, Pathogenesis and pathology of rheumatoid arthritis

Andrew A. Joyce, MD Assistant Professor University of Utah School of Medicine Salt Lake City, Utah Chapter 78, Low back pain

Michelle Jung, MD, FRCPC Clinical Assistant Professor Division of Rheumatology University of Calgary Calgary, Alberta, Canada Chapter 141, Assessing disease activity and outcome in systemic lupus erythematosus

Ruba Kado, MD Clinical Instructor in Internal Medicine Division of Rheumatology University of Michigan Medical School Ann Arbor, Michigan Chapter 71, Interleukin-17, interleukin-12, and interleukin-23 inhibitors

Tsuneyasu Kaisho, MD, PhD Professor Department of Immunology Institute of Advanced Medicine Wakayama Medical University Wakayama, Japan Chapter 7, Principles of innate immunity

Natasha Kamal, MD University of Maryland School of Medicine GastroenterologyInternal Medicine Baltimore, Maryland Chapter 38, The gastrointestinal tract in rheumatic disease

David Kane, PhD, FRCPI Clinical Professor of Rheumatology Department of Rheumatology Trinity College Dublin Consultant Rheumatologist Tallaght University Hospital Dublin, Ireland Chapter 46, Musculoskeletal ultrasonography

Chapter 139, Pathogenesis of systemic lupus erythematosus

Timothy L. Karr, PhD Associate Research Professor The Biodesign Institute Arizona State University Tempe, Arizona Chapter 18, Proteomics

Dimitrios G. Kassimos, MD, MSc, PhD Consultant Rheumatologist Rheumatology401 General Military Hospital of Athens Athens, Greece Chapter 207, Neuropathic arthropathy

Daniel L. Kastner, MD, PhD Scientific Director, Division of Intramural Research Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch National Human Genome Research Institute National Institutes of Health Bethesda, Maryland Chapter 174, Monogenic autoinflammatory diseases

Jeffrey N. Katz, MD, MSc Professor of Medicine and Orthopedic Surgery Orthopedics and Medicine Harvard Medical School Director Orthopedic and Arthritis Center for Outcomes Research Department of Orthopedics and Division of Rheumatology, Immunology and Allergy Brigham and Women’s Hospital Boston, Massachusetts Chapter 58, Indications for and long-term complications of total hip and knee arthroplasty

Chapter 135, Genetics of systemic lupus erythematosus

David Kendler, MD Professor of Medicine Medicine University of British Columbia Vancouver, British Columbia, Canada Chapter 48, Dual x-ray absorptiometry and measurement of bone

Randall E. Keyser, PhD Associate Professor Rehabilitation Science George Mason University Fairfax, Virginia Chapter 41, The muscles in rheumatic disease

Munther A. Khamashta, MD, PhD, FRCP Emeritus Professor of Medicine King’s College London London, United Kingdom GSK-Gulf Medical Expert(Lupus) Dubai, United Arab Emirates Chapter 147, Antiphospholipid syndrome: pathogenesis, diagnosis, and management

Dinesh Khanna, MD, MS Professor of Medicine Division of Rheumatology University of Michigan Medical School Ann Arbor, Michigan Chapter 151, Outcomes measures in systemic sclerosis

Kiran Khokhar, MBBS, BSc, MRCP (UK) Rheumatology Registrar Leeds Institute of Rheumatic and Musculoskeletal Medicine & NIHR Leeds Biomedical Research Centre Leeds, United Kingdom Chapter 187, Imaging of osteoarthritis

Mitsuhiro Kawano, MD, PhD

David Kiefer, MD

Professor Department of Rheumatology Graduate School of Medical Science Kanazawa University Ishikawa, Japan

Mr. Rheumazentrum Ruhrgebiet Herne Germany Mr. Rheumatology Ruhr-University Bochum Bochum, Germany

Chapter 178, IgG4-related disease

Jonathan Kay, MD Timothy S. and Elaine L. Peterson Chair in Rheumatology Professor of Medicine and of Population and Quantitative Health Sciences Division of Rheumatology Department of Medicine Division of Epidemiology Department of Population and Quantitative Health Sciences UMass Chan Medical School and UMass Memorial Medical Center Worcester, Massachusetts Chapter 75, Biosimilars in rheumatology Chapter 215, Miscellaneous arthropathies

Chapter 124, Imaging in spondyloarthritis

Lauren K. King, MD, MSc Rheumatologist Medicine St. Michael’s Hospital Unity Health Toronto Clinician Scientist Trainee Medicine University of Toronto Toronto, Ontario, Canada Chapter 188, Assessment of the patient with osteoarthritis and measurement of outcomes

Richard M. Keating, MD, MHS

Margreet Kloppenburg, MD, PhD

Associate Program Director, Rheumatology Fellowship Division of Rheumatology Scripps Clinic/Scripps Green Hospital La Jolla, California

Professor Department of Rheumatology Professor Clinical Epidemiology Leiden University Medical Center Leiden, The Netherlands

Chapter 65, Immunosuppressive agents: cyclosporine, cyclophosphamide, azathioprine, mycophenolate mofetil, and tacrolimus

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Chapter 190, Management of osteoarthritis

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CONTRIBUTORS

Sharon L. Kolasinski, MD

Jay I. Lakkis, MD

Ronald M. Laxer, MDCM, FRCPC

Professor of Clinical Medicine Division of Rheumatology University of Pennsylvania Philadelphia, Pennsylvania

Assistant Professor in Clinical Medicine Weill Cornell Medicine–New York-Presbyterian Hospital New York, New York

Professor of Pediatrics and Medicine Division of Rheumatology University of Toronto Faculty of Medicine Toronto, Ontario, Canada

Chapter 190, Management of osteoarthritis

Kathleen D. Kolstad, MD, PhD Clinical Instructor Department of Medicine Division of Rheumatology University of California Los Angeles Los Angeles, California Chapter 158, Clinical significance of autoantibodies in inflammatory muscle disease

Leah C. Kottyan, PhD Associate Professor and Interim Director Center for Autoimmune Genomics and Etiology Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio Chapter 135, Genetics of systemic lupus erythematosus

Virginia Byers Kraus, MD, PhD Mary Bernheim Distinguished Professor of Medicine Adjunct Professor of Orthopaedics and Pathology Duke Molecular Physiology Institute Duke University School of Medicine Durham, North Carolina Chapter 189, Preclinical and early osteoarthritis

Leo R.W. Kronberger, MD Orthopedic Department Balgrist University Hospital Orthopedic Clinic Schulthess Clinic Zurich, Switzerland Chapter 111, Bacterial native joint arthritis

Jeffrey M. Kroopnick, MD Division of Endocrinology Diabetes and Nutrition Department of Medicine University of Maryland School of Medicine Baltimore, Maryland Chapter 200, Pathophysiology of osteoporosis

Tore K. Kvien, MD, PhD Professor Emeritus of Rheumatology University of Oslo Faculty of Medicine Department of Rheumatology Division of Rheumatology and Research Diakonhjemmet Hospital Oslo, Norway Chapter 102, Multidisciplinary nonpharmacologic approach to rheumatoid arthritis

Joshua LaBaer, MD, PhD Executive Director, Biodesign Institute Director, Virginia G. Piper Center for Personalized Diagnostics Professor, School of Molecular Sciences Arizona State University Tempe, Arizona Chapter 18, Proteomics

Robert Lafyatis, MD Thomas Medsger, Professor of Medicine Division of Rheumatology and Clinical Immunology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Chapter 150, Etiology and pathogenesis of systemic sclerosis

Chapter 39, The kidneys in rheumatic diseases

Robert B.M. Landewé, MD, PhD Professor of Clinical Immunology & Rheumatology Amsterdam University Medical Center Academic Medical Center Amsterdam The Netherlands Consultant Rheumatologist Zuyderland Medical Center Heerlen, The Netherlands Chapter 27, Interpreting the medical literature for the rheumatologist Chapter 49, Use of imaging as an outcome measure in clinical trials

Carol A. Langford, MD, MHS Director Center for Vasculitis Care and Research Harold C. Schott Chair in Rheumatic and Immunologic Diseases Cleveland Clinic Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Cleveland, Ohio Chapter 165, Takayasu arteritis

Marciana L. Laster, MD, MSCR Assistant Professor Pediatrics David Geffen School of Medicine at UCLA Los Angeles, California Chapter 204, Osteomalacia, rickets, and renal osteodystrophy

Augustin Latourte, MD, PhD Assistant Professor Rheumatologist Rheumatology Hôpital Lariboisière Paris, France Chapter 212, Hemochromatosis

Arthur N. Lau, MD, MSc, FRCPC Associate Professor Department of Medicine McMaster University Hamilton, Ontario, Canada Chapter 203, Glucocorticoid-induced osteoporosis

Viktoryia Laurynenka, PhD Research Associate Center for Autoimmune Genomics and Etiology Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio Chapter 135, Genetics of systemic lupus erythematosus

Robert A. Lavin, MD, MS Associate Professor Neurology University of Maryland School of Medicine Director of Chronic Pain Management Department of Neurology VA Maryland Health Care System Adjunct Professor Department of Occupational Medicine Johns Hopkins University School of Medicine Baltimore, Maryland Chapter 60, Principles of pharmacologic pain management

Chapter 107, Management of juvenile idiopathic arthritis

Suzanne C. Li, MD, PhD Professor of Pediatrics Division of Pediatric Rheumatology Joseph M. Sanzari Children’s Hospital Hackensack Meridian School of Medicine Hackensack, New Jersey Chapter 109, Systemic autoimmune rheumatic diseases in children

Katherine P. Liao, MD, MPH Associate Professor of Medicine and Biomedical Informatics Harvard Medical School Division of Rheumatology, Inflammation, and Immunity Brigham and Women’s Hospital Rheumatology Section and the Massachusetts Veterans Epidemiology Research and Information Center VA Boston Healthcare System Boston, Massachusetts Chapter 89, Classification and epidemiology of rheumatoid arthritis

Scott M. Lieberman, MD, PhD Associate Professor Division of Rheumatology, Allergy & Immunology Stead Family Department of Pediatrics Carver College of Medicine University of Iowa Iowa City, Iowa Chapter 109, Systemic autoimmune rheumatic diseases in children

Jean W. Liew, MD, MS Section of Rheumatology Department of Medicine Boston University School of Medicine Boston, Massachusetts Chapter 180, The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease

Geoffrey O. Littlejohn, MBBS(Hons), MD, MPH Clinical Professor of Medicine Monash University Emeritus Director Monash Rheumatology Monash Medical Centre Clayton, Victoria, Australia Chapter 206, Diffuse idiopathic skeletal hyperostosis

Eva S. Liu, MD Assistant Professor of Medicine Harvard Medical School Division of Endocrinology Brigham and Women’s Hospital Boston, Massachusetts Chapter 204, Osteomalacia, rickets, and renal osteodystrophy

Lawrence Lo, MD Division of Musculoskeletal Imaging and Intervention Department of Radiology Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Chapter 43, Conventional radiography and computed tomography

CONTRIBUTORS Rik J. Lories, MD, PhD

Anne-Marie Malfait, MD, PhD

Maureen D. Mayes, MD, MPH

Full Professor Skeletal Biology and Engineering Research Center KU Leuven and Division of Rheumatology University Hospitals Leuven Leuven, Belgium

The George W Stuppy, MD, Chair of Arthritis, and Professor Division of Rheumatology Rush University Medical Center Chicago, Illinois

Professor of Medicine Division of Rheumatology University of Texas Health Science Center Houston McGovern School of Medicine Houston, Texas

Chapter 130, Animal models of psoriatic arthritis

Thomas A. Luger, MD Professor of Dermatology Department of Dermatology University of Münster Münster, Germany Chapter 34, The skin in rheumatic disease

Ingrid E. Lundberg, MD, PhD Professor of Rheumatology Division of Rheumatology Department of Medicine, Solna Karolinska Institutet Stockholm, Sweden Chapter 157, Etiology and pathogenesis of inflammatory muscle disease (myositis)

Raashid A. Luqmani, B Med Sci, BM, BS, DM, FRCP, FRCPE Professor of Rheumatology Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science University of Oxford Consultant Rheumatologist Rheumatology Nuffield Orthopaedic Centre Oxford, United Kingdom Chapter 164, Antineutrophil cytoplasm antibody–associated vasculitis

Chapter 183, Clinical features of osteoarthritis

Tamir Malley, MRCP Specialist Registrar in Rheumatology Rheumatology Department Nuffield Orthopaedic Centre Oxford, United Kingdom Chapter 164, Antineutrophil cytoplasm antibody–associated vasculitis

Julia Manasson, MD Instructor Medicine Division of Rheumatology NYU Grossman School of Medicine New York, New York Chapter 22, The microbiome in rheumatic diseases

Lyn M. March, AM, MBBS, MSc (Epidemiology), PhD, FRACP, FAFPHM Liggins Professor of Rheumatology and Musculoskeletal Epidemiology University of Sydney and Kolling Institute Professorial Rheumatology Department Royal North Shore Hospital St Leonards, New South Wales, Australia Chapter 51, Treatment recommendations and “treat to target”

Pedro M. Machado, FRCP, PhD

Alejandro Olivé Marqués, MD, PhD

Centre for Rheumatology & Department of Neuromuscular Diseases University College London Department of Rheumatology & Queen Square Centre for Neuromuscular Diseases University College London Hospitals NHS Foundation Trust Department of Rheumatology Northwick Park Hospital London North West University Healthcare NHS Trust London, United Kingdom

Rheumatology Service Rheumatology Hospital Universitari Germans Trias i Pujol Badalona Barcelona, Spain

Chapter 180, The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease

Klaus P. Machold, MD Associate Professor of Internal Medicine Department of Rheumatology Medical University of Vienna Vienna, Austria Chapter 32, Synovial fluid analysis

C. Ronald MacKenzie, MD Attending Physician Department of Rheumatology and Medicine C. Ronald MacKenzie Chair in Ethics and Medicine Hospital for Special Surgery Professor of Clinical Medicine and Medical Ethics Department of Medicine and Medical Ethics Weill Cornell Medicine New York, New York Chapter 57, Outcomes and perioperative management of patients with inflammatory arthritis and systemic lupus erythematosus undergoing total joint arthroplasty

Tanya J. Major, PhD, BSc(Hons), BA Post-Doctoral Fellow Department of Biochemistry University of Otago Dunedin, New Zealand Chapter 193, Etiology and pathogenesis of gout

Chapter 173, Adult-onset Still disease

Javier Márquez, MD, MSc Rheumatologist Department of Internal Medicine Hospital Pablo Tobon Uribe Medellin, Antioquia, Colombia Chapter 112, Mycobacterial, brucellar, fungal, and parasitic arthritis

Paul Martin, PhD, MPhil, BSc Research Fellow Versus Arthritis Centre for Musculoskeletal Research University of Manchester Manchester, United Kingdom Chapter 16, Big Data analysis

Manuel Martínez-Lavín, MD Chief Rheumatology Department National Institute of Cardiology Professor of Rheumatology National Autonomous University Mexico City, Mexico Chapter 214, Digital clubbing and hypertrophic osteoarthropathy

Eric L. Matteson, MD, MPH Professor Emeritus of Medicine Divisions of Rheumatology and Epidemiology Mayo Clinic College of Medicine and Science Rochester, Minnesota Chapter 91, Extraarticular features of rheumatoid arthritis

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Chapter 148, Classification and epidemiology of systemic sclerosis

Timothy McAlindon, MD, MPH, MRCP Professor of Medicine Tufts University School of Medicine Chief Division of Rheumatology Tufts Medical Center Boston, Massachusetts Chapter 208, Osteonecrosis

Edward F. McCarthy, MD Professor of Pathology and Orthopaedic Surgery Pathology Johns Hopkins University School of Medicine Baltimore, Maryland Chapter 218, Bone tumors

Geraldine M. McCarthy, MD Mater Misericordiae University Hospital School of Medicine University College Dublin Dublin, Ireland Chapter 197, Basic calcium phosphate crystal deposition disease

Michael F. McDermott, MB, BCh, BAO, MRCPI, DMed Professor of Experimental Rheumatology University of Leeds—St James’s University Hospital National Institute of Health Research—Leeds Musculoskeletal Biomedical Research Unit Leeds Institute of Rheumatic and Musculoskeletal Medicine Leeds, United Kingdom Chapter 174, Monogenic autoinflammatory diseases

Patrick J. McDonnell, JD Principal Litigation Law Offices of McDonnell & Associates King of Prussia, Pennsylvania Chapter 87, Complex regional pain syndrome

Dennis McGonagle, PhD, FRCPI Professor of Investigative Rheumatology Leeds Institute of Rheumatic & Musculoskeletal Medicine University of Leeds Leeds, United Kingdom Chapter 118, Enthesopathies Chapter 129, Etiology and pathogenesis of psoriatic arthritis

Alexa Simon Meara, MD, MS Assistant Professor Internal Medicine The Ohio State University Columbus, Ohio Chapter 179, Immune-mediated complications of checkpoint inhibitors

Jay J. Mehta, MD, MSEd Associate Professor of Clinical Pediatrics Pediatric Rheumatology Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Chapter 109, Systemic autoimmune rheumatic diseases in children

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CONTRIBUTORS

Andrew R. Melville, MA, MSc, MBBS, MRCP

Jonathan J. Miner, MD, PhD

Esperanza Naredo, MD, PhD

Clinical Research Fellow Institute of Infection Immunity & Inflammation University of Glasgow Glasgow, Scotland

Associate Professor of Medicine Division of Rheumatology Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Department of Rheumatology Bone and Joint Research Unit Hospital Universitario Fundación Jiménez Díaz and Universidad Autónoma de Madrid Madrid, Spain

Chapter 100, Management of rheumatoid arthritis in csDMARD-naïve patients Chapter 154, Raynaud phenomenon

Chapter 90, Clinical features of rheumatoid arthritis

Joseph F. Merola, MD, MMSc

Deeba Minhas, MD

Associate Professor Dermatology Brigham and Women’s Hospital Boston, Massachusetts

Clinical Lecturer Rheumatology University of Michigan Ann Arbor Michigan

Chapter 128, Extraarticular manifestations and comorbidities in psoriatic arthritis

Chapter 88, Fibromyalgia and related syndromes

Robert G. Micheletti, MD

Rikke Helene Moe, PhD, PT, MSc

Associate Professor of Dermatology and Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Researcher National Advisory Unit on Rehabilitation in Rheumatology Diakonhjemmet Hospital Division of Rheumatology and Research Oslo, Norway

Chapter 170, Cutaneous vasculitis and panniculitis

Laëtitia Michou, MD, PhD Associate Professor of Medicine Université Laval Endocrinology and Nephrology Unit CHU de Quebec Research Centre Quebec City, Quebec, Canada Chapter 205, Paget disease of bone

Rob Middleton, BM BCh, MA(Cantab), MRCS Academic Clinical Fellow Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford, United Kingdom Chapter 83, The knee

Disha Midha, BM, BCom, BSc, Diploma in Innovation Management Dr Cardiology Royal Free London NHS Foundation Trust London, United Kingdom Chapter 36, The cardiovascular system in rheumatic disease

Jamal A. Mikdashi, MD, MPH, MBA Associate Professor of Medicine Division of Rheumatology and Clinical Immunology University of Maryland School of Medicine Baltimore, Maryland Chapter 172, Primary angiitis of the central nervous system

Frederick W. Miller, MD, PhD Scientist Emeritus Environmental Autoimmunity Group Clinical Research Branch National Institute of Environmental Health Sciences National Institutes of Health Durham, North Carolina Chapter 159, Management of inflammatory muscle disease

Kirsten Minden, MD Professor of Health Services Research Program Area Epidemiology and Health Services Research Deutsches Rheuma-Forschungszentrum Berlin Consultant in Pediatric Rheumatology Charité Universitätsmedizin Berlin Department of Pediatric Respiratory Medicine Immunology and Critical Care Medicine Berlin, Germany Chapter 104, Classification and epidemiology of juvenile idiopathic arthritis

Chapter 102, Multidisciplinary nonpharmacologic approach to rheumatoid arthritis

Ingrid Möller, MD, PhD Instituto Poal de Reumatología Human Anatomy and Embryology Unit Department of Experimental Pathology and Therapeutics Faculty of Medicine Bellvitge Campus University of Barcelona Barcelona, Spain Chapter 31, Aspiration and injection of joints and periarticular tissue and intralesional therapy

Renuka Mopuru, MD Assistant Professor Department of Ophthalmology and Visual Sciences University of Texas Medical Branch Galveston, Texas Chapter 35, Ocular manifestations of rheumatic diseases

Parisa Mortaji, BS, MD Department of Medicine University of Colorado Aurora, Colorado Chapter 98, Preclinical rheumatoid arthritis

Alisa A. Mueller, MD, PhD Rheumatology Fellow Division of Rheumatology, Inflammation and Immunity Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Chapter 63, Methotrexate

Elena Myasoedova, MD, PhD Associate Professor of Internal Medicine Division of Rheumatology Mayo Clinic College of Medicine and Science Rochester, Minnesota Chapter 91, Extraarticular features of rheumatoid arthritis

Gauthier Namur, MD Dr Department of Nuclear Medicine Centre Hospitalier Chrétien Liège, Belgium Chapter 47, Bone scintigraphy and positron emission tomography

Chapter 31, Aspiration and injection of joints and periarticular tissue and intralesional therapy

Victoria Navarro-Compán, MD, PhD Rheumatology Department University Hospital La Paz IdiPaz, Madrid, Spain Chapter 120, Clinical features of axial spondyloarthritis

Barbara Neerinckx, MD, PhD, prof dr Rheumatology University Hospitals Leuven/Skeletal Biology and Engineering Center KU Leuven Leuven, Belgium Chapter 123, Animal models of spondyloarthritis Chapter 130, Animal models of psoriatic arthritis

Amanda E. Nelson, MD, MSCR Associate Professor of Medicine Division of Rheumatology, Allergy, and Immunology and Thurston Arthritis Research Center University of North Carolina at Chapel Hill Chapel Hill, North Carolina Chapter 181, Epidemiology and classification of osteoarthritis

Alessandra Nerviani, MD, PhD Centre for Experimental Medicine and Rheumatology William Harvey Research Institute Queen Mary University of London London, United Kingdom Chapter 33, Minimally invasive procedures

Philippa J.A. Nicolson, BPhty, PhD Versus Arthritis Foundation Fellow Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences University of Oxford Oxford, United Kingdom Chapter 53, Principles of rehabilitation: physical and occupational therapy

Ellen B. Nordal, MD, PhD Senior Consultant Department of Pediatrics University Hospital of Northern NorwayAssociate Professor Department of Clinical Medicine University of Tromsø Tromsø, Norway Chapter 105, Clinical features of juvenile idiopathic arthritis

Ulrich Nöth, MD Professor and Director Department of Orthopaedics and Trauma Surgery Evangelisches Waldkrankenhaus Spandau Berlin, Germany Chapter 15, Principles of tissue engineering and cell- and gene-based therapy

Eleana Ntatsaki, MRCP (Rheumatology) (UK), MA, MedED, FHEA Consultant Rheumatologist Department of Rheumatology Ipswich Hospital Ipswich, United Kingdom Honorary Senior Clinical Lecturer University College London Medical School London, United Kingdom Chapter 161, Classification and epidemiology of vasculitis

CONTRIBUTORS Tilman Obenhuber, MD

Gisela Orozco, PhD

Carlo Patrono, MD

Division of Infectious Diseases and Hospital Epidemiology University Hospital Zurich Zurich, Switzerland Internal Medicine Hospital Zollikerberg Zollikerberg, Switzerland

Dr Division of Musculoskeletal and Dermatological Sciences The University of Manchester Manchester, United Kingdom

Professor of Pharmacology Catholic University School of Medicine Rome, Italy

Chapter 111, Bacterial native joint arthritis

Chester V. Oddis, MD Professor of Medicine Division of Rheumatology and Clinical Immunology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Chapter 156, Clinical features, classification, and epidemiology of inflammatory muscle disease

Alexis R. Ogdie-Beatty, MD, MSCE Associate Professor of Medicine Hospital of the University of Pennsylvania Associate Professor of Epidemiology in Biostatistics and Epidemiology Philadelphia, Pennsylvania Chapter 126, Classification and epidemiology of psoriatic arthritis

Ahmed Omar, MBBCh, MRCP, MSc Staff Physician Mount Sinai Hospital Division of Rheumatology Toronto, Ontario, Canada Chapter 116, Reactive arthritis

Michael J. Ombrello, MD Principal Investigator National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health Bethesda, Maryland Chapter 17, Principles and techniques in molecular biology

Antonina Omisade, PhD Psychologist Acquired Brain Injury Queen Elizabeth II Health Sciences Centre Halifax, Nova Scotia, Canada Chapter 143, Management of central nervous system lupus

Karen B. Onel, MD Chief Division of Pediatric Rheumatology Hospital for Special Surgery (HSS) Professor of Clinical Pediatrics Weill Cornell Medicine New York, New York Chapter 103, Evaluation of children with rheumatologic complaints

Voon H. Ong, PhD, FRCP Senior Lecturer in Rheumatology Centre for Rheumatology University College London (UCL) Royal Free Hospital London, United Kingdom Chapter 149, Clinical and serologic features of systemic sclerosis

Philippe Orcel, MD, PhD Honorary Professor of Rheumatology University of Paris Faculty of Medicine Former Chief Department of Musculoskeletal Diseases Rheumatology and Bone Diseases Hospital Lariboisière, Assistance Publique–Hôpitaux de Paris Paris, France Chapter 213, Gaucher disease

Chapter 26, Principles of genetic epidemiology

Carl Orr, MB, BCh, BAO, MRCPI, BMedSci, MSc, LMD, PhD Consultant Rheumatologist St Vincent’s University Hospital and University College Dublin Dublin, Ireland Chapter 131, Management of psoriatic arthritis

John J. O’Shea, MD Scientific Director National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health Bethesda, Maryland Chapter 9, Signal transduction in immune cells Chapter 10, Cytokines

Caroline Ospelt, MD, PhD Professor of Experimental Rheumatology Center of Experimental Rheumatology Department of Rheumatology University Hospital of Zurich University of Zurich Zurich, Switzerland Chapter 20, Epigenetics

Monika Østensen, MD Professor Consultant Rheumatology Department of Rheumatology Sorlandet sykehus Kristiansand Kristiansand, Norway Chapter 59, Medication management during preconception, pregnancy, and lactation

Seza Özen, MD Professor Pediatrics Hacettepe University Faculty of Medicine Ankara, Turkey Chapter 169, IgA vasculitis (Henoch–Schönlein purpura)

Elizabeth Park, MD Instructor Division of Rheumatology Columbia University Irving Medical Center/ New York Presbyterian Hospital New York, New York Chapter 101, Management of rheumatoid arthritis in patients with prior exposure to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)

Matthew J.S. Parker, MBChB, MRCP, FRACP Staff Specialist Department of Rheumatology Royal Prince Alfred Hospital Clinical Lecturer University of Sydney Sydney, Australia Chapter 210, Hemophilia-associated arthritis

Ejaz Pathan, MD, PhD, MRCP Consultant Rheumatologist Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne, United Kingdom Chapter 116, Reactive arthritis

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Chapter 61, Nonsteroidal antiinflammatory drugs

Lourdes M. Perez-Chada, MD, MMSc Psoriasis and Psoriatic Arthritis Clinical Research Fellow Dermatology Brigham and Women’s Hospital Boston, Massachusetts Chapter 128, Extraarticular manifestations and comorbidities in psoriatic arthritis

Luc Pijnenburg, MD Rheumatology Medical University Louis Pasteur Attending Physician Rheumatology Unit University Hospital Hautepierre Strasbourg, France Chapter 213, Gaucher disease

Michael H. Pillinger, MD Professor of Medicine and Biochemistry and Molecular Pharmacology Division of Rheumatology Department of Medicine NYU Grossman School of Medicine Section Chief Rheumatology VA New York Harbor Health Care System New York Campus U.S. Department of Veterans Affairs New York, New York Chapter 11, Inflammation and its chemical mediators

Carlos Pineda, MD, PhD General Director Instituto Nacional de Rehabilitación Mexico City, Mexico Chapter 214, Digital clubbing and hypertrophic osteoarthropathy

Nicolò Pipitone, MD, PhD Rheumatology Unit Department of Internal Medicine Azienda Ospedaliera ASMN Istituto di Ricovero e Cura a Carattere Scientifico Reggio Emilia, Italy Chapter 166, Polymyalgia rheumatica and giant cell arteritis

Costantino Pitzalis, MD, PhD, FRCP Centre for Experimental Medicine and Rheumatology William Harvey Research Institute Queen Mary University of London London, United Kingdom Chapter 33, Minimally invasive procedures

Denis Poddubnyy, MD, MSc (Epi) Professor of Rheumatology Rheumatology Unit Department of Gastroenterology, Infectious Diseases and Rheumatology Charité—Universitätsmedizin Berlin Head of the Spondyloarthritis Liaison Research Group Epidemiology German Rheumatism Research Centre Berlin, Germany Chapter 125, Management of axial spondyloarthritis

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CONTRIBUTORS

Janet E. Pope, MD, MPH, FRCPC

Soumya Raychaudhuri, MD, PhD

Professor of Medicine Medicine Division of Rheumatology University of Western Ontario Head Division of Rheumatology St. Joseph’s Health Care London, Ontario, Canada

Professor of Medicine and Biomedical Informatics Harvard Medical School Associate Physician Divisions of Rheumatology and Genetics Brigham and Women’s Hospital Boston, Massachusetts Institute Member Medical and Population Genetics Broad Institute Cambridge, Massachusetts Visiting Professor UK Centre for Genetics and Genomics Versus Arthritis University of Manchester Manchester, United Kingdom

Chapter 141, Assessing disease activity and outcome in systemic lupus erythematosus

Anna Postolova, MD, MPH Allergy/Immunology/Rheumatology Menlo Medical Clinic Menlo Park, California Chapter 158, Clinical significance of autoantibodies in inflammatory muscle disease

Andrew J. Price, MB BChir, BSc, DPhil, FRCS Professor of Orthopaedic Surgery Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Consultant Orthopaedic Surgeon Nuffield Orthopaedic Centre Oxford, United Kingdom Chapter 83, The knee

Katherine P. Pryor, MD, MS Clinical Fellow Division of Rheumatology Brigham and Women’s Hospital Boston, Massachusetts Chapter 209, Rheumatoid manifestations of endocrine and metabolic diseases and treatments

Luca Quartuccio, MD, PhD Prof Department of Medicine Rheumatology Clinic Academic Hospital Santa Maria della Misericordia University of Udine Udine, Italy Chapter 171, Cryoglobulinemia

Lars Rackwitz, MD Senior Consultant Department of Orthopaedics and Trauma Surgery Evangelisches Waldkrankenhaus Spandau Berlin, Germany Chapter 15, Principles of tissue engineering and cell- and gene-based therapy

Helga Radner, MD Medical University Vienna Department of Internal Medicine III Division of Rheumatology Vienna, Austria Chapter 42, Multimorbidity

Aardra Rajendran, MD Internal Medicine Resident Johns Hopkins Hospital Baltimore, Maryland Chapter 145, Systemic lupus erythematosus in pregnant patients and neonatal lupus

Sofia Ramiro, MD, PhD Rheumatology Leiden University Medical Center Leiden, The Netherlands Rheumatology Zuyderland Medical Center Heerlen, The Netherlands Chapter 120, Clinical features of axial spondyloarthritis

Chapter 94, Genetics of rheumatoid arthritis

Anthony C. Redmond, PhD Professor and Head Section of Clinical Biomechanics and Physical Medicine Leeds Institute of Rheumatic and Musculoskeletal Medicine University of Leeds NIHR Leeds Biomedical Research Centre Leeds Teaching Hospitals NHS Trust Leeds, United Kingdom Chapter 84, The ankle and foot

Westley H. Reeves, MD Marcia Whitney Schott Professor of Medicine Division of Rheumatology, Allergy & Clinical Immunology University of Florida College of Medicine Gainesville, Florida Chapter 138, Autoantibodies in systemic lupus erythematosus

Elaine F. Remmers, PhD Associate Investigator Inflammatory Disease Section National Human Genome Research Institute National Institutes of Health Bethesda, Maryland Chapter 17, Principles and techniques in molecular biology

Luis Requena, MD Professor of Dermatology Department of Dermatology Fundación Jeménez Díaz Universidad Autónoma Madrid, Spain Chapter 170, Cutaneous vasculitis and panniculitis

Gary Reynolds, BSc, MRCP, PhD Clinical Lecturer Translational and Clinical Research Institute Newcastle University Newcastle Upon Tyne, United Kingdom Chapter 74, Emerging therapeutic targets

John A. Reynolds, MRCP, PhD, MBChB. BMedSc Clinical Senior Lecturer Rheumatology Research Group Institute of Inflammation and Ageing College of Medical and Dental Sciences University of Birmingham Honorary Consultant Rheumatologist Rheumatology Department Sandwell and West Birmingham NHS Trust Birmingham, United Kingdom Chapter 67, Overview of biologic agents

Clio Ribbens, MD, PhD Head of Clinic Department of Rheumatology University Hospital of Liège Liège, Belgium Chapter 47, Bone scintigraphy and positron emission tomography

Bethan Richards, MBBS, MMed(ClinEpi), M Sports Med, PhD Head Department of Rheumatology Royal Prince Alfred Hospital Camperdown, New South Wales, Australia Deputy Director Institute for Musculoskeletal Health Sydney Local Health District Clinical Senior Lecturer University of Sydney Sydney, New South Wales, Australia Chapter 51, Treatment recommendations and “treat to target”

Bruce Richardson, BS, MD, PhD Huetwell Professor of Medicine Medicine University of Michigan Ann Arbor, Michigan Chapter 140, Drug-induced lupus

Pascal Richette, MD, PhD Professor of Rheumatology Rheumatology Hôpital Lariboisière Assistance Publique-Hôpitaux de Paris Paris, France Chapter 212, Hemochromatosis

Christopher T. Ritchlin, MD, MPH Professor of Medicine Center for Musculoskeletal Research University of Rochester Medical Center Rochester, New York Chapter 129, Etiology and pathogenesis of psoriatic arthritis

Susan Y. Ritter, MD, PhD Associate Physician Division of Rheumatology, Inflammation and Immunity Brigham and Women’s Hospital Instructor in Medicine Harvard Medical School Boston, Massachusetts Chapter 176, Relapsing polychondritis

Philip C. Robinson, MBChB, PhD University of Queensland Faculty of Medicine Brisbane, Australia Royal Brisbane & Women’s Hospital Metro North Hospital & Health Service Queensland, Australia Chapter 180, The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease

William H. Robinson, MD, PhD Professor of Medicine Division of Immunology and Rheumatology Stanford School of Medicine Stanford Palo Alto, California Chapter 12, The complement system

Valerie J. Rogers, MBBS, MRCPCH, BA (Hons) QTS Consultant Paediatric Rheumatologist Department of Paediatric Rheumatology Bristol Royal Hospital for Children Bristol, United Kingdom Consultant in Paediatric and Adolescent Chronic Pain Bath Centre for Pain Services Royal National Hospital For Rheumatic Diseases Bath, United Kingdom Chapter 217, Hypermobility syndrome

CONTRIBUTORS Paul L. Romain, MD

Jane E. Salmon, MD

Hans-Georg Schaible, MD

Corresponding Member of the Faculty of Medicine Harvard Medical School Division of Rheumatology and Clinical Immunology Beth Israel Deaconess Medical Center Boston, Massachusetts

Collette Kean Research Chair Medicine-Rheumatology Hospital for Special Surgery Professor Department of Medicine Weill Cornell Medical College New York, New York

Director University Hospital Jena Institute of Physiologie I Jena, Germany

Chapter 28, Ethics in clinical trials

Ivan O. Rosas, MD Professor of Medicine Baylor College of Medicine Pulmonary, Critical Care and Sleep Section Houston, Texas Chapter 37, The lungs in rheumatic disease

Ann K. Rosenthal, MD Associate Chief of Staff for Research and Development Clement J. Zablocki VA Medical Center Will and Cava Ross Professor of Medicine Chief of Rheumatology Associate Dean of Research Medical College of Wisconsin Milwaukee, Wisconsin Chapter 196, Calcium pyrophosphate deposition disease (pseudogout)

Elka Rubin Medical Student University of Arizona Tucson, Arizona Chapter 44, Magnetic resonance imaging

Martin Rudwaleit, MD Professor of Rheumatology Department of Internal Medicine and Rheumatology Klinikum Bielefeld University of Bielefeld Bielefeld, Germany Chapter 117, Classification and epidemiology of spondyloarthritis

Bram A. Rutgers, MD, PhD Department of Rheumatology and Clinical Immunology University Medical Center Groningen University of Groningen Groningen, The Netherlands Chapter 162, Biology and immunopathogenesis of vasculitis

Marite Rygg, MD, PhD Professor Department of Clinical and Molecular Medicine NTNU—Norwegian University of Science and Technology Consultant Department of Pediatrics St. Olavs Hospital University Hospital of Trondheim Trondheim, Norway Chapter 105, Clinical features of juvenile idiopathic arthritis

Kenneth G. Saag, MD, MSc Anna Waters Professor and Director Division of Clinical Immunology and Rheumatology Department of Medicine University of Alabama at Birmingham Birmingham, Alabama Chapter 62, Systemic glucocorticoids in rheumatology

Chapter 136, Immunopathology of systemic lupus erythematosus

Isidro B. Salusky, MD Distinguished Professor of Pediatrics David Geffen School of Medicine at UCLA Los Angeles, California Chapter 204, Osteomalacia, rickets, and renal osteodystrophy

Carlo Salvarani, MD Professor of Rheumatology Rheumatology Azienda USL-IRCCS di Reggio Emilia and UNIMORE Reggio Emilia, Italy Chapter 166, Polymyalgia rheumatica and giant cell arteritis

Linda J. Sandell, PhD Professor Orthopaedic Surgery Washington University St. Louis, Missouri Chapter 2, The articular cartilage

Vaneet K. Sandhu, MD Associate Professor Rheumatology Loma Linda University Loma Linda, California Assistant Professor Medicine University of California, Riverside Riverside, California Chapter 134, Clinical features of systemic lupus erythematosus

Maria Sandovici, MD, PhD Department of Rheumatology and Clinical Immunology University Medical Center Groningen University of Groningen Groningen, The Netherlands Chapter 162, Biology and immunopathogenesis of vasculitis

Anne-Lene Sand-Svartrud National Advisory Unit on Rehabilitation in Rheumatology Division of Rheumatology and Research Diakonhjemmet Hospital Oslo, Norway Chapter 102, Multidisciplinary nonpharmacologic approach to rheumatoid arthritis

Carla R. Scanzello, MD, PhD Section Chief Rheumatology Corporal Michael J. Crescenz VA Medical Center Associate Professor of Medicine Rheumatology University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania Chapter 185, Pathogenesis and pathology of osteoarthritis

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Chapter 6, Scientific basis of pain

Jose U. Scher, MD Associate Professor of Medicine Division of Rheumatology NYU Grossman School of Medicine Director Psoriatic Arthritis Center NYU Langone Health Director Microbiome Center for Rheumatology and Autoimmunity (MiCRA) NYU Grossman School of Medicine New York, New York Chapter 22, The microbiome in rheumatic diseases

Georg Schett, MD Professor of Rheumatology and Immunology Department of Internal Medicine 3 Friedrich Alexander University (FAU) Erlangen, Germany Chapter 13, Osteoimmunology

Adam I. Schiffenbauer, MD Staff Clinician Environmental Autoimmunity Group National Institute of Environmental Health Sciences National Institutes of Health Bethesda, Maryland Chapter 159, Management of inflammatory muscle disease

Alan L. Schiller, MD Founding Chair of Pathology Nova Southeastern University Medical School Director Pathology Residency Program Miami, Florida Irene Heinz Given and John Laporte Given Professorship of Pathology and Chair Emeritus Icahn School of Medicine The Mount Sinai Medical Center NYC New York, New York Chapter 218, Bone tumors

Naomi Schlesinger, MD Professor of Medicine Chief Division of Rheumatology Rutgers—Robert Wood Johnson Medical School New Brunswick, New Jersey Chapter 194, Clinical features of gout

Benjamin E. Schreiber, MBBS, MA, MRCP Consultant in Pulmonary Hypertension and Rheumatology Rheumatology Royal Free Hospital Honorary Senior Lecturer Department of Medicine University College London London, United Kingdom Chapter 36, The cardiovascular system in rheumatic disease

Daniella M. Schwartz, MD Assistant Clinical Investigator Food Allergy Research Unit Laboratory of Allergic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland Chapter 9, Signal transduction in immune cells Chapter 10, Cytokines

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CONTRIBUTORS

Aziz Shaibani, MD Director Nerve and Muscle Center of Texas Houston Neurocare Clinical Professor of Medicine Baylor College of Medicine Houston, Texas Chapter 55, Placebo, nocebo, caring, and healing in rheumatology

Leena Sharma, MD Chang-Lee Professor of Preventive Rheumatology Professor of Medicine and Preventive Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois Chapter 182, Local and systemic risk factors for incidence and progression of osteoarthritis

Robert H. Shmerling, MD Corresponding Member of the Faculty of Medicine Harvard Medical School Division of Rheumatology and Clinical Immunology Beth Israel Deaconess Medical Center Boston, Massachusetts Chapter 28, Ethics in clinical trials

Bernadette C. Siaton, MD Assistant Professor of Medicine Division of Rheumatology and Clinical Immunology University of Maryland School of Medicine Baltimore, Maryland Chapter 86, Entrapment neuropathies and compartment syndromes

Richard M. Siegel, MD, PhD Global Head, Translational Medicine Autoimmunity, Transplantation and Inflammation Novartis Institutes for BioMedical Research Basel, Switzerland Chapter 10, Cytokines

Daniela Sieghart, PhD Junior Scientist Medical University of Vienna Vienna, Austria Chapter 96, Autoantibodies in rheumatoid arthritis

Stuart L. Silverman, MD Clinical Professor of Medicine Cedars-Sinai Medical Center Clinical Professor of Medicine UCLA David Geffen School of Medicine Los Angeles, California Chapter 199, Clinical evaluation and clinical features of osteoporosis

Julia F. Simard, ScD Associate Professor Departments of Epidemiology & Population Health, and Medicine (Immunology and Rheumatology) Stanford University School of Medicine Stanford, California Chapter 23, Principles of epidemiology

Barry P. Simmons, MD Associate Professor of Orthopaedic Surgery Harvard Medical School Chief Emeritus Hand and Upper Extremity Service Brigham and Women’s Hospital Boston, Massachusetts Chapter 81, The wrist and hand

Robert W. Simms, MD Emeritus Professor of Medicine Boston University School of Medicine

Professor of Medicine Dartmouth Geisel School of Medicine Hanover, New Hampshire Chapter 155, Localized scleroderma and scleroderma-like syndromes

Nora G. Singer, MD Professor of Medicine and Pediatrics Case Western Reserve University School of Medicine Director Division of Rheumatology The Metro Health System Cleveland, Ohio Chapter 103, Evaluation of children with rheumatologic complaints

Emily Sirotich, BSc Department of Health Research Methods, Evidence, and Impact McMaster University Hamilton, Ontario, Canada Canadian Arthritis Patient Alliance Toronto, Ontario, Canada Chapter 180, The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease

Judith A. Smith, MD, PhD Associate Professor of Pediatrics Division of Allergy Immunology and Rheumatology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Chapter 108, The juvenile-onset spondyloarthropathies

Jeffrey A. Sparks, MD, MMSc Assistant Professor of Medicine Department of Medicine Division of Rheumatology, Inflammation, and Immunity Brigham and Women’s Hospital Boston, Massachusetts Chapter 42, Multimorbidity Chapter 175, Sarcoidosis

John Stack, MD Mater Misericordiae University Hospital School of Medicine, University College Dublin Dublin, Ireland Chapter 197, Basic calcium phosphate crystal deposition disease

David Stanley, MB, BS, BSc (Hons), FRCS Consultant Orthopaedic Surgeon Parkhead Consultancy Sheffield, United Kingdom Chapter 80, The elbow

Virginia D. Steen, MD Professor of Medicine Medstar Georgetown University Hospital Rheumatology Division Washington, DC Chapter 152, Management of systemic sclerosis

Allen C. Steere, MD Professor of Medicine Harvard Medical School Director Translational Research in Rheumatology Massachusetts General Hospital Boston, Massachusetts Chapter 114, Lyme and other tickborne diseases

Stacy E. Smith, MD

Coen A. Stegeman, MD, PhD

Chief and Distinguished Barbara N. Weissman Chair Division of Musculoskeletal Imaging and Intervention Department of Radiology Medical Director Orthopaedic and Arthritis Center Clinical Director Quantitative Musculoskeletal Imaging Group Imaging Director STRATUS Center for Simulation in Medical Education Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts

Professor Department of Nephrology University Medical Center Groningen University of Groningen Groningen, The Netherlands

Chapter 43, Conventional radiography and computed tomography

Josef S. Smolen, MD Emeritus Professor Division of Rheumatology Department of Medicine 3 Medical University of Vienna Vienna, Austria Chapter 99, Assessment of the patient with rheumatoid arthritis and the measurement of outcomes

Daniel H. Solomon, MD, MPH Professor Division of Rheumatology Brigham and Women’s Hospital Professor Medicine Harvard Medical School Boston, Massachusetts Chapter 42, Multimorbidity

Chapter 162, Biology and immunopathogenesis of vasculitis

Günter Steiner, PhD Prof Director of the Ludwig Boltzmann Institute for Arthritis and Rehabilitation Medical University of Vienna Department of Medicine III Division of Rheumatology Vienna, Austria Chapter 96, Autoantibodies in rheumatoid arthritis

Andre F. Steinert, MD Professor and Head Department of Orthopaedics, Arthroplasty, Trauma and Shoulder Surgery Rhön-Klinikum Campus Bad Neustadt Bad Neustadt, Germany Chapter 15, Principles of tissue engineering and cell- and gene-based therapy

George Stojan, MD Global SLE Medical Affairs Director at UCB Baltimore, Maryland Chapter 160, Metabolic, drug-induced, and other noninflammatory myopathies

Vibeke Strand, MD, MACR, FACP Adjunct Clinical Professor Division of Immunology/Rheumatology Stanford University Palo Alto California Chapter 141, Assessing disease activity and outcome in systemic lupus erythematosus

CONTRIBUTORS Paul Sufka, MD

Louise M. Topping, BSc, PhD

Désirée van der Heijde, MD, PhD

Rheumatologist Rheumatology HealthPartners St. Paul, Minnesota

Kennedy Institute of Rheumatology University of Oxford Oxford, United Kingdom

Professor of Rheumatology Rheumatology Leiden University Medical Center Leiden, The Netherlands

Chapter 180, The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease

James K. Sullivan, BA Medical Student Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Cleveland Ohio Chapter 58, Indications for and long-term complications of total hip and knee arthroplasty

Pawel Szulc, MD, PhD University of Lyon Lyon, France Chapter 201, Biochemical markers of bone turnover in postmenopausal osteoporosis

Chen Tang, MD Division of Rheumatology Cedars-Sinai Medical Center Los Angeles, California Chapter 93, Imaging of rheumatoid arthritis

Shiyu Tang, PhD Postdoctoral Fellow Department of Diagnostic Radiology & Nuclear Medicine University of Maryland School of Medicine Baltimore, Maryland Chapter 45, Functional magnetic resonance imaging

Peter C. Taylor, MA, PhD, FRCP Professor of Rheumatology Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences University of Oxford Botnar Research Centre Headington, Oxford, United Kingdom Chapter 70, Tumor necrosis factor inhibitors

Robert Terkeltaub, MD Chief Rheumatology Section Medicine VA Healthcare System Professor of Medicine Division of Rheumatology, Allergy, and Immunology University of California, San Diego San Diego, California Chapter 195, Management of gout and hyperuricemia

Afton R. Thomas, DO Assistant Professor of Medicine Division of Rheumatology and Clinical Immunology University of Maryland School of Medicine Baltimore, Maryland Chapter 86, Entrapment neuropathies and compartment syndromes

Jennifer E. Thorne, MD, PhD Cross Family Professor Ophthalmology Johns Hopkins University School of Medicine Professor Epidemiology Johns Hopkins University Bloomberg School of Public Health Baltimore, Maryland Chapter 35, Ocular manifestations of rheumatic diseases

Chapter 95, Animal models of rheumatoid arthritis

Michael Toprover, MD Assistant Professor of Medicine Division of Rheumatology Department of Medicine NYU Grossman School of Medicine New York, New York Chapter 11, Inflammation and its chemical mediators

Karina Torralba, MD, MACM Chief Division of Rheumatology Department of Medicine Loma Linda University Loma Linda, California Chapter 134, Clinical features of systemic lupus erythematosus

Zahi Touma, MD, PhD Associate Professor of Medicine University of Toronto Department of Medicine Toronto Western Hospital Toronto, Ontario, Canada Chapter 24, Principles of clinical outcome assessment

Adriana H. Tremoulet, MD, MAS Associate Director Kawasaki Disease Research Center University of California San Diego School of Medicine La Jolla, California Director Kawasaki Disease Clinic Rady Children’s Hospital-San Diego San Diego, California Chapter 168, Kawasaki disease

Leendert Trouw, PhD Associate Professor and Group Leader Leiden University Medical Center Leiden, The Netherlands Chapter 96, Autoantibodies in rheumatoid arthritis

Rocky S. Tuan, PhD Vice-Chancellor and President The Chinese University of Hong Kong Institute for Tissue Engineering and Regenerative Medicine Hong Kong SAR, China Chapter 15, Principles of tissue engineering and cell- and gene-based therapy

Ilker Uçkay, MD, Prof. Dr. med. Infectiology Balgrist University Hospital Zurich, Switzerland Chapter 111, Bacterial native joint arthritis

Hisanori Umehara, MD, PhD Director of Rheumatology and Immunology Nagahama City Hospital Shiga, Japan Chapter 178, IgG4-related disease

Kornelis S.M. van der Geest, MD, PhD Department of Rheumatology and Clinical Immunology University Medical Center Groningen University of Groningen Groningen, The Netherlands Chapter 162, Biology and immunopathogenesis of vasculitis

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Chapter 49, Use of imaging as an outcome measure in clinical trials

Floris A. van Gaalen, MD, PhD Associate Professor Department of Rheumatology Leiden University Medical Center Leiden, The Netherlands Chapter 119, Inflammatory back pain

Margot Van Mechelen, MD, PhD, Dr Rheumatology University Hospitals Leuven/Skeletal Biology and Engineering Center KU Leuven Leuven, Belgium Chapter 123, Animal models of spondyloarthritis

Ronald F. van Vollenhoven, MD, PhD Professor and Chair Rheumatology and Clinical Immunology Amsterdam University Medical Centers Director Amsterdam Rheumatology Center Amsterdam, The Netherlands Chapter 66, Kinase inhibitors and other synthetic agents

Claire Y.J. Vandevelde, MD, MRCP Consultant Rheumatologist Leeds Teaching Hospitals NHS Trust Leeds, United Kingdom Chapter 187, Imaging of osteoarthritis

John Varga, MD Frederick G L Huetwell Professor of Internal Medicine Chief Division of Rheumatology Department of Internal Medicine University of Michigan Ann Arbor, Michigan Chapter 150, Etiology and pathogenesis of systemic sclerosis

Dimitrios Vassilopoulos, MD Professor of Medicine (Rheumatology) National and Kapodistrian University of Athens School of Medicine Chair, 2nd Department of Medicine and Laboratory Hippokration General Hospital Athens, Greece Chapter 113, Viral infections

Douglas J. Veale, MD, FRCPI, FRCP(Lon) Director of Translational Research The Centre for Arthritis and Rheumatic Disease St. Vincent’s University Hospital Professor of Medicine University College Dublin Fellow Conway Institute of Biomolecular and Biomedical Medicine Dublin, Ireland Chapter 131, Management of psoriatic arthritis

Gwenny M. Verstappen, PharmD, PhD Rheumatology and Clinical Immunology University of Groningen University Medical Center Groningen Groningen, The Netherlands Chapter 146, Sjögren syndrome

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CONTRIBUTORS

Sebastien Viatte, MD, PhD

Abdulla Watad, MD

Lecturer in Genetics Centre for Genetics and Genomics Versus Arthritis and Lydia Becker Institute of Immunology Centre for Musculoskeletal Research The University of Manchester Manchester, United Kingdom

Doctor Internal Medicine B Sheba Medical Centre Tel Aviv, Israel Senior Lecturer Division of Rheumatology Sheba Medical Center Tel Aviv University Tel-Hashomer, Israel

Chapter 94, Genetics of rheumatoid arthritis

Tonia L. Vincent, MBBS, PhD, FRCP Professor of Musculoskeletal Biology Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences Kennedy Institute of Rheumatology Honorary Consultant Rheumatologist Oxford University Hospitals Trust Oxford, United Kingdom Chapter 184, Animal models of osteoarthritis

Edward M. Vital, PhD, MRCP(UK) Associate Professor Honorary Consultant and NIHR Clinician Scientist Leeds Institute of Rheumatic and Musculoskeletal Medicine University of Leeds Leeds Biomedical Research Centre Leeds Teaching Hospitals NHS Trust Leeds, United Kingdom Chapter 73, Inhibitors of B cells

Isabell S. von Loga, AB, MBBS Alumni Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences Kennedy Institute of Rheumatology University of Oxford Oxford, United Kingdom Chapter 184, Animal models of osteoarthritis

Dawn M. Wahezi, MD Chief Division of Pediatric Rheumatology Director Pediatric Rheumatology Fellowship Program Associate Professor Albert Einstein College of Medicine Bronx, New York Chapter 109, Systemic autoimmune rheumatic diseases in children

Daniel J. Wallace, MD Rheumatology Cedars-Sinai Medical Center Los Angeles, California Chapter 134, Clinical features of systemic lupus erythematosus

Zachary S. Wallace, MD, MSc Clinical Epidemiology Program and Rheumatology Unit Division of Rheumatology, Allergy, and Immunology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Chapter 180, The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease

Gary Warburton, DDS, MD, FDSRCS, FACS Professor of Oral & Maxillofacial Surgery Oral & Maxillofacial Surgery University of Maryland School of Dentistry Baltimore, Maryland Chapter 85, The temporomandibular joint

Chapter 118, Enthesopathies

Richard A. Watts, MA, DM, FRCP Honorary Professor Norwich Medical School University of East Anglia Norwich, United Kingdom Chapter 161, Classification and epidemiology of vasculitis

Michael E. Weinblatt, MD John R. and Eileen K. Riedman Professor of Medicine Harvard Medical School Division of Rheumatology, Inflammation and Immunity Brigham and Women’s Hospital Boston, Massachusetts Chapter 63, Methotrexate

Matthew R. Weir, MD Professor and Director Division of Nephrology Medicine University of Maryland School of Medicine, Baltimore, Maryland Chapter 39, The kidneys in rheumatic diseases

Michael H. Weisman, MD Adjunct Professor of Medicine Division of Immunology and Rheumatology Stanford University Professor of Medicine, Emeritus Division of Rheumatology Cedars-Sinai Medical Center Distinguished Professor of Medicine, Emeritus David Geffen School of Medicine at University of California, Los Angeles Los Angeles, California Chapter 134, Clinical features of systemic lupus erythematosus

Pamela F. Weiss, MD, MSCE Associate Professor of Pediatrics Perelman School of Medicine University of Pennsylvania Attending Physician Division of Rheumatology Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Chapter 108, The juvenile-onset spondyloarthropathies

Harriet Branford White, MB ChB, DPhil, FRCS (Tr & Orth) Trauma and Orthopaedic Registrar North West Thames Rotation St Mary’s Hospital Imperial NHS Trust London, United Kingdom Chapter 218, Bone tumors

Kenneth E. White, PhD David D. Weaver Professor of Genetics IUPUI Chancellor’s Professor Director Division of Molecular Genetics and Gene Therapy Vice-Chair for Research

Departments of Medical & Molecular Genetics and Medicine/Nephrology IU-Simon Cancer Center Indiana University School of Medicine Indianapolis, Indiana Chapter 3, Bone structure and function

David J. Wilkinson, BSc, MRes, PhD Department of Musculoskeletal Biology and Ageing Sciences Institute of Life Course and Medical Sciences University of Liverpool Liverpool, United Kingdom Chapter 14, Joint tissue destruction and proteolysis

David E. Williams, BEng, PhD Dr. School of Engineering Cardiff University Cardiff, Wales Chapter 5, Biomechanics of peripheral joints and spine

Richard Williams, BSc, MSc, PhD Professor of Immunology Kennedy Institute of Rheumatology University of Oxford Oxford, United Kingdom Chapter 95, Animal models of rheumatoid arthritis

Hannah Wilson, BM BCh, MA(Oxon), MRCS Research Fellow Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences University of Oxford Oxford, United Kingdom Chapter 83, The knee

Kevin L. Winthrop, MD, MPH Professor of Infectious Diseases and Public Health Department of Medicine OHSU-PSU School of Public Health Oregon Health & Science University Portland, Oregon Chapter 76, Infections in rheumatoid arthritis: biologic therapy and JAK inhibitors

Claudia M. Witt, MD, MBA Professor and Chair Institute for Complementary and Integrative Medicine University Hospital Zurich and University Zurich Zurich, Switzerland Professor of Medicine Center for Integrative Medicine University of Maryland School of Medicine Baltimore, Maryland Chapter 56, Complementary and alternative medicine

Gerhard Witzmann, MD Department of Rheumatology Hietzing Hospital Vienna, Austria Appendix: Classification and diagnostic criteria

John B. Wong, MD Professor of Medicine Tufts University School of Medicine Vice Chair of Academic Affairs Chief Division of Clinical Decision Making Department of Medicine Tufts Medical Center Boston, Massachusetts Chapter 25, Principles of health economics

Anthony D. Woolf, BSc, MBBS, FRCP Professor Bone and Joint Research Group Royal Cornwall Hospitals Trust Truro, Cornwall, United Kingdom Chapter 29, History and physical examination

CONTRIBUTORS

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B. Paul Wordsworth, MA, MB, BS, FRCP

Jinoos Yazdany, MD, MPH

Md Yuzaiful Md Yusof, PhD, MRCP(UK)

Emeritus Professor of Clinical Rheumatology Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences University of Oxford Oxford, United Kingdom Honorary Consultant Rheumatologist Department of Rheumatology Nuffield Orthopaedic Centre Headington, United Kingdom

Professor of Medicine University of California, San Francisco San Francisco, California

NIHR Academic Clinical Lecturer and LTHT Consultant Rheumatologist Leeds Institute of Rheumatic and Musculoskeletal Medicine University of Leeds Leeds Biomedical Research Centre Leeds Teaching Hospitals NHS Trust Leeds, United Kingdom

Chapter 216, Heritable connective tissue disorders

Chapter 180, The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease

David A. Young, PhD Professor Skeletal Research Group Newcastle University Newcastle upon Tyne, United Kingdom Chapter 14, Joint tissue destruction and proteolysis

Huji Xu, MD, PhD

Stephen P. Young, BSc(Hons), PhD

Department of Rheumatology and Immunology Shanghai Changzheng Hospital Second Military Medical University Shanghai, China

Reader in Experimental Rheumatology Institute of Inflammation and Ageing University of Birmingham Birmingham, United Kingdom

Chapter 122, Genetics of axial spondyloarthritis

Chapter 19, Metabolomics

Chapter 73, Inhibitors of B cells

Haoyang Zhuang, PhD Division of Rheumatology, Allergy, & Clinical Immunology University of Florida College of Medicine Gainesville, Florida Chapter 138, Autoantibodies in systemic lupus erythematosus

Preface​ Rheumatology, eighth edition, builds on the success of the seven prior editions. The most notable change is recognizing the retirement of Professor Alan Silman along with the addition of Professor Désirée van der Heijde to the group of Editors. Professor Silman was one of the original international group that oversaw the return of the third edition of this text in 2003. Professor van der Heijde is internationally recognized for her research in clinical and imaging outcomes in rheumatology, particularly in the study of rheumatoid arthritis and the spondyloarthropathies. Her addition to the Editorial team has refocused our efforts to provide a strong component in both imaging and the spondyloarthropathies to this edition.​ Designed to meet the needs of the practicing rheumatologist, this medical reference book provides extensive coverage of rheumatic and musculoskeletal diseases from basic scientific principles to practical points of clinical management in a lucid and logical manner. As stated by the late Professor Jan Dequeker in his review of the fourth edition, “​Rheumatology is the most comprehensive, authoritative rheumatology text designed to meet the complete needs of all practicing and academic rheumatologists as well as arthritis-related health care professionals and scientists interested in disorders of the musculoskeletal system. The edition is firmly grounded on modern medical science, integrating the relevant basic biology with current clinical practice, easily accessible, user-friendly, and a beautifully illustrated color publication.” Dr. Harry Brown, in his review of the sixth edition, noted that “[m]y lasting impression of this book was the very same as the first time I opened these two lavish volumes and that was—wow. I would suspect this is the nearest you would get to an encyclopaedia of rheumatology.”​ For this new edition, every chapter has been either substantially revised or, in many cases, entirely rewritten, following a rigorous editorial policy to

ensure that the content and format of the book remain consistent and meet the highest possible standards. Each chapter has been updated to incorporate a broad range of new information. Seven completely new chapters cover basic biomedical and translational science, disease and outcome assessment, new and early emerging disease, including relationship of COVID-19 and rheumatic disease, clinical therapeutics, including immune-mediated complications of checkpoint inhibitors, and patient management. The text has been streamlined, ensuring that each chapter contains the most critical and current information in the field, while supplemental materials (including extra tables, figures, videos, and bonus text) are conveniently located online. The index has also been improved, making it easier for the reader to find topics of interest.​ The production of this edition of R ​ heumatology has been a greatly enjoyable team effort. We would like to thank the authors who have contributed to this and previous editions of the book, as well as the excellent team at Elsevier, including Nancy Duffy, Jessica McCool, Ann Anderson, Daniel Fitzgerald, and Bridget Hoette.​ We look forward to bringing you the ninth edition in another 4 years.​ Marc C. Hochberg Ellen M. Gravallese Josef S. Smolen Désirée van der Heijde Michael E. Weinblatt Michael H. Weisman

xxvii

Acknowledgments​ We would like to acknowledge the tremendous work of the contributors to this edition of R ​ heumatology, without whom this book would not have been possible. In addition, we would like to recognize our mentors: Drs. Eva Alberman, Ronald J. Anderson, Laurie Glimcher, Ramzi Cotran, the late Georg Geyer, Lawrence E. Shulman, Carl Steffen, Alfred D. Steinberg, Mary Betty Stevens, Nathan J. Zvaifler, and K. Frank Austen.​ We would also like to thank our in-office administrative and editorial support (Aida Medina, Marion Skobek) for all of their hard work and diligence. Last, but certainly not least, we want to acknowledge our patients,

who continue to provide stimulating challenges to us in our clinical practices, especially during the COVID pandemic with the use of telerheumatology.​ Marc C. Hochberg Ellen M. Gravallese Josef S. Smolen Désirée van der Heijde Michael E. Weinblatt Michael H. Weisman

xxix

Contents Volume One

SECTION 2 Clinical Basis of Rheumatic Disease

SECTION 1

23. Principles of epidemiology

Scientific Basis of Rheumatic Disease

24. Principles of clinical outcome assessment

193

Julia F. Simard and Elizabeth V. Arkema

198

Sindhu R. Johnson and Zahi Touma

A.  Anatomy and Physiology 1. The synovium

25. Principles of health economics 1

26. Principles of genetic epidemiology

Andrew Filer and Christopher D. Buckley

2. The articular cartilage

8

Linda J. Sandell and Brian Johnstone

3. Bone structure and function David B. Burr, Teresita Bellido, and Kenneth E. White

4. Tendons and ligaments

215

Robert B.M. Landewé

28. Ethics in clinical trials 31

209

Gisela Orozco and Stephen Eyre

27. Interpreting the medical literature for the rheumatologist 18

203

John B. Wong

222

Paul L. Romain and Robert H. Shmerling

Stephanie G. Dakin and Andrew J. Carr

5. Biomechanics of peripheral joints and spine

38

David E. Williams and Cathy Holt

6. Scientific basis of pain

49

Hans-Georg Schaible

Approach to the Patient

B.  Immunology and Inflammation 7. Principles of innate immunity

55

29. History and physical examination

62

30. Laboratory tests in rheumatic disorders

72

31. Aspiration and injection of joints and periarticular tissue and intralesional therapy

Tsuneyasu Kaisho and Shizuo Akira

8. Principles of adaptive immunity Sergei P. Atamas and Martin F. Flajnik

9. Signal transduction in immune cells Eric P. Hanson, Daniella M. Schwartz, Michael Bonelli, John J. O’Shea, and Martin Aringer

10. Cytokines

80

John J. O’Shea, Massimo Gadina, Daniella M. Schwartz, Richard M. Siegel, and Joshua Farber

11. Inflammation and its chemical mediators

96 109

13. Osteoimmunology

115

Georg Schett and Aline Bozec

14. Joint tissue destruction and proteolysis David J. Wilkinson and David A. Young

15. Principles of tissue engineering and cell- and gene-based therapy

130

281

Renuka Mopuru, Benjamin C. Chaon, Jennifer E. Thorne, and Douglas A. Jabs

290

37. The lungs in rheumatic disease

299 305

Natasha Kamal and Raymond K. Cross

137

39. The kidneys in rheumatic diseases

312

Jay I. Lakkis and Matthew R. Weir

145

40. The nervous system in rheumatic disease

326

Shamik Bhattacharyya

158

Joshua LaBaer and Timothy L. Karr

165

Stephen P. Young

20. Epigenetics

271

Markus Böhm, Thomas A. Luger, and Jan Ehrchen

38. The gastrointestinal tract in rheumatic disease

Elaine F. Remmers and Michael J. Ombrello

19. Metabolomics

265

Alessandra Nerviani, Frances Humby, and Costantino Pitzalis

Tracy J. Doyle, Ivan O. Rosas, and Paul F. Dellaripa

Paul Martin, Kimme Hyrich, and Nophar Geifman

18. Proteomics

260

Klaus P. Machold

Disha Midha, Benjamin E. Schreiber, David P. D’Cruz, and John (Gerry) Coghlan

C.  Systems Biology 17. Principles and techniques in molecular biology

32. Synovial fluid analysis

36. The cardiovascular system in rheumatic disease

Lars Rackwitz, Ulrich Nöth, Andre F. Steinert, and Rocky S. Tuan

16. Big Data analysis

247

Esperanza Naredo and Ingrid Möller

35. Ocular manifestations of rheumatic diseases 120

241

Eugen Feist and Gerd-Rüdiger Burmester

34. The skin in rheumatic disease

William H. Robinson

225

Anthony D. Woolf

33. Minimally invasive procedures

Ruth Fernandez-Ruiz, Michael Toprover, and Michael H. Pillinger

12. The complement system

SECTION 3

171

41. The muscles in rheumatic disease

333

Sarfaraz A. Hasni and Randall E. Keyser

42. Multimorbidity

340

Helga Radner, Jeffrey A. Sparks, and Daniel H. Solomon

Caroline Ospelt and Steffen Gay

21. Precision medicine and pharmacogenomics in rheumatology

178

Mary Abraham, Jeffrey D. Greenberg, and Bruce N. Cronstein

22. The microbiome in rheumatic diseases

183

Julia Manasson, Steven B. Abramson, and Jose U. Scher

xxxi

Contents

xxxii

SECTION 4

66. Kinase inhibitors and other synthetic agents

C.  Biologic Agents

Evaluation of the Patient: Imaging Techniques 43. Conventional radiography and computed tomography

345

Stacy E. Smith and Lawrence Lo

44. Magnetic resonance imaging

358

Elka Rubin and Garry E. Gold

45. Functional magnetic resonance imaging

367

Shiyu Tang and Rao P. Gullapalli

46. Musculoskeletal ultrasonography

373

David Kane

47. Bone scintigraphy and positron emission tomography

383

Clio Ribbens and Gauthier Namur

48. Dual x-ray absorptiometry and measurement of bone

393

Mohammed Almohaya, Mohammed Almehthel, and David Kendler

49. Use of imaging as an outcome measure in clinical trials

527

Ronald F. van Vollenhoven

402

Désirée van der Heijde and Robert B.M. Landewé

67. Overview of biologic agents

535

Benjamin A. Fisher, John A. Reynolds, Roy Jefferis, and Caroline Gordon

68. Interleukin-1 inhibitors

541

Cem Gabay

69. Interleukin-6 inhibitors

548

Berber de Boer and Thomas W.J. Huizinga

70. Tumor necrosis factor inhibitors

556

Peter C. Taylor and Maha A. Azeez

71. Interleukin-17, interleukin-12, and interleukin-23 inhibitors

578

Ruba Kado and David A. Fox

72. Inhibitors of T-cell costimulation

583

Ernest H.S. Choy

73. Inhibitors of B cells

587

Md Yuzaiful Md Yusof, Edward M. Vital, and Paul Emery

74. Emerging therapeutic targets

596

John D. Isaacs and Gary Reynolds

75. Biosimilars in rheumatology

SECTION 5

604

Jonathan Kay

76. Infections in rheumatoid arthritis: biologic therapy and JAK inhibitors

Principles of Management

617

Kevin L. Winthrop

A. General 50. The patient perspective

411

Maarten de Wit

51. Treatment recommendations and “treat to target”

415

Lyn M. March and Bethan Richards

52. Arthritis patient education, self-management, and health promotion

77. Neck pain

430

78. Low back pain

Rana S. Hinman, Philippa J.A. Nicolson, and Kim L. Bennell

54. Multidisciplinary approaches to managing chronic pain in arthritis 438 Alice Elizabeth Berry and Sarah Bennett

55. Placebo, nocebo, caring, and healing in rheumatology

57. Outcomes and perioperative management of patients with inflammatory arthritis and systemic lupus erythematosus undergoing total joint arthroplasty

676

George S.M. Dyer and Barry P. Simmons

684

Matthew L. Brown and William D. Bugbee

455

83. The knee

693

Hannah Wilson, Rob Middleton, and Andrew J. Price

462

84. The ankle and foot

707

Anthony C. Redmond

85. The temporomandibular joint

718

Gary Warburton, Sharon Gordon, and Max R. Emmerling

467

86. Entrapment neuropathies and compartment syndromes

721

Afton R. Thomas and Bernadette C. Siaton

B.  Small Molecules

87. Complex regional pain syndrome 475

Robert A. Lavin and Timothy J. Atkinson

61. Nonsteroidal antiinflammatory drugs

671

David Stanley and Amjid Ashraf Ali

82. The hip

Bonnie L. Bermas and Monika Østensen

60. Principles of pharmacologic pain management

656

George L.D. Cox

81. The wrist and hand

James K. Sullivan and Jeffrey N. Katz

59. Medication management during preconception, pregnancy, and lactation

79. The shoulder

447

Susan M. Goodman and C. Ronald MacKenzie

58. Indications for and long-term complications of total hip and knee arthroplasty

638

Andrew A. Joyce and Zacharia Isaac

80. The elbow

Brian Berman, Claudia M. Witt, and Chris D’Adamo

627

Leslie Barnsley

443

Elisa Frisaldi, Aziz Shaibani, and Fabrizio Benedetti

56. Complementary and alternative medicine

Regional and Widespread Pain

424

Pamela Donlan and Maura D. Iversen

53. Principles of rehabilitation: physical and occupational therapy

SECTION 6

482

732

Christopher Chang, Patrick J. McDonnell, and M. Eric Gershwin

88. Fibromyalgia and related syndromes

740

Deeba Minhas and Daniel J. Clauw

Carlo Patrono

62. Systemic glucocorticoids in rheumatology

490

Kenneth G. Saag and Frank Buttgereit

63. Methotrexate

501

Alisa A. Mueller and Michael E. Weinblatt

64. Synthetic disease-modifying antirheumatic drugs and leflunomide 509 Vivian P. Bykerk and Boulos Haraoui

65. Immunosuppressive agents: cyclosporine, cyclophosphamide, azathioprine, mycophenolate mofetil, and tacrolimus Kavitta B. Allem and Richard M. Keating

SECTION 7 Rheumatoid Arthritis 89. Classification and epidemiology of rheumatoid arthritis

749

Katherine P. Liao

518

90. Clinical features of rheumatoid arthritis Richard D. Brasington, Jr. and Jonathan J. Miner

756

Contents 91. Extraarticular features of rheumatoid arthritis

763

Elena Myasoedova and Eric L. Matteson

92. Common comorbidities in rheumatoid arthritis

771 778

799

115. Acute rheumatic fever

805

116. Reactive arthritis

Daniela Sieghart, Leendert Trouw, and Günter Steiner

97. Pathogenesis and pathology of rheumatoid arthritis

982

B. Other Infection-Related Disease 114. Lyme and other tickborne diseases

Richard Williams and Louise M. Topping

96. Autoantibodies in rheumatoid arthritis

113. Viral infections

789

Sebastien Viatte and Soumya Raychaudhuri

95. Animal models of rheumatoid arthritis

967

Dimitrios Vassilopoulos and Leonard H. Calabrese

Chen Tang, Lindsy Forbess, and Ami Ben-Artzi

94. Genetics of rheumatoid arthritis

112. Mycobacterial, brucellar, fungal, and parasitic arthritis Javier Márquez and Luis R. Espinoza

Jeffrey R. Curtis and Michael D. George

93. Imaging of rheumatoid arthritis

xxxiii

989

Allen C. Steere

996

Carlos Eduardo de Barros Branco and Luiza Guilherme Guglielmi

1007

Ejaz Pathan, Ahmed Omar, and Robert D. Inman

815

Ellen M. Gravallese and Anna Helena Jonsson

98. Preclinical rheumatoid arthritis

835

Parisa Mortaji and Kevin D. Deane

99. Assessment of the patient with rheumatoid arthritis and the measurement of outcomes

841

Daniel Aletaha and Josef S. Smolen

100. Management of rheumatoid arthritis in csDMARD-naïve patients 852 Andrew R. Melville and Maya H. Buch

101. Management of rheumatoid arthritis in patients with prior exposure to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)

Spondyloarthritis and Psoriatic Arthritis 117. Classification and epidemiology of spondyloarthritis

1023

Martin Rudwaleit

118. Enthesopathies

1027

Dennis McGonagle and Abdulla Watad

860

Elizabeth Park and Joan M. Bathon

102. Multidisciplinary nonpharmacologic approach to rheumatoid arthritis

SECTION 10

119. Inflammatory back pain 120. Clinical features of axial spondyloarthritis

869

Turid Heiberg, Anne-Lene Sand-Svartrud, Rikke Helene Moe, and Tore K. Kvien

1036

Floris A. van Gaalen

1039

Sofia Ramiro and Victoria Navarro-Compán

121. Pathogenesis and pathophysiology of axial spondyloarthritis

1045

Dirk Elewaut, Elisabeth Gilis, and Ann-Sophie De Craemer

122. Genetics of axial spondyloarthritis

1051

Matthew A. Brown and Huji Xu

123. Animal models of spondyloarthritis

Volume Two

1056

Barbara Neerinckx and Margot Van Mechelen

124. Imaging in spondyloarthritis

1061

Xenofon Baraliakos, David Kiefer, and Jürgen Braun

SECTION 8

125. Management of axial spondyloarthritis

Pediatric Rheumatology

126. Classification and epidemiology of psoriatic arthritis

103. Evaluation of children with rheumatologic complaints

875 884 894

Ellen B. Nordal, Marite Rygg, and Anders Fasth

106. Etiology and pathogenesis of juvenile idiopathic arthritis

1092

1108

Monica Guma, Christopher T. Ritchlin, and Dennis McGonagle

1118

Rik J. Lories and Barbara Neerinckx

131. Management of psoriatic arthritis 929

1100

Lourdes M. Perez-Chada and Joseph F. Merola

130. Animal models of psoriatic arthritis 913

Roberta A. Berard, Philip J. Hashkes, and Ronald M. Laxer

108. The juvenile-onset spondyloarthropathies

128. Extraarticular manifestations and comorbidities in psoriatic arthritis 129. Etiology and pathogenesis of psoriatic arthritis

907

Robert A. Colbert

107. Management of juvenile idiopathic arthritis

127. Clinical features of psoriatic arthritis Laure Gossec

Kirsten Minden

105. Clinical features of juvenile idiopathic arthritis

1087

M. Elaine Husni and Alexis R. Ogdie-Beatty

Nora G. Singer and Karen B. Onel

104. Classification and epidemiology of juvenile idiopathic arthritis

1072

Denis Poddubnyy

1122

Douglas J. Veale and Carl Orr

Pamela F. Weiss and Judith A. Smith

109. Systemic autoimmune rheumatic diseases in children

936

Joyce C. Chang, Suzanne C. Li, Scott M. Lieberman, Dawn M. Wahezi, and Jay J. Mehta

110. Rehabilitation and psychosocial issues in juvenile idiopathic arthritis

951

Sabrina Cavallo

SECTION 11 Systemic Lupus Erythematosus and Related Diseases 132. Epidemiology and classification of systemic lupus erythematosus 1131 Candace H. Feldman and Karen H. Costenbader

SECTION 9

133. Preclinical features of systemic lupus erythematosus

Infection-Related Rheumatic Diseases

134. Clinical features of systemic lupus erythematosus

A. Infectious Arthritis

135. Genetics of systemic lupus erythematosus

111. Bacterial native joint arthritis Leo R.W. Kronberger, Tilman Obenhuber, and Ilker Uçkay

1139

Judith A. James

1147

Vaneet K. Sandhu, Michael H. Weisman, Daniel J. Wallace, and Karina Torralba

1166

Viktoryia Laurynenka, Leah C. Kottyan, Jennifer A. Kelly, and John B. Harley

961

136. Immunopathology of systemic lupus erythematosus Jane E. Salmon and Vivette D. D’Agati

1177

Contents

xxxiv

137. Animal models of systemic lupus erythematosus

1192

David I. Daikh

138. Autoantibodies in systemic lupus erythematosus

1387

Adam I. Schiffenbauer and Frederick W. Miller

1198

Westley H. Reeves, Haoyang Zhuang, and Shuhong Han

139. Pathogenesis of systemic lupus erythematosus

159. Management of inflammatory muscle disease

1205

160. Metabolic, drug-induced, and other noninflammatory myopathies

1395

Lisa Christopher-Stine and George Stojan

Sarthak Gupta and Mariana J. Kaplan

140. Drug-induced lupus

1211

Bruce Richardson

141. Assessing disease activity and outcome in systemic lupus erythematosus

1220

Michelle Jung, Janet E. Pope, and Vibeke Strand

142. Management of nonrenal and non–central nervous system lupus

1227

José A. Gómez-Puerta, Gerard Espinosa, and Ricard Cervera

143. Management of central nervous system lupus

1235

John G. Hanly, Antonina Omisade, and John D. Fisk

144. Management of renal lupus

1241

Antonis Fanouriakis, George Bertsias, and Dimitrios T. Boumpas

145. Systemic lupus erythematosus in pregnant patients and neonatal lupus

1247 1254

Alan N. Baer and Gwenny M. Verstappen

147. Antiphospholipid syndrome: pathogenesis, diagnosis, and management

The Vasculitides 161. Classification and epidemiology of vasculitis

1405

Richard A. Watts and Eleana Ntatsaki

162. Biology and immunopathogenesis of vasculitis

1418

Elisabeth Brouwer, Maria Sandovici, Coen A. Stegeman, Kornelis S.M. van der Geest, and Bram A. Rutgers

163. Polyarteritis nodosa and Cogan syndrome

1427

Lindsy Forbess

Aardra Rajendran, Tayseer G. Haroun, Prateek Chaudhary, and Megan E.B. Clowse

146. Sjögren syndrome

SECTION 14

164. Antineutrophil cytoplasm antibody–associated vasculitis

1438

Raashid A. Luqmani and Tamir Malley

165. Takayasu arteritis

1449

Carol A. Langford

166. Polymyalgia rheumatica and giant cell arteritis

1455

Carlo Salvarani, Francesco Ciccia, and Nicolò Pipitone

1272

Mary-Carmen Amigo and Munther A. Khamashta

167. Behçet disease

1467

Ahmet Gül

168. Kawasaki disease

1475

Jane C. Burns and Adriana H. Tremoulet

SECTION 12

169. IgA vasculitis (Henoch–Schönlein purpura)

Systemic Sclerosis

170. Cutaneous vasculitis and panniculitis

148. Classification and epidemiology of systemic sclerosis

1283

171. Cryoglobulinemia

1496

Salvatore De Vita, Saviana Gandolfo, and Luca Quartuccio

1289

Christopher P. Denton and Voon H. Ong

150. Etiology and pathogenesis of systemic sclerosis

1486

Robert G. Micheletti, Luis Requena, and Jeffrey P. Callen

Bochra Jandali and Maureen D. Mayes

149. Clinical and serologic features of systemic sclerosis

1480

Seza Özen and Yelda Bilginer

172. Primary angiitis of the central nervous system

1502

Jamal A. Mikdashi

1302

Robert Lafyatis and John Varga

151. Outcomes measures in systemic sclerosis

1319

Dinesh Khanna

152. Management of systemic sclerosis

1326

Tracy M. Frech and Virginia D. Steen

153. Emerging therapies for systemic sclerosis

1338

Oliver Distler and Anna-Maria Hoffmann-Vold

154. Raynaud phenomenon

Other Systemic Illnesses 173. Adult-onset Still disease

1511

Elena Riera Alonso and Alejandro Olivé Marqués

1345

Andrew R. Melville and Jill J.F. Belch

155. Localized scleroderma and scleroderma-like syndromes

SECTION 15 174. Monogenic autoinflammatory diseases

1519

Adriana A. de Jesus, Michael F. McDermott, Daniel L. Kastner, and Raphaela Goldbach-Mansky

1351

Robert W. Simms

175. Sarcoidosis

1547

Jeffrey A. Sparks and Elizabeth V. Arkema

176. Relapsing polychondritis

1557

Susan Y. Ritter

SECTION 13

177. The systemic amyloidoses

Inflammatory Muscle Disease

178. IgG4-related disease

156. Clinical features, classification, and epidemiology of inflammatory muscle disease

1357

1371

Ingrid E. Lundberg

158. Clinical significance of autoantibodies in inflammatory muscle disease Kathleen D. Kolstad, Audra Horomanski, Anna Postolova, Lorinda Chung, and David F. Fiorentino

1572

Hisanori Umehara, Dai Inoue, and Mitsuhiro Kawano

Rohit Aggarwal, Dana P. Ascherman, and Chester V. Oddis

157. Etiology and pathogenesis of inflammatory muscle disease (myositis)

1562

Joel N. Buxbaum

1381

179. Immune-mediated complications of checkpoint inhibitors

1582

Alexa Simon Meara and Cassandra Calabrese

180. The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease Jean W. Liew, Rebecca Grainger, Zachary S. Wallace, Jonathan S. Hausmann, Emily Sirotich, Wendy Costello, Suleman Bhana, Paul Sufka, Pedro M. Machado, Jinoos Yazdany, and Philip C. Robinson

1589

Contents

SECTION 16

204. Osteomalacia, rickets, and renal osteodystrophy

Osteoarthritis

205. Paget disease of bone

181. Epidemiology and classification of osteoarthritis

xxxv 1796

Marciana L. Laster, Isidro B. Salusky, and Eva S. Liu

1803

Laëtitia Michou and Jacques P. Brown

1595

Amanda E. Nelson

182. Local and systemic risk factors for incidence and progression of osteoarthritis

1605

SECTION 19

1614

Other Arthropathies and Miscellaneous Disorders

Leena Sharma

183. Clinical features of osteoarthritis Joel A. Block and Anne-Marie Malfait

184. Animal models of osteoarthritis

1620

Isabell S. von Loga and Tonia L. Vincent

185. Pathogenesis and pathology of osteoarthritis

1628

Jay Ghadiali, Edward F. DiCarlo, and Carla R. Scanzello

186. Genetics and epigenetics of osteoarthritis

1645

Matlock A. Jeffries

187. Imaging of osteoarthritis

1652

Kiran Khokhar, Andrew J. Barr, Claire Y.J. Vandevelde, Andrew J. Grainger, and Philip G. Conaghan

188. Assessment of the patient with osteoarthritis and measurement of outcomes

1667 1673

Virginia Byers Kraus

190. Management of osteoarthritis

1679

Sharon L. Kolasinski and Margreet Kloppenburg

191. Emerging treatments for osteoarthritis

1811

Geoffrey O. Littlejohn

207. Neuropathic arthropathy

1818

Dimitrios G. Kassimos and Paul Creamer

208. Osteonecrosis

1824

Timothy McAlindon and John A. Carrino

209. Rheumatoid manifestations of endocrine and metabolic diseases and treatments

1833

Katherine P. Pryor and Simon M. Helfgott

Lauren K. King, Aileen M. Davis, and Gillian A. Hawker

189. Preclinical and early osteoarthritis

206. Diffuse idiopathic skeletal hyperostosis

1684

Francis Berenbaum

210. Hemophilia-associated arthritis

1840

Matthew J.S. Parker and Jane F. Bleasel

211. Rheumatologic manifestations of hemoglobinopathies

1848

Daniela Garelick, Hannah du Preez, and David Isenberg

212. Hemochromatosis

1853

Pascal Richette and Augustin Latourte

213. Gaucher disease

1857

Philippe Orcel, Luc Pijnenburg, and Rose-Marie Javier

214. Digital clubbing and hypertrophic osteoarthropathy

1863

Manuel Martínez-Lavín and Carlos Pineda

215. Miscellaneous arthropathies

SECTION 17

216. Heritable connective tissue disorders 217. Hypermobility syndrome 1693

Hyon K. Choi

193. Etiology and pathogenesis of gout

1882

B. Paul Wordsworth and M. Kassim Javaid

Crystal-Related Arthropathies 192. Epidemiology and classification of gout

1868

Thomas Bardin and Jonathan Kay

218. Bone tumors 1700

1902

Jacqui Clinch and Valerie J. Rogers

1907.e1

Edward F. McCarthy, Alan L. Schiller, Harriet Branford White, and Andrew Bassim Hassan

Tanya J. Major and Nicola Dalbeth

194. Clinical features of gout

1713

Naomi Schlesinger

195. Management of gout and hyperuricemia

1716 1724

Ann K. Rosenthal

197. Basic calcium phosphate crystal deposition disease

1735

John Stack and Geraldine M. McCarthy

SECTION 18 Metabolic Bone Disease 198. Epidemiology and classification of osteoporosis

1743

Christopher R. Holroyd, Elaine Dennison, and Cyrus Cooper

199. Clinical evaluation and clinical features of osteoporosis

1752

Stuart L. Silverman and Deborah T. Gold

200. Pathophysiology of osteoporosis

1760

Jeffrey M. Kroopnick

201. Biochemical markers of bone turnover in postmenopausal osteoporosis

1765

Richard Eastell and Pawel Szulc

202. Management of osteoporosis

1774

Chad L. Deal and Abby G. Abelson

203. Glucocorticoid-induced osteoporosis Arthur N. Lau, Jonathan Hwang, and Jonathan D. Adachi

1907.e17

Lukas Haupt and Gerhard Witzmann

Robert Terkeltaub

196. Calcium pyrophosphate deposition disease (pseudogout)

Appendix: Classification and Diagnostic Criteria

1788

Index

I1

Section

1

SCIENTIFIC BASIS OF RHEUMATIC DISEASE A.  Anatomy and Physiology The synovium Andrew Filer • Christopher D. Buckley

Key Points ■ The synovium is a thin mesenchymal membrane that lines diarthrodial joints, tendon sheaths, and bursae. It consists of intimal and subintimal zones (also called lining and sublining layers) ■ In health, the intimal layer is 20 to 40 μm thick in cross section and is interspersed with yolk sac–derived macrophages. The subintima can be up to 5 mm in thickness and contains adipose tissue, blood and lymphatic vessels and both resident fibroblasts and infiltrating cells in a collagenous extracellular matrix (ECM) rich in type I collagens. ■ Specialized functions of the synovium include control of synovial fluid production and composition and providing chondrocyte nutrition and repair. ■ The normal synovium produces very low levels of proinflammatory cytokines and some antiinflammatory, proresolving cytokines and eicosanoids. In addition, the low level of expression of receptor activator of nuclear factor-κB ligand (RANKL), with a high level of expression of osteoprotegerin (OPG), results in a low RANKL/OPG ratio. This homeostatic balance is likely to be important in preventing osteoclastogenesis in the normal, noninflamed synovium. ■ Mesenchymal markers expressed by synovial fibroblasts, such as cadherin-11, endosialin (CD248), fibroblast activation protein (FAP), and podoplanin (gp38), may be critical for the development of the synovial lining by facilitating cellular organization, compaction, and matrix development. In pathologic settings, synovial fibroblasts appear to promote inflammation, cartilage invasion, and bone destruction. ■ Synovial fibroblasts carry positional and topographic memory that may provide the molecular basis for site-specific differences in the pattern of joint involvement in different rheumatologic diseases.

DEFINITIONS The study of synovial tissue is of major importance in understanding the pathogenesis of inflammatory arthritis, including rheumatoid arthritis (RA) and seronegative spondyloarthritis (SpA). There is also growing evidence that mesenchymal cells in the synovium play a role in the pathogenesis of osteoarthritis (OA).1 Despite this, our knowledge of the architecture of the synovial membrane, particularly in normal subjects, is surprisingly limited, mainly because of the lack of good tissue and cell-specific markers and the difficulty in obtaining synovial tissue in the early as opposed to later stages of disease. Synovium is the soft tissue lining the spaces of diarthrodial joints, tendon sheaths, and bursae. The term includes both the continuous surface layer of cells (intima) and the underlying tissue (subintima). Whereas the intima is composed of specialized tissue-resident macrophages and fibroblasts, the subintima contains adipose tissue, blood and lymphatic vessels, and a cellular content of both resident fibroblasts and infiltrating cells in a collagenous extracellular matrix (ECM). Between the intimal surfaces is a small amount of fluid, usually rich in hyaluronan (hyaluronic acid). Together, this structure provides a nonadherent surface between tissue elements. Unlike serosal surfaces, which also have nonadherent properties, synovium is derived from ectoderm, does not contain a basal lamina, and lacks any formal epithelial structure. In normal subjects, the intimal layer is 20 to 40 μm thick in cross

1

section, and the areolar subintima can be up to 5 mm in thickness. At many sites, there is no discrete membrane, especially where subintima consists of fat pad or fibrous tissue. Synovium is variable in its structure. Intimal cells may be absent. Superficial bursae contain little or no hyaluronan-rich fluid.2 Ganglia are herniated sacs containing hyaluronan-rich fluid but do not occur at sites of mechanical shearing and do not have a typical intima and so may not be considered synovial tissue. Diseased synovial tissue may lose any recognizable lining structure and may only be definable by its relation to the joint. These variations probably reflect the interplay of several factors in synovial embryogenesis and histogenesis.

EMBRYOLOGY In the early embryonic limb bud a central core, or blastema, appears that ultimately forms the skeleton. Within this core, foci of cartilage appear, each destined to become bone. Blastemal cells around cartilage foci form a perichondrial envelope showing strong CD44 expression. The area where this envelope lies between cartilage elements is known as the interzone, from which the synovium forms. The perichondrium, forming a sleeve around each cartilage element, subsequently invades the cartilage to form bone marrow. Thus, synovial and bone marrow stromal cells come from the same embryonic stock, and this is reflected in their transcriptional and functional abilities.3,4 Shortly before the joint cavity forms, CD55 expression appears on cells along the joint line,5 followed later by vascular cell adhesion molecule-1 (VCAM-1) expression. After cavity formation, the intimal layer also takes on a higher level of expression of CD44 and β1 integrins compared with subintima. Expression of these three markers (CD44, CD55, VCAM-1 [CD106]) confirms the strong similarity between synovial and bone marrow stromal cells. The mechanism of cavity formation is not fully understood; a working hypothesis implicates interactions between interzone cells that express the transcriptional factor gdf5 and that bear CD44 (a hyaluronan receptor) and hyaluronan itself.6–8 Shortly before cavity formation, the cells of the potential joint line show high uridine diphosphoglucose dehydrogenase (UDPGD) activity, which suggests increased hyaluronan synthesis. At the time of cavity formation, high levels of hyaluronan appear along the joint line, saturate CD44, and induce disaggregation; at low concentrations, hyaluronan crosslinks CD44 molecules on adjacent cells, inducing cell aggregation. Cavity formation might be expected to require lysis of matrix fibers. However, in human joints, cavity formation is not associated with high local levels of matrix metalloproteinases (MMPs) at the joint line. In fact, matrix fibers appear to run only parallel to the joint line before cavity formation; apoptotic cells found in the interzone at this time are not localized to the joint line and are unlikely to contribute to cavity formation. It appears, therefore, that development of the joint cavity arises more from differential tissue expansion than through loss of solid elements. This has led to the concept of a continuous influx model of joint development whereby synovial joint development involves a continuous influx of cells into the interzone.8 1

SECTION 1  Scientific Basis of Rheumatic Disease

2

human cell types at a single-cell level and to connect this information with classical cellular descriptions of morphology and location.24

STRUCTURE The microscopic anatomy of synovial tissue was first fully described by Key,9 who divided synovium into three main types on the basis of subintimal structure: fibrous, areolar, and adipose (Fig. 1.1, a to c). He also noted that subintima may be periosteum, perimysium, or even hyaline or fibrocartilage. Areolar synovium is the most specialized form (see Fig. 1.1, a). It is often crimped into folds, which may disappear when stretched. Less often it carries projections or villi. A more or less continuous layer of intimal cells comprising macrophages and fibroblasts lies two or three deep on the tissue surface.10,11 Immediately beneath these cells are capillaries. Further into the tissue, there is a plexus of small arterioles and venules,12,13 often associated with mast cells. Lymphatic vessels can be found in all types of normal synovial tissue, although they are infrequent in the fibrous type of normal synovium.14 In normal synovium, most lymphatic vessels are found in the deep subintima and fibrous layers, but in synovium from patients with inflammatory arthritis, lymphatic vessels are widespread and numerous. Nerve fibers are present, chiefly in association with blood vessels.15 Three different layers of tissue matrix may be distinguished. The intima is associated with a fine fibrillar matrix with few type I collagen fibers.16 Beneath this is a layer relatively rich in type I collagen, which forms a physical membrane. Deeper is a loose layer that allows the membrane to move freely. Beyond the loose layer lies ligament, tendon, or periosteum. Adipose synovium occurs as fat pads and within villi (see Fig. 1.1, b). It has a complete intimal cell layer and a superficial net of capillaries. The intima may lie directly on adipocytes, but there is usually a band of collagen-rich substratum, and the deeper tissue is fat. Villi usually have a central arteriole and venule but can be avascular. The amount of fat in villi varies and probably decreases with age, with an increase in fibrous tissue. Fibrous synovium is more difficult to define, consisting of fibrous tissue such as ligament or tendon on which lies an intermittent layer of cells (see Fig. 1.1, c). Fibrous synovium may be indistinguishable from fibrocartilage, especially in the annular pads found in finger and toe joints.

CELL TYPES FOUND IN THE SYNOVIUM AS REVEALED BY SINGLE-CELL ANALYSIS Recent advances in single-cell analysis have permitted unparalleled observations of the cell types/cell states that make up the synovium. New technologies, including mass cytometry, gene expression profiling by RNA sequencing (RNA-seq), and multiplexed functional assays, have enabled the analysis of cell function with unprecedented detail.17,18 Emerging observations have revealed distinct populations of synovial fibroblasts,19 macrophages,20 and lymphocytes21 that are expanded in diseases such as RA. For example, in RA, tissue inflammation is characterized by expansion of a CD90+CD34− population of sublining fibroblasts.19 In particular, a CD90+CD34− subpopulation of interleukin (IL)-6-producing, MHC class II–expressing fibroblasts18 is markedly expanded in the synovium of patients who have a high degree of synovitis, as measured by immune cell infiltration. Functional studies in mice using adoptive transfer experiments22 have demonstrated the ability of these fibroblasts to drive inflammation, while their lining layer counterparts drive bone and cartilage damage in an inflammation-independent manner. The activation of the sublining fibroblast phenotype surrounding blood vessels in the synovium is driven by Notch3-mediated crosstalk with arterial vessels and pericytes.23 Functionally blocking this Notch3 crosstalk, by genetic knockout or with a therapeutic blocking antibody, prevented the onset of severe disease in a serum transfer model of arthritis.23 These findings in diseased tissue are now being complemented by advances from international consortia such as the Human Cell Atlas, which aim to define all

a

b

INTIMAL CELLS Two types of intimal cells have been defined by electron microscopy, one consistent with a macrophage (type A) and the other with a fibroblast (type B).25 It is now generally accepted—from immunohistochemical studies and other lines of evidence—that intimal macrophages are yolk sac–derived and are distinct from circulating precursors from the bone marrow.26 Intimal fibroblasts, on the other hand, are nonhematopoietic cells and are tissue derived.16,25,27,28 In normal healthy synovium, synovial fibroblasts are the dominant cell population.29 Immunohistochemical and cytochemical methods have superseded electron microscopy as tools for cell identification.30 Intimal macrophages can be distinguished by their nonspecific esterase (NSE) activity and expression of surface markers such as CD68 and CD163. Often they are CD45 positive and express podoplanin/gp38 (Fig. 1.2). Recent studies have shown that lining layer (intimal) macrophages that express CD206 and MerTk are responsible for inducing remission in RA.20 Intimal fibroblasts show prominent expression of VCAM-1, intercellular adhesion molecule 1, CD44, β1 and β3 integrins, and CD55 (complement decay-accelerating factor [DAF]). In most disease states, including OA and RA, intimal cells increase in size and number (Fig. 1.3). This is not due simply to hyperplasia but to a complex change in cell populations, in terms of both origin and function, which may be dominated by macrophage influx and movement from the sublining to the lining layers.29,31

SYNOVIAL MACROPHAGES Macrophages are present in both the intima and subintima. Intimal macrophages carry typical macrophage lineage markers (Fig. 1.4). Macrophages also express the immunoglobulin receptor FcγRIIIa. Strong FcγRIIIa expression is restricted to a subset of macrophages that correspond closely to sites of macrophage activation in rheumatoid disease: synovial, alveolar, serosal, scleral, and salivary gland; lymphoid tissue and bone marrow; and Kupffer cells.32 Subintimal macrophages are FcγRIIIa dull or negative. Macrophages also express Z39Ig, an inducible cell surface receptor linked to the classic complement pathway; Z39Ig expression can occur during macrophage differentiation and induce activation of the transcription factor nuclear factor-κB (NF-κB) and production of matrix-degrading metalloproteinase (MMP)-9.33 Macrophages make up a minority of cells in normal intima (Figs. 1.4 and 1.5). In disease, the proportion of macrophages increases (see Figs. 1.2 and 1.3). Distribution varies, but a common pattern is a superficial layer of macrophages with an intimal phenotype; beneath this a layer of intimal fibroblasts, and further beneath and beyond the limits of the intima is a zone of NSE-weak, strongly CD14+ and FcγRI+ macrophages, associated with venules. The deep, strongly CD14+ cells may be recently recruited macrophages, derived from blood monocytes.34 In addition, there may be a small number of antigen-presenting interdigitating dendritic cells in normal synovial intima; these are more frequent in disease with greater overlap of markers, which confounds interpretation.35,36 Cells with some features of osteoclasts, such as expression of tartrate-­resistant acid phosphatase and the vitronectin receptor, also often appear in inflamed synovium. However, within synovium remote from bone, fully differentiated osteoclasts expressing calcitonin receptor appear to be restricted to pigmented villonodular synovitis and giant cell tumors of tendon sheath.

c

FIG. 1.1  (a) Areolar form of synovium (hematoxylin and eosin [H&E]). (b) Adipose form of synovium (H&E). (c) Fibrous form of synovium (H&E). (Magnification ×200.)

CHAPTER 1  The synovium CD248

Protein disulphide isomerase

CD90

Endo180

FAP

3

CD68

100 µm

Nuclei

FIG. 1.2  Stromal markers differentially expressed in the lining and sublining. FAP, Fibroblast activation protein-α.

FIG. 1.3  Synovium in rheumatoid arthritis (×400) showing a thickened intimal layer containing mainly CD68+ macrophages (red) on the surface and weakly CD55+ fibroblastic cells beneath (blue).

FIG. 1.4  Synovial macrophages. Normal synovium (×200) stained for CD68+ macrophages (red).

SYNOVIAL FIBROBLASTS AND THE STROMA The anatomical term stroma was originally derived from the Greek word describing a platform on which to lie and is used to describe the supporting substance of a tissue. Its principal role is to maintain the microenvironment required by the parenchyma, the important functional elements of each body system. The stroma includes the cells of mesenchymal origin; the nerves, the vessels, and the epithelia that reside in a tissue in steady state; and the extracellular matrices and fluids that these cells produce. Traditionally, the diversity of stromal cells, and in particular fibroblast phenotype and function and

FIG. 1.5  Normal synovium (×200) stained for CD55+ fibroblasts, which are the predominant cell in the normal synovium intimal layer (contrast with Fig. 1.3).

their roles beyond those of space filling and ECM homeostasis, has been underplayed in the synovium.37,38 We now know that these cells vary phenotypically at different anatomical sites and contribute significantly to the identity of individual tissues, providing the so-called “stromal postcode.”39 Furthermore it is known that rather than acting as a bystander to the body’s protective mechanisms and to disease processes, the fibroblast is capable of actively participating and indeed orchestrating inflammation and immunity.40 The fibroblast communicates with resident and infiltrating cells via cytokines and cell contact–dependent mechanisms, playing a central role in the pathogenesis of synovial pathology. The synovial intima contains cells that are adapted to hyaluronan production. In normal synovium, CD68-negative intimal fibroblasts express high enzymatic activity for UDPGD.41 UDPGD converts UDP glucose into UDP glucuronate, one of the two substrates required by hyaluronan synthase for hyaluronan polymer assembly. Unlike the activity of many other enzymes, UDPGD activity in intimal fibroblasts is reduced, rather than enhanced, in diseased tissue. Synovial intimal fibroblasts express CD55 (see Fig. 1.5), a feature distinguishing them from intimal macrophages.42,43 Cells disaggregated from inflamed synovium and grown in tissue culture display fibroblast characteristics and ramifying processes with production of high levels of MMPs.44 Recent studies, supported by functional experiments in mice, suggest that intimal (lining layer) fibroblasts produce MMPs and mediate tissue damage, whereas subintimal (sublining layer) fibroblasts produce cytokines and chemokines and mediate tissue inflammation. Synovial intimal fibroblasts also show prominent expression of several adhesion molecules,11,45,46 including VCAM-1. Expression of VCAM-1 (Fig. 1.6) is particularly unusual, being absent from most other normal fibroblast populations, but CD44 and β1 integrins are present at lower levels. The role of VCAM-1

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SECTION 1  Scientific Basis of Rheumatic Disease

with respect to intimal fibroblasts is puzzling, reflecting its embryologic similarities to bone marrow fibroblasts, which are also VCAM-1 positive. Expression of VCAM-1 may modulate cell trafficking because its ligand, α4β1 integrin, is present on mononuclear leukocytes but not granulocytes. Intimal fibroblasts may allow transmigration of polymorphs but not mononuclear cells into synovial fluid, potentially trapping inflammatory cell infiltrates within the synovial membrane in disease states such as RA. The presence of both clusterin (a glycoprotein involved in recycling and apoptosis) and (gp38) podoplanin (a membrane glycoprotein with diverse functions) has been reported in normal synovial fibroblasts; interestingly, podoplanin (which in the setting of neoplasia is associated with poor prognosis and metastatic disease) has been shown to be highly expressed in RA synovial fibroblasts with their attendant migratory and invasive potential47,48 (Fig. 1.7). Under inflammatory conditions, fibroblasts can act as organ-specific sentinel cells, where they play a role in the switch from acute resolving to chronic persisting inflammation. In addition to contributing to the recruitment and emigration of inflammatory cells into and out of the joint, they modulate the survival and retention of infiltrating leukocytes. Interestingly, new data raise the possibility of epigenetically programmed aggressive fibroblasts “spreading” arthritis from inflamed to uninflamed joints in the early stages of arthritis but at the same time offer the possibility of specifically targeting stromal subpopulations of choice.49 The expression of two other surface molecules by synovial fibroblasts is noteworthy. Complement receptor 2 (CR2, CD21) is not expressed by normal intimal fibroblasts but can be induced on synovial fibroblasts in culture, in contrast to other fibroblast populations.50 DAF, VCAM-1, and CR2 are all involved in B-lymphocyte survival, as is a bone marrow stromal cell marker, BST-1, reported to be expressed on fibroblasts in rheumatoid, but not normal, synovial intima.51 Other molecules associated with bone marrow stromal cells such as the chemokine stromal cell–derived factor-1 (CXCL12) and bone morphogenetic proteins and their receptors,52–54 are expressed by synovial fibroblasts under various conditions. Moreover, lubricin, otherwise

known as superficial zone protein, a glycoprotein found in synovium and the superficial zone of articular cartilage,55 derives from the same gene as megakaryocyte-stimulating factor. A defect of this gene leads to CACP (camptodactyly-arthropathy-coxa vara-pericarditis) syndrome. As indicated earlier, these patterns of gene expression may reflect a common embryologic origin for synovial and bone marrow stromal cells. Self-renewing mesenchymal stem cells that compare favorably with bone marrow–derived mesenchymal stem cells in terms of their ability to differentiate into bone, cartilage, and adipose tissue have been isolated from the normal synovium; it is unclear which component of the synovial membrane is home to these cells,56,57 but expression of the mesenchymal stromal cell marker CD248 in the sublining layer (see Fig. 1.7) suggests that they may derive from this anatomical compartment.58

INTIMAL MATRIX Intimal matrix has an amorphous or fine fibrillar ultrastructure. It is poor in type I collagen but contains minor collagens III, IV, V, and VI,59,60 as well as laminin, fibronectin, and chondroitin-6-sulfate–rich proteoglycan, which, with collagen IV, are components of basement membrane; however, the basement membrane is conspicuous by its absence beneath the intimal layer. The looser structure of intimal matrix may be explained by the absence of entactin, which links other components in basement membrane together. Intimal microfibrils are of two types: fibrillin-1 microfibrils form a basketwork around cells, and collagen VI microfibrils form a uniform mesh. Intimal matrix contains large amounts of hyaluronan (Fig. 1.8), which lessens in concentration by 20 to 50 μm deep. This may indicate diffusion from the surface toward clearing lymphatics.

FIG. 1.8 Normal synovium stained for hyaluronan using a histochemical probe FIG. 1.6  Normal synovium (×200) stained for vascular cell adhesion molecule 1.

derived from proteoglycan core protein hyaluronan-binding region. Staining is most intense surrounding the lining cells and decreases further into the tissue. (Magnification ×200.)

Normal synovium

Rheumatoid synovium

b

a

CD45

CD31

GP38

CD248

FIG. 1.7  Stromal markers differentially expressed in rheumatoid arthritis. (a) Normal synovium. (b) Rheumatoid synovium.

CHAPTER 1  The synovium

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VASCULAR NETWORK A rich microvascular network lies beneath the synovial surface in the subintima.12,13 Capillaries (prominent in children and decreasing with age) occur just below the intima (Fig. 1.9). Some capillaries are fenestrated, and fenestrae tend to face the tissue surface61; 50 to 100 μm beneath the surface, small venules are prominent. About 200 μm beneath the surface, larger venules, together with arterioles and lymphatics (Fig. 1.10),14 form an anastomosing quadrilateral array. Vessels with lymphatic staining characteristics are prominent in RA synovium. It has been proposed that failure of lymphatic drainage of synovial fluid is a cause of villous proliferation in RA synovial tissue. If this is correct, it is likely to be due to overloading of existing lymphatic channels with hyaluronan-rich extracellular fluid and leukocytes rather than a lack of lymphatic channels.14 Apart from the fenestration of superficial capillary endothelial cells, there is little evidence of specialization in synovial endothelium. Endothelial cells enlarge in inflamed tissue, and microvascular proliferation can occur, but these events are common to inflammation at many sites. Tissue-specific adhesion molecules, or addressins, have been sought in the synovium, but nothing conclusive has been found, unlike what is seen in the skin and gut, both epithelial organs.

CELL ORIGINS AND RECRUITMENT Evidence to date indicates that both intimal and subintimal macrophages derive from bone marrow via circulating monocytes, many of which probably arrive through subintimal venules and migrate to the intima. Whether tissue resident macrophages also contribute remains unclear, but recent studies suggest that nonclassical monocytes or macrophages can contribute to the persistence or resolution of arthritis.34 Intimal fibroblasts are thought to arise by division within synovium. They might be a discrete self-replicating population, distinct from subintimal fibroblasts, but several pieces of evidence argue against this. Rates of cell division within the intima are very low, even in disease. After arthroplasty or synovectomy, intimal cells—likely replaced from the subintima rather than arising from intimal rests—reappear and express CD55, UDPGD, and VCAM-1. Disaggregated and cultured synovial fibroblasts lose VCAM-1 and CD55 expression, but the majority, apparently including cells of subintimal origin, readily express these markers after cytokine stimulation, in contrast

FIG. 1.11  Normal synovium (×200) stained with an antibody to detect the interleukin-1 receptor antagonist.

to fibroblasts of dermal or subcutaneous origin. These findings suggest that synovial fibroblasts, in both the intima and subintima, belong to a specialized population with a propensity to express VCAM-1 and CD55 and are more similar to bone marrow than skin fibroblasts.3,4 Two studies10,11 have demonstrated the range of cells that can be found in the synovial subintima. CD3+ T cells, including CD4+, CD8+, and memory T cells, can be found within the normal synovial tissue; although they are likely to be simply trafficking through the normal synovium, their role, if any, in the homeostasis of synovial tissue is unknown. It is also possible to detect B cells, plasma cells, and granzyme B+ cells in normal synovium, although they are present in small numbers. Although production of inflammatory cytokines, including IL-1, IL-6, and tumor necrosis factor (TNF),11 can be detected in normal synovial tissue, expression levels are far lower than those seen in inflamed synovial tissue such as in RA. The amount of antiinflammatory cytokine production, at least in the case of IL-1 receptor antagonist (the naturally occurring inhibitor of IL-1), IL-10, and other proresolving factors, is far greater than the amount of inflammatory cytokine seen (Fig. 1.11).62 This would achieve the desired result of suppressing an inflammatory process in the normal synovial tissue. Similarly, the amount of receptor activator of NF-κB ligand (RANKL), an essential factor for the development of osteoclasts, seen in normal synovial tissue is low.11 The low level of expression of RANKL, with high level of expression of osteoprotegerin (OPG), results in a low RANKL/ OPG ratio. The net result of this is to suppress the formation of osteoclasts within the normal synovium and preserve homeostasis within the normal joint.

FUNCTION

FIG. 1.9  Normal synovium (×200) stained with factor VIII to demonstrate the vascular network.

Elucidating all of the functions of synovial tissue has proven to be remarkably difficult.63 Similar to other connective soft tissue, synovium provides a deformable packing that allows movement of adjacent, relatively nondeformable tissues. The difference between synovium and other soft connective tissue is that it allows most of the movement to occur between, rather than within, tissues. Areolar synovium may also have specialized viscoelastic properties for coping with the stretching, rolling, and folding it undergoes during joint movement. Functions of the tissue relating to the synovial cavity include the following: ■ Maintenance of an intact nonadherent tissue surface ■ Lubrication of cartilage ■ Control of synovial fluid volume and composition ■ Nutrition of chondrocytes within joints

MAINTENANCE OF THE TISSUE SURFACE

FIG. 1.10  Normal synovium (×200) stained with lymphatic vessel endothelial hyaluronan receptor-1 antibody to demonstrate the lymphatic network.

Synovial surfaces must be nonadherent to allow continued articular movement. Animal models suggest that production of hyaluronan by intimal fibroblasts may be important in inhibiting adhesion.64 Plasminogen activator and decay-accelerating factor (DAF) from intimal fibroblasts may also inhibit fibrin formation and scarring. To retain synovial fluid, the intimal matrix consists of a fibrous mat of a particular porosity that allows free exchange of crystalloids and proteins but inhibits rapid transit of the viscous hyaluronan solution that is an important component of the fluid. The vasculature is likely to be important in both intimal cell nutrition and recruitment of new cells. New macrophages are derived from blood monocytes that are thought to enter the tissue through venules, and perivascular fibroblasts may provide the main pool of intimal fibroblast precursors.

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SECTION 1  Scientific Basis of Rheumatic Disease

LUBRICATION The ability of synovial fluid to lubricate cartilage surfaces depends on the presence of glycoproteins, especially a glycoprotein known as both lubricin and superficial zone protein because of its localization to the surface of synovium and cartilage.55 Whatever the precise forces acting on fluid volume, the presence of hyaluronan is likely to be the main factor responsible for retaining a constant volume of fluid during exercise.65 This fluid is probably important as a cushion for synovial tissue and as a reservoir of lubricant for cartilage. It is likely that mechanical stimulation of intimal fibroblasts dictates the rate of synthesis and exportation of hyaluronan into the synovial fluid compartment. Thus, when synovial fluid volume is high, reduced mechanical stresses on intimal fibroblasts result in a reduced rate of hyaluronan production and vice versa. Two distinct mechanisms create joint effusions. When synovium is mechanically irritated by worn bone and cartilage, the composition of the fluid remains reasonably normal. Excessive production of hyaluronan by intimal fibroblasts stimulated by frictional forces retains plasma dialysate in the synovial cavity; in synovitis, the effusion is an accumulation of exudate similar to a pleural effusion (i.e., an overspill from the inflammatory edema in synovial tissue created by increased vascular permeability). Recent theories about possible low-grade inflammatory and immune reactions contributing to the pathogenesis of osteoarthritis suggest that these two mechanisms of effusion development may not be as distinct as originally thought.66 Additionally, recent proteomic evidence suggests that the increased vascular permeability, as seen in inflammation, may be related not only to an increase in interendothelial gaps but also to glycocalyceal damage and aquaporin upregulation.67

CHONDROCYTE HEALTH AND NUTRITION The synovium provides the major structure that aids chondrocyte nutrition. In normal joints, a surprisingly large proportion of hyaline cartilage lies within 50 μm of a synovial surface. In any one position, only a small proportion of cartilage is opposed to the other articular surface, and synovium packs most of the space between less congruent areas. In immature joints, the incomplete subchondral plate may contribute to nutrition, but in adult joints, this route is unlikely to be significant. Nutrition of areas of cartilage that do not come into close contact with synovium (concave articular surfaces in particular) must take an indirect route. Although a small proportion of nutrition may be imparted by smearing of a thin film of fluid over these surfaces during movement, indirect routes through cartilage matrix and the apposed articular cartilage may be more important.7 Blood vessels in synovium provide the most direct route for cartilage nutrition, but there is no evidence that they are structurally adapted to this function. The fenestrae seen in superficial capillaries are present in tendon sheath synovium at sites where there is no cartilage (or tendon) dependent on their supply of small molecules. Diarthrodial joints (in both cartilage and synovium) have been found to express high levels of transforming growth factor-β (TGF-β), a latent complex that requires activation to induce a biologic response. In vivo experiments suggest that shearing of synovial fluid from physiologic joint motion may play an important role in TGF-β activation, which may be essential to maintain the biochemical content and structural integrity of healthy cartilage.68,69

immunopathology in disease states. Although the architecture of the normal synovium is not as homogeneous as previously portrayed, consistencies across the broad spectrum of normal synovial tissues can be contrasted with those seen in chronically inflamed synovial tissue. The marked increase in synovial lining layer thickness with a reversal of the normal ratio of type A to type B intimal cells, which favors type B cells in normal synovium and type A cells in RA, is an example of this. Numerous other examples can be given, including the changes in subintimal cell content and cytokine and chemokine production,70 vascular and lymphatic changes, and production of MMPs and stimulators of osteoclast formation. Cadherin-11 expression on synovial fibroblasts has been found to promote invasive behavior of fibroblasts and is increased by IL-17 and TNF-α, cytokines relevant to RA pathophysiology.71–73 Inhibition of cadherin-11 interactions interfered with both synovial inflammation and cartilage invasion by pannus without having any effect on bone erosion (which is predominantly osteoclast dependent) or immunosuppression. Inflammation could be reduced substantially by antibodies to cadherin-11 or a cadherin-Fc fusion protein.

SUMMARY Despite the biologic importance of understanding how the synovium responds to damage and drives inflammation, remarkably little is known about how stromal cells (as opposed to leukocytes) change during synovial development and inflammation. Difficulties in accessing synovial tissue from normal subjects and patients with early disease and the lack of good cell markers have proved to be obstacles to such work. However, synovial stromal cells are a functionally heterogeneous group, with some displaying proinflammatory and destructive properties but others being immune regulatory and helping facilitate tissue repair. This has led to a dilemma: Which stromal cells should be targeted, and which should be retained? A clear understanding of the biology and significance of synovial tissue biology is therefore essential to provide a coherent rationale for targeting stromal cells in the future treatment of patients with arthritis. As advances in our understanding of the synovial cells responsible for the different forms of arthritis are achieved, a more targeted form of treatment for synovial diseases is likely to emerge.

ACKNOWLEDGMENT The authors thank Drs. Malcolm Smith and Mihir Wechalekar, whose chapter in a previous edition informed much of the present discussion.

REFERENCES 1. 2. 3.

4.

5. 6.

SYNOVIUM AS A TARGET FOR IMMUNEMEDIATED DISEASE Synovial joints are involved in several immunologic and inflammatory disorders, including RA, systemic lupus erythematosus, and seronegative SpA. Perhaps the most important reason for studying the biology of the synovium is to obtain insight into which immunopathologic processes are likely to be suitable therapeutic targets in inflammatory arthritides and in particular whether the synovial fibroblast is a therapeutic target.3,4 Autoimmune responses to synovial antigens might theoretically occur, but despite considerable effort, evidence for a specific synovial antigen is lacking. Moreover, associated targeting of other tissues such as pericardium or uveal tract requires an explanation. Few, if any, synovium-specific antigens are known, and when rheumatic disorders are associated with autoantibodies, the antigens involved are ubiquitous. Understanding the microarchitecture of the normal synovium, including the wide range in microscopic appearances, cellular infiltrates, and production of cytokines, enzymes, and other biologically relevant proteins, assists in understanding the relevant changes in synovial tissue architecture and

7.

8. 9. 10. 11.

12. 13. 14. 5. 1 16.

Roelofs AJ, Kania K, Rafipay AJ, et al. Identification of the skeletal progenitor cells forming osteophytes in osteoarthritis. Ann Rheum Dis. 2020;79(12):1625–1634. Canoso JJ, Stack MT, Brandt KD. Hyaluronic acid content of deep and subcutaneous bursae of man. Ann Rheum Dis. 1983;42:171–175. Filer A, Antczak P, Parsonage GN, et al. Stromal transcriptional profiles reveal hierarchies of anatomical site, serum response and disease and identify disease specific pathways. PLoS ONE. 2015;10(3):e0120917. Filer A, Parsonage G, Smith E, et al. Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fibroblasts: site-specific versus activation-dependent survival of T cells and neutrophils. Arthritis Rheum. 2006;54(7):2096–2108. Edwards JC, Wilkinson LS. Distribution in human tissues of the synovial lining–associated epitope recognised by monoclonal antibody 67. J Anat. 1996;188:119–127. Craig FM, Bayliss MT, Bentley G, et al. A role for hyaluronan in joint development. J Anat. 1990;171:17–23. Edwards JC, Wilkinson LS, Jones HM, et al. The formation of human synovial joint cavities: a possible role for hyaluronan and CD44 in altered interzone cohesion. J Anat. 1994;185:355–367. Shwartz Y, Viukov S, Krief S, Zelzer E. Joint development involves a continuous influx of gdf5-positive cells. Cell Reports. 2016;15(12):2577–2587. Key JA. The synovial membrane of joints and bursae. In: Cowdry EV, ed. Special cytology. New York: PB Hoeber; 1932. Singh JA, Arayssi T, Duray P, et al. Immunohistochemistry of normal human knee synovium: a quantitative study. Ann Rheum Dis. 2004;63:785–790. Smith MD, Barg E, Weedon H, et al. Microarchitecture and protective mechanisms in synovial tissue from clinically and arthroscopically normal knee joints. Ann Rheum Dis. 2003;62:303–307. Davies DV. The structure and functions of the synovial membrane. Br Med J. 1950;1:92–95. Wilkinson LS, Edwards JC. Microvascular distribution in normal human synovium. J Anat. 1989;167:129–136. Xu H, Edwards J, Banerji S, et al. Distribution of lymphatic vessels in normal and arthritic human synovial tissues. Ann Rheum Dis. 2003;62:1227–1229. Mapp PI. Innervation of the synovium. Ann Rheum Dis. 1995;54:398–403. Ghadially FN. Fine structure of joints. In: Sokoloff L, ed. The Joints and Synovial Fluid. New York: Academic Press; 1978:105–176.

CHAPTER 1  The synovium 17. 18.

19. 20.

21. 22. 23. 24. 25. 26. 27. 28.

29. 30.

31. 32.

33. 34. 35. 36.

37. 38. 39. 40. 41. 42.

43. 44. 5. 4 46.

Ermann J, Rao DA, Teslovich NC, et al. Immune cell profiling to guide therapeutic decisions in rheumatic diseases. Nat Rev Rheumatol. 2015;11(9):541–551. Zhang F, Wei K, Slowikowski K, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20(7):928–942. Mizoguchi F, Slowikowski K, Wei K, et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun. 2018;9(1):789. Alivernini S, MacDonald L, Elmesmari A, et al. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med. 2020;26(8):1295–1306. Rao DA, Gurish MF, Marshall JL, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017;542(7639):110–114. Croft AP, Campos J, Jansen K, et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature. 2019;570(7760):246–251. Wei K, Korsunsky I, Marshall JL, et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature. 2020;582(7811):259–264. https://www.humancellatlas.org/. Barland P, Novikoff AB, Hamerman D. Electron microscopy of the human synovial membrane. J Cell Biol. 1962;14:207–220. Schramek D, Leibbrandt A, Sigl V, et al., Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature, 2010;468(7320):98–102. Edwards JC. The nature and origins of synovium: experimental approaches to the study of synoviocyte differentiation. J Anat. 1994;184:493–501. Edwards JC, Willoughby DA. Demonstration of bone marrow derived cells in synovial lining by means of giant intracellular granules as genetic markers. Ann Rheum Dis. 1982;41:177–182. Henderson B, Revell PA, Edwards JC. Synovial lining cell hyperplasia in rheumatoid arthritis: dogma and fact. Ann Rheum Dis. 1988;47:348–349. Edwards JCW, Wilkinson LS. Immunohistochemistry of synovium. In: Henderson B, Edwards JCW, Pettifer ER, eds. Mechanisms and Models in Rheumatoid Arthritis. New York: Academic Press; 1995:133–150. Buckley CD. Macrophages form a protective cellular barrier in joints. Nature. 2019;572(7771):590–592. Bhatia A, Blades S, Cambridge G, et al. Differential distribution of Fc gamma RIIIa in normal human tissues and co-localization with DAF and fibrillin-1: implications for immunological microenvironments. Immunology. 1998;94:56–63. Lee MY, Kim WJ, Kang YJ, et al. Z39Ig is expressed on macrophages and may mediate inflammatory reactions in arthritis and atherosclerosis. J Leukoc Biol. 2006;80:922–928. Misharin AV, Cuda CM, Saber R, et al. Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice. Cell Rep. 2014;9(2):591–604. Poulter LW, Janossy G. The involvement of dendritic cells in chronic inflammatory disease. Scand J Immunol. 1985;21:401–407. Wilkinson LS, Worrall JG, Sinclair HD, et al. Immunohistological reassessment of accessory cell populations in normal and diseased human synovium. Br J Rheumatol. 1990;29:259–263. Patel R, Filer A, Barone F, et al. Stroma: fertile soil for inflammation. Best Pract Res Clin Rheumatol. 2014;28(4):565–576. Naylor AJ, Filer A, Buckley CD. The role of stromal cells in the persistence of cchronic inflammation. Clin Exp Immunol. 2013;171(1):30–35. Buckley CD, Barone F, Nayar S, et al. Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annu Rev Immunol. 2015;33:715–745. McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis—shaping the immunological landscape. Nat Rev Rheumatol. 2016;12(1):63–68. Wilkinson LS, Pitsillides AA, Worrall JG, et al. Light microscopic characterization of the fibroblast-like synovial intimal cell (synoviocyte). Arthritis Rheum. 1992;35:1179–1184. Medof ME, Walter EI, Rutgers JL, et al. Identification of the complement decay-accelerating factor (DAF) on epithelium and glandular cells and in body fluids. J Exp Med. 1987;165:848–864. Stevens CR, Mapp PI, Revell PA. A monoclonal antibody (Mab 67) marks type B synoviocytes. Rheumatol Int. 1990;10:103–106. Krane SM, Goldring SR, Dayer JM. Interactions among lymphocytes, monocytes and other synovial cells in the rheumatoid synovium. Lymphokines. 1982;7:75–87. Edwards JC. Synovial intimal fibroblasts. Ann Rheum Dis. 1995;54:395–397. Connolly M, Veale DJ, Fearon U. Acute serum amyloid A regulates cytoskeletal rearrangement, cell matrix interactions and promotes cell migration in rheumatoid arthritis. Ann Rheum Dis. 2011;70:1296–1303.

7

47. Boland JM, Folpe AL, Hornick JL, et al. Clusterin is expressed in normal synoviocytes and in tenosynovial giant cell tumors of localized and diffuse types: diagnostic and histogenetic implications. Am J Surg Pathol. 2009;33:1225–1229. 48. Ekwall AK, Eisler T, Anderberg C, et al. The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplastic synovial lining layer in rheumatoid arthritis. Arthritis Res Ther. 2011;13:R40. 49. Lefèvre S, Knedla A, Tennie C, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med. 2009;15(12):1414–1420. 50. Leigh RD, Cambridge G, Edwards JCW. Expression of B-cell survival cofactors on synovial fibroblasts. Br J Rheumatol. 1996;1:110. 51. Lee BO, Ishihara K, Denno K, et al. Elevated levels of the soluble form of bone marrow stromal cell antigen 1 in the sera of patients with severe rheumatoid arthritis. Arthritis Rheum. 1996;39:629–637. 52. Fowler Jr MJ, Neff MS, Borghaei RC, et al. Induction of bone morphogenetic protein-2 by interleukin-1 in human fibroblasts. Biochem Biophys Res Commun. 1998;248:450–453. 53. Marinova-Mutafchieva L, Taylor P, Funa K, et al. Mesenchymal cells expressing bone morphogenetic protein receptors are present in the rheumatoid arthritis joint. Arthritis Rheum. 2000;43:2046–2055. 54. Seki T, Selby J, Haupl T, et al. Use of differential subtraction method to identify genes that characterize the phenotype of cultured rheumatoid arthritis synoviocytes. Arthritis Rheum. 1998;41:1356–1364. 55. Jay GD, Britt DE, Cha CJ. Lubricin is a product of megakaryocyte stimulating factor gene expression by human synovial fibroblasts. J Rheumatol. 2000;27:594–600. 56. Arufe MC, De la Fuente A, Fuentes I, et al. Chondrogenic potential of subpopulations of cells expressing mesenchymal stem cell markers derived from human synovial membranes. J Cell Biochem. 2010;111:834–845. 57. Sakaguchi Y, Sekiya I, Yagishita K, et al. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum. 2005;52:2521–2529. 58. Naylor AJ, Azzam E, Smith S, et al. The mesenchymal stem cell marker CD248 (endosialin) is a negative regulator of bone formation in mice. Arthritis Rheum. 2012;64(10):3334–3343. 59. Ashhurst DE, Bland YS, Levick JR. An immunohistochemical study of the collagens of rabbit synovial interstitium. J Rheumatol. 1991;18:1669–1672. 60. Revell PA, al-Saffar N, Fish S, et al. Extracellular matrix of the synovial intimal cell layer. Ann Rheum Dis. 1995;54:404–407. 61. Suter ER, Majno G. Ultrastructure of the joint capsule in the rat: presence of two kinds of capillaries. Nature. 1964;202:920–921. 62. Haworth O, Buckley CD. Pathways involved in the resolution of inflammatory joint disease. Semin Immunol. 2015;27(3):194–199. 63. Edwards JCW. Functions of synovial lining. In: Henderson B, Edwards JCW, eds. The Synovial Lining in Health and Disease. London: Chapman & Hall; 1987:41–74. 64. Yagi M, Mitsui Y, Gotoh M, et al. Role of the hyaluronan-producing tenosynovium in preventing adhesion formation during healing of flexor tendon injuries. Hand Surg. 2012;17:13–17. 65. Levick JR, McDonald JN. Fluid movement across synovium in healthy joints: role of synovial fluid macromolecules. Ann Rheum Dis. 1995;54:417–423. 66. Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis: an inflammatory dis ease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. 2001;44:1237–1247. 67. Shahrara S, Volin MV, Connors MA, et al. Differential expression of the angiogenic Tie receptor family in arthritic and normal synovial tissue. Arthritis Res. 2002;4:201–208. 68. Albro MB, Cigan AD, Nims RJ, et al. Shearing of synovial fluid activates latent TGF-beta. Osteoarthritis Cartilage. 2012;20:1374–1382. 69. Fava R, Olsen N, Keski-Oja J, et al. Active and latent forms of transforming growth factor beta activity in synovial effusions. J Exp Med. 1989;169:291–296. 70. Parsonage G, Falciani F, Burman A, et al. Global gene expression profiles in fibroblasts from synovial, skin and lymphoid tissue reveals distinct cytokine and chemokine expression patterns. Thromb Haemost. 2003;90(4):688–697. 71. Kiener HP, Niederreiter B, Lee DM, et al. Cadherin 11 promotes invasive behavior of fibroblast-like synoviocytes. Arthritis Rheum. 2009;60:1305–1310. 72. Park YE, Woo YJ, Park SH, et al. IL-17 increases cadherin-11 expression in a model of autoimmune experimental arthritis and in rheumatoid arthritis. Immunol Lett. 2011;140:97–103. 73. Vandooren B, Cantaert T, ter Borg M, et al. Tumor necrosis factor alpha drives cadherin 11 expression in rheumatoid inflammation. Arthritis Rheum. 2008;58:3051–3062.

2

The articular cartilage Linda J. Sandell • Brian Johnstone

Key Points n The composition of cartilage extracellular matrix (ECM) close to cells in the territorial matrix is different than that in the more distant interterritorial matrix. Composition also varies between different types of cartilage and from surface to deep articular cartilage. n The ECM of cartilage contains a specific proteoglycan—aggrecan—that provides a very high fixed charge density and therefore an osmotic environment, with water retention being essential for tissue resilience. Aggrecan is also part of a network in which globular domains interact with other molecules. n Fibrillar networks with collagen as the major constituent provide the tensile properties essential for load distribution and dissipation. The fibers contain other matrix proteins (e.g., those bound at their surface) that mediate interactions with other tissue structures, including neighboring fibers, which enhances their mechanical qualities. n The cells in cartilage maintain function of the ECM via controlled turnover in response to minor damage caused by fatigue and altered load by removing malfunctioning matrix constituents by breakdown and producing new ones to achieve repair. n The cell obtains feedback on the quality of the ECM via a number of cell surface receptors such as integrins, discoidin domain receptor 2 (DDR-2), hyaluronan receptors, and proteoglycans with specificity for different matrix molecules. n Cartilage ECM contains growth factors and proenzymes that are sequestered by binding to matrix macromolecules, and these substances can be released upon degradation of the carrier molecules. n As a result of degradation of cartilage matrix, the fragments formed are released into surrounding fluids and can be used as indicators of the ongoing process, the so-called molecular marker technology. n Fragments of ECM components can activate innate immune responses such as complement.

Articular cartilage has two major roles in the function of joints: it takes up and distributes load such that a given point of the underlying bone can handle very high strain, and it provides low-friction movement. One key feature of joint diseases is deterioration of joint function, which results from progressive damage to articular cartilage by degradation of the structural components important for properties of the tissue. Progressive joint destruction leads to loss of the cartilage that is accompanied by alterations in underlying bone in the common disease of osteoarthritis (OA) (Fig. 2.1). Mechanisms triggering this tissue destruction are not known in detail, but it is clear that excessive load may induce a remodeling process that fails to restore normal cartilage. Stimulation of chondrocytes by cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) induces the cells to degrade their surrounding matrix and can, over an extended period, result in total dissolution of cartilage in vitro. The identity of the individual enzyme or enzymes responsible for specific fragmentation of a particular matrix protein is not known, but in some cases, candidates have been established. A repair response often accompanies the ongoing tissue destruction, but if this response is not sufficient, tissue failure ensues. A prerequisite for understanding the mechanisms of tissue destruction and failed repair is to know the functions of molecules in the extracellular matrix (ECM) and how they are assembled into larger networks. It is equally important to understand the mechanisms involved in their degradation. One important and basic clinical observation in joint diseases such as rheumatoid arthritis (RA) and OA is that after joint replacement the inflammation recedes and the symptoms that have been plaguing patients are ameliorated or disappear in the majority of cases. This brings up the question of whether the components released from cartilage actually stimulate the inflammatory reaction. The main structural matrix molecules in cartilage are aggrecan, a large proteoglycan, and several members of the collagen family, chiefly type II collagen. Aggrecan has a primary role in the function of cartilage to take up load and resist deformation. The collagen network provides tensile properties, and the specialized pericellular type VI collagen network may have a role in protecting the cell and guiding matrix assembly. A set of molecules close to the cells has specific functions in binding to particular cell surface receptors and thereby provide signaling of conditions in the matrix. 8

This chapter focuses on describing the individual cartilage macro­ molecules and, where possible, their functional properties and their implications for tissue assembly. In some instances, candidate enzymes have been implicated in having roles in the degradation of specific macromolecules and will be discussed.

OVERALL TISSUE ORGANIZATION The part of the matrix closer to cells, the territorial matrix, has a somewhat different composition and structure than the matrix at some distance, the interterritorial matrix (Fig. 2.2) (for references, see Heinegård and colleagues1). Examples of components found in both compartments are collagen type II fibers and aggrecan; in contrast, collagen type VI is found particularly in the territorial matrix, and cartilage oligomeric matrix protein (COMP) and cartilage intermediate layer protein (CILP) are primarily found in the interterritorial matrix of normal cartilage. There is also a difference in the composition of cartilage from the superficial to deep layers. In the superficial layer, collagen fibers are thinner and arranged in parallel with the surface of the tissue; in the deeper layer, the fibers are thicker and arranged perpendicular to the surface, with a transition zone in between them (Fig. e2.1; also see Fig. 2.1). The superficial part of cartilage is enriched with a number of noncollagenous molecules, notably lubricin and asporin. Other molecules are much less abundant in this part of the tissue, as exemplified by aggrecan, which is particularly enriched toward the deeper parts of the tissue.1A Certain molecules such as CILP are found primarily in the middle portions of articular cartilage. Although a number of cartilage components have been described in recent years, our understanding of what specific requirements and functions are met by molecules with such a restricted localization in tissue is still very limited. Different types of cartilage have markedly different compositions. Articular cartilage appears very similar between sites, but multivariate analyses of proteomics data have demonstrated differences between knee and hip articular cartilage.2

AGGRECAN The major structure of aggrecan, illustrated in Fig. 2.3,1 consists of a core protein to which approximately 100 chondroitin sulfate glycosaminoglycan chains are attached, each built from a disaccharide unit that is repeated some 50 times but with extensive variability. Each disaccharide contains uronic acid with a negatively charged carboxyl group and an N-acetylgalactosamine with a sulfate in either the 4 or the 6 position. Each chain will therefore contribute around 100 negatively charged groups. The glycosaminoglycans are linked to a serine residue of the protein core via their reducing terminal end. The chains are clustered, and clustering differs between the two regions, referred to as CS domain 1 and CS domain 2 (see Fig. 2.3). In addition, the aggrecan molecule has some 30 chains of another glycosaminoglycan, keratan sulfate, attached to its core protein. Keratan sulfate has a disaccharide building block of galactose and an N-acetylglucosamine with a sulfate in the 6 position. These chains are shorter and particularly enriched closer to the N-terminal end of the protein core, in the so-called keratan sulfate–rich region. The proteoglycan core protein contains globular domains flanking the three domains carrying glycosaminoglycan chains. The one most N-terminal, the hyaluronan-binding domain (G1 globe), contributes specific high-affinity binding of the aggrecan molecule to hyaluronan (see below). After a short interglobular domain there is a second globular domain (G2) that has structural similarities to the G1 globe but does not bind hyaluronan and has no known function. In the very C-terminal end of the aggrecan molecule, there is a G3 globe with a lectin homology domain; it contributes by binding to other proteins (e.g., fibulins and tenascins), which themselves can form molecular complexes involving several such molecules (see Fig. 2.2). Mutations that abolish binding of the G3 domain to the fibulins and tenascins have been shown to lead to familial osteochondritis dissecans.3

CHAPTER 2  The articular cartilage

8.e1

SCHEMATIC ILLUSTRATION OF STEPS IN COLLAGEN FIBER ASSEMBLY WITH THE PUTATIVE PENTAMERIC MICROFIBRIL INDICATED

Collagen fibrillogenesis is a multistep process. Fibers formed vary in size

C-terminal propeptide

N-terminal propeptide Procollagen molecule

Percentage

Collagen molecule 30 25 20 15 10 5 0

Superficial

Percentage

18 38 58

30 25 20 15 10 5 0

Gap

78 98 118 138 158 178

Intermediate

18 38 58

Percentage

Overlap

Fibril

78 98 118 138 158 178

Articular cartilage Superficial

30 25 20 15 10 5 0

Deep Intermediate

18 38 58

78 98 118 138 158 178

Deep

Nanometers Pericellular

Territorial

Interterritorial

FIG. E2.1  The organization of collagen fibers at different distances from the surface of articular cartilage is shown, as well as differences in fibril diameters between the pericellular, territorial, and interterritorial compartments.

CHAPTER 2  The articular cartilage

9

NORMAL AND OA JOINTS SHOWING ORGANIZATION OF THE ARTICULAR CARTILAGE IN DIFFERENT COMPARTMENTS NORMAL JOINT

OSTEOARTHRITIC JOINT

Cartilage depth (mm)

Normal cartilage 0

Col6 TSP-1

Superficial Intermediate

Territorial Pericellular

Deep 2

Aggrecan Protein abundance

Decreased bone volume (trabeculae) Interterritorial

Compartments

Calcified cartilage

Tidemark

Thickened subchondral bone Cartilage destruction

Altered compartments

Bone

Altered cartilage Superficial

Pericellular

Intermediate

Territorial Tidemark Bone

Deep Calcified cartilage

FIG. 2.1  As an example, one cartilage protein (cartilage intermediate layer protein [CILP]) shows a distinct change in localization from distribution in normal cartilage in intermediate parts of the tissue and rather selectively in the interterritorial matrix to a prominence at the superficial parts and primarily in the pericellular compartment in the diseased cartilage. The different distribution of matrix proteins with depth of the articular cartilage is illustrated by way of three examples in the left diagram. OA, Osteoarthritis.

Many aggrecan molecules will noncovalently bind to a single, very long strand of hyaluronan, thereby forming large aggregates containing more than 100 aggrecan molecules, each with thousands of negatively charged groups as part of their numerous glycosaminoglycan side-chains. These charges are thus fixed in the tissue, and the presence of counterions results in an osmotic environment that retains water. This has an essential role in cartilage function by resisting compression and distributing load. The noncovalent interaction of aggrecan via its G1 globular domain with hyaluronan is stabilized by link protein, which has a structure similar to the hyaluronan-binding domain of aggrecan. This link protein noncovalently binds to both this domain of the proteoglycan and hyaluronan. In normal cartilage turnover, as well as in pathology, the aggrecan molecule is cleaved by enzymes called aggrecanases (i.e., ADAMTS-4 [a disintegrin and metalloproteinase with thrombospondin motifs] and ADAMTS-5)4,5 (see Fig. 2.3). One site of this cleavage is in the interglobular domain between the hyaluronan-binding G1 globe and the G2 globe. The cleavage occurs between the amino acids EGE and ARG (for references, see elsewhere6). The new N- and C-terminals formed have been used to develop antibodies that recognize the fragments produced only by the cleavage. These antibodies have in turn been used to demonstrate such fragments in body fluids and tissue extracts.6,7 The cleavage occurring in the domain carrying the chondroitin sulfate chains results in shortening of the aggrecan, with ensuing decreased number of fixed charged groups (see Fig. 2.3). With aging, shorter aggrecan molecules accumulate, the extreme being hyaluronan-binding domain with no glycosaminoglycan-binding structures remaining.8 Indeed, in adults, a major proportion of the aggrecan molecules found in the interterritorial matrix at a distance from the cells do not contain the G3, C-terminal globular lectin homology domain, probably a result of the gradual turnover of the aggrecan molecules. Furthermore there is substantial accumulation of the G1 domain, apparently retained by being bound to hyaluronan.9 This fragment can be identified in tissue either via its new C-terminal as represented by an -EGE373-COOH sequence formed through cleavage by aggrecanase or via a further matrix metalloproteinase (MMP) cleavage that forms a C-terminal -PEN341-COOH sequence.10

Even from early experiments,11,12 it was clear that chondrocytes have a remarkable capacity to replace aggrecan molecules removed from tissue by enzymatic cleavage. It appears that a normal chondrocyte should be able to replace even large amounts of proteoglycans lost unless suppressed by cytokines such as IL-1 and TNF-α. There is some evidence that the aggrecan degradation encountered in early joint disease, such as OA, is effectively counterbalanced by increased synthesis and deposition of the molecule such that no overall loss takes place.13,14

COLLAGEN FIBRILLAR NETWORKS A major function of the ropelike collagen fiber networks in cartilage is to provide tensile strength and distribute the load so that excessive local force is not applied to the underlying bone. One type of fiber contains a core of collagen type II with a minor constituent of collagen type XI connected via a number of molecules bound at its surface. The other fibrillar network contains collagen type VI as a filamentous network primarily in the territorial matrix. This network is connected by a set of linker molecules to other molecules in the matrix, including collagen type II fibers and the major proteoglycans. These networks are discussed separately.

FIBERS WITH COLLAGEN TYPE II AS THE MAIN CONSTITUENT The major fibrillar network in cartilage contains primarily collagen type II with a minor constituent of collagen type XI.15 The collagen molecule forming the fibers is made up of three parallel, tightly associated polypeptide chains forming a very stable triple helix. It is extremely asymmetric—300 nm long and 1.5 nm in diameter. The amino acid hydroxyproline is found in abundance in collagen. It is essential for stability of the molecule because of the hydrogen bonds formed to the hydroxyl group. Collagen type II is produced as a procollagen that does not form fibrils until the propeptides at both ends of the C- and N-terminals are cleaved off (see Fig. e2.1). The molecules then form fibers by interactions with other collagen molecules such that a large part of the surface of the molecule is engaged and the collagen molecules are positioned so that they form a so-called quarter stagger

10

SECTION 1  Scientific Basis of Rheumatic Disease SCHEMATIC ILLUSTRATION OF THE ORGANIZATION OF SPECIFIC CARTILAGE ECM MACROMOLECULES INTO NETWORKS

sc oid

in

PRELP Collagen VI

HS-PG (syndecan)

+

rin

HS-PG (syndecan)

Integrin Chondrocyte

CHAD

+

Aggrecan

NC4

SS

Biglycan/decorin

o Asp

Di

Matrilin-3

Matrillin 1/3

SS

rin

COMP

Collagen IX

Collagen II/XI

eg

Collagen II/XI

Procollagen II

Decorin

Collagen XIII

Fibronectin

Int

INTERTERRITORIAL

TERRITORIAL

Fibromodulin

PERICELLULAR

CILP HA KS HA

CS

CD44 COM

P

Collage

n II

Fibulin

Link protein

FIG. 2.2  Indicated are the interactions between ECM proteins and specific receptors at the cell surface. Note the different molecular composition of the territorial matrix closer to the cell than in the interterritorial matrix at some distance. CD44, Receptor for hyaluronan; CHAD, chondroadherin; CILP, cartilage intermediate layer protein; COMP, cartilage oligomeric matrix protein; CS, chondroitin sulfate; ECM extracellular matrix; HA, hyaluronan; HS-PG, heparan sulfate proteoglycan; KS, keratan sulfate; NC4, N-terminal globular domain of collagen 9.

arrangement in relation to one another. It appears that the dimensions of the formed fiber depend on the relative proportion of collagens type II and XI, with the typical ratio being on the order of 50:1. This may depend on the presence of a central core of microfibrils of collagen type II and XI that direct assembly of the fiber.16 Collagen fibers in the superficial and deep layers of articular cartilage are different in dimension and direction. Thus, whereas fibers in the superficial layer of articular cartilage are thin and run in parallel, the thicker fibers in the deeper parts of cartilage run perpendicular to the surface. In the transition zone layer, fibers run at an angle (see Fig. e2.1).17 The organization can be seen as Benninghoff arcades on polarized light microscopy. Collagen fiber formation is influenced by matrix molecules such as decorin, asporin, fibromodulin, COMP, and a special variant of an oversulfated chondroitin sulfate chain. In several of these cases, the molecules are also retained bound at the surface of the collagen fiber. This is particularly evident for collagen type IX, which has part of the molecule extending out from the fiber. These molecules appear to have roles in providing sites for interaction with other matrix molecules, including other fibers (see Fig. 2.2). An important feature of the collagen fiber network is that the interactions become sealed by covalent cross-link formation after the fibers are assembled outside the cell. This cross-linking depends on the oxidation of lysine and hydroxylysine residues by lysyl oxidase to provide an aldehyde function that forms a Schiff base with a neighboring lysine amino group. These are then rearranged to become stable pyridinoline groups that cross-bridge between the molecules and within the molecules of a fiber. These cross-links are important for mechanical stability of the collagen. The propeptides are not metabolized during the degradation of the collagen and eventually end up in urine, where they can be measured as indicators of collagen breakdown.18

Collagen type XI Collagen type XI consists of a major triple-helical portion, similar in size to that of collagen types I and II but, in contrast to these collagens, the N-terminal propeptides are retained with the molecule incorporated into

the fiber. Some reports have indicated that the retained N-terminal parts are exposed at the surface of the fibers, with the major triple-helical portion being located more centrally in the fiber.19 Collagen type XI together with collagen type II appears to form the initial microfibrils that regulate further assembly of the cartilage collagen fiber, at least in skeletal morphogenesis.16 Interestingly, collagen type XI forms cross-links to primarily other collagen type XI molecules.20 There are examples of mutations in collagen type XI chains with ensuing major growth disturbances, thus indicating a role in cartilage growth and stability.21

Collagen type IX This molecule is a member of the FACIT collagens (fibril-associated collagens with interrupted triple helices) and is found bound at the surface of the fibrils that have collagen type II as the major constituent. Collagen type IX contains three different α chains that form three triple-helical domains (col1, col2, and col3) lying between four noncollagenous domains (NC1, NC2, NC3, and NC4). The NC4 domain with its adjacent col3 triple helix protrudes from the fibers and is available for interactions with other molecules in the ECM (Fig. 2.2),22 such as COMP and fibromodulin. Collagen type IX often contains a chondroitin sulfate side chain bound at the NC3 domain. Its role in function of the collagen is not known. Functionally, collagen type IX has been shown to interact with matrilins, COMP, and, in particular, collagen type II. The collagen is actually covalently cross-linked to collagen type II in the fibers of adults.23 When collagen type IX is added in vitro to fibril-forming systems of collagen type II, assembly and fiber formation are retarded. Mutations in collagen type IX lead to severe growth disturbances, such as pseudoachondroplasia or multiple epiphyseal dysplasia. Some of these disturbances are similar to those with a mutated COMP molecule, which is of special interest in view of the high-affinity interaction that this protein shows with all four NC domains of collagen type IX. Furthermore early lesions of articular cartilage similar to those found in OA develop in mice with knockout of collagen type IX.24

CHAPTER 2  The articular cartilage

MOLECULES REGULATING COLLAGEN FIBER ASSEMBLY The dimensions and orientation of collagen fibers vary between the different zones and layers of articular cartilage. Fibers in the territorial matrix close to cells are thinner and have similar dimensions in different layers of cartilage. In contrast, other fibers in the interterritorial matrix are thicker but have larger and more variable diameters in the deeper layers. This regulation of fiber diameter is achieved by a number of macromolecules that bind to collagen. The exact role of individual molecules in achieving the final dimensions and direction of the fibers is not clear, although there are a number of examples in which inactivation of individual genes of the involved proteins leads to altered dimensions of collagen fibrils. It is notable that asporin, similar to decorin, inhibits collagen fiber formation and that levels of these proteins are selectively very high in superficial parts of the articular cartilage, where collagen fibers are thin.25 The extremely long half-life of collagen type II, in excess of 100 years,9,26 indicates that very little collagen is eliminated over the life of an individual; however, at the same time, fibers defective as a result of fatigue have to be repaired. It is possible that the differences in the dimensions of the fibers in the interterritorial matrix result from adding newly synthesized collagen molecules at the fiber surface, increasing the diameter to provide mechanical stability. A number of molecules bound at the surface of collagen fibers are likely to prevent further accretion of collagen. It is plausible that these molecules will need to be removed before new collagen molecules can be added to a fiber for remodeling or repair. It appears that even though the collagen itself does not turn over, molecules on the fiber’s surface are continuously removed and replenished.

Cartilage oligomeric matrix protein COMP is a molecule primarily found in cartilage, where it is quite abundant at a concentration of around 0.1% of the tissue’s wet weight. The molecule is made up of five identical subunits, each with a molecular weight of around 87,000 Da. The five subunits are held together by a coiled-coil domain close to the N-terminal end, and disulfide bridges further stabilize the binding. The subunits are made up of several modules, including some binding calcium. At the C-terminal end, there is a globular domain that is involved in interactions with other proteins in the matrix. The molecule can be viewed as a bouquet of tulips tied together at their stalks (Fig. 2.2).27 COMP is a member of the thrombospondin family and is also referred to as thrombospondin-5. Cartilage also contains other thrombospondins that share the same properties, with thrombospondin-1 and thrombospondin-4 being particularly abundant. These thrombospondins, however, contain an extension beyond the coiled-coil domain in the N-terminal that has a heparinbinding motif, in this manner adding additional interacting sites. Whereas thrombospondin-4 contains five identical subunits, thrombospondin-1 contains only three.1 The three-dimensional structure of the C-terminal domain of thrombospondin 1 has been resolved, and its organization has been found to be stabilized by a large number of calcium ions.28 As the C-terminal domain of the various thrombospondins shows a great deal of conservation, it is likely that its structure is similar in all five members of the family. COMP has been shown to bind to collagens type I and II,1 where each individual C-terminal globular domain provides high affinity in the nanomolar range. Four binding sites are evenly distributed along the collagen molecule. There is one at each end and two positioned along the filament such that the distance is similar between the four binding sites. Even though each COMP molecule has five identical binding sites, an individual molecule can engage only one binding site on each collagen molecule and not span the distance between two such sites. Therefore each COMP molecule has the potential to bind to five different collagen molecules. The quarter stagger arrangement of collagen in the fiber and the fact that a pentameric microfibril unit appears to exist29 may relate to the four similarly spaced collagen binding sites in the molecule. COMP accelerates and provides faster collagen fibril formation in vitro. It appears that this effect is mediated by the COMP molecule bringing together several collagen molecules to facilitate their interactions in the forming fiber. The COMP molecule does not remain bound directly to the surface of the forming fiber. The molecule thus appears to function as a catalyst to enhance fibril formation. In the cartilage of growing individuals and notably in growth plates, COMP is primarily localized close to the cells in the territorial matrix, where it may have a role in stimulating collagen fibril formation.30 It has the ability to interact with all four NC domains of collagen type IX with similar high affinity in the nanomolar range. The interaction is mediated via the C-terminal globular domains (Fig. 2.2).

11

In adults, COMP is localized primarily in the interterritorial matrix and may be bound to collagen type IX or one of the matrilins, which in turn bind to the surface of the collagen fiber (Fig. 2.2). The role of COMP in adult cartilage appears to be stabilization of the fiber network. Mutations in the calcium-binding domain of COMP, as well as in the C-terminal domain, have been shown to lead to severe growth disturbances in the form of pseudoachondroplasia or multiple epiphyseal dysplasia. A feature of these conditions is that material retained in the endoplasmic reticulum of chondrocytes contains both COMP and collagen type IX.31 In contrast, the COMP-null mouse shows no detectable alteration in phenotype.32 It is possible that other molecules compensate for the lack of COMP function in such mice. In OA, COMP is significantly upregulated in early stages, in an apparent attempt at repair. At the same time, the protein already deposited is cleaved and released from the tissue. COMP fragments in body fluids may prove useful as biomarkers for arthritic diseases.33

Decorin Decorin was the first molecule in the leucine-rich repeat (LRR) protein family to be cloned and sequenced. This family of molecules in the ECM contains four subclasses with a total of 12 members, all of which appear to share the function of binding to collagen (Fig. e2.2).1 One functional domain of these molecules is a central LRR region, where residues, particularly leucine, are found at conserved locations in each repeat of some 25 amino acids, albeit somewhat variably long. Most of these molecules have 10 to 11 such repeats, and the entire domain contains a disulfide loop structure at each end. One subgroup contains molecules with only 6 repeats. One variable of almost all of the molecules in the family is an N-terminal extension of generally less than 20 amino acids, which may contain a variety of substituents (Fig. e2.2). Some of the molecules also have a C-terminal extension. There is also variation in glycosylation of the repeat domain, which usually contains a few N-linked oligosaccharides. In some of the small LRR proteins, such as fibromodulin and lumican, some of the oligosaccharides may contain a variably long array of 6-O-sulfated lactosamine repeat disaccharides (Fig. 2.3) extended to form the glycosaminoglycan keratan sulfate. The three-dimensional structures of decorin34 and biglycan35 have been resolved by x-ray crystallography. These molecules contain one (decorin) or two (biglycan) glycosaminoglycan chains bound at the N-terminal extension. These chains are chondroitin sulfate or dermatan sulfate, depending on the tissue. In articular cartilage, the chain is a dermatan sulfate, in which a few of the glucuronic acid residues have been epimerized to iduronic acid, thereby increasing its structural variability. In fibers, the glycosaminoglycan chains are free to interact with other molecules. Thus, decorin can crossbridge to neighboring collagen fibers, as well as to other molecules in the local environment (Fig. 2.2).1 Based on the x-ray crystallographic data presented, the LRR family of molecules forms a curved structure in which two molecules form a dimer in the crystals that overlap in opposite directions in about 50% of their length such that the N-terminus of one molecule is located in the middle of the curved domain of the other.34 The presence of the proteoglycan as a monomer or a dimer has specific relevance for interactions and functions; a monomeric molecule has only one of each interacting site, but a dimer may exhibit two of each binding site. Decorin binds tightly to the fibril-forming collagens with a KD in the nanomolar range. Binding is close to the C-terminus of the collagen as shown for collagen type I. Binding occurs via the LRR region and particularly involves repeats 4 and 5.1 The critical sequence has been identified as SYIRIADTNIT.36 Decorin binding inhibits collagen fiber formation in vitro in a dose-dependent manner. Accordingly, decorin knockout mice have irregular collagen fibers with increased diameter, particularly prominent in skin.37 They do not show increased early joint pathology, indicating that other molecules compensate for the lack of decorin in cartilage.

Fibromodulin and lumican Fibromodulin and lumican belong to the same subclass of LRR proteins but with a gene arrangement distinct from that of decorin. Other members of this subgroup are keratocan, osteoadherin, and proline and arginine-rich end leucine-rich repeat protein (PRELP). All of these molecules except PRELP contain tyrosine sulfate residues in the N-terminal extension. Notably, the number of such sulfate residues is variable both with regard to the relative proportion of candidate tyrosine residues that are sulfated within a given molecule and with regard to the number of such tyrosine residues that may carry a sulfate. One extreme is represented by fibromodulin, which contains

SECTION 1  Scientific Basis of Rheumatic Disease

12

PROTEOGLYCAN AGGREGATE STRUCTURE AND ORGANIZATION

Hyaluronan Link protein G1 globe Hyaluronan binding region

MMP cleavage sites

ADAMTS cleavage sites

EGF homology (spliced) CRP

G2 globe KS rich region

G3 globe CS domain 1

CS domain 2

O-linked oligosaccharides N-linked oligosaccharides HO 4 O

SO3 CH2OH 6 5 3

O 2

1

O

4 HO

OH

Keratan sulfate

CH2OH 6 5

COO-

O 2

1

3

O

O

4 HO

NH Ac

n

6

5

HO O 2

3 SO3-

1 OH

4 O

SO3 CH2OH 6 5 3

O 2

1

0.5µm

O

NH Ac

Chondroitin sulfate

n

FIG. 2.3  Depiction of the structure and organization of the proteoglycan aggregate. Also shown is a rotatory shadowing electron micrograph (courtesy Matthias Mörgelin, Lund University, Sweden) of an aggregate isolated from tissue. The sites for degradation by the primary active ADAMTS-4 and ADAMTS-5 are indicated, as well as one site for cleavage of MMP. CRP, C-reactive protein; CS, chondroitin sulfate; EGF, epidermal growth factor; MMP, matrix metalloproteinase.

up to nine sulfate residues; osteoadherin contains up to eight, lumican up to four, and keratocan only one.38 PRELP, in contrast, contains a cluster of basic residues that contribute heparin-binding activity for this molecule.39 The function of the domain with clustered tyrosine sulfate residues is becoming clearer. The domains in fibromodulin and osteoadherin mimic heparin in many interactions and bind growth factors (e.g., fibroblast growth factor 2 [FGF-2]), cytokines (e.g., oncostatin M and IL-10), MMPs (e.g., MMP-13 for fibromodulin), and a number of matrix proteins via their heparin-binding domains (e.g., PRELP and chondroadherin).40 Thus, the fibromodulin on a collagen fiber appears to extend its tyrosine sulfate domain, which can bind to molecules with cationic domains. One such charged structure is the NC4 domain of collagen type IX, which has been shown to interact with the anionic N-terminal extension of fibromodulin (Fig. 2.2).40 All of the molecules in this family appear to bind to collagen via their LRR domain with dissociation constants ranging from 1 to 10 nM.1 Only in a few cases has it been established exactly where along the collagen the LRR protein binds. Collagen binding of fibromodulin has been studied extensively. It has been shown that the molecule inhibits fibril formation in vitro. Fibromodulinnull mice show altered collagen fibril dimensions, particularly apparent in the tail tendon. Unexpected in view of the inhibitory effects observed in vitro, the tendon contains a much larger number of thin fibrils. An explanation appears to be a higher abundance of the related lumican molecule, which could be shown to bind to the same site on the collagen, albeit with somewhat lower affinity. It thus appears that lumican may guide early events in fibril formation. The molecule may then be competed away by fibromodulin to introduce a different function. Because the mRNA levels and therefore synthesis of lumican were lower in null mice, it appears that the higher levels of this protein were caused by retarded elimination apparently secondary to lack of competition by fibromodulin.1 These findings illustrate the complexity of fibril formation, which takes place in many steps involving various molecules with different roles.

Fibromodulin is bound in the gap region on collagen fibers.1 It appears to be bound via its protein core with exposure of a keratan sulfate chain, as well as the tyrosine sulfate domain, which then become available to interact with PRELP and the NC4 domain of collagen type IX located on neighboring fibers, enhancing stability and other collagen network properties. Fibromodulin is a target in joint disease. In a model of articular cartilage destruction caused by stimulation with IL-1 in explant culture, it has been shown that fibromodulin is degraded after aggrecan and that the molecule is initially cleaved by MMP-13 to release almost the entire N-terminal tyrosine sulfate domain, while the remainder of the molecule is initially retained in the tissue, probably bound to the collagen.41 At the same time, MMP-13 can release the NC4 domain of collagen type IX from cartilage.42 This results in loss of function, with impaired noncovalent associations between collagen fibers likely leading to impaired maintenance of matrix structure. This may represent a central mechanism in the swelling and surface fibrillation in early OA. It is of interest to note that the particular fibromodulin fragment retained in the tissue is found only in pathologic tissue and not in normal tissue, although there is continuous turnover of matrix constituents in response to altered load, including removal of damaged components. This normal turnover appears to involve different mechanisms of cleavage.

Other leucine-rich repeat proteins PRELP is distinguished by having a basic, heparin-binding N-terminal domain.43 This mediates binding to molecules with heparan sulfate side chains, including perlecan and cell surface syndecan and glypican. Simultaneously, the protein binds via its LRR domain to two sites on fibril-forming collagen types I and II. Thus, the molecule has the potential to bridge from the collagen network back to the cell surface to provide feedback to cells on the condition of the matrix. Little is known of alterations in PRELP in joint disease. It is known that the isolated heparin-binding domain of PRELP binds to osteoclast precursors via cell surface proteoglycans. The peptide becomes internalized

CHAPTER 2  The articular cartilage

12.e1

STRUCTURAL FEATURES OF THE ECM LRR PROTEINS CS/DS chain CS/DS chain

Biglycan Decorin

O-linked oligosaccharide SO4 SO4 SO4 SO4 SO4 SO4 SO4 SO4 SO4

Asporin

SO4 SO4 SO4 SO4

Tyrosine sulfation

SO4

SO4 SO4 SO4 SO4

SO4 SO4 SO4

SO4 SO4 SO4 SO4 SO4 SO4

SO4

+++ +++++

** ***

KS chain N-linked oligosaccharide

Fibromodulin CHAD Lumican PRELP

OSAD

Keratocan OSAD

Epiphycan Osteoglycin Mimecan Opticin

FIG. E2.2  Note the variability in the N-terminal domain between molecules, which shows negatively charged groups of different character (glycosaminoglycan, tyrosine sulfate, polyaspartate, or a cluster of basic amino acids). The C-terminal extensions of two members have distinct features. The dimeric form found for decorin and biglycan on x-ray crystallography is illustrated schematically. CHAD, Chondroadherin; CS, chondroitin sulfate; ECM, extracellular matrix; LRR, leucine-rich repeat; OSAD, osteoadherin.

CHAPTER 2  The articular cartilage and translocates to the nucleus, where it inhibits nuclear factor κB (NF-κB), a downstream target of receptor activator of NF-κB ligand (RANKL), an important stimulator of osteoclast development, resulting in inhibition of osteoclast formation. Indeed, PRELP has been used to prevent the development of osteoporosis in ovariectomized mice.44 Asporin is a close relative of decorin but differs in having a variably long polyaspartate sequence at the N-terminus. The number of aspartate residues varies among individuals.45 It has been demonstrated in studies of several cohorts of individuals in Asia that OA is overrepresented in those with 14 such residues versus those with 13 residues in the asporin N-terminal structure.46 In a different study from the United Kingdom, no such pronounced relationship could be discerned, indicating that other factors are also involved.47 One function of the polyaspartate sequence appears to be calcium binding, for which there may be a difference between the 13 and 14 aspartate variants.48 Asporin binds to collagen at the same sites that decorin does48; thus, it may have roles in regulating mineralization, which is relevant to the development of OA. There is a set of LRR proteins with only six repeats, including epiphycan, mimecan, and opticin.1 They all contain N-terminal extensions carrying glycosaminoglycan chains (epiphycan), tyrosine sulfate residues (mimecan), or O-glycosidically linked oligosaccharides (opticin) (Fig. e2.2). Mimecan has also been named osteoglycin. They do show interesting differences between different types of cartilage. Mimecan is present in articular cartilage, menisci, and intervertebral disks but virtually absent in nasal and tracheal cartilage, but epiphycan is prominent in the latter cartilage and absent from the others. Opticin is particularly prominent in connective tissues other than those of joints. There is limited knowledge regarding alterations of these proteins in joint disease.

Heparin and heparan sulfate proteoglycans A glycosaminoglycan not prominent in cartilage is heparan sulfate, which has structural features overlapping those of heparin. Heparan sulfate is found as side chains of extracellular perlecan (discussed later), which has a very large protein core with several domains interacting with a number of other proteins in the ECM. The proteoglycan contains an N-terminal domain with some three glycosaminoglycan chains and a C-terminal domain with up to two chains. These chains may be heparan sulfate or chondroitin sulfate (discussed later). Heparan sulfate contains two types of disaccharide repeats consisting of either a glucuronic acid and an N-acetylglucosamine or an iduronic acid and an N-acetylglucosamine. The hexosamine carries an O-sulfate group, and some of the residues have an additional N-sulfate instead of the N-acetyl group. Also, the uronic acid may be sulfated, usually in its 2 position. Thus, there is extensive variability in the building blocks, which are then assembled in variably long stretches with different repeat stretches of low- and high-sulfated residues. Other heparan sulfate–containing proteoglycans are found at the cell surface of the chondrocyte. These include four different syndecans,49 which contain a domain intercalated in the cell membrane, and some six glypicans, which are joined via a glycosylphosphoinositide linkage.50 The syndecans contain an intracellular signaling domain and, as discussed later, they are involved in a number of cell reactions, and bound molecules can induce signal transduction.

FIBERS AND NETWORKS WITH COLLAGEN TYPE VI AS THE MAIN CONSTITUENT There is a different fibrillar network in cartilage with a more restricted distribution in tissue. It has collagen type VI as a major constituent and is primarily present in the territorial matrix surrounding the cells (Fig. 2.1).

Collagen type VI Collagen type VI has a distinctive network of beaded filaments. This molecule contains three different α chains with a central triple-helical domain flanked by globular domains. The N-terminal portion contains between one and nine von Willebrand factor A (vWFA)-like repeats depending on the gene from which it is produced. In addition, the C-terminal portions of all chains contain vWFA repeats, as well as other motifs with less clear functions. The vWFA domain is found in many proteins, where it is involved in protein–protein interactions.51 While still within the cell, two collagen type VI molecules associate in an antiparallel fashion such that the dimer is flanked by the N-terminal domains, and the two C-terminal domains are placed so that they form two interior globular structures along the filament formed by the two triple helices. Two such dimers associate laterally to form a tetramer, with the globular domains at each end representing a pair of the vWFA-rich

13

globules. The two globular structures representing the C-terminals are found internally in the triple-helical central filament.51 The tetramer is secreted from the cell, and its N-terminal structures are sites for associations with fibrils involving both end-to-end and side-to-side interactions. This process appears to be governed by other molecules, particularly members of the LRR protein family.

Biglycan and decorin Biglycan and decorin both bind with high affinity to the collagen type VI N-terminal domain, independent of their glycosaminoglycan side chains. This binding is a prerequisite for formation of the collagen type VI beaded filament network in vitro. Regulation of collagen type VI assembly also depends on the presence of the chondroitin–dermatan sulfate side chains, where the two present in biglycan provide more efficient filament formation than the single chain in decorin. The two closely related proteoglycans appear to bind to the same site, which interestingly does not seem to involve the triple-helical domain in this collagen.52–54

Matrilins Cartilage matrix protein (CMP, matrilin-1) was the first of the four matrilins identified. These proteins (for references, see Klatt and colleagues55) contain vWFA domains. Matrilin-1 has two such domains in each of the three identical subunits with a molecular mass of around 50,000 Da; matrilin-3, with four subunits, has only one such domain. Matrilin-1 and matrilin-3 are quite restricted to cartilage and show similar distribution between different tissues; the others have a more general distribution. Interestingly, matrilin-1 is even further restricted and not found in articular cartilage and intervertebral disks but it is particularly prominent in tracheal cartilage. The protein is present in the more immature cartilage of the femoral head during earlier phases of development and can be seen in the early bone anlagen. Data indicate roles in collagen network function and integrin binding.55 Its two vWFA homology domains (only one in matrilin-3) may mediate the ability of the protein to bind to collagen. Matrilin-1 was initially isolated because of its apparent ability to bind to aggrecan. Matrilin-1 can be isolated from cartilage as a mixed polymer that contains subunits of matrilin-1, as well as matrilin-3. The functional significance of this heterocomplex is not understood.56 Mutations in matrilin-3 can induce multiple epiphyseal dysplasia or pseudoachondroplasia with skeletal malformations, similar to those caused by mutations in the interacting partners of the proteins, such as collagen IX.57

A module cross-linking to other matrix constituents Decorin and biglycan appear to also have roles in the completed network. Collagen type VI isolated from chondrosarcoma cartilage–like tissue contains biglycan or decorin bound at the N-terminal globules. The proteoglycan in turn has a bound member of matrilin-1, -2, or -3. This interaction is tight with a dissociation constant on the order of nanomolar. The matrilin, in turn, binds to a procollagen type II molecule or a completed collagen fiber. Alternatively, matrilin can bind to an aggrecan molecule (Fig. 2.2).54 Thus, collagen type VI seems to be a center in a scaffold that binds to the other major networks in the matrix. Collagen type VI is found only in the territorial matrix closer to cells and is absent from the interterritorial matrix. Information on alterations in collagen type VI in joint disease is limited, but it is important to note that the protein is found to be particularly enriched in tissue subjected to load.

MOLECULES INTERACTING AT THE CELL SURFACE AND MODULATING CHONDROCYTE BEHAVIOR Chondrocytes have the ability to both degrade the matrix and replenish lost molecules with new constituents in a process of remodeling the tissue in response to material fatigue or altered load. The cells are guided in this endeavor by receptors at their surface that recognize specific molecules in the matrix (Fig. 2.2). Binding elicits specific signals that will either induce cellular spreading and migration by engaging the cytoskeleton or lead to alterations in transcription and protein synthesis. Other stimuli that affect cells include mechanical forces, which provide signals that crosstalk with those from other interactions at the cell surface. Indeed, some data indicate that some of the signals elicited by mechanical load involve integrins.58

INTEGRIN-BINDING PROTEINS The integrins are dimers of an α chain noncovalently bound to a β chain. The cells in connective tissues contain either a β1 or a β3 chain in conjunction

14

SECTION 1  Scientific Basis of Rheumatic Disease

with one of many α chains. The various integrins have different preferred ECM ligand proteins and are catalogued as families by their preferred ligands.59 For example, members of one family contain a β1 chain in combination with an α1, α2, α10, or α11 chain and bind to collagens. These integrins have different tissue distributions such that the one with α10 appears to be unique to cartilage, but the others have more ubiquitous distributions. Their binding to collagen may elicit different responses and result primarily in either altered production of enzymes degrading the matrix or production of building blocks such as collagen molecules. The collagen-binding integrins do not appear to be specific for a particular fibril-forming molecule. One exception is chondroadherin. This protein appears to be restricted to cartilage and can bind α2β1 integrin but not other integrins containing the same β chain.

Chondroadherin Chondroadherin is a member of the LRR protein family that is in its own subclass. It differs from other LRR family members in that the C-terminal cysteine loop is double and the protein has a short C-terminal extension of basic amino acids. The protein has no N-terminal extension. Chondroadherin specifically binds the α2β1 integrin1,60 via a sequence in one of its C-terminal disulfide loops. Initial integrin binding elicits signals that do not induce cell spreading. However, the C-terminal short extension peptide of chondroadherin contains a different cell-binding sequence that engages the heparan sulfate chains of cell surface proteoglycans, notably syndecans.61 The combined engagement of integrins and heparan sulfate leads to cell spreading, as well as enhanced integrin activity. Chondroadherin is present in articular cartilage but virtually absent from menisci. The protein is particularly enriched during growth in the prehypertrophic zone of the growth plate where cell multiplication is slowed, in line with its in vitro effects on cell behavior.

Fibronectin Fibronectin62 is present in most tissues and can actually form its own fibrils, which appear to have roles in guiding matrix assembly and cell migration. The protein contains two identical subunits held together by disulfide bonds close to their C-terminal end. It contains a collagen-binding domain with preference for denatured collagen (gelatin). There are integrin-binding domains in which the RGD (arginine–glycine–aspartic acid) sequence represents the classic motif of integrin binding. This motif in fibronectin preferentially binds α5β1 integrin, although αVβ3 integrin can also interact. Fibronectin also has other integrin-binding domains.63 Also, the two heparin-binding domains on each subunit, each some 20 kDa, can interact with heparan sulfate proteoglycans at the cell surface, including syndecan.64 Fragments of fibronectin, when added to cartilage in explant culture or injected into a joint, will stimulate chondrocytes to produce proteases and induce cartilage breakdown.65,66 In contrast, intact fibronectin molecules will not have this effect. It is possible that fragmentation of fibronectin is one mechanism for propagating joint destruction in disease. Fibronectin is upregulated in articular cartilage at very early stages of OA in many species, including humans.13 The functional consequences of this are not known, but it may be part of an attempt at repair. A result is greater availability of fibronectin that, when fragmented, furthers tissue degradation.

DISCOIDIN DOMAIN 2–CONTAINING RECEPTOR In addition to integrins, the cell surface discoidin domain receptor 2 (DDR-2) binds collagen type II, inducing upregulation of MMP-13 production. This has been shown to be upregulated in mice in which OA is developing.67

HYALURONAN Hyaluronan is an extremely long glycosaminoglycan chain that is distinct from all others in that it is not covalently bound to a protein core in most tissues, including cartilage. It does not contain any sulfate groups. It is made up of one to several thousand repeating disaccharides of glucuronic acid and N-acetylglucosamine. As discussed earlier, hyaluronan specifically binds to a domain in aggrecan in a noncovalent manner that is essential for the formation of aggregates. Hyaluronan also interacts with specific cell surface receptors: CD44,68 which interacts with a minimally long hexasaccharide sequence of the polymer, and RHAMM.69 The interactions with hyaluronan are important for organizing the pericellular environment and providing signals to the cell. CD44 occurs in many different splice forms with variable presence on different cells, but a role for such variability in joint disease in unclear.

LIGANDS FOR HEPARIN SULFATE/SYNDECANS The heparin-binding domains present in fibronectin are also found in other matrix proteins; for example, most members of the thrombospondin family, with the exception of COMP, many MMPs, CILP, and PRELP.1 As discussed earlier, isolated heparin-binding domain fragments can have various effects, depending on their fine structure, ranging from inducing cartilage breakdown in vitro and in vivo to decreasing bone breakdown by targeting osteoclast precursors. The N-terminal tyrosine sulfate domain of fibromodulin can mimic heparin in many interactions and bind other proteins to crossbridge networks, as well as sequester growth factors.

OTHER MOLECULAR FUNCTIONS In joint disease, inflammation is a frequent component causing pain and limiting function. The inflammation is usually chronic, and one issue is whether components from cartilage can propagate the inflammatory activity. It is a long-standing observation that when cartilage is removed in joint arthroplasty the inflammation recedes, thus indicating that factors released from the tissue have a role in propagating inflammation. It has been shown that some patients with RA have circulating antibodies to collagen type II. Furthermore arthritis can be elicited by injecting mice and rats with collagen type II (collagen-induced arthritis). The disease can be transferred by antibodies to specific collagen type II epitopes.70 It is hence possible that antibody binding activates complement and inflammation. Matrix proteins may activate innate immunity. Fibromodulin has been shown to be as active as immune complexes71 in activating the classical pathway of complement, although it does not bind to the same site. Fibromodulin binds to the head domains of C1q rather than to the triple-helical stalk region with ensuing deposition and activation of C4 and C3. Fibromodulin can also recruit factor H by binding to a different site than that for C1q and thereby inhibit further activation of the complement cascade. Whether different fragments released in disease will have different roles in complement activation remains to be shown. In other experiments, it has been demonstrated that biglycan can also bind the triple-helical stalk of the complement factor C1q and, in doing so, inhibit activation of the classical pathway of complement. It appears that other LRR proteins such as biglycan and decorin can also bind factors involved in regulating the complement cascade. One example is a tight interaction with C4BP having a role in regulating complement activity.72 Cartilage oligomeric matrix protein is a potent activator of the alternative pathway via its C-terminal globular domain. Interestingly, this activity can be observed in synovial fluid from subjects with both OA and RA, as well as in blood in the form of COMP-C3b complexes created between the activator COMP and the C3b fragment formed.73

BINDING AND SEQUESTERING GROWTH FACTORS IN THE EXTRACELLULAR MATRIX The ECM of cartilage contains a number of factors that are sequestered and thereby bind to specific interaction partners. On degradation of the matrix, it is predicted that these factors are released and affect cellular activities. In particular, a number of growth factors have been found to have the capacity to bind to matrix proteins.

Transforming growth factor-β Transforming growth factor (TGF)-β has been shown to bind to a number of matrix proteins, and binding to some members of the LRR protein family has been investigated in particular. All three TGF-β variants bind to bacterially expressed decorin, biglycan, and fibromodulin, as well as to these proteins with the full range of posttranslational modifications. There are indications that asporin can also bind TGF-β. It has been demonstrated that active TGF-β is released from decorin on treatment with MMP-3. Indeed, cartilage contains substantial amounts of TGF-β, which has been extracted and purified from the tissue.

Fibroblast growth factor Some matrix proteins contain heparan sulfate side chains, which are likely to bind growth factors within the FGF family. In the case of syndecan at the cell surface, these side chains appear to be involved in presenting the growth factor to its receptor.74

OTHER MOLECULES IN THE EXTRACELLULAR MATRIX Perlecan was found to have a central role in cartilage development when a mouse with the gene inactivated was developed. Most of these mice die during

CHAPTER 2  The articular cartilage early development as a result of problems with the heart and major blood vessels, but those that survive until birth show major growth disturbances, with an extensively altered growth plate lacking a large proportion of the collagen fibers.75 Further studies have revealed that chondroitin sulfate side chains specific for perlecan can actually accelerate and catalyze collagen fiber formation.76 GP-39 is a protein upregulated in OA. It shares homology with a chitinase, but its true activity is not known.77 GP-39 is also expressed in a number of other tissues, particularly in disease. Cartilage matrix also contains a number of proteins that are made elsewhere and are normally found primarily in the circulation. There is a preference for certain proteins, and low-molecular-weight basic proteins (e.g., lysozyme) in particular appear to bind to the matrix.78 Whether these molecules contribute specific functions is not known.

MATRIX PROTEIN FRAGMENTS AS INDICATORS OF DISEASE In processes resulting in destruction of cartilage tissue, proteolytic enzymes degrade ECM proteins and some of the fragments formed end up in body fluids. Sensitive immunoassays can quantify the fragments in synovial fluid, serum, or urine. This biomarker technology may provide the means of assaying ongoing active processes and be used in diagnosis of joint disease— importantly, before clinical symptoms become apparent. Measuring the activity of the tissue-destroying process is also important in documenting the effects of therapeutic intervention. One example of a potential biomarker is COMP, which can be used to identify patients who will have the most extensive joint destruction in both OA and RA.33,79 Also, a number of collagen fragments created by cleavage with collagenases, as well as by subsequent gelatinase activity, have been used to monitor disease.80,81 Eventually, it is hoped to be able to identify indicators specific to a particular pathologic process in a given tissue. Thus, it should be possible to identify the activity of a process in the meniscus versus in cartilage, for example.

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relatively low cost.90 In a study with 7-year follow-up, 80% of patients rated themselves as improved, with those younger than 35 years feeling the most improvement.91 Approximately 10% of cartilage biopsies after MF contain hyaline cartilage, with the majority being predominantly fibrocartilage.92 Although patients demonstrated improved knee function at 24 months after MF, there was inconclusive durability and treatment failure beyond 5 years. Autologous matrix–induced chondrogenesis combines MF surgery with the application of a bilayer collagen membrane that physically stabilizes the clot. In a study using a chitosan biomaterial with MF, there was greater lesion filling and superior repair tissue quality compared with MF treatment alone; however, clinical symptoms were equivalent in the groups studied.93

IMPLANTED CELL-BASED THERAPIES In the mid-1990s, the implantation of harvested and expanded autologous chondrocytes for cartilage repair became one of the earliest forms of cell therapies to be granted FDA approval after bone marrow cell transplants. There is now a large research interest in developing therapies with a myriad of different cell types, biomaterials, and techniques, such as 3D bioprinting, to try to improve on this cell therapy. The use of stem and progenitor cells derived from many tissues, including cells modified to be more stem cell– like with molecular techniques, is currently being studied.

AUTOLOGOUS CHONDROCYTE IMPLANTATION

Cartilage ECM molecules have extremely long half-lives, and the cells of cartilage are not renewed post-puberty. It is difficult to imagine how newly synthesized molecules would fully and functionally integrate into the cartilage matrix. However, anecdotally, it is believed that some individuals can repair cartilage to a limited extent, and there are animal models that demonstrate genetic differences in the ability to repair cartilage.82 When cartilage is damaged, a number of repair strategies have been developed, including (1) replacing bad cartilage with good cartilage from the same joint, (2) using patient chondrocytes, (3) attempting to recruit or implant patient stem cells, and (4) attempting to replace the cartilage matrix with an artificial matrix. We will briefly review recent advances in these technologies.

Autologous chondrocyte implantation (ACI) is a two-part procedure in which chondrocytes are isolated from intact non–weight-bearing regions of the joint, expanded in the laboratory, and reimplanted into the defect. ACI is approved for use in the United States and is most useful for younger patients who have single defects larger than 2 cm. Disadvantages include the need for two-stage procedures and an open arthrotomy, expense, and a significant rate of reoperation for graft hypertrophy, specifically with first-generation ACI treatments. In a series of more than 200 patients treated with ACI for larger lesions, ACI provided durable outcomes with a survivorship of 71% at 10 years and improved function in 75% of patients.94 Magnetic resonance imaging findings confirmed complete defect filling in half of patients at final follow-up. The first generation of this procedure used a periosteal patch harvested during surgery that was sewn over the defect, with harvested and expanded cells injected under it. Second-generation ACI uses a porcine collagen membrane in place of the patch and third-generation (so-called matrix-associated autologous chondrocyte implantation, MACI) treatment utilizes a matrix into which the cells are directly embedded. As noted for the other techniques, studies suggest improvement with all three versions, but more well-designed, long-term clinical studies of ACI, particularly the MACI technique, are still needed.

REPLACING CARTILAGE

STEM/PROGENITOR CELLS OF OTHER TISSUES

Intact cartilage from the same joint is used to replace damaged cartilage in surgical techniques including mosaicplasty or surgery using morcellized cartilage. Osteochondral autologous transplantation (OAT) mosaicplasty83 involves an open or arthroscopic transplantation of multiple cylindrical osteochondral grafts from the low weight-bearing periphery of the articular surface, thus providing a hyaline cartilage–covered resurfacing.84 It has been reported that OAT mosaicplasty has acceptable long-term clinical outcomes, given the appropriate indication for surgery, with a limitation being the defect size.85 However, this and all other cartilage repair or regeneration techniques need longer-term studies before any can be deemed a gold standard. Osteochondral allograft transplantation is also used, particularly for larger defects in the knee. If the cartilage defect is too large for an autograft or a patient has failed a cartilage repair procedure, implantation of a fresh osteochondral allograft (OCA) is a single-stage technique, which is particularly advantageous in a setting of extensive subchondral bone loss.86 Chondrocyte viability seems to be very important in this technique. A study of 60 patients with femoral condylar allografts showed 85% graft survival rate at 10 years.87

The limited expansion capacity of dedifferentiated chondrocytes and their increasing inefficiency at redifferentiation during extended culture has led to the use of cells termed either mesenchymal stromal cells or mesenchymal stem cells (MSCs) for autologous cartilage repair of larger defects.95 MSCs are found in numerous human tissues, including bone marrow, adipose tissue, and synovial membrane.96 Cell-based therapy is becoming an established element of modern health care and is predicted to grow as knowledge and implementation of cell biology, biomaterials, and regenerative medicine increases. MSCs are defined as adherent self-renewing, fibroblastoid-like cells that can differentiate into osteoblasts, adipocytes, and chondrocytes in vitro.97 These characteristics are present in cells derived from the bone marrow, adipose tissue, and synovial joint tissues. These cells can be differentiated in vitro to chondrocytes and used for cartilage tissue engineering. Alternatively, they are injected into the joint as MSCs, where it is hypothesized that they may differentiate into chondrocytes, but any therapeutic effects are more likely due to these cells providing factors and immune inhibitors that facilitate joint repair.98 Bone marrow MSCs were found to be at least as effective as chondrocytes for articular cartilage repair in improving symptoms of patients. However, chondrogenically induced bone marrow MSCs can result in transient fibrocartilaginous repair tissue or terminal differentiation to form calcified cartilage, subchondral bone overgrowth, or intralesional osteophyte formation.99 However, it is actually not established that MSCs (or any of the cell types discussed below) contribute directly to the above outcomes. Adipose-derived MSCs, now called adipose-derived stem cells (ASCs), offer the advantage that they are abundant in adipose tissue or liposuction

REPAIR AND REGENERATION OF CARTILAGE

MICROFRACTURE Another surgical technique, microfracture (MF), involves making multiple holes in the subchondral bone to recruit bone marrow cells to populate the cartilage defect.88,89 MF is considered a first-line treatment given its minimally invasive nature, technical ease, limited surgical morbidity, and

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SECTION 1  Scientific Basis of Rheumatic Disease

samples.100 There are many efforts to fabricate or regenerate articular cartilage using scaffolds and growth factors with ASCs.101 Cells from the synovium, synovial fluid, periosteum, infrapatellar fat pad, trabecular bone, and muscle have also been used to differentiate chondrocytes, but no definitive positive regeneration has been documented. There is the possibility of recruiting these native cells from the tissues to the cartilage defect, but this has not yet been productive. The area of cell-based strategies for cartilage repair is thus under intensive study. However, the field has not moved as fast as was predicted, primarily because of safety, cost, efficacy, and regulatory hurdles.102

PROGENITOR CELLS OF ARTICULAR CARTILAGE Although it was long-held dogma that articular cartilage contains no stem/ progenitor cells, cell tracing studies indicate that such cells exist in cartilage during its development and postnatal growth.103 The evidence indicates that these chondroprogenitor cells generate the stable articular chondrocytes during the appositional growth of the tissue. In addition, a limited pool of these cells remain throughout life and, at least in vitro, undergo chondrogenic differentiation with reduced potential for terminal differentiation toward the hypertrophic phenotype, in contrast with MSCs. These chondroprogenitors can also be cloned, which may be advantageous in tissue engineering strategies, where selected clones could be used for creating new cartilage.104 Furthermore knowledge that such cells remain in adult tissue provides a new target for therapeutics that could limit their loss, increase their proliferation, and/or stimulate their differentiation.

TISSUE-ENGINEERED CARTILAGE In order to engineer novel cartilage implants,105 all of the above mentioned cell types, including combinations of certain types, are being combined with scaffolds made from a myriad of biomaterials, some including bioactive factors.105 These are produced with a variety of methods that include 3D bioprinting of the cells themselves.106 There is great interest in these techniques, but at this point these are experimental therapies and none are approved for clinical use.

ACKNOWLEDGMENT The authors acknowledge the contributions of Drs. Heinegård, Lorenzo, Önnerfjord, and Saxne, co-authors of the previous version of this chapter.

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Responses to altered oxygen tension are distinct between human stem cells of high and low chondrogenic capacity. Stem Cell Res Ther. 2016;7:154. 105. Johnstone B, Alini M, Cucchiarini M, et al. Eur Cell Mater. 2013;25:248–267. 106. Daly AC, Freeman FE, Gonzalez-Fernandez T, et al. 3D bioprinting for cartilage and osteochondral tissue engineering. Adv Health Mater. 2017;6(22):1700298.

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Bone structure and function David B. Burr • Teresita Bellido • Kenneth E. White

Key Points n Bone is organized differently and for different functions at the organ, tissue, and molecular levels. n Noncollagenous proteins function as structural support in the bone matrix and regulate mineral deposition, crystal growth, and cell attachment. n Bone mineralization is affected through hormonal action (fibroblast growth factor 23 [FGF-23]) as well as through the bioactivity of intracellular and secreted matrix proteins with emerging roles (dentin matrix protein-1, FAM20c, and matrix extracellular phosphoglycoprotein). n Growth factors, including insulin-like growth factor 1, the autocrine/paracrine FGFs, and transforming growth factor-β, play key roles in bone growth and structure. n Osteoclasts are the primary bone-resorptive cells and originate from precursors of the hematopoietic lineage upon stimulation with receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor. n Whereas the rate of osteoclast generation determines the extension of the boneremodeling unit, the life span of osteoclasts determines the depth of resorption. n Osteoblasts are responsible for bone formation and originate from mesenchymal progenitors that also give rise to chondrocytes, muscle cells, and adipocytes. n Osteocytes form a network that senses mechanical and hormonal environmental cues and orchestrates the function of osteoblasts and osteoclasts. n Osteocytes produce and secrete factors (sclerostin/Sost, RANKL, osteoprotegerin) that affect other bone cells by paracrine/autocrine mechanisms and secrete hormones (FGF-23) that affect other tissues by endocrine mechanisms. n Four dynamic processes—growth, modeling, remodeling, and repair—control skeletal development and adaptation, defined by the relationship of bone resorption and bone formation to each other.

INTRODUCTION Bone is a complex natural composite material that undergoes millions of loading cycles during a lifetime without failure. Its structure is hierarchical, being organized differently at the organ (whole bone), tissue (material), and molecular (collagen–mineral) levels. The mechanical functions of bone are the most widely recognized and are often described in terms of strength and stiffness. Although strength and stiffness are important, bone is particularly effective at dissipating energy that could cause a fracture over repeated cycles of loading. Beyond its mechanical function, the marrow cavity and the porous trabecular bone in the ends of long bones and in the vertebrae and iliac crest are regions in which red blood cells are formed and stored. Bone is in fact a primary blood-storing organ. Additionally, bone is the body’s primary storehouse of calcium and phosphorus; 99% of the body’s calcium is stored in bone. These minerals are necessary for the proper function of a variety of systems in the body and are essential for enzyme reactions, blood clotting, the proper function of contractile proteins in muscles, and the transmission of nerve impulses.

ORGANIZATION OF BONE MACROSCOPIC (ORGAN) LEVEL Bone at the organ level consists of the diaphysis (shaft), the metaphysis, and the epiphysis (Fig. 3.1). In the long bones of growing children, the growth plate separates the epiphysis from the metaphysis. The primary component of the diaphysis is cortical or compact bone. The haversian canals in cortical bone create a porosity of about 3% to 5%, although this increases in older age and with osteoporotic changes to the skeleton. Compact bone is also found surrounding the spongy bone of the vertebral body and in the skull. It is very strong and provides both support and protection. Cancellous (trabecular or spongy) bone is found in the metaphyses of the long bones and in the vertebrae, surrounded by cortical bone. During growth, the primary spongiosa is composed mostly of disorganized woven 18

bone or primary lamellar bone surrounding a core of calcified cartilage. It is separated from the remodeled, more highly oriented secondary spongiosa by an arbitrary boundary. The secondary spongiosa reflects patterns of stress and functions largely to funnel stresses to the stronger and more massive cortical bone. In regions beneath joint surfaces, it also attenuates forces generated by mechanical loading and may protect the joint surface from loading-related trauma. The cancellous bone itself is composed of plates and rods of bone, each about 200 μm thick, with a porosity of about 75% to 85%. The marrow in the spaces between the trabecular struts is where red blood cells are formed (red marrow). In osteoporosis, the differentiation of cells in the bone lineage can be partly diverted to adipocytes, and the marrow becomes more fatty (yellow marrow). Because cancellous bone has a large surface area in contact with vascular marrow, it is ideal for the longterm exchange of calcium ions. In osteopenia, regions of cancellous bone are affected first. This is why the vertebral column, which is mainly composed of cancellous bone, is affected earlier and more severely in osteoporosis than even the femoral neck and hip.

MICROSCOPIC (TISSUE) LEVEL At the microstructural level, bone is organized differently for different functions (Fig. 3.2). In humans, bone tissue can be divided into three broad categories based partly on the arrangement of the collagen fibers and partly on whether it has replaced preexisting bone: (1) woven bone, (2) primary bone, and (3) secondary bone. Woven bone is characterized by randomly oriented collagen fibers, which tend to be smaller in diameter than those in more highly organized primary or secondary bone. Woven bone is not lamellar, is very porous, and may become highly mineralized. Woven bone can be deposited de novo without any bony or cartilaginous substrate or anlage, but it can also be formed as part of the process of endochondral ossification, either at the growth plate during development or during fracture repair. Woven bone proliferates rapidly because it has a large cell-volume ratio, which makes its role in fracture repair ideal. It is often found associated with osteosarcoma, probably because of proliferation especially of the cellular periosteum. The function of woven bone is primarily mechanical, rapidly providing both temporary strength and scaffolding upon which lamellar bone may be deposited. However, it can also be associated with pathologic processes that involve inflammatory cytokines. Primary bone must be deposited on a preexisting substrate and is organized into lamellar layers. Because of this, trabecular plates, which are composed mainly of primary lamellae, cannot be replaced after they are perforated. This accounts for the loss of trabeculae with age and is part of the reason that it is difficult to reverse osteoporotic changes after trabecular connectivity has been lost. Primary lamellar bone also forms in rings around the endocortical and periosteal surfaces of whole bone (circumferential lamellae). Primary lamellar bone itself is not very vascular and can become very dense. Primary bone can also be arranged in concentric rings around a central canal—much like a secondary haversian system, except without a definable cement line. These primary osteons tend to be small with few concentric lamellae. In reality, primary osteons are modified vascular channels that have “filled in” by the addition of lamellae to the surface of the vascular space. Secondary bone is the product of the resorption of preexisting bone and its replacement with new bone. This can occur within dense cortical bone (resulting in a secondary osteon, or haversian system) or begin on the surfaces of trabeculae (sometimes called a hemi-osteon). The distinction between primary and secondary bone is important because it is likely that control of primary bone apposition is different from replacement of preexisting bone by secondary bone. A secondary haversian system has a central vascular canal 50 to 90 μm in diameter. The blood vessels in the canal have the characteristics of capillaries and are generally paired within the canal. Venous sinusoids and lymphatic vessels are not found in haversian canals, although it has been suggested that prelymphatic vessels may exist.1 The vessel walls

CHAPTER 3  Bone structure and function contain no smooth muscle but are fenestrated capillaries lined by an incomplete layer of endothelial cells, similar to vessels in other blood-forming organs like the spleen and bone marrow.2 The vessel is accompanied about 60% of the time by two to seven unmyelinated or poorly myelinated nerve fibers.3 Because the capillaries have no smooth muscle, these nerves do not serve a vasomotor function but are primary sensory nerves or autonomic nerves from the sympathetic nervous system. Both primary afferents and sympathetic nerve fibers express neuropeptides that may play some role in regulating bone remodeling. Afferent nerve fibers also express GAP43, which is associated with axonal growth and may reflect the need for vessel growth and reinnervation during bone remodeling. Lining cells (resting osteoblasts) cover the haversian canal, which is surrounded by a series of concentric lamellae containing bone cells— osteocytes. The relationship between the size of the osteon and the size of its

Epiphysis

Epiphyseal plate

Longitudinal growth

Cancellous bone

Metaphysis

Osteoclastic resorption Diaphysis Osteoblastic formation

Cortical bone

FIG. 3.1 Bone consists of the diaphysis (shaft), the metaphysis, and the epiphysis. In growing children, the growth (epiphyseal) plate separates the epiphysis from the metaphysis. During growth, the periosteal surface of the metaphysis must be constantly resorbed, while concurrent bone formation occurs on the endocortical surface to convert the thin-walled but flared metaphysis into the narrower but thicker-walled diaphysis (McNeal tetrachrome stain).

canal is a measure of the balance between bone resorption (osteon diameter) and bone formation (canal diameter). The secondary osteon is bounded by a cement line, probably composed largely of sulfated glycosaminoglycans.4 The cement line forms an effective boundary that can arrest cracks in bone and stop them from growing to a critical size.

COMPOSITION OF BONE Bone is composed of organic and mineralized components, mainly consisting of a matrix of cross-linked type I collagen mineralized with nanocrystalline, carbonated apatite. Bone matrix incorporates a small fraction of noncollagenous proteins that serve to control collagen assembly and size as well as the process of mineralization and cell attachment. The mineral comprises about 65% to 67% of the bone by weight, the organic component about 22% to 25%, and water the remaining fraction (≈10%). Within the organic fraction, type 1 collagen makes up about 90%, with the remainder accounted for by several minor collagens (types III and V) and a variety of noncollagenous proteins, most of them extracellular, with cell protein accounting for about 15% of the noncollagenous proteins in bone. Type I collagen in bone is formed by a triple helix composed of two α1 chains and a single α2 chain. At either end of the collagen molecule are an N-telopeptide and a C-telopeptide, which can be cleaved when bone is resorbed and that are used to measure bone resorption biochemically. These individual triple-helical collagen molecules self-associate into a periodic arrangement of parallel molecules spaced in quarter-staggered array at distances of 40 nm between their ends to form collagen fibrils (Fig. e3.1). The holes plus the overlap zones give the collagen its banded appearance with a D-periodic spacing of 67 nm on average. The spaces between the ends of the collagen molecules are known as hole zones, and the 35-nm gap zones that run longitudinally parallel between the molecules are known as pores. Hydroxyapatite [Ca10(PO4)6(OH)2], which has small and poorly formed crystals, nucleates within these spaces. However, most of the mineral in bone, about 75%, is in the form of more highly carbonated apatite that forms plates about 300 nm long that lie outside the collagen fibril (extrafibrillar).5,6 The initial deposition of mineral—or primary mineralization—occurs rapidly after new bone is deposited, with about two thirds of the eventual mineral content achieved within about 3 weeks.7 As the bone tissue matures, the mineral crystals grow, become more platelike, and orient themselves parallel to one another and to the collagen fibrils. This process of crystal growth is sometimes called secondary mineralization and occurs over the next year or so until full mineralization is achieved. In cancellous bone, the c-axis or long axis of the mineral crystal aligns with the longitudinal axis of the trabeculae; in cortical bone the mineral orients to the long axis of the osteon. Other elements can easily substitute into the hydroxyapatite crystal, changing

Woven bone

FIG. 3.2  The three general microscopic types of bone, defined morphologically. Woven bone is composed of disorganized, randomly oriented collagen fibers. It is found at sites of fracture or inflammation. Lamellar bone can be divided into primary and secondary. Primary bone is deposited in layers by direct apposition on a substrate. It is found circling the endocortical and periosteal circumferences of a long bone and within trabeculae. Secondary bone is formed by replacement of primary bone through the process of resorption and subsequent new bone formation. (Woven bone: polarized light. Primary lamellar bone: left, basic fuchsin; right, polarized light. Secondary osteonal bone: left, toluidine blue; right, scanning electron microscopy image.)

19

Primary lamellar bone

Secondary osteonal bone

CHAPTER 3  Bone structure and function COLLAGEN

Hole zones

67 nm

Periodic staggered structure Mineral associated with gaps in stagger “Young Bone”: Cross-links associated with N and C end terminals of collagen Enzymatic cross-links Pore zones “Old Bone”: Non–end terminal associated cross-links Nonenzymatic cross-links

FIG. E3.1  In the collagen fibril, molecules are organized in a quarter-staggered array, with hole and pore zones between them where mineral can deposit. The hole zones give the collagen fibril its banded appearance when viewed by electron microscopy. Cross-links are formed either through the action of enzymes (divalent and trivalent cross-links) or through nonenzymatic processes, the latter forming advanced glycation end products that can make bone behave in brittle fashion.

19.e1

SECTION 1  Scientific Basis of Rheumatic Disease

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PG GROWTH FACTOR TGF- FGF Biglycan

OPG

Perlecan

PGs increase local growth factor concentrations

Decorin

RANKL

Binding to PG controls factor availability and therefore activity

Collagen fibrils BONE MATRIX

PGs provide ligand-receptor stabilization Cell membrane Betaglycan TGF-RII

RANK TGF-RI/RII

Syndecan FGFR dimer

its character and its ability to withstand mechanical loads. Collagen fibers can become cross-linked through the action of enzymes, which results in immature or reducible (divalent) cross-links that mature through the action of lysyl oxidase to irreducible (trivalent) cross-links such as pyridinoline and deoxypyridinoline. Because divalent cross-links are rapidly converted into mature trivalent cross-links under normal circumstances, the quantity of divalent cross-links in bone is an indirect measure of remodeling rate. Divalent and trivalent cross-links are associated with the N- and C-terminals of the collagen molecule. Cross-links can also be formed between the fibers without the action of enzymes. These cross-links are formed by the condensation of arginine, lysine, and free sugars or through various oxidation reactions, which results in the formation of advanced glycation end products. Accumulation of advanced glycation end products occurs in diabetes, making the bone more brittle and increasing the risk of fracture. The skeletal noncollagenous proteins comprise 10% to 15% of total bone protein. These molecules constitute a wide range of polypeptide species and have roles in multiple skeletal processes in addition to functioning as structural scaffolding within the bone matrix. One important feature of bone that has been largely overlooked until recently is water, which comprises about 10% of bone volume and can be found in either free-flowing or bound forms. Water stabilizes collagen structure8 but also allows sliding at the interface between the mineral and the collagen, which increases the ductility and toughness of bone.9 Because proteoglycans are hydrophilic, they may be important in retaining the water in some compartments.

PROTEOGLYCANS Proteoglycans (PGs) are a ubiquitous family of molecules composed of a core protein and one or several covalently attached sulfated glycosaminoglycan chains. The glycosaminoglycans are linear polymers of repeated disaccharide units of hexosamine and hexuronic acid, except for keratan sulfate, in which hexuronic acid is replaced by galactose. The core proteins attached to the glycosaminoglycans are a diverse protein group and range in size from 10 to 500 kDa. The wide variety of protein structure may aid in directing the unique functional roles of each PG family. The bone matrix contains PG families of several primary structures, including the following: 1. Hyaluronan/CD44, chondroitin sulfate–containing PGs are expressed in several regions of bone. Hyaluronan is expressed in focal regions within periosteum and endosteum and surrounding most of the major bone cell types, including osteoblasts, osteoprogenitor cells, osteoclasts, and osteocyte lacunae. CD44 is a cell-surface hyaluronan receptor that may play roles in guiding bone development and has been localized to osteoclasts, osteocytes, and bone marrow cells.10 Versican, a chondroitin sulfate–containing PG, may be enriched

Receptor signaling modified by PG expression

FIG. 3.3  Proteoglycans (PGs) regulate growth factors at several levels in the bone matrix and in bone cells. These polypeptides trap and locally concentrate endocrine and paracrine growth factors within the matrix. Soluble PGs such as decorin, biglycan, and perlecan also modulate activity through binding, thus controlling the concentrations of bioavailable factor. Membrane-bound PGs such as betaglycan and syndecan modulate ligand–receptor interactions and thus play roles in regulating intracellular signaling. FGF, Fibroblast growth factor; FGFR, fibroblast growth factor receptor; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor-κB; RANKL, receptor activator of nuclear factor-κB ligand; TGF-β, transforming growth factor-β; TGF-βRI/RII, transforming growth factor-β receptor types I and II. (Adapted from Lamoureux F, Baud’huin M, Duplomb L, et al. Proteoglycans: key partners in bone cell biology. Bioessays 2007;29:758–71.)

during early osteoid formation and may provide a temporary framework in newly formed cartilage matrix during bone development.11 Results from cultured mesenchymal cells derived from a mouse model carrying a disrupted versican gene (the hdf transgenic mouse) also suggest that mature versican PG may play a role in directing limb chondrocyte aggregation depending on the surrounding extracellular matrix (ECM).12 2. Heparan sulfate PGs (HSPGs) are produced by osteoblast and osteoclast lineage cells. These molecules play important roles in cell–cell interactions during bone formation by trapping autocrine and paracrine heparin-binding fibroblast growth factor (FGF) family members, as well as acting as coreceptors with the FGF receptors. Also, other secreted molecules bind HSPGs, such as transforming growth factor-β (TGF-β, betaglycan) and osteoprotegerin (OPG) (syndecans). The bioactivity of these factors is modulated by HSPGs, potentially through focusing of concentrations of these potent molecules near differentiating cells. . Small leucine-rich PGs are the most abundant of the PGs in bone 3 matrix and include decorin, biglycan, fibromodulin, lumican, and osteoadherin. These molecules help to provide the structural organization of the bone matrix and interact with specific growth factors and collagen to increase factor concentration and bioactivity in the matrix (Fig. 3.3). The localization of these proteins in mature bone varies; whereas decorin may localize with specific matrix areas, biglycan is evenly distributed throughout the matrix. Whereas decorinnull animals have alterations in collagen fibril size and bone shape,13 biglycan-null animals demonstrate reduced bone mass because of lower osteoblast numbers and also show reduced numbers of osteoclasts.14 Small leucine-rich PGs play an essential role in the regulation of growth factor activity. In this regard, decorin, biglycan, and fibromodulin all possess the ability to bind to TGF-β; however, decorin is the best characterized of these proteins for the ability to bind this factor. Decorin enhances TGF-β binding with its cognate receptors and enhances its bioactivity and, in concert, may act to sequester TGF-β in the collagen fibrils, thus reducing its activity. TGF-β activity is associated with increased apoptosis of osteoprogenitors; therefore biglycan and decorin appear to be essential for maintaining mature osteoblast numbers through regulation of the proliferation and survival of bone marrow progenitor cells.

OSTEOCALCIN Osteocalcin (OC) is a polypeptide posttranslationally modified to carry dicarboxylic glutamyl (Gla) residues, which relies on vitamin K for proper production (another identifier for OC is bone γ-carboxyglutamic acid [Gla]

CHAPTER 3  Bone structure and function protein [BGLAP or BGP]). In humans, vitamin K is primarily a cofactor in the enzymatic reaction that converts glutamate residues into γ-carboxyglutamate residues in these vitamin K–dependent proteins including OC but also in proteins involved in blood clotting such as factor IX. These Gla-containing motifs are thought to enhance calcium binding, which may function to control mineral deposition and bone remodeling. A nine-residue domain proximal to the N-terminal of secreted OC shares high homology with the corresponding regions in known propeptides of the γ-carboxyglutamic acid–containing blood coagulation factors. This common structural feature may be involved in the posttranslational targeting of these proteins for γ-carboxylation. Osteocalcins may also act as a hormone to regulate the activity of osteoclasts and their precursors. In support of this, the skeleton of the OC-null animal manifests osteopetrosis compared with wild-type litter mates. In humans, OC is expressed largely by osteoblasts and osteocytes, and the measurement of this protein in serum has been used as a marker of bone turnover. OC messenger RNA (mRNA) is upregulated by vitamin D through interactions with trans-acting factors in vitamin D response elements in the OC promoter.15 Because of its cell-specific expression, the OC promoter has proven to be invaluable as an active, functional DNA to drive foreign complementary DNAs in osteoblasts in transgenic animals.

OSTEOPONTIN Osteopontin (OPN), also referred to as secreted phosphoprotein-1, is a member of the SIBLING (small integrin-binding ligand N-linked glycoprotein) family, which is a group of noncollagenous ECM proteins involved in bone mineralization. The genes coding for these proteins are localized to human chromosome band 4q21-25, have similar exon arrangements, and include those coding for dentin matrix protein-1, dentin sialoprotein, dentin phosphoprotein, integrin-binding sialoprotein, and matrix extracellular phosphoglycoprotein (MEPE). The SIBLING proteins share common structural features, such as multiple phosphorylation sites, a highly acidic nature, the presence of an arginine–glycine–aspartic acid cell attachment domain, and proteolysis-resistant acidic serine aspartate–rich MEPE-associated motif. Osteopontin has a high sialic acid content and is produced by osteoblasts under stimulation by calcitriol. OPN is expressed within cement lines and may thus act as a promoter of adhesion and allow the arrangement of dissimilar tissues together in biologic composites such as teeth and bone.16 OPN binds tightly to hydroxyapatite and may be involved in the anchoring of osteoclasts to the mineral of bone matrix. The vitronectin receptor, which has specificity for OPN, is focused within the osteoclast plasma membrane in the regions involved in the binding process. Long bones from OPN-null mice are indistinguishable from those from wild-type litter mates by radiography, but the relative amount of mineral in the more mature areas of the bone (central cortical bone) of the OPN-null mice is significantly increased, as is the mineral maturity (mineral crystal size and perfection) throughout all regions of the bone.17 In vitro, exogenous OPN inhibits inorganic pyrophosphate (PPi)-dependent mineralization of a cultured osteoblast cell line.18 These findings indicate that OPN is a potent inhibitor of mineral formation as well as crystal growth and proliferation.

OSTEONECTIN Osteonectin, also referred to as secreted protein acidic and rich in cysteine (SPARC), is a phosphoprotein that is the most abundant noncollagenous polypeptide expressed in bone. The mature protein binds selectively to hydroxyapatite, collagen fibrils, and vitronectin at distinct sites and may allow proper organization of the bone matrix through contacts with the cellular surface. Osteonectin also inhibits cellular proliferation through arrest of cells in the G1 phase of the cell cycle. It may regulate the activity of platelet-derived growth factor, vascular endothelial growth factor, and FGF-2. The osteonectin crystal structure has revealed a novel follistatin-like component and an extracellular calcium–binding region containing two EF-hand motifs. Osteonectin-null mice develop severe osteopenia, which indicates that this gene may have roles in osteoblast proliferation and in mineralization.

ALKALINE PHOSPHATASES AND ECTONUCLEOTIDE PYROPHOSPHATASE AND PHOSPHODIESTERASES Alkaline phosphatases are widely distributed and are membrane-bound glycoproteins that hydrolyze monophosphate esters.19 The liver–bone–kidney alkaline phosphatase, referred to as tissue-nonspecific alkaline phosphatase (encoded by the ALPL gene), acts as a lipid-anchored phosphoethanolamine

21

and pyridoxal 5′-phosphate ectophosphatase. Loss-of-function mutations in the ALPL gene lead to hypophosphatasia, which is characterized by marked defects in bone mineralization and is lethal in the infantile form. The PPi produced by cells inhibits mineralization by binding to crystals, and the presence of PPi may thus prevent the soft tissues from undergoing mineralization. The degradation of PPi to inorganic phosphate by ALPL in bones and teeth may facilitate crystal growth; therefore it is thought that loss of function of the ALPL gene in hypophosphatasia results in accumulation of PPi and reduced skeletal mineralization. Ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1) is a type II transmembrane glycoprotein and a member of the ENPP family. ENPP1 has broad specificity and cleaves phosphodiester bonds of nucleotides and nucleotide sugars as well as pyrophosphate bonds of nucleotides and nucleotide sugars. This protein may function to hydrolyze nucleoside 5′-triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates. Loss-of-function mutations in ENPP1 result in autosomal recessive hypophosphatemic rickets type 2, characterized by a ricketic phenotype and elevation of FGF-2320 (see later discussion).

THROMBOSPONDINS 1 AND 2 The thrombospondins (TSPs) are a family of secreted glycoproteins of high molecular mass. TSP1 and TSP2 share high homology and form 450-kDa homotrimers. Both TSP1 and TSP2 are expressed by mesenchymal cells and chondrocytes during cartilage formation. As osteoblasts replace the mineralizing cartilage, TSP2 expression decreases in chondrocytes and increases in the matrix within areas undergoing ossification. TSP1 and TSP2 are strong antiangiogenic factors and therefore may also play a role in controlling blood vessel organization in forming bone. In developing animals, TSP1 and TSP2 are expressed in temporal and spatial patterns distinct for each gene. TSP1 (mouse gene, Thbs1) and TSP2 (Thbs2) have both been disrupted in mice and have unique phenotypes associated with each gene. Thbs1 is a regulator of TGF-β in vivo, and null animals have lower viability and prolonged wound healing. For skeletal phenotypes, this model has spine curvature and craniofacial alterations. Thbs2-null mice have increased cortical bone density, higher numbers of mesenchymal stem cells, and a resistance to bone loss due to ovariectomy. The fact that the Thbs2-null mice demonstrate less bone resorption than wild-type controls after ovariectomy may suggest a role for this molecule in estrogen-dependent reductions in bone mass and in the control of osteoclast function.

PROTEINS INVOLVED IN MINERALIZATION Fibroblast growth factor 23 Fibroblast growth factor 23 is a phosphaturic hormone produced in bone (Fig. 3.4), and the encoding gene was identified as the mutated gene in autosomal dominant hypophosphatemic rickets (ADHR), a metabolic bone disorder of isolated renal phosphate wasting.21 Full-length FGF-23 (32 kDa) is the biologically active form of the protein and is inactivated upon cleavage into 20- and 12-kDa protein fragments. Intracellular cleavage of FGF-23 occurs between R179 and S180 within a highly charged subtilisin-like proprotein convertase (SPC) proteolytic site (R176H177T178R179/S180AE). The human FGF-23 ADHR mutations R176Q, R179Q, and R179W destroy this site and stabilize the full-length active form of the protein. The production and secretion of whole-molecule, bioactive FGF-23 is a dynamic process. Within the trans-Golgi network, UDP-GalNAc transferase 3 (GALNT3) O-glycosylates FGF-23 on T180. This glycosylation stabilizes bioactive FGF-23 by inhibiting cleavage between residues R179 and S180 via the SPC furin (PCSK3). The importance of this event is underscored by the fact that patients with GALNT3 inactivating mutations do not efficiently produce bioactive FGF23.22 The GALNT3-mediated FGF-23 glycosylation can be sterically hindered through prior phosphorylation of S180 by the novel kinase FAM20C,23 thus providing a molecular interaction that controls the ability of osteoblasts and osteocytes to regulate serum phosphate concentrations and potentially bone mineralization (see Fig. 3.4). FGF-23 acts in the kidney to inhibit phosphate reabsorption by reducing expression of the proximal tubule type I sodium–phosphate cotransporters Npt2a24 and Npt2c. The subsequent low serum phosphate level results in marked osteomalacia and rickets, fracture, and dental anomalies. Application of in situ hybridization to adult trabecular bone revealed the presence of FGF-23 mRNA in osteocytes and flattened bone-lining cells. In regions of active bone formation, newly formed osteocytes and osteoprogenitor cells also express FGF-23.25 FGF-23 levels are elevated in vivo by increased serum phosphate and 1,25-dihydroxyvitamin D concentrations, and FGF-23 then completes the feedback loop by

SECTION 1  Scientific Basis of Rheumatic Disease

22

BONE MATRIX MINERALIZATION Osteonectin OC

OPN MEPE

Matrix mineralization

Osteocytes

alkaline phosphatase, and FGF-23 in mature embedded osteocytes. The relationship of DMP1 to cell differentiation is currently unknown. Interestingly, FAM20c, a novel secreted kinase,28 has been shown to phosphorylate the SIBLING proteins DMP1 and MEPE (see next section). Loss of FAM20c in mice results in a Dmp phenotype,29 which indicates a complex relationship between the phosphorylation of ECM proteins and their normal functions.

PHEX DMP1 AP

PPi

Pi

Matrix extracellular phosphoglycoprotein FGF-23

ENPP Intracellular PPi

Dietary Pi

Pi reabsorption

Kidney

FIG. 3.4  Bone matrix mineralization involves an interplay of factors and is controlled by the balance between inorganic phosphate (Pi) and inorganic pyrophosphate (PPi) and the expression of key local and systemic factors. Whereas an excess in Pi induces mineralization, PPi inhibits it. Proteins expressed in osteocytes and osteoblasts regulate mineralization. Specifically, whereas PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) and dentin matrix protein-1 (DMP1) induce mineralization, fibroblast growth factor 23 (FGF-23) inhibits mineralization. Inhibition of mineralization by FGF-23 is believed to be caused by inhibition of Pi reabsorption in the kidney, which reduces blood and bone Pi levels. Induction of mineralization by PHEX and DMP1 may be secondary to inhibition of FGF-23 and thus increases in circulating Pi. The Pi levels in the extracellular matrix depend on dietary intake and on its rate of synthesis from PPi catalyzed by alkaline phosphatase (AP). Conversely, the levels of PPi depend on its conversion from Pi by ectonucleotide pyrophosphatase/phosphodiesterase enzymes (ENPPs). Other bone-derived proteins, such as matrix extracellular phosphoglycoprotein (MEPE), osteopontin (OPN), osteocalcin (OC), and osteonectin, coordinately regulate mineralization, likely through direct interactions with the mineralized matrix. (Adapted from Bellido T, Plotkin LI, Bruzzaniti A. Bone cells. In: Burr DB, Allen MR, editors. Basic and Applied Bone Biology. San Diego: Academic Press; 2014, p. 27–46.)

reducing phosphate reabsorption and 1,25-dihydroxyvitamin D production in the kidney. Evidence also indicates that FGF-23 is directly regulated by parathyroid hormone (PTH) in osteocytes.26 Whether FGF-23 has direct effects on the skeleton is uncertain because the FGF-23 coreceptor α-Klotho is predominantly expressed in the kidney and parathyroid glands. However, because FGF-23 is produced in bone, FGF-23 expression and its actions on serum phosphate concentrations may be coordinated with intraskeletal signals to allow proper bone formation and mineralization.

PHEX X-linked hypophosphatemia, a disorder of rickets and osteomalacia, is caused by inactivating mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome).27 PHEX encodes a protein that is similar to the M13 family of membrane-bound metalloproteases such as neutral endopeptidase and endothelin-converting enzymes 1 and 2 (see Fig. 3.4). These proteases are known to cleave small peptide hormones. Mutations in PHEX lead to dramatic overexpression of FGF-23; however, the PHEX substrate and molecular mechanisms underlying this increase are currently unknown.

Dentin matrix protein-1 Dentin matrix protein-1 (DMP1), similar to OPN, is a member of the SIBLING gene family. DMP1 is highly expressed in osteocytes and is composed of 513 residues but is secreted in bone and dentin as 37-kDa N-terminal (residues 17–253) and 57-kDa C-terminal (residues 254–513) fragments from a 94-kDa full-length precursor (see Fig. 3.4). Recombinant DMP1 binds calcium-phosphate ions and the N-telopeptide region of type I collagen with high affinities, so in vivo DMP1 may regulate local mineralization processes in bone and teeth. The C-terminal portion of DMP1 has been implicated in DNA binding, in gene regulation, and as an integrin-binding protein. Inactivating mutations in DMP1 result in the metabolic bone disease autosomal recessive hypophosphatemic rickets, which is associated with elevated FGF-23 levels in these patients. As shown in the Dmp1null mouse (and in the Hyp mouse model of X-linked hypophosphatemia), the primary cellular defect caused by loss of Dmp1 may be an alteration in osteoblast to osteocyte maturation, leading to inappropriate expression of typically “osteoblastic” or “early osteocyte” genes such as type I collagen,

Another member of the SIBLING family found in the mineralizing matrix is MEPE (see Fig. 3.4). MEPE is predominantly expressed in odontoblasts and osteocytes embedded in the mineralized matrix. In vitro studies of human osteoblast cell cultures indicate that MEPE expression is the highest during the mineralization phase.30 Mepe-null mice display increased trabecular and cortical bone mass because of increases in both osteoblast number and activity, and these mice are also resistant to age-dependent trabecular bone loss.31 Taken together, these findings indicate that MEPE likely has a role as an important gene for the negative regulation of skeletal mineralization.

GROWTH FACTORS Multiple growth factors, either produced within bone or circulating to bone, are critical for skeletal development and function. These factors may be sequestered within bone matrix via the bloodstream or may be produced by the major bone cell types and act as paracrine and autocrine factors.

Insulin-like growth factors The insulin-like growth factors IGF-1 (somatomedin C) and IGF-2 (somatomedin A) are produced primarily in the liver but are also produced in bone. These factors predominantly circulate complexed with IGF binding proteins (IGFBPs) to facilitate their transport to tissues. IGFBPs can either enhance or inhibit IGF activity. IGF-1 and -2 act through the IGF-1 receptors (IGFR1 and IGFR2) and possess bioactivity that promotes cell proliferation and differentiation. The IGF-1-null mouse has reduced cortical bone and femur length; however, trabecular density is increased. In vitro findings suggest that IGF-1 also increases osteoclastogenesis, and IGF-1-null mice have reduced levels of receptor activator of nuclear factor-κB ligand (RANKL) in osteoblasts isolated from bone marrow. Therefore IGF-1 may regulate osteoclastogenesis through direct and indirect actions. Overexpression of IGF-1 specifically in osteoblasts leads to increased bone mineral density and increased trabecular volume, although osteoblast numbers are not increased.32 These studies suggest that IGF-1 acts directly on osteoblasts to enhance their function. Specific removal of IGFR1 from osteoblasts results in decreased trabecular number and volume and a dramatic decrease in bone mineralization, which further supports the role of the IGFs with regard to osteoblasts. Less is known regarding the functions of IGF-2 in bone. However, it has been suggested that IGF-2 may be a local regulator of bone cell metabolism.

Bone morphogenetic protein family Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily. There are now more than 20 BMP-related proteins, which are classified into subgroups based on structure and function. These factors play important roles in skeletal development by directing the fate of mesenchymal cells, through differentiation of these precursor cells into cells of the osteoblastic lineage, and by inhibiting their differentiation into myoblastic lineage cells. BMPs also increase osteoclastogenesis, which is tightly coordinated with osteoblastogenesis. BMPs activate specific receptors and induce cell signaling by phosphorylating cytoplasmic receptor–regulated Smads, which enter the nucleus to recruit transcription factors and enhance gene expression. The human disorder fibrodysplasia ossificans progressiva is a disease of dramatic ectopic bone formation, which can be accelerated after blunt trauma. A recurrent mutation in activin receptor IA/activin-like kinase 2, a BMP type I receptor, was reported as the molecular cause of fibrodysplasia ossificans progressiva.33 These findings underscore the potent effects of BMP signaling on bone formation.

Fibroblast growth factors Members of the FGF family of proteins primarily act as paracrine and autocrine factors and bind to one or several of four FGF receptors (FGFRs). FGFRs normally exist as an inactivated monomer. With FGF binding in the presence of heparin/heparan sulfate, the FGFRs dimerize, which leads to the autophosphorylation of tyrosine residues. The FGF family has potent effects on bone development. This is clearly evident by the fact that activating mutations in FGFR1 and FGFR2 are responsible for disorders of craniosynostosis and limb patterning, and FGFR1 and FGFR3 mutations result in

CHAPTER 3  Bone structure and function disorders of hypochondroplasia and achondroplasia. The FGFs interact with HSPGs and are sequestered within the mineralizing matrix. In addition, the HSPG syndecan may stabilize FGF–FGFR interactions and promote FGF signaling and bioactivity. The FGF family members play important roles in bone development and formation. Expression of several FGF ligands, including FGF-2, FGF-5, FGF-6, FGF-7, and FGF-9, has been observed in mesenchyme surrounding the initial congregations of cells that proliferate and differentiate to form bone. In limb bud, FGFR1 and FGFR2 are expressed in condensing mesenchyme. In rat growth plates, mRNAs encoding all four FGFRs and FGF-2 can be detected, and FGF-2 is also present in osteoblasts. FGF-2 treatment of osteoblasts enhances the binding of Runx2 to the Cbfa1 consensus sequence in the OC promoter and may therefore have a role in differentiation.

Transforming growth factor-β Transforming growth factor-β controls proliferation, differentiation, and other functions in many cell types. TGF-β1, TGF-β2, and TGF-β3 all function through the type I and type II TGF receptors. The type I TGF-β receptor forms a heterodimer with the type II TGF-β receptor. TGF-β stimulation leads to activation of SMAD2 and SMAD3, which form complexes with SMAD4 that accumulate in the nucleus and regulate the transcription of target genes. Transforming growth factor-β is the most abundant growth factor in human bone; it is localized within the bone matrix and has functions both during embryonic development and in mature bone. During embryonic development, TGF-β1 plays a role in cell migration, controlling epithelial– mesenchymal interactions, and the formation of cellular condensations, which influence bone shape. This factor also plays a key role in inducing mesenchymal cell differentiation to either chondrocytes or osteoblasts. In adult bone, TGF-β1 controls osteoblast differentiation, which affects matrix formation and mineralization. TGF-β1 inhibits the expression of the differentiation markers Runx2 and OC in osteoblast cell lines, and its functions interplay with those of other systems in bone such as the PTH and the Wnt/β-catenin systems. The skeletal disorder Camurati–Engelmann disease (CED) highlights the importance of TGF-β1 in skeletal formation. CED is a progressive diaphyseal dysplasia characterized by hyperostosis and sclerosis of the diaphyses of the long bones. The TGFB1 gene was screened and three different heterozygous missense mutations were found in exon 4 in the nine families examined. All of the mutations in patients with CED were located either at C225 or near R218, which suggests the importance of this region in activating TGF-β1 in the bone matrix.

Platelet-derived growth factor and vascular endothelial growth factor All platelet-derived growth factors (PDGFs) and vascular endothelial growth factors (VEGFs) are dimers of disulfide-linked polypeptide chains, encoded by nine different genes that direct production of four different PDGF chains (PDGF-A, PDGF-B, PDGF-C, and PDGF-D) and five different VEGF chains (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor). All members of these families carry a growth factor core domain that is necessary for receptor activation. PDGFs mediate their bioactivity through two receptors, PDGFR-α and PDGFR-β. These receptors both have five extracellular immunoglobulin loops for ligand binding and an intracellular tyrosine kinase domain. The VEGFs act through a homologous family of receptors, VEGFR1, VEGFR2, and VEGFR3. PDGFs act primarily as paracrine growth factors. Platelet-derived growth factor is chemotactic and mitogenic for osteoblasts and osteoprogenitor cells, and it upregulates cytokines that are crucial to bone healing. This factor also destabilizes blood vessels during healing to allow sprouting of new vessels. VEGF is produced by many cell types, including fibroblasts, hypertrophic chondrocytes, and osteoblasts. VEGF may act not only in bone angiogenesis and vascular differentiation but also in aspects of development, such as chondrocyte and osteoblast differentiation, as well as osteoclast recruitment.

BONE CELLS Bone development and the adaptation of the adult skeleton to mechanical needs and hormonal changes depend on the ability of bone cells to resorb and form bone in the right places and at the right time. Bone growth, modeling, and remodeling are defined by the spatial and temporal relationship between bone resorption and bone formation. Osteoclasts resorb bone, osteoblasts form bone, and osteocytes detect the need for bone augmentation or reduction and coordinate the activity of osteoclasts and osteoblasts.

23

OSTEOCLASTS Osteoclasts are the primary bone-resorptive cells. They are needed for bone modeling, which leads to changes in the shape of bones, and for bone remodeling, which maintains the integrity of the adult skeleton. Osteoclasts originate from precursors of the monocyte/macrophage family of the hematopoietic lineage that differentiate to multinucleated cells upon stimulation with RANKL and macrophage colony-stimulating factor (M-CSF) (Fig. 3.5). Upon completing bone resorption, all osteoclasts undergo programmed cell death or apoptosis and disappear from the bone surface.

Osteoclast morphology and function Osteoclasts adhere firmly to bone through the interactions established between integrins expressed in the osteoclast membranes with collagen, fibronectin, and other bone matrix proteins. Expression of αV and α3 integrin is induced during osteoclast differentiation, and the integrin binds to the amino acid sequence Arg-Gly-Asp present in OPN and bone sialoprotein. The importance of these events for osteoclast activity is underscored by the inhibition of resorption with competitive Arg-Gly-Asp ligands34 and a progressive increase in bone mass caused by osteoclast dysfunction in mice null for β3 integrin. The intimate contact between the osteoclast and the bone matrix creates a space called the sealing zone. There is also polarization of the osteoclast fibrillar actin into a circular structure called the actin ring, containing podosomes composed of an actin core surrounded by αVβ3 integrins and associated cytoskeletal and signaling proteins. Thus, the area in which the osteoclast apposes the bone is isolated from the general extracellular space and becomes acidified by the activity of a proton pump and a chloride channel.34 The low pH in this area dissolves the mineral and exposes the organic matrix, which is subsequently degraded by the activity of lysosomal cathepsin K and matrix metalloproteases. These degrading enzymes are transported into acidified vesicles that fuse with the osteoclast plasmalemma, forming a villous structure referred to as the ruffled border. This structure and the actin ring are essential features of a resorbing osteoclast, and abnormalities of either structure lead to arrested bone resorption. The cytoplasmic domains of integrins serve as platforms for signaling proteins involved in osteoclast function, such as the kinase Src, which is crucial for osteoclast attachment and resorption. Src regulates podosome disassembly and ruffled membrane formation by its ability to interact with the focal adhesion–related kinase Pyk2 and the proto-oncogene c-Cbl. Rho, Rac, and the guanine nucleotide exchange factor Vav3, which activates guanosine diphosphatases into guanosine triphosphatases, also play a central role in modifying the resorptive capacity of osteoclasts by modulating the actin cytoskeleton. Osteoclast resorption products are transported in vesicles through the cytosol to the basolateral surface and discharged to the extracellular milieu or directly released to the surrounding fluid after osteoclast retraction from the resorption pits.

Osteoclast formation and differentiation Mature, multinucleated osteoclasts are formed by fusion of mononuclear precursors of the monocyte/macrophage lineage (see Fig. 3.5). The earliest recognized osteoclast precursor is the granulocyte–macrophage colony-forming unit, which also gives rise to granulocytes and monocytes. Osteoclast precursors proliferate in response to growth factors such as interleukin-3 (IL-3) and colony-stimulating factors like granulocyte–macrophage colony-stimulating factor (GM-CSF) and M-CSF to form postmitotic, committed mononucleated osteoclast precursors, which differentiate and fuse to form multinucleated osteoclasts under the influence of RANKL, a member of the tumor necrosis factor (TNF) family of ligands. M-CSF and RANKL are critical for osteoclastogenesis, and deletion of M-CSF, RANKL, or RANK (the receptor for RANKL expressed by osteoclasts and their precursors) inhibits osteoclast differentiation, leading to osteopetrosis in mice. Both M-CSF and RANKL are expressed by bone marrow stromal cells and osteoblastic cells, as well as T lymphocytes and other cell types in pathologic settings. Importantly, osteocytes have now been found to be a major source of M-CSF and RANKL, as well as OPG, the RANKL decoy receptor,35,36 and deletion of RANKL from osteocytes leads to osteopetrosis,36 demonstrating a central role of osteocytes in osteoclastogenesis (see Fig. 3.5). Whereas M-CSF contributes to osteoclast differentiation, migration, and survival by binding to its receptor c-Fms on osteoclast precursors, RANKL facilitates osteoclast formation via direct binding to the receptor RANK. RANKL is expressed on the cell surface and is also secreted as a soluble form. Although the soluble form of RANKL is found in the circulation and its presence is sufficient to induce differentiation of osteoclast precursors in vitro, its actual role in osteoclast formation in vivo remains unproven.

24

SECTION 1  Scientific Basis of Rheumatic Disease OSTEOCLAST GENERATION AND FATE

Stromal osteoblastic cells

Osteocytes

M-CSF, RANKL

OPG

Hematopoietic monocyte/ macrophage Monocytes Determination

Preosteoclast Proliferation survival

Fusion

Commitment differentiation

Polarization

Resorption

Maturation

Apoptosis

FIG. 3.5  Osteoclast differentiation is governed by receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) secreted by osteoblasts and osteocytes, which control various steps of the osteoclast differentiation process, including precursor proliferation, commitment, differentiation, and maturation. Osteoprotegerin (OPG), which is also secreted by osteoblasts and osteocytes, acts as a decoy receptor for RANKL and reduces osteoclast differentiation. (From Bellido T, Plotkin LI, Bruzzaniti A. Bone cells. In: Burr DB, Allen MR, editors. Basic and Applied Bone Biology. San Diego: Academic Press; 2014, p. 27–46.)

RANKL expression is upregulated by hormones and cytokines known to induce osteoclast generation. This explains the long-observed property of primary osteoblastic cells or osteoblastic cell lines that, upon treatment with vitamin D, PTH, or IL-11, IL-6, TNF, and IL-1, support osteoclast development when co-cultured with osteoclast precursors derived from spleen or bone marrow. RANKL mediates several aspects of osteoclast differentiation, including fusion of mononucleated precursors into multinucleated cells, acquisition of osteoclast-specific markers, attachment of osteoclasts to the bone surfaces, stimulation of resorption, and promotion of osteoclast survival. Although M-CSF contributes to RANKL effects, RANKL appears to play a dominant role in bone resorption. Thus, whereas M-CSF-null mice recover with time from the decreased osteoclast number and activity, RANKL knockout mice do not. Furthermore RANKL appears to stimulate osteoclast formation and resorption in mice even in the absence of functional M-CSF.37 RANKL activates several signal transduction pathways involving the recruitment of the adapter protein TRAF6 (TNF receptor–associated factor 6) to the intracellular domain of the receptor RANK. TRAF6 in turn activates kinase-dependent signaling as well as transcription factors. Among them, NF-κB has been shown to undergo nuclear translocation, leading to upregulation of c-Fos. c-Fos, in turn, binds to nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and upregulates genes crucial for osteoclast differentiation and function. Although other signaling pathways are activated by RANKL in osteoclasts, the evidence that deletion of NF-κB, c-fos/ AP1, and NFATc1 leads to osteoclast dysfunction demonstrates the crucial role of these genes in osteoclasts.37 Osteoprotegerin is an inhibitor of RANK activation and osteoclastogenesis that also belongs to the TNF family of receptors. OPG is a secreted protein with no transmembrane domain, and therefore it has no direct signaling capabilities. OPG suppresses osteoclast formation and resorption by binding to RANKL, thereby impeding RANKL interaction with RANK.

Osteoclast apoptosis All osteoclasts undergo apoptosis and disappear from the bone surface after completing bone resorption. High concentrations of extracellular calcium, similar to those present in resorption cavities, induce osteoclast apoptosis in vitro and may be the triggering event. Fas ligand stimulates osteoclast apoptosis, and Fas-deficient mice exhibit more osteoclasts and decreased bone mass, which suggests that this pathway controls osteoclast life span in vivo. Osteoclast apoptosis might also result from loss of survival signals provided by integrin interactions with the matrix or by changes in the production of cytokines or growth factors that preserve osteoclast viability. Potential antiapoptotic factors are M-CSF and RANKL, the same cytokines that induce osteoclast differentiation. TNF-α and IL-1 also delay osteoclast apoptosis. All of these cytokines activate the extracellular signal–regulated kinases (ERKs), the activation of which

is required for osteoclast survival. Phosphatidylinositol 3′-kinase (PI3-K) and its target the kinase Akt are required for osteoclast differentiation but not for survival. Instead, mammalian target of rapamycin (mTOR), another PI3-K target, is required for the antiapoptotic actions of M-CSF, RANKL, and TNF-α in osteoclasts. Because mTOR is also activated by ERKs, it appears to be a point of convergence in the action of prosurvival kinases in osteoclasts. RANKL, TNF-α, and IL-1 also activate NF-κB, a transcription factor shown to inhibit apoptosis in various cell types. Downregulation of NF-κB mRNA inhibits IL-1-dependent survival, and blockade of NF-κB binding to DNA with specific oligonucleotides induces apoptosis. However, osteoclast precursors lacking NF-κB subunits have normal survival rates, and inhibition of NF-κB activation via a dominant-negative IKK2 does not affect the ability of IL-1 to promote osteoclast survival. Therefore the relevance of NF-κB signaling for osteoclast survival is still controversial.

Regulation of osteoclast generation and survival In the bone-remodeling unit, whereas the rate of osteoclast generation determines the extension of the bone-remodeling unit, the life span of osteoclasts determines the depth of resorption. Although both genesis and apoptosis of osteoclasts lead to changes in osteoclast number and bone resorption, alteration of osteoclast life span might represent a more effective mechanism to accomplish rapid changes in bone resorption rate. Sex steroids have profound effects on osteoclasts. Both estrogens and androgens inhibit osteoclast generation by regulating the production of pro-osteoclastogenic cytokines (e.g., IL-6 and IL-1) by cells of the stromal/oste oblastic lineage. Estrogens also induce apoptosis of mature osteoclasts. This, together with an inhibitory effect of the hormones on osteoblast generation, leads to attenuation of the rate of bone remodeling. Mice receiving excess glucocorticoids exhibit reduced osteoclast progenitors, but cancellous osteoclast number does not decrease in the early phases of the disease because glucocorticoids prolong the life spans of preexisting osteoclasts. This effect may account for the early transient increase in bone resorption in patients with hyperglucocorticoidism. In contrast to the rapid prosurvival effect of glucocorticoids on mature osteoclasts, glucocorticoids induce a decrease in osteoclast formation caused by a reduction in the pool of osteoblastic cells that support osteoclastogenesis. This effect leads to the typical low remodeling rate observed in chronic glucocorticoid-induced osteoporosis.

OSTEOBLASTS Osteoblasts are the cells responsible for bone formation. They originate from mesenchymal progenitors, which also give rise to chondrocytes, muscle cells, and adipocytes (Fig. 3.6). Commitment of mesenchymal cells to the osteoblastic lineage depends on the specific activation of transcription

CHAPTER 3  Bone structure and function

25

OSTEOBLAST GENERATION AND FATE AP1 Smad 1/4/5 Transcription factors

Twist1 Dermo1

-catenin

Mesenchymal stem cell

Osteochondral precursor

Runx2 Rbp-Jk

Runx2 Dlx3,5,6 Rbp-Jk -catenin

Preosteoblast

Rbp-Jk Osx NFAT2 -catenin

FRA-1/ATF4 -catenin

Immature osteoblast

Mature osteoblast

Osteocyte

Lining cell

Apoptotic osteoblast

FIG. 3.6  Osteoblastogenesis is controlled by transcription factors that affect the proliferation and differentiation of osteoblast precursors. Mature osteoblasts can surround themselves by bone matrix and differentiate further to become osteocytes, flatten to cover the quiescent bone surface as lining cells, or die by apoptosis. (From Bellido T, Plotkin LI, Bruzzaniti A. Bone cells. In: Burr DB, Allen MR, editors. Basic and Applied Bone Biology. San Diego: Academic Press; 2014, p. 27–46.)

factors induced by morphogenetic and developmental proteins that carry out the functions of bone matrix protein secretion and bone mineralization. Upon completion of bone matrix formation, some mature osteoblasts remain entrapped in bone as osteocytes, some flatten to cover quiescent bone surfaces as bone-lining cells, and most die by apoptosis.

Osteoblast function The main function of osteoblasts is to synthesize collagen type I and other specialized matrix proteins that serve as a template for the subsequent mineral deposition in the form of hydroxyapatite. Mature osteoblasts actively engaged in this process are recognized by their location on the bone surface and by their morphologic features typical of cells secreting high levels of proteins: cuboidal shape with large nucleus, enlarged Golgi apparatus, and extensive endoplasmic reticulum. Osteoblasts express high levels of alkaline phosphatase and OC, and the level of these proteins in blood reflects the rate of bone formation. Interaction of osteoblasts among themselves, with lining cells, and with bone marrow cells is established by adhesion junctions, tight junctions, and gap junctions. Adhesion junctions mainly mediated by cadherins and tight junctions serve to join cells and facilitate their anchorage to the ECM. Changes in the expression level of the major cadherins expressed in osteoblasts, N-cadherin and cadherin 11, influence osteoblast differentiation and survival. Intercellular communication among osteoblasts and neighboring cells is maintained by cell coupling via gap junctions. Opening of gap junction channels contributes to coupling and the coordination of responses within a cell population. The major gap junction protein expressed in bone cells is connexin 43. Its absence or dysfunction leads to impaired osteoblast differentiation, premature apoptosis of osteoblasts and osteocytes, and deficient response to hormones and pharmacotherapeutic agents.38 Furthermore gap junction communication is fundamental for the maintenance of a continuum from bone, where osteocytes reside, through bone surface cells, osteoblasts and osteoclasts, bone marrow cells, and endothelial cells of the blood vessels.39 This functional syncytium might be responsible for the coordinated response of the bone tissue to changes in physical and chemical stimuli, as will be discussed later. Interactions between osteoblasts and the bone matrix via integrins also modulate osteoblast differentiation, function, and survival. In particular, loss of antiapoptotic signals provided by the ECM causes apoptosis, a phenomenon referred to as anoikis.

Osteoblast formation and differentiation The process of osteoblastogenesis can be divided into steps comprising proliferation, ECM development and maturation, mineralization, and apoptosis. Each stage is characterized by activation of specific transcription factors and genes leading to a succession of osteoblast phenotypic markers (see Fig. 3.6). Transcription factors of the helix–loop–helix family (Id, Twist, and Dermo) are expressed in proliferating osteoblast progenitors and are responsible for maintaining the osteoprogenitor population by inhibiting the expression of genes that characterize the osteoblast mature phenotype. Transcription

factors of the activating protein family, such as c-fos, c-jun, and junD, are expressed during proliferation as well as later in the differentiation pathway and may activate or repress transcription. Runx2 and osterix are essential for establishing the osteoblast phenotype. Their absence from the mouse genome results in lack of skeletal mineralization and perinatal lethality. Runx2 and osterix regulate the expression of other genes that control bone formation and remodeling, including OC and RANKL. Runx2 regulates differentiation, survival, and function of osteoblasts by affecting several signaling pathways, including those activated by Wnts, BMPs, integrins, and the PTH receptor.

Osteoblast apoptosis Upon completing the process of bone formation, 60% to 70% of osteoblasts die by apoptosis; the rest become lining cells or osteocytes. Apoptosis occurs throughout all stages of osteoblast life.40 The prevalence of osteoblast apoptosis in bone sections can be quantified by measuring fragmented DNA. Apoptosis of cultured osteoblasts has been extensively studied using several methods,41 including increased activity of initiator or effector caspases, the presence of cleaved genomic DNA by TUNEL or ISEL assay, and nuclear fragmentation and chromatin condensation using fluorescent dyes that bind to DNA. Examination of the nuclear morphology of cells transfected with fluorescent proteins containing a nuclear localization sequence has proven a particularly useful tool for studying apoptosis in cells co-transfected with genes of interest. Cell detachment from the substrate, changes in the composition of the plasma membrane, and changes revealing cell shrinkage are also features that have been used to detect and quantify apoptotic cells.

Regulation of osteoblast generation and apoptosis Most major regulators of skeletal homeostasis influence both generation and survival of osteoblasts. The BMP and Wnt signaling pathways promote osteoblast differentiation, but whereas BMPs induce osteoblast apoptosis, Wnts inhibit it. BMPs induce apoptosis of mature osteoblasts as well as of mesenchymal osteoblast progenitors in interdigital tissues during the development of the hands and feet. Wnt signaling has a profound effect on bone as shown by the high-bone-mass phenotype of mice and humans with activating mutations of low-density lipoprotein receptor–related protein 5 (LRP5), which together with Frizzled proteins are receptors for Wnt ligands. Wnts stimulate differentiation of undifferentiated mesenchymal cells toward the osteoblastic lineage and stimulate differentiation of preosteoblasts. Canonical Wnt signaling in osteoblasts also affects osteoclasts by enhancing the expression of the RANKL decoy receptor OPG, which leads to inhibition of osteoclast development. In addition, Wnt signaling inhibits apoptosis of mature osteoblasts and osteocytes.42 The increased bone formation exhibited by mice lacking the Wnt antagonist known as secreted Frizzled-related protein-1 (sFRP-1) is associated with decreased osteoblast and osteocyte apoptosis. The prevalence of osteoblast and osteocyte apoptosis is also decreased in mice expressing the high bone mass–activating mutation of LRP5 (G171V), which exhibits reduced ability to bind the Wnt antagonist sclerostin secreted by osteocytes. Consistent with this, sclerostin induces osteoblast apoptosis

26

SECTION 1  Scientific Basis of Rheumatic Disease

in vitro. Moreover, reduction of sclerostin levels by PTH and mechanical loading increases osteoblast number and activity as a result of stimulation of osteoblast differentiation and increased survival.43,44 Activation of Wnt signaling in vitro by ligands known to activate the so-called canonical as well as noncanonical pathways also prevents apoptosis of osteoblast progenitors and differentiated osteoblasts through a mechanism that involves the Src/ ERK and PI3/AKT prosurvival kinases.45 Glucocorticoids induce rapid bone loss resulting from a transient increase in resorption caused by delayed osteoclast apoptosis. This initial phase is followed by a sustained and profound reduction in bone formation and turnover caused by decreased osteoblast and osteoclast generation and increased osteoblast apoptosis. Both persistent excess of PTH, as in hyperparathyroidism, and intermittent elevation of PTH (by daily injections) increase the number of osteoblasts. Sustained PTH elevation inhibits the expression of sclerostin, with a consequent increase in Wnt signaling and in differentiation of osteoblast precursors. A major effect of intermittent elevation of PTH is inhibition of apoptosis of osteoblasts, which thereby prolongs their life span and ability to form bone.

OSTEOCYTES Osteocytes are former osteoblasts that become entombed during the process of bone deposition and are regularly distributed throughout the mineralized bone matrix. Osteocyte bodies are individually encased in lacunae and exhibit cytoplasmic dendritic processes that run along narrow canaliculi excavated in the mineralized matrix. Osteocytes communicate with each other, with cells on the bone surface, and with cells of the bone marrow through gap junctions established between cytoplasmic processes of neighboring cells. Today it is accepted that osteocytes are the mechanosensory cells. Osteoblasts and osteoclasts are present on bone only transiently, in low number, and in variable locations. On the other hand, osteocytes are the most abundant resident cells and are present in the entire bone volume. Osteocytes are also the core of a functional syncytium that extends from the mineralized bone matrix to the bone surface and the bone marrow and all the way to the blood vessels. This strategic location permits the detection of variations in mechanical signals as well as in levels of circulating factors and allows amplification of the signals leading to adaptive responses.

Osteocyte apoptosis: Consequences and regulation Osteocytes are long-lived cells. However, similar to osteoblasts and osteoclasts, osteocytes die by apoptosis, and decreased osteocyte viability accompanies the bone fragility syndromes that characterize glucocorticoid excess, estrogen withdrawal, and mechanical disuse.34 Conversely, preservation of osteocyte viability might explain at least part of the antifracture effects of bisphosphonates, which cannot be completely accounted for by changes in bone mineral density.46

Preservation of osteocyte viability by mechanical stimuli Osteocytes interact with the ECM in the pericellular space through discrete sites in their membranes, which are enriched in integrins and vinculin, as well as through transverse elements that tether osteocytes to the canalicular wall. Loading of the bones induces ECM deformation and fluid flow through the canaliculi, producing tension in the tethering elements and strain on osteocyte membranes. The consequent integrin engagement leads to intracellular signaling. Physiologic levels of mechanical strain imparted by stretching or pulsatile fluid flow prevent apoptosis of cultured osteocytes. Mechanotransduction is accomplished by molecular complexes assembled at caveolin-rich domains of the plasma membrane and composed of integrins, cytoskeletal proteins, and kinases, including the focal adhesion kinase FAK and Src, which results in activation of the ERK pathway and osteocyte survival. Intriguingly, a ligand-independent function of the estrogen receptor is indispensable for mechanically induced ERK activation in both osteoblasts and osteocytes. This observation is consistent with reports that mice lacking estrogen receptor-α and estrogen receptor-β exhibit a poor osteogenic response to loading. In vivo mechanical forces also regulate osteocyte life span. Apoptotic osteocytes are found in unloaded bones or in bones exposed to high levels of mechanical strain. In both cases, increased osteocyte apoptosis is observed before any evidence of increased osteoclast resorption. Apoptotic osteocytes accumulate in areas subsequently removed by osteoclasts. Targeted ablation of osteocytes in transgenic mice is sufficient to induce osteoclast recruitment and resorption, leading to bone loss. These findings led to the notion that dying osteocytes become the beacons for osteoclast recruitment to the vicinity and the resulting increase in bone resorption.47 Whether living

osteocytes continually produce molecules that restrain osteoclast recruitment or whether in the process of undergoing apoptosis osteocytes produce pro-osteoclastogenic signals remains to be determined. Taken together with the evidence that osteocyte apoptosis is inhibited by estrogens and bisphosphonates,46,48 these findings raise the possibility that preservation of osteocyte viability contributes to the ability of these agents to inhibit remodeling.

Osteocyte apoptosis and aging One of the purported functions of the osteocyte network is to detect microdamage and trigger its repair. During aging, there is an accumulation of microdamage and a decline in osteocyte density accompanied by decreased prevalence of osteocyte-occupied lacunae, an index of premature osteocyte death. Age-related loss of osteocytes caused by apoptosis could be partially responsible for the disparity between bone quantity and quality that occurs with aging. The decline in physical activity and thus reduced skeletal loading with old age is a potential mechanism for the increased prevalence of osteocyte (and osteoblast) apoptosis, as is the loss of estrogen in women during and after menopause.

Hormonal regulation of osteocyte life span Estrogen and androgen deficiency both lead to increased prevalence of osteocyte apoptosis. Conversely, estrogens and androgens inhibit apoptosis of osteocytes as well as osteoblasts.48 This antiapoptotic effect is due to rapid activation of the Src/Shc/ERK signaling pathway through nongenotropic actions of the classical receptors for sex steroids. This effect requires only the ligand-binding domain of the receptor, and unlike the classical genotropic action of the receptor protein, it is eliminated by nuclear targeting. Excess of glucocorticoid activity in bone may also contribute to induction of osteocyte (and osteoblast) apoptosis because aged mice exhibit higher serum levels of corticosterone, elevated adrenal weight, and increased expression in bone of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), the enzyme that amplifies glucocorticoid action. The apoptotic effect of glucocorticoids is reproduced in cultured osteocytes and osteoblasts in a manner strictly dependent on the glucocorticoid receptor.40 Induction of osteocyte and osteoblast apoptosis by glucocorticoids can result from the direct action of the steroids, because overexpression of the enzyme that inactivates glucocorticoids, 11β-HSD2, specifically in these cells abolishes the increase in apoptosis. Strikingly, in the osteocytic MLO-Y4 cell line, the proapoptotic effect of glucocorticoids is preceded by cell detachment caused by interference with FAK-mediated survival signaling generated by integrins. In this mechanism, Pyk2 (a member of the FAK family) becomes phosphorylated and subsequently activates proapoptotic JNK signaling. The proapoptotic actions of glucocorticoids may involve suppression of the synthesis of locally produced antiapoptotic factors, including IGF-1- and IL-6type cytokines, as well as matrix metalloproteins, and stimulation of the proapoptotic Wnt antagonist SFRP-1.

Regulation of bone formation by osteocytes: Sclerostin Osteocytes express sclerostin, the product of the Sost gene, which antagonizes several members of the BMP family of proteins and also binds to LRP5/LRP6, preventing canonical Wnt signaling. Loss of Sost in humans causes the high-bone-mass disorders van Buchem syndrome and sclerosteosis. In addition, administration of an antisclerostin antibody increases bone formation and restores the bone lost after ovariectomy. Conversely, transgenic mice overexpressing Sost exhibit low bone mass.49 These lines of evidence demonstrate that sclerostin derived from osteocytes exerts a negative feedback control at the earliest step of mesenchymal stem cell differentiation toward the osteoblast lineage. Moreover, PTH and mechanical loading downregulate the expression of sclerostin in osteocytes, which reveals a novel mechanism of bone anabolism triggered by osteocytes.

Osteocytes as mediators of the anabolic actions of canonical Wnt signaling in bone Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions had remained elusive because genetic activation or deletion of components of the pathway in osteoblasts or their precursors only affects bone resorption, without evident effects on bone formation.50,51 A recent study demonstrates that activation of canonical Wnt signaling exclusively in osteocytes increases (not decreases) resorption and induces bone anabolism, leading to high bone remodeling with bone gain. This effect is due to the fact that activation of the pathway in osteocytes not only decreases OPG as in osteoblasts but also increases RANKL, leading to a higher RANKL-to-OPG ratio that favors resorption, and in this setting, Wnt signaling also favors osteoblast–osteocyte differentiation.52

CHAPTER 3  Bone structure and function

27

BONE MARROW Canopy

Osteoblast precursors

Osteoclast precursors Marrow capillary Lining cells

Bone remodeling compartment BRC

RANKL M-CSF OPG

Osteoblasts

Sclerostin Dkk-1

Osteocytes

Bone

FIG. 3.7  Osteocytes sense the need for bone resorption and send signals to lining cells, which retract from the bone surface to allow the formation of a canopy under which remodeling occurs, called the bone-remodeling compartment (BRC). Osteoclast precursors are transported to the BRC by marrow capillaries, differentiate to mature osteoclasts under the influence of pro-osteoclastogenic and antiosteoclastogenic cytokines (receptor activator of nuclear factor-κB ligand [RANKL], macrophage colony-stimulating factor [M-CSF], and osteoprotegerin [OPG]) derived from osteocytes, and initiate bone remodeling. Osteoblast precursors from the bone marrow or the circulation differentiate into mature, bone-synthesizing cells in response to factors released from the bone matrix by resorption. Differentiation and function of osteoblasts are controlled by molecules derived from osteocytes, including sclerostin and Dkk-1. (From Bellido T, Plotkin LI, Bruzzaniti A. Bone cells. In: Burr DB, Allen MR, editors. Basic and Applied Bone Biology. San Diego: Academic Press; 2014, p. 27–46.)

Thus, these findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone.

Regulation of bone resorption by osteocytes: RANKL and osteoprotegerin The cues that signal bone resorption are not completely understood. Apoptotic osteocytes could regulate the recruitment of osteoclast precursors and their differentiation in two ways. Osteocyte apoptosis may indirectly stimulate osteoclastogenesis by inducing stromal/osteoblastic cells to secrete RANKL. In addition, osteocytes can directly secrete RANKL. Indeed, in vitro, purified osteocytes express higher levels of RANKL than osteoblasts and bone marrow stromal cells. The severe osteopetrotic phenotype observed in mice lacking RANKL in osteocytes and their resistance to bone loss induced by tail suspension strongly suggests that osteocytes are a major source of RANKL in vivo. Osteocytes also secrete OPG, which, as in osteoblasts, is regulated by the Wnt/β-catenin pathway. Mice lacking β-catenin in osteocytes are osteoporotic because of increased osteoclast numbers, but their osteoblast function is normal. Emerging evidence also points to osteocytes as an additional source of secreted M-CSF in bone. Together, these new findings suggest that osteocytes control the bone-remodeling process by regulating osteoclast and osteoblast differentiation and function.

Osteocytes and the bone-remodeling compartment Lining cells play an important function in initiating bone remodeling by retracting from quiescent bone surfaces and allowing the formation of a canopy over osteoclasts and osteoblasts in the bone multicellular unit.53 On the endocortical surface, this canopy presumably encases bone marrow osteoblast precursors and is penetrated by blood vessels that provide hematopoietic osteoclast progenitors. The canopy, associated capillaries, osteocytes, osteoclasts, and osteoblasts form a compartment, the bone-remodeling compartment (BRC), which is separated from the rest of the marrow and can sequester molecules that regulate the cells that remodel bone (Fig. 3.7). The signals that trigger lining cell detachment in a particular bone area are unknown. Premature apoptosis of osteocytes has been shown to precede osteoclast accumulation and resorption,47 which raises the possibility that osteocytes release molecules that induce lining cell retraction, facilitating access of osteoclast precursors to bone surfaces. However, the molecular entities responsible for this purported osteocytic function remain unknown. As discussed earlier, osteocytes express M-CSF,54 which stimulates proliferation of preosteoclasts, and RANKL,55,56 the master cytokine inducer of osteoclast differentiation, both of which could reach the BRC. In turn, growth factors released from the bone matrix upon resorption stimulate osteoblastogenesis. It is also likely that osteocyte-derived sclerostin reaching the BRC through the canalicular system and secretion of the other Wnt antagonist Dkk-1 by osteocytes as well

as osteoblasts influence the rate of bone formation, providing an additional level of control of osteoblast activity. Based on these lines of evidence, the BRC might provide a supportive environment for differentiation of osteoclast and osteoblast progenitors. Thus, regulation of the bone-remodeling rate by hormonal and mechanical stimuli could be accomplished by controlling the balance between resorption and formation within the BRC through the regulation of osteocytic molecules, including sclerostin, RANKL, and OPG.

GROWTH, MODELING, REMODELING, AND REPAIR Four dynamic processes are involved in skeletal development and adaptation. These are defined by the relationship of bone resorption and bone formation to each other (Table 3.1). These mechanisms include a coordinated system that first involves the activation (A) of cell populations followed by the resorption (R) of preexisting tissue and/or the formation (F) of new or replacement tissue. Bone growth serves to increase bone mass through bone formation. Resorption of bone is not part of the growth process, and the function of growth is only to increase mass, not to adapt the developing structure to its mechanical needs. Growth can occur on a substrate but may involve ossification directly from fibrous tissue (intramembranous bone formation) or by formation of a model with cartilage first and then replacement of the cartilage with bone (endochondral ossification). Modeling uses the tissue formed during the growth process to further increase bone mass and to shape its geometry to mechanical needs. Modeling occurs through the activation of cells followed by either formation or resorption. Formation and resorption are coordinated processes in modeling but do not occur sequentially on the same surface of bone. Remodeling, on the other hand, is defined by the sequential processes on the same bone surface of activation– resorption–formation (the A-R-F sequence). The function of remodeling is bone maintenance, not increase in bone mass, and the removal of microdamage. Bone’s repair function, which restores its mechanical properties after a complete fracture or trabecular microfracture, usually occurs through the process of endochondral ossification, which forms a cartilage callus that also includes woven bone to bridge the fracture gap. This is eventually replaced through remodeling with replacement by lamellar bone. Growth, modeling, and remodeling are present concurrently in all growing children. When skeletal maturity is reached, growth naturally stops. Modeling slows down or stops but may still be present at a reduced rate on trabecular surfaces and on the periosteal surface of the bone. At maturity, the predominant process is bone remodeling, which maintains the bone that has been formed and repairs microscopic damage that may be sustained in bone during normal daily activities. Dysfunction in the remodeling process is associated with the loss of bone found in osteoporosis.

28

SECTION 1  Scientific Basis of Rheumatic Disease

Table 3.1

Dynamic Processes of Skeletal Development and Adaptation Process

Mechanism

Morphology

Function

Growth Modeling

F A-F

Woven, lamellar Primary lamellar

Increased mass Net increased mass or Adaption of architecture

A-R

Control of drift and curvature Secondary lamellar (osteons, hemi-osteons)

Remodeling

A-R-F

Repair

F

Woven Rapid mechanical adaptation

THE METAPHYSEAL CUTBACK THAT OCCURS THROUGH MODELING PROCESSES DURING GROWTH TO SHAPE THE BONE Growth

This bone removed by modeling

Bone maintenance Repair of microdamage Prevention of bone loss Repair of fractures

A, Activation; F, formation; R, resorption.

Diaphysis Metaphyseal cutback

GROWTH Growth of bone occurs through two different skeletal processes, one involving formation of bone from fibrous membranes and the other involving the formation of a skeletal anlage, or model. Intramembranous bone formation occurs at centers of ossification via direct mineralization in highly vascular fibrous tissues through the action of mesenchymal cells. The calvaria of the skull is the best example of intramembranous bone formation, with the individual bones of the skull acting as centers that eventually grow together at the sutures. Apposition of bone on the periosteal surface of long bones also occurs through intramembranous ossification. In the long bones, development generally occurs by the initial condensation of mesenchyme or hyaline cartilage in the form of the eventual skeletal structure. This cartilage model mineralizes over time and becomes detectable as a primary center of ossification. Some bones are formed from a single ossification center, although most of the long bones form secondary centers of ossification at the ends (epiphyses), which eventually fuse to the bone that developed from the primary ossification center (diaphysis) (Fig. e3.2). The secondary centers allow growth to occur at a cartilaginous growth plate until skeletal maturity in the late teens or (for the vertebral bodies) in the early part of the third decade of life. The growth plate slowly converts into primary spongiosa that becomes remodeled into lamellar trabecular plates in the metaphysis of the bone.

MODELING Long bones must grow both in length and in diameter (Fig. 3.8). At the ends of the long bones—near the epiphyses—growth of bone demands that the wider joint surface continually be reshaped and narrowed as it moves down into the metaphysis and diaphysis. Modeling is a continuous and prolonged process—unlike remodeling, which is episodic—and involves a coordinated process of bone resorption on some surfaces, while other surfaces undergo bone formation. Bone modeling occurs on both periosteal and endocortical envelopes and sculpts bone shape while allowing for expansion of the marrow cavity and periosteal diameter of the diaphysis. At the metaphysis, this occurs by osteoclastic resorption on the periosteal surfaces. As growth continues, however, bone is added to the periosteal surface by osteoblasts and simultaneously removed from the endocortical surface by osteoclasts. This increases whole-bone diameter and expands the marrow cavity, necessary for the formation of blood. It serves a second purpose: to increase the mechanical strength of the bone while at the same time not increasing its mass or weight at the same rate. Bone curvature is also adjusted during growth through a process known as drift, in which the periosteal surface on one side of the bone undergoes apposition while the opposite periosteal surface undergoes resorption. Likewise, different portions of the endocortical surface form or resorb bone in coordination to maintain the cortical thickness of the diaphysis.

REMODELING The quantum concept of bone-remodeling states that bone is replaced in packets through the coupled activity of osteoclasts and osteoblasts. Coupling between osteoclasts and osteoblasts is the reason that it was difficult for so many years to control the processes involved in bone loss. When bone resorption is suppressed, formation is also suppressed because these activities are linked by intercellular signaling mechanisms that are not fully understood. In remodeling, resorption and formation are coupled but in fact may not be

Diaphyseal enlargement

Diaphyseal drift

FIG. 3.8 During growth, metaphyseal bone is removed by modeling processes to shape the bone. Subsequent enlargement of the diaphysis occurs through direct periosteal apposition, which is often accompanied by resorption on the endocortical surface to enlarge the marrow cavity. Bone can also change its location and curvature through “drift.” Arrows indicate the direction of drift, with smaller circular cells representing osteoblasts and bone formation and larger ellipsoidal cells representing osteoclasts and bone resorption. (From Martin RB, Burr DB, Sharkey NA. Skeletal Tissue Mechanics. New York: Springer; 1998, p. 62, with permission.)

balanced. Coupling and balance are not the same; whereas balance refers to the relationship between the amount of bone resorbed and the amount formed, coupling denotes only that the processes are linked in some way. Resorption and formation are in balance in the healthy skeleton, but when these are out of balance, the amount of bone that is resorbed can be either greater or less than the amount that is subsequently formed. Thus, even though cells are coupled, bone can be lost or added in several different ways based on the altered balance of resorption and formation. In actuality, one almost never finds a balance in favor of bone formation in a remodeling system, although this has been shown to occur with anabolic treatments for osteoporosis, such as the intermittent administration of recombinant human PTH (1-34) (teriparatide).57 More often, the balance is in favor of resorption. This is the case in osteoporosis, in which global resorption is increased but formation at each of the erosion sites is normal or reduced, which leads to a deficit in bone mass. This coupled system is termed a bone multicellular unit (BMU) because different cell populations are involved. A BMU typically consists of about 10 osteoclasts and several hundred osteoblasts. When cut in longitudinal section, the BMU shows the sequential aspects of the A-R-F system and the various cell populations that are involved (Fig. e3.3). Each of the phases in this sequence is location, magnitude, and rate specific, so that alterations in the magnitude or timing of one can produce morphologic features characteristic of specific skeletal abnormalities (Fig. 3.9). Activation is initiated by chemical or mechanical signals but actually involves a series of events that include recruitment of precursor cells, differentiation and proliferation of cells, and migration to the site of activity. In humans, these processes take about 5 to 10 days. Bone resorption by mature osteoclasts takes about 3 weeks at a given site, although osteoclasts moving longitudinally through bone at a rate of about 40 μm/day may live much longer than this. There is a period of reversal during which there is neither bone resorption nor formation; this may represent a period like the activation period during which osteoblasts are undergoing differentiation and proliferation from their precursors. This is followed by a period of bone formation that lasts about 3 months. As unmineralized bone—or osteoid—is laid down, it subsequently begins to mineralize, quickly at first and then more slowly over the following year. This sequence of events occurs on all four skeletal envelopes (periosteal, endocortical, trabecular, and intracortical). Changes in bone mass can occur simply through changes in activation frequency. Changes in activation frequency may lead only to transient changes

CHAPTER 3  Bone structure and function

28.e1

Primary spongiosa L2, 37 y.o. male

Secondary spongiosa

Cortical bone

Diaphyseal cortical bone

FIG. E3.2  At the organ level, bone consists of compact (cortical) bone, which forms a shell around the more porous, cancellous (trabecular) bone, or spongiosa. In the cancellous regions of the long bones, such as the proximal tibia shown here, the primary spongiosa is separated from the secondary spongiosa by an arbitrary boundary. Primary spongiosa is composed of primary bone, often laid down during growth on a calcified cartilage core that is subsequently remodeled. Secondary spongiosa is remodeled, reflects patterns of stress, and directs these stresses to the cortical shell.

Osteoblasts

Osteoid

Capillary bud

Osteoclasts Erosion surface

FIG. E3.3   A bone multicellular unit (BMU). This system shows the sequential aspects of the activation-resorption-formation (A-R-F) system and the various cells that are involved. At the head of the resorption front (also called the cutting cone), there is a capillary bud, which supplies nutrients to the multicellular osteoclasts that are decalcifying and resorbing bone matrix. Behind the resorption front, teams of osteoblasts are lined up along the wall of the BMU, laying down new bone, or osteoid, that will subsequently become mineralized. Some of these osteoblasts will eventually embed themselves and become terminally differentiated osteocytes (McNeal tetrachrome stain).

CHAPTER 3  Bone structure and function FIG. 3.9  The entire bone-

THE BONE-REMODELING SEQUENCE

Migration

Proliferation Nucleation

Maturation

Differentiation Rate

Rate

Recruitment

Duration

Duration 21 days

5 days

90 days

~200 days

tio iza

on

ral M

Fo r

ine

m

Re ve r

ati

sa

l

ion pt or Re s

va ti

on

n

10 days

Ac ti

remodeling sequence, not including mineralization, takes about 4 months in humans. Many cellular processes occur during each part of the activationresorption-formation (A-R-F) sequence of events. The amount of resorption and formation is determined both by the individual activity of the cells and by the duration of the cells’ lifetimes. In cross-section, formation requires about four times longer than the resorption of the same amount of bone and, consequently, there are many more osteoblasts in bone than osteoclasts. (From Burr DB. Orthopedic principles of skeletal growth and remodeling. In: Carlson DS, Goldstein SA, editors. Bone Biodynamics in Orthodontic and Orthopedic Treatment. Craniofacial Growth Series, vol. 27. Ann Arbor: Center for Human Growth and Development of the University of Michigan; 1992, p. 15–50.)

29

FRACTURE HEALING INVOLVES SEVERAL STAGES IN THE REPAIR (OR REGENERATION) PROCESS Regeneration, not repair Three sequential, yet overlapping stages Normal bone

Healed fracture

FIG. 3.10  An injury to bone is typically followed by the development of a hematoma with associated inflammatory responses. This phase is followed by the development of a periosteal bridging callus (at least in separated and unstable fractures) that is composed of calcified cartilage. Over time, this cartilage callus remodels to become bone, and eventually the bone is reshaped through modeling processes to achieve something close to its original dimensions. (With permission from Dr. Stuart Warden.)

Inflammation Injury

Hematoma/inflammation

Days

Remodeling

Regeneration

Weeks

in bone mass if resorption and formation are in balance. Early losses of bone mass solely caused by increased activation frequency may resolve after several months as the newly resorbed sites are refilled. Likewise, bone mass may change because some aspect of the recruitment, proliferation, migration, or differentiation of either osteoclasts or osteoblasts is interrupted. These changes may be manifested as alterations of resorption–formation balance but may be caused by activation defects during cell maturation.

Regeneration

Remodeling

Months/years

REPAIR Fracture healing involves several stages in the repair (or regeneration) process (Fig. 3.10). The injury is typically followed by the development of a hematoma with associated inflammatory responses. This phase is followed within a week or so by a regenerative phase characterized by the formation of a cartilage callus. Also, there is direct woven bone apposition on

30

SECTION 1  Scientific Basis of Rheumatic Disease

periosteal surfaces through a process typical of intramembranous ossification. This unites the two ends of the bone to stabilize the fracture, but the bone is still not mechanically adapted to normal loads and may be quite weak. The callus subsequently matures to primary bone over a period of months via processes similar to those involved in endochondral ossification. Over time, the cartilage callus remodels via the A-R-F sequence of events to become lamellar bone, and eventually the bone is reshaped through modeling processes to achieve something close to its original dimensions. When this process is complete, the bone will be geometrically and mechanically similar to its prefracture state. The rate and extent of healing depend on the fracture and on the mechanical environment. Large amounts of motion increase the size of the cartilage callus and interrupt its remodeling to bone. Small amounts of motion and juxtaposition of the fractured ends of the bone can allow healing without the development of much, or any, callus. Small loads also facilitate healing. A variety of local factors can influence healing. Nonunions can occur if early signals for repair (e.g., from TGF-β and other growth factors and cytokines) are not received, if there is compromise to the local blood supply, or if there are complicating factors caused by infection or bone death caused by radiation or thermal injuries. Comorbid conditions (e.g., poor diet, smoking, calcium or vitamin D deficiencies, and excessive alcohol intake) can prolong the time required to heal a fracture. Any agent that suppresses bone turnover (e.g., bisphosphonates or RANKL inhibitors) will prevent the cartilage callus from fully remodeling to lamellar bone.

23.

24. 25. 26.

27. 28. 29. 30.

31.

32.

33. 34.

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Tendons and ligaments Stephanie G. Dakin • Andrew J. Carr

Key Points n Tendinopathy, enthesopathy, and desmopathy are common causes of musculoskeletal pain and disability. n Aging, cumulative mechanical stress, acute injury, genetic predisposition, and metabolic disorders are important contributing factors. n Inflammation is present in tendinopathic and ruptured tendons and is associated with pain. n Inflammatory signatures differ between different stages of disease. n Diseased tendons highly express markers of fibroblast activation. n Healthy and diseased tendons are composed of distinct tendon cell subsets. n Diseased tendons and ligaments heal by fibrosis resulting in tissue with reduced structural and functional integrity. n Development of focused therapies that target the underlying disease-stage specific mechanisms is essential.

INTRODUCTION Tendons and ligaments are connective tissue structures facilitating the stabilization and movement of joints. Tendons connect muscle to bone; ligaments connect bone to bone. The enthesis is a connective tissue–dense region positioned between a tendon/ligament and bone. Both tendons and ligaments have a highly organized ultrastructure, which confers the mechanical properties required for their function. Tendons and ligaments share a similar structure, consisting of a hierarchical arrangement of collagen fiber bundles oriented along the long axis of the tissue.1 Other major constituents are water and noncollagenous matrix. While tendons and ligaments both respond to mechanical load, exercise, and stress deprivation, there are some differences between these structures. These include compositional differences in extracellular matrix and site-specific adaptations of some tendons, which can be characterized, broadly speaking, according to their function as either positional (where the tendon is important in maintaining position of the joint) or energy storing (where the tendon’s main role is associated with the storage and release of elastic stress energy). Sites commonly affected by tendinopathy include the shoulder (the supraspinatus tendon), elbow, knee (the patellar tendon), and ankle (the Achilles tendon). Disease of the ligaments, termed desmopathy, frequently affects high-motion joints such as the knee (collateral and cruciate ligaments) and ankle (collateral ligaments).

CLASSIFICATION OF DISEASE AFFECTING TENDONS AND LIGAMENTS Pathology of the tendons and ligaments is classified based on the chronicity of onset and location. Both tendons and ligaments are susceptible to damage and the effects of aging. Disease affecting these structures is commonly the result of cumulative microtrauma that occurs over a prolonged period (intrinsic) or may an arise in the form of acute trauma resulting from an impact or penetrating object (extrinsic). The efficacy of the ensuing repair is dependent on numerous factors, including the location of the injured tendon (intra- vs. extrasynovial) or ligament (intra- vs. extraarticular). Clinical presentations of intrinsic tendon pathology can be variable. Patients may experience pain and loss of function with a structurally intact tendon or present with a “spontaneous” tendon rupture without preexisting pain or perceived loss of function. There is also considerable individual variation between the degree of pain experienced by a patient and the extent of structural tendon disease present. It is not clear whether these distinct clinical presentations represent isolated disease entities or divergent ends of a spectrum of disease process and progression. The site of tendon pathology can also vary, affecting the midbody of the tendon (e.g., Achilles) or occurring at the enthesis (e.g., supraspinatus, extensor carpi radialis, and Achilles). It is not presently known whether common mechanisms

4

are shared between tendon disease affecting the midbody and enthesis or whether the presence of pathology at one site is likely to influence the other. Furthermore, tendon/entheseal pathology is often associated with inflammatory disease at immune-privileged sites such as the gastrointestinal tract. It is unclear whether systemic inflammation in other tissues triggers the development of tendon/entheseal pathology.

ETIOLOGY OF TENDINOPATHY, ENTHESOPATHY, AND DESMOPATHY Terminology commonly used to describe musculoskeletal soft tissue pathology is listed in Table 4.1. For the purpose of this chapter, the terms tendinopathy, enthesopathy, and desmopathy are used throughout to describe disease affecting tendons, the enthesis, and ligaments, respectively. Musculoskeletal soft tissue disease is a common and significant health care problem both in sports injuries and in the aging population, causing pain and impeding activities of daily living. The etiology of intrinsic tendinopathy, enthesopathy, and desmopathy is complex and not fully understood. Multiple factors are implicated, including interplay between the effects of repetitive wear and tear, daily exercise, and aging. Genetic susceptibility is an additional predisposing factor, demonstrated by individuals who have sustained damage to multiple tendons and ligaments within their body. Studies of siblings suggest that genetic factors have a role in the progression of full thickness tears of the rotator cuff,2 and variations within the Tenascin C gene have been reported to be associated with Achilles ruptures.3 The importance of inflammation as a contributor to the pathogenesis of tendon and ligament injury has been contentious in recent years. While the phenotypes of the key cells orchestrating inflammation have not been fully characterized, there is a growing body of recent evidence to support the contribution of inflammation to the onset and progression of tendinopathy and enthesopathy, as shown in Table 4.2.

PATHOPHYSIOLOGY OF TENDON AND LIGAMENTS Histopathologic evaluation of diseased tendons shows increased cellularity, increased vascularity, and matrix disorganization compared to healthy tendon tissues (Fig. 4.1). Increased cellularity can be attributed to fibroblast proliferation, with local infiltration of inflammatory cells to the damaged site. Calcific deposits and lipid droplets may be found in tendons with established or end-stage disease. Immunohistochemical techniques facilitate improved in situ identification of the cell types present in diseased tendons. Diseased tendons highly express markers of activated fibroblasts and immune cells, including myeloid and lymphoid cells. Sections of diseased tendon tissues show significantly increased numbers of macrophages, T cells, mast cells, and natural killer (NK) cells compared to healthy tendons.25–27 Studies also suggest a key role for several alarmins including hypoxia-induced elements, cytokines, and heat shock proteins affecting tissue rescue mechanisms in tendon pathology.15,16 Cutting-edge laboratory platforms are advancing our understanding of the composition of tendons and ligaments. A recent study used CITE-seq to identify the cell types present in healthy and diseased human tendons. This study showed that tendons are composed of myeloid, lymphoid, endothelial, and tendon cell subsets.28 In support of previous studies, diseased tendons showed increased cellularity compared to healthy tendons. Importantly, this study identified five distinct tendon cell subsets in healthy and diseased tendons, highlighting that tendon cells are not a homogeneous population. In this study, distinct tendon cell populations were characterized by expression of PTX3, SCX, SMMC, FAP, and PRG4. A recent study performed single-cell RNA sequencing of murine Achilles tendons.29 This study supported heterogeneity of cell populations within tendons, identifying 11 distinct cell populations and three populations of tendon fibroblasts. This murine study 31

SECTION 1  Scientific Basis of Rheumatic Disease

32 Table 4.1

Table 4.2

Commonly Used Terms to Describe Pathology Affecting Tendons and Ligaments

Inflammatory and Nociceptive Molecules Described in Tendinopathy and Enthesopathy

Terminology

Meaning

Molecule

Potential Role

Tendinopathy/desmopathy

Used to describe disorders affecting tendons and ligaments respectively. Does not assume knowledge of underlying pathology Implies disease of tendon or ligament is accompanied by an inflammatory response Implies disease develops due to a primarily degenerative process in the absence of inflammation Tendon pathology develops due to effects of repetitive cyclic loading and aging, resulting in cumulative microdamage (intrinsic) Occurs as a consequence of traumatic injury; e.g., laceration or cutaneous injury (extrinsic) Pathology affecting the entheseal region of a tendon

IL-1β

Inflammation in surrounding tissues including synovium and subacromial bursa4,5 Inflammation within tendon6 Inflammation within tendon7 Inflammation within tendon8 Inflammation and alarmin within tendon9 Prostaglandin production10,11 Damage sensing12–14 Damage sensing15–17 NF-κB-mediated inflammation18–20 Fibroblast activation12,21

Tendonitis/desmitis

Tendinosis

Tendon/ligament disease

Tendon/ligament injury

Enthesopathy

a

b

IL-6 IL-17 IL-21R IL-33 COX-2 TLR4 S100 series alarmins pSTAT-1 PDPN, VCAM-1, CD248, FAPα, CD90 (THY1) TGFβ Substance P Glutamate

Tissue repair and fibrosis22 Nociceptive neuromodulator23 Nociceptive neuromodulator24

CD248, Endosialin; COX2, cyclooxygenase-2; FAPα, fibroblast activation protein alpha; IL-1β, interleukin 1 beta; IL-6, interleukin 6; IL-17, interleukin 17; IL-21R, interleukin 21 receptor; IL-33, interleukin 33; NF-κB, nuclear factor κB; S100 calcium binding proteins; PDPN, podoplanin; pSTAT-1, phosphorylated signal transducer and activator of transcription 1; TGFβ, transforming growth factor beta; THY1, thymocyte differentiation antigen 1; TLR4, toll-like receptor 4; VCAM-1, vascular cell adhesion protein 1.

c

FIG. 4.1  Histologic features of healthy and diseased supraspinatus (shoulder) tendons. Hematoxylin and eosin stained sections of (a) healthy supraspinatus tendon showing organized collagen fiber bundles and relative low cellularity. (b) Biopsy of a patient with painful supraspinatus tendinopathy and (c) tissue section from a patient with a painful supraspinatus tendon tear. Diseased tendons show increased cellularity and vascularity compared to healthy tendon.

suggested pericytes as a candidate progenitor cell population for fibroblasts that compose adult tendons. Harvey et al.30 used single-cell transcriptomics to identify a tubulin polymerization-promoting protein family member 3–expressing (Tppp3+) cell population as a potential marker of tendon stem cells. This study suggested that a Tppp3+Pdgfra+ tendon stem cell population may have a shared role in PDGF signaling in tendon regeneration and fibrosis. Collectively, these studies provide new and important biological insights into resident tendon populations, advancing understanding of how tendon cells behave in health and disease. Generating cellular atlases of tendons and ligaments will in turn inform the cellular basis of disease affecting these tissues, informing how we might more precisely target cell types implicated in disease therapeutically in the future.

INFLAMMATION ACTIVATION PATHWAYS SHOW PLASTICITY IN TENDON DISEASE Macrophages play an essential role in orchestrating inflammation and tissue repair. The signaling pathways underpinning activation of macrophages to become M1 or M2 subtypes have been revised to highlight receptors and key signaling mediators in common and distinct pathways. These include proinflammatory pathways regulated by type I interferons (IFNs) and nuclear factor κB (NF-κB), profibrotic pathways containing signal transducer and activator of transcription 6 (STAT6), and inflammation-resolving pathways involving glucocorticoid receptor activation.31 These macrophage activation pathways have recently been investigated in tissue biopsies from patients with supraspinatus tendon disease. Tendon biopsies from patients

with intact tendinopathy showed expression of genes and proteins induced by type I IFNs and NF-κB.25 Conversely, biopsies from patients with large to massive tendon tears showed expression of genes and proteins induced by STAT6 and glucocorticoid receptor activation pathways. This transition in inflammation signature suggests that the type of inflammation differs between tendinopathic (intact) and large to massive supraspinatus tendon tears. Tendinopathic shoulder tendons show a markedly proinflammatory signature, whereas torn shoulder tendons exhibit low-level chronic inflammation. The persistence of chronic inflammation is an important feature of tendon disease, demonstrated by the retention of inflammatory cells, failure of clearance of apoptotic cells, and disorganized extracellular matrix (Fig. 4.2). Failure to resolve tendon inflammation may be conducive to the development of fibrosis. Improved understanding of tendon inflammation signatures and the phenotypes of lymphoid and stromal cells populating these tissues will inform the development of disease-stage specific therapeutic targets to moderate tendon inflammation.

FIBROBLAST ACTIVATION IN TENDON DISEASE Resident fibroblasts comprise the majority cell population in tendons. Emerging evidence supports the prominent contribution of these cells in the generation and maintenance of chronic inflammation.21 Fibroblast activation is a pathological feature of cancer and rheumatoid arthritis (RA) in which resident stromal cells fail to switch off their inflammatory programme (Fig. 4.3). Phenotypic alterations in synovial fibroblasts from patients with RA are known to play an important role in the switch from resolving to persistent disease.32,33 Activated fibroblasts are found in damaged, inflamed,

CHAPTER 4  Tendons and ligaments

33

a

b

c

FIG. 4.2  Expression of inflammation activation proteins in tendon disease. (a and b) Representative immunofluorescence images of sections of diseased supraspinatus tendons stained for macrophage activation markers including those of the STAT6 pathway (CD206, green), the glucocorticoid receptor pathway (CD163, red), the interferon pathway (IRF5, violet), and the NF-κB pathway (IDO1, red). MerTK (violet) represents Mer tyrosine kinase, a macrophage apoptotic cell receptor. (c) Representative immunofluorescence images of sections of diseased supraspinatus tendons stained for markers of alarmins (TLR4, red) and fibroblast activation including podoplanin (PDPN, green) and CD106 (VCAM-1, violet). Nuclei are stained with POPO-1 nuclear counterstain. Scale bar, 20 μm.

or healing tissues and promote the retention of immune cells, regulating their behavior and release of proinflammatory cytokines, chemokines, prostanoids and extracellular matrix proteins.33 Markers of fibroblast activation include podoplanin (PDPN), CD106 (VCAM-1) and CD248 (tumor endothelial marker-1/endosialin), fibroblast activation protein (FAP), and CD90 (Thy-1). Fibroblast activation is also a recognized feature of tendon disease and has been identified in functionally distinct positional shoulder21 and energy-storing Achilles tendons,12 suggesting that common pathological mechanisms are conserved across soft tissues of the joint.34 Importantly, this fibroblast activation signature has been shown to persist, even after the resolution of clinical symptoms.21 These findings suggest that fibroblasts show capacity for “inflammation memory,” which may increase susceptibility to recurrent injury. Recent work studying synovial tissues from patients with RA identified functionally distinct fibroblast subsets that mediate inflammation and damage.35 These fibroblast subsets show distinct anatomical compartmentalisation in RA synovium, segregating lining and sublining layers. Further research is required to elucidate the precise phenotype and function of fibroblast subsets populating tendons and ligaments in health and disease.

DISEASED TENDONS SHOW DYSREGULATED RESOLUTION RESPONSES Improved understanding of inflammatory processes in tendon disease has prompted investigation into the biological processes determining whether tendon inflammation either persists or resolves. Recent research identified

receptors implicated in resolving inflammation, showing that the lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) and the resolvin E1 receptor (ERV1) were expressed in diseased tendon tissues and tendon-derived stromal cells.18,19,25 Specialized proresolving mediators (SPMs) including lipoxins, resolvins, protectins, and maresins, are families of lipid mediators concerned with resolving inflammation that have been identified in incubations of patient-derived tendon cells.18–20 Under IL-1β-stimulated conditions, tendon stromal cells isolated from patients with chronic tendon disease show elevated levels of proinflammatory eicosanoids including the prostaglandins PGE2 and PGF2α and increased levels of SPMs compared to respective cells isolated from the tendons of healthy volunteers. These findings suggest that diseased tendon stromal cells show dysregulated resolution responses.20 Importantly, incubation of diseased tendon cells in stable analogues of proresolving mediators has been shown to moderate the proinflammatory phenotype of these cells, dampening release of PGE2 and upregulating concentrations of SPMs in these incubations.18–20 These findings may inform new therapeutic approaches targeting tendon stromal cells that potentiate resolution of tendon inflammation.

PAIN AND NEUROPEPTIDES The peripheral nervous system plays an important role in the regulation of tendon function and repair. In healthy tendons, neuromodulators are predominantly found in the paratenon, the loose connective tissue layer surrounding the tendon.36 During tendon repair, there is peripheral nerve ingrowth into the tendon and neurotransmitters including substance P

34

SECTION 1  Scientific Basis of Rheumatic Disease CELLULAR AND MOLECULAR FEATURES OF CHRONIC INFLAMMATION IN TENDON DISEASE

Primed tendon cell IRF5

Injury

Alarmins

CD163

PDPN CD106 CD248

CD206

IRF1 Alternatively activated Mφ

Pro-inflammatory Mφ

Primed tendon cell IRF1

Impaired clearance of apoptotic cells

IRF5

PDPN CD106 CD248 CD90 TLR4

Chronic inflammatory fibrosis

T cell Resident tendon cell

Resolution

Resident tendon cell

Monocyte

Angiogenesis

FIG. 4.3  Cellular and molecular features of chronic inflammation in tendon disease. After exposure to inflammatory stimuli and activation of alarmins, diseased tendon cells become “primed,” expressing markers of fibroblast activation including PDPN, CD106, CD248, and CD90, reflecting a phenotypic shift in their inflammatory profile. Other proinflammatory molecules expressed by tendon cells include damage-associated molecular pattern TLR4, IRF1, and IRF5. Macrophages show a mixed signature, expressing proinflammatory markers (IRF1, IRF5) and markers of alternative macrophage activation, including CD206 and CD163. Chronic inflammation and fibrosis develop due to impaired resolution of inflammation and failure of clearance of apoptotic cells. With successful resolution, expression of proinflammatory mediators is moderated, although some degree of stromal fibroblast activation persists. This stromal “memory” may sensitize tendon cells and increase susceptibility to further episodes of inflammation and recurrent tendon disease. PDPN, Podoplanin; TLR4, Toll-like receptor 4. (Adapted from Dakin et al. 2018.12)

and glutamate are present.23,24 This peripheral neural phenotype is maintained in cells derived from diseased tendons, which show increased mRNA expression of nociceptive neuromodulators including metabotropic glutamate receptor 2 (mGluR2), N-methyl-d-aspartate receptor (NMDAR1), and kainite receptor 1 compared to cells derived from healthy tendons.37 Consequently, antagonists of neuropeptides and neurotransmitters have been investigated as potentially useful therapies for the management of painful tendon disorders. However, a proportion of patients with significant radiological and histopathological evidence of tendon disease do not experience pain, suggesting a mismatch between the presence of structural tendon disease and pain perception. This may be attributable to the activation of central as well as peripheral pain pathways38 and the poorly understood interactions between these systems.

EXTRACELLULAR MATRIX TURNOVER IN HEALTH AND DISEASE The ability of tendons and ligaments to act as elastic energy stores and resist tensile loads is attributable to their highly organized structure and the interactions between components of the extracellular matrix (ECM). Key elements of this are the dense fibrillar network of parallel-oriented collagen fibers, proteoglycans, and glycoproteins. Collagens are the major proteins of the tendon ECM and constitute approximately 65% of the tissue dry weight. Ninety-five percent is type 1 collagen, with the remaining proportion composed of collagen types II, III, IV, V, VI, IX, XII, and XIV. The noncollagenous portion of tendon is composed of glycoproteins and proteoglycans, which have important roles in assembly and organization and maintenance of the ECM and confer the ability to resist tensile forces associated with loading by binding water. Tendon disease is associated with numerous molecular changes to the ECM, including increased amounts of collagen III mRNA and protein.39 Collagen III fibrils have a smaller average diameter than type I fibrils, resulting in formation of a collagen mesh rather than highly aligned fibrils, impacting the strength of the repair. Increased amounts of fibronectin, tenascin C, aggrecan, and biglycan found in samples of diseased tendons are consistent with increased matrix turnover and remodeling associated with the condition.40 Analysis of the extracellular proteome of human supraspinatus tendons revealed damage to pericellular and elastic fiber niches in torn and aged tissue,41 highlighting the susceptibility of these structures to damage. Homeostasis and remodeling of the ECM is mediated by matrix

Table 4.3

Enzymes Implicated in Extracellular Matrix Turnover and Remodeling Molecule

Potential Significance

MMP-3, MMP-10, TIMP-3 ADAM-12, MMP-23 MMP-7, TIMP-2, TIMP-3, TIMP-4 MMP-1, MMP-2, MMP-3, MMP-9, MMP-19, MMP-25, TIMP-1, ADAM-8, ADAM-12

Reduced in painful tendons42 Increased in painful tendons42 Reduced in ruptured tendons42 Increased in ruptured tendons42,43

ADAM, A disintegrin and metalloproteinase; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase.

metalloproteinase enzymes (MMPs) and their respective tissue inhibitors (TIMPs). In tendon disease, expression and activity of numerous MMPs and TIMPs is altered as a consequence of increased proteolytic activity and turnover within the tendon ECM, summarized in Table 4.3. During the repair process, damaged tendons and ligaments remodel by fibrosis, defined as the scarring or hardening of tissues. During fibrosis, the composition of the ECM changes and increased production of proteoglycans, glycosaminoglycans, and collagen type III is associated with matrix disorganization. This results in the formation of tendon or ligament that is inferior in structure and function compared to healthy tissue and prone to recurrent disease. Fibrosis is the product of chronic inflammatory reactions induced by a variety of stimuli including tissue injury.44 Fibrotic pathways are poorly studied in diseased musculoskeletal soft tissues. Important regulators of fibrosis in other connective tissues include Th2 cytokines such as IL-13 and TGF-β1, angiogenic factors (VEGF), growth factors (PDGF), and caspases, which have been investigated as potential targets of antifibrotic drugs.44–47 A recent study identified reduced expression of TGFβ-1, TGFβ receptor (R)1, and TGFβ R2 proteins in diseased compared to healthy tendons.22 Downregulation of TGFβ pathways in established tendon disease may be a protective response to limit disease-associated fibrosis. The disruption of the TGFβ axis with disease suggests that associated downstream pathways may be important for maintaining healthy tendon homeostasis. Further studies are required to investigate the expression profile of fibrotic mediators in earlier stages of tendon disease to improve understanding of the targetable mechanisms underpinning tendon fibrosis.

CHAPTER 4  Tendons and ligaments

TREATMENT OF TENDON AND LIGAMENT PATHOLOGY Treatment should be tailored according to the type of disease and severity of injury. The presence of bilateral disease should be assessed. The goals of therapy for disorders of tendons and ligaments should be to: n Relieve pain. n Restore function. n Address the underlying tissue pathobiology. n Optimize tissue repair and promote return of homeostasis. n Reduce likelihood of recurrent disease.

MEDICAL TREATMENTS Numerous treatments have been advocated for patients with chronic painful tendinopathy. These include physiotherapy, nonsteroidal antiinflammatory drugs (NSAIDs), local corticosteroid or sclerosing injections, biologics including platelet-rich plasma (PRP) and stem cell therapies, high-volume injections, and dry needling. However, few have shown clinical benefit in placebo-controlled randomized clinical trials. Controlled-motion exercise therapies are frequently used for the treatment of lower limb tendinopathies.48,49 Prolonged immobilization is known to have deleterious effects on the quality of tendon and ligament repair and local tissue mechanics. Further controlled studies tailored to distinct tendons and ligaments are required to identify the optimum exercise regimes to promote improved reparative function. NSAIDs are frequently used to manage tendon and ligament pain. The effects of cyclooxygenase inhibition on tissue healing are inconclusive. Total inflammatory blockade may be potentially deleterious given that inflammation is necessary for the local debridement of tissues and initiation of healing. Inflammation also stimulates resolution, which promotes the restoration of tissue homeostasis after injury.50 Cyclooxygenase-2 (COX-2)-selective NSAIDs have been shown to diminish endogenous resolution responses,51,52 which may impair the tissue’s innate ability to heal. Furthermore, prolonged use of NSAIDs is known to have a deleterious effect on collagen synthesis,53 which is likely to influence tissue repair processes. Local injection of corticosteroids is a commonly used treatment for tendinopathy with limited evidence to support its use. Reported deleterious effects associated with corticosteroid treatment include reduced tendon cell viability, proliferation, and adverse effects on tissue mechanical properties.54,55 The use of biological therapies for tendon and ligament disease has grown significantly in recent years. Biological therapies such as PRP and stem cells aim to promote tissue regeneration and improved quality of repair. Studies investigating the use of PRP to treat tendinopathy have shown mixed results. While positive outcomes have been reported for a small number of randomized controlled clinical trials,56,57 other trials have suggested the use of PRP does not significantly improve clinical outcome.58,59 One significant problem is that the composition of biological products such as PRP is not standardized and varies between individuals and preparation methods. Reported deleterious tissue effects of PRP on treated tendons include reduced cellularity and vascularity and increased apoptosis.60 The ability of bone marrow derived mesenchymal stem cells to promote tendon repair has been investigated in athletic horses with tendinopathy.61,62 One equine study suggested that implantation of bone marrow–derived mesenchymal stem cells into the superficial digital flexor tendon (SDFT) was safe and appeared to reduce reinjury rate.62 Pas et al. recently reported a lack of evidence for stem cell therapy as a treatment for tendon disorders in a systematic review.63 Their review identified two human clinical trials that evaluated bone marrow–derived stem cells in shoulder rotator cuff repair surgery and found lower retear rates compared with historical controls or the literature. Another trial used allogenic adipose-derived stem cells to treat lateral epicondylar tendinopathy. They concluded that no evidence (Level 4) was found for the therapeutic use of stem cells for tendon disorders. Collectively, the current lack of effective treatments, combined with the prolonged rehabilitation and high risk of recurrent disease, compounds the difficulties associated with the successful medical management of tendon and ligament disorders.

SURGICAL TREATMENTS Treatment of extrinsic musculoskeletal soft tissue injury as a consequence of external trauma necessitates appropriate surgical repair. Ruptures that develop as a result of intrinsic tendon disease may be treated conservatively with rest, stabilization, and rehabilitative physiotherapy or may require surgical repair. Surgical repair of tendon tears such as those in the shoulder are associated with high failure rates.64 Consequently, implantation of scaffolds to augment tendon repair is common, and there are a variety of scaffolds in

35

current clinical use. These commercially available scaffolds can be biological or synthetic in composition, have a broad range of applications, and are not tailored for the repair of torn tendons. A study by Rashid et al. investigated the native response of rotator cuff tendons after surgical repair and augmentation with commercially available extracellular matrix patches.65 Their findings raised concerns regarding the use of these patches in rotator cuff augmentation on the basis of early tissue response in vivo. Novel electropsun nanofiber scaffolds have been developed to enhance endogenous repair mechanisms through biophysical cues and are now entering clinical trials. Such bioactive scaffolds have the potential to be used in combination with growth factors and cells.66,67 Of critical importance is the effective translation of new therapies from the laboratory to the clinic, and this will require a well-designed program of clinical trials that are designed to assess both their safety and efficacy.68

RECENT EVIDENCE FROM RANDOMIZED CONTROLLED TRIALS OF TENDON THERAPIES Unfortunately, there is relatively little high-quality evidence from randomized controlled trials of tendon therapies. In the UKUFF Trial,69 patients were randomized to receive either open or minimally invasive surgery. No difference was found in the primary outcome measure, the Oxford Shoulder Score, at 2 years postsurgery, indicating that there was no advantage or disadvantage to using either traditional open or more recent arthroscopic techniques. A significant repair failure rate was observed in this trial, which included magnetic resonance imaging (MRI) follow-up at 12 months postsurgery. The overall failure rate was 40%, ranging from 25% in small tears in 50-year-olds to over 80% in large and massive tears in patients aged over 70. The authors commented that focus should be placed on a more biological solution to rotator cuff repair if patient outcomes are to be improved and these high rates of tear recurrence are to be reduced. In the CSAW Trial,70 patients were randomized to receive either arthroscopic subacromial decompression, placebo surgery, or observational only. Three hundred thirteen patients were followed for 12 months, with the primary outcome being a patient-reported outcome measure (the shoulder score) at 12 months. There was no difference between the two surgical groups. There was a significant difference between the surgical groups and the observational group at 12 months, but this was within the minimal clinically important difference and is of doubtful clinical significance. This trial concluded that arthroscopic decompression surgery for shoulder pain in patients who have failed conservative treatment with cortisone injection and physiotherapy has no advantage over a placebo operation. In addition, neither of the surgeries appears to have a clinically significant advantage over observation only, suggesting that current trends of increasing use of this surgery should be considered carefully and reversed. In the United Kingdom, NHS England has placed this operation on a list of procedures of limited value and there has been a significant decrease in the number of operations performed in the 18 months since publication. Evidence is emerging that global rates of this surgery have also decreased following publication. A similar paper published in the British Medical Journal in 2018 (the FIMPACT)71 also compared arthroscopic decompression with placebo surgery and reported the same outcome with no advantage of decompression surgery over placebo. The publication of two high-quality randomized trials is important and significantly improves the evidence base in this area of tendon treatment with surgery. A further randomized trial (the PATH-2 study) was performed on the Achilles tendon72 to investigate the use of PRP in patients being treated surgically for Achilles tendon rupture. Two hundred thirty patients were randomized to receive either platelet-rich plasma injection or placebo with a dry needle in association with Achilles tendon repair. The trial found no difference in outcomes between the two groups and concluded that there is no evidence to indicate that injections of PRP can improve objective muscle tendon function, patient-reported function, or quality of life after acute Achilles tendon rupture when compared with a placebo treatment.

CONCLUSIONS Tendons and ligaments are capable of modulating their synthetic activity in response to their chemical and physical environments. Injured and aging tendons and ligaments attempt to repair through an inflammatory process. This invariably results in fibrosis and persistent tissue abnormality, which increases susceptibility to recurrent injury. The etiology of intrinsic tendon disease is complex and multifactorial, including interplay between the effects of repetitive wear and tear, daily exercise, and aging. Pathology results in substantial and permanent change

36

SECTION 1  Scientific Basis of Rheumatic Disease

in the tissue, including increased cellularity, vascularity, matrix disorganization, and altered composition. Identification of the phenotypes and functions of stromal cell populations in healthy and diseased tendons from well-defined patients is essential to advance understanding of the cellular basis of disease. This is critical to inform the development of effective new therapies targeting stromal cells driving disease. Enhanced understanding of the perceived mismatch between the presence of structural tendon disease and pain perception is vital to improve patient management. Finally, further multicenter placebo-controlled randomized clinical trials are required to determine the efficacy of established treatments for patients with tendon and ligament disorders.

REFERENCES 1. Kastelic J, Galeski A, Baer E. The multicomposite structure of tendon. Connect Tissue Res. 1978;6(1):11–23. 2. Gwilym SE, Watkins B, Cooper CD, et al. Genetic influences in the progression of tears of the rotator cuff. J Bone Joint Surg Br. 2009;91(7):915–917. 3. Collins M, Raleigh SM. Genetic risk factors for musculoskeletal soft tissue injuries. J. Sports Sci. Med. 2009;54:136–149. 4. Gotoh M, Hamada K, Yamakawa H, et al. Interleukin-1-induced glenohumeral synovitis and shoulder pain in rotator cuff diseases. J Orthop Res. 2002;20(6):1365–1371. 5. Ko JY, Wang FS, Huang HY, Wang CJ, Tseng SL, Hsu C. Increased IL-1beta expression and myofibroblast recruitment in subacromial bursa is associated with rotator cuff lesions with shoulder stiffness. J Orthop Res. 2008;26(8):1090–1097. 6. Legerlotz K, Jones ER, Screen HR, Riley GP. Increased expression of IL-6 family members in tendon pathology. Rheumatology (Oxford). 2012 7. Millar NL, Akbar M, Campbell AL, et al. IL-17A mediates inflammatory and tissue remodelling events in early human tendinopathy. Sci Rep. 2016;6:27149. 8. Campbell AL, Smith NC, Reilly JH, et al. IL-21 receptor expression in human tendinopathy. Mediators Inflamm. 2014;2014:481206. 9. Millar NL, Gilchrist DS, Akbar M, et al. MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease. Nat Commun. 2015;6:6774. 10. Tsuzaki M, Bynum D, Almekinders L, Yang X, Faber J, Banes AJ. ATP modulates load-inducible IL-1beta, COX 2, and MMP-3 gene expression in human tendon cells. J Cell Biochem. 2003;89(3):556–562. 11. Tsuzaki M, Guyton G, Garrett W, et al. IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells. J Orthop Res. 2003;21(2):256–264. 12. Dakin SG, Newton J, Martinez FO, et al. Chronic inflammation is a feature of Achilles tendinopathy and rupture. Br J Sports Med. 2018;52(6):359–367. 13. Akbar M, Gilchrist DS, Kitson SM, et al. Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis. RMD Open. 2017;3(2):e000456. 14. Thankam FG, Roesch ZK, Dilisio MF, et al. Association of inflammatory responses and ECM disorganization with HMGB1 upregulation and NLRP3 inflammasome activation in the injured rotator cuff tendon. Sci Rep. 2018;8(1):8918. 15. Millar NL, Murrell GA, McInnes IB. Alarmins in tendinopathy: unravelling new mechanisms in a common disease. Rheumatology (Oxford). 2013;52(5):769–779. 16. Mosca MJ, Carr AJ, Snelling SJB, Wheway K, Watkins B, Dakin SG. Differential expression of alarmins-S100A9, IL-33, HMGB1 and HIF-1alpha in supraspinatus tendinopathy before and after treatment. BMJ Open Sport Exerc Med. 2017;3(1):e000225. 17. Crowe LAN, McLean M, Kitson SM, et al. S100A8 & S100A9: alarmin mediated inflammation in tendinopathy. Sci Rep. 2019;9(1):1463. 18. Dakin SG, Colas RA, Newton J, et al. 15-Epi-LXA4 and MaR1 counter inflammation in stromal cells from patients with Achilles tendinopathy and rupture. FASEB J. 2019 fj201900196R. 19. Dakin SG, Colas RA, Wheway K, et al. Proresolving mediators LXB4 and RvE1 regulate inflammation in stromal cells from patients with shoulder tendon tears. Am J Pathol. 2019 20. Dakin SG, Ly L, Colas RA, et al. Increased 15-PGDH expression leads to dysregulated resolution responses in stromal cells from patients with chronic tendinopathy. Sci Rep. 2017;7(1):11009. 21. Dakin SG, Buckley CD, Al-Mossawi MH, et al. Persistent stromal fibroblast activation is present in chronic tendinopathy. Arthritis Res Ther. 2017;Jan 25;19(1):16. 22. Goodier HC, Carr AJ, Snelling SJ, et al. Comparison of transforming growth factor beta expression in healthy and diseased human tendon. Arthritis Res Ther. 2016;18(1):48. 23. Ackermann PW, Franklin SL, Dean BJ, Carr AJ, Salo PT, Hart DA. Neuronal pathways in tendon healing and tendinopathy—update. Front Biosci. 2014;19:1251–1278. 24. Schizas N, Weiss R, Lian O, Frihagen F, Bahr R, Ackermann PW. Glutamate receptors in tendinopathic patients. J Orthop Res. 2012;30(9):1447–1452. 25. Dakin SG, Martinez FO, Yapp C, et al. Inflammation activation and resolution in human tendon disease. Sci. Transl. Med. 2015;7(311). 311ra173. 26. Kragsnaes MS, Fredberg U, Stribolt K, Kjaer SG, Bendix K, Ellingsen T. Stereological quantification of immune-competent cells in baseline biopsy specimens from achilles tendons: results from patients with chronic tendinopathy followed for more than 4 years. Am J Sports Med. 2014;42(10):2435–2445. 27. Millar NL, Hueber AJ, Reilly JH, et al. Inflammation is present in early human tendinopathy. Am J Sports Med. 2010;38(10):2085–2091. 28. Kendal AR, Layton T, Al-Mossawi H, et al. Multi-omic single cell analysis resolves novel stromal cell populations in healthy and diseased human tendon. Sci Rep. 2020;10(1):13939. 29. De Micheli AJ, Swanson JB, Disser NP, et al. Single-cell transcriptomic analysis identifies extensive heterogeneity in the cellular composition of mouse Achilles tendons. Am J Physiol Cell Physiol. 2020;319(5):C885–C894.

30. Harvey T, Flamenco S, and Fan CM, A Tppp3(+)Pdgfra(+) tendon stem cell population contributes to regeneration and reveals a shared role for PDGF signalling in regeneration and fibrosis. Nat Cell Biol. 2019;21(12):1490–1503. 31. Murray PJ, Allen JE, Biswas SK, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20. 32. Buckley CD, Filer A, Haworth O, Parsonage G, Salmon M. Defining a role for fibroblasts in the persistence of chronic inflammatory joint disease. Ann Rheum Dis. 2004;63(Suppl 2): ii92–ii95. 33. Couppe C, Kongsgaard M, Aagaard P, et al. Differences in tendon properties in elite badminton players with or without patellar tendinopathy. Scand J Med Sci Sports. 2013;23(2):e89–e95. 34. Dakin SG, Coles M, Sherlock JP, Powrie F, Carr AJ, Buckley CD. Pathogenic stromal cells as therapeutic targets in joint inflammation. Nat Rev Rheumatol. 2018;14(12):714–726. 35. Croft AP, Campos J, Jansen K, et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature. 2019;570(7760):246–251. 36. Ackermann PW, Salo PT, Hart DA. Neuronal pathways in tendon healing. Front Biosci. 2009;14:5165–5187. 37. Dean BJ, Snelling SJ, Dakin SG, Murphy RJ, Javaid MK, Carr AJ. Differences in glutamate receptors and inflammatory cell numbers are associated with the resolution of pain in human rotator cuff tendinopathy. Arthritis Res Ther. 2015;17:176. 38. Dean BJ, Gwilym SE, Carr AJ. Why does my shoulder hurt? A review of the neuroanatomical and biochemical basis of shoulder pain. Br J Sports Med. 2013;47(17):1095–1104. 39. Riley G. The pathogenesis of tendinopathy. A molecular perspective. Rheumatology (Oxford). 2004;43(2):131–142. 40. Riley G. Tendinopathy—from basic science to treatment. Nat Clin Pract Rheumatol. 2008;4(2):82–89. 41. Hakimi O, Ternette N, Murphy R, Kessler BM, Carr A. A quantitative label-free analysis of the extracellular proteome of human supraspinatus tendon reveals damage to the pericellular and elastic fibre niches in torn and aged tissue. PLoS One. 2017;12(5):e0177656. 42. Jones GC, Corps AN, Pennington CJ, et al. Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon. Arthritis Rheum. 2006;54(3):832–842. 43. Riley GP, Curry V, DeGroot J, et al. Matrix metalloproteinase activities and their relationship with collagen remodelling in tendon pathology. Matrix Biol. 2002;21(2):185–195. 44. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol. 2004;4(8):583–594. 45. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146. 46. Wynn TA. IL-13 effector functions. Annu Rev Immunol. 2003;21:425–456. 47. Parsons CJ, Takashima M, Rippe RA. Molecular mechanisms of hepatic fibrogenesis. J. Gastroenterol. Hepatol. 2007;22(Suppl 1):S79–S84. 48. van der Plas A, de Jonge S, de Vos RJ, et al. A 5-year follow-up study of Alfredson’s heeldrop exercise programme in chronic midportion Achilles tendinopathy. Br J Sports Med. 2012;46(3):214–218. 49. van Ark M, Cook JL, Docking SI, et al. Do isometric and isotonic exercise programs reduce pain in athletes with patellar tendinopathy in-season? A randomised clinical trial. J Sci Med Sport. 2015 50. Serhan CN, Hamberg M, Samuelsson B. Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc Natl Acad Sci U S A. 1984;81(17):5335–5339. 51. Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med. 1999;5(6):698–701. 52. Gilroy DW, Lawrence T, Perretti M, Rossi AG. Inflammatory resolution: new opportunities for drug discovery. Nat Rev Drug Discov. 2004;3(5):401–416. 53. Christensen B, Dandanell S, Kjaer M, Langberg H. Effect of anti-inflammatory medication on the running-induced rise in patella tendon collagen synthesis in humans. J Appl Physiol. 2011;110(1):137–141. 54. Dean BJ, Lostis E, Oakley T, Rombach I, Morrey ME, Carr AJ. The risks and benefits of glucocorticoid treatment for tendinopathy: a systematic review of the effects of local glucocorticoid on tendon. Semin Arthritis Rheum. 2014;43(4):570–576. 55. Metcalfe D, Achten J, Costa ML. Glucocorticoid injections in lesions of the achilles tendon. Foot Ankle Int. 2009;30(7):661–665. 56. Randelli P, Arrigoni P, Ragone V, Aliprandi A, Cabitza P. Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg. 2011;20(4):518–528. 57. Rha DW, Park GY, Kim YK, Kim MT, Lee SC. Comparison of the therapeutic effects of ultrasound-guided platelet-rich plasma injection and dry needling in rotator cuff disease: a randomized controlled trial. Clin. Rehabil. 2013;27(2):113–122. 58. Castricini R, Longo UG, De Benedetto M, et al. Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med. 2011;39(2):258–265. 59. Kesikburun S, Tan AK, Yilmaz B, Yasar E, Yazicioglu K. Platelet-rich plasma injections in the treatment of chronic rotator cuff tendinopathy: a randomized controlled trial with 1-year follow-up. Am J Sports Med. 2013;41(11):2609–2616. 60. Carr AJ, Murphy R, Dakin SG, et al. Platelet-rich plasma injection with arthroscopic acromioplasty for chronic rotator cuff tendinopathy: a randomized controlled trial. Am J Sports Med. 2015;43(12):2891–2897. 61. Smith RK, Werling NJ, Dakin SG, Alam R, Goodship AE, Dudhia J. Beneficial effects of autologous bone marrow-derived mesenchymal stem cells in naturally occurring tendinopathy. PLoS One. 2013;8(9):e75697. 62. Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RK. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet J. 2012;44(1):25–32. 63. Pas H, Moen MH, Haisma HJ, Winters M. No evidence for the use of stem cell therapy for tendon disorders: a systematic review. Br J Sports Med. 2017;51(13):996–1002.

CHAPTER 4  Tendons and ligaments 64. Carr AJ, Cooper CD, Campbell MK, et al. Clinical effectiveness and cost-effectiveness of open and arthroscopic rotator cuff repair [the UK Rotator Cuff Surgery (UKUFF) randomised trial]. Health Technol. Assess. Rep. 2015;19(80):1–218. 65. Rashid MS, Smith RDJ, Nagra N, et al. Rotator cuff repair with biological graft augmentation causes adverse tissue outcomes. Acta Orthop. 2020:1–7. 66. Hakimi O, Mouthuy PA, Zargar N, Lostis E, Morrey M, Carr A. A layered electro spun and woven surgical scaffold to enhance endogenous tendon repair. Acta Biomater. 2015;26:124–135. 67. Rothrauff BB, Lauro BB, Yang G, Debski RE, Musahl V, Tuan RS. Braided and stacked electrospun nanofibrous scaffolds for tendon and ligament tissue engineering. Tissue Eng Part A. 2017;23(9-10):378–389. 68. Stace ET, Dakin SG, Mouthuy PA, Carr AJ. Translating regenerative biomaterials into clinical practice. J Cell Physiol. 2016;231(1):36–49.

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69. Carr A, Cooper C, Campbell MK, et al. Effectiveness of open and arthroscopic rotator cuff repair (UKUFF): a randomised controlled trial. Bone Joint J. 2017;99-B(1):107–115. 70. Beard DJ, Rees JL, Cook JA, et al. Arthroscopic subacromial decompression for subacromial shoulder pain (CSAW): a multicentre, pragmatic, parallel group, placebo-controlled, threegroup, randomised surgical trial. Lancet. 2018;391(10118):329–338. 71. Paavola M, Malmivaara A, Taimela S, et al. Subacromial decompression versus diagnostic arthroscopy for shoulder impingement: randomised, placebo surgery controlled clinical trial, BMJ, 2018;362:k2860. 72. Keene DJ, Alsousou J, Harrison P, et al. Platelet rich plasma injection for acute Achilles tendon rupture: PATH-2 randomised, placebo controlled, superiority trial. BMJ. 2019;367:l6132.

5

Biomechanics of peripheral joints and spine David E. Williams • Cathy Holt

Key Points ■ Diarthrodial joints in the body act as levers with varying levels of mechanical advantage depending on their dynamic nature and load-bearing capacity. ■ Surface joint motion is a combination of rolling, sliding, and gliding. ■ Joints can be classified based on rotational and translational degrees of freedom of movement. ■ Joint lubrication is a combination of boundary lubrication, fluid film lubrication, or a mixture depending on the joint loading and relative movement of the joint surfaces. ■ Fluid film lubrication supports contact loads through the pressure developed in the film. ■ Boundary lubrication protects surfaces via a layer of lubricant, preventing surface-tosurface contact. ■ Many tissues in the body are nonhomogeneous and anisotropic, behaving differently when loaded in different locations and directions. ■ Many tissues in the body are viscoelastic in response to load, and this depends on structural composition and fluid content. ■ A characteristic stress–strain curve of collagenous tissues (e.g., tendon and ligament) is an initial toe region followed by a steep linear region before failure. ■ Moderate mechanical loading strengthens vertebrae and (eventually) intervertebral disks and articular cartilage. ■ Severe spinal loading arises mostly from muscle tension and from inertial forces generated during accelerations and falls.

INTRODUCTION Biomechanics is the application of mechanical engineering principles to living organisms. It can be examined at different levels, including the cellular level (e.g., response of cells to an externally applied force or deformation), tissue level (e.g., strain of the anterior cruciate ligament during normal gait), and whole-joint level (e.g., joint movement and contact forces during activities of daily living [ADLs]). Engineering principles may be used to understand the causes and progressions of many musculoskeletal diseases. A basic understanding of these principles is beneficial for clinicians and medical professionals, and it facilitates a multidisciplinary approach to understanding the biologic mechanisms of disease that may be driven by mechanical factors. This chapter presents a comprehensive introduction of engineering mechanics pertaining to whole-joint and tissue mechanics in the human body.

BIOMECHANICS OF WHOLE JOINTS AND SPINE The effects of a musculoskeletal disease are often seen at the microscopic level, but the symptoms of the disease are commonly found at the wholejoint level. For example, the symptoms of osteoarthritis, including joint pain, stiffness, and reduced range of motion, are accompanied by the formation of clefts and fissures in articular cartilage (AC) along with bony spurs (osteophytes) and joint space closing. To understand and quantify functional capabilities of a joint and how they change during the onset and progression of rheumatic disease and in response to treatment, it is important to examine the movement and transmission of forces through the synovial joint. This must include an appreciation of the construct stiffness and the response of individual tissues in the joint. This chapter concentrates on the biomechanics of the whole joint in terms of movement and loading. Biomechanics can be applied to understand the movement of the person, the individual joints, or the bones, along with the effects of the forces and moments acting on them. Two types of analyses can be applied: 1. Kinematics, which is the study of movement of a rigid body. 2. Kinetics, which is the study of forces applied to the body.

WHOLE-JOINT MOVEMENT Kinematics can be broken down further into surface joint motion (SJM) and range of motion (ROM), and both of these can be defined in the three 38

anatomic planes. SJM is used to measure the motion between articulating surfaces of joints in any plane and can be measured using simple radiography or stereophotogrammetric techniques. This motion can involve one joint surface that is just rolling on the other, one surface sliding on another, or a combination of the two (gliding). Single radiographs can provide the description of a relative uniplanar motion of two adjacent bones. As one bone rotates about another bone, at any instant there is a stationary point (i.e., zero velocity), which is defined as the instantaneous center of rotation (ICR). The ICR can be found by identifying displacement of two points on a bone as it moves from one position to another in relation to the other bone, which is considered stationary. Therefore the ICR of a joint can be identified using a series of successive radiographs of the joint in different poses. The ICR pathway can also be used to describe the relative movement between contact points of bones, or joint contacts.1 For a particular joint in a single plane of movement, the ICR is a parameter that can describe the effect of a pathology on joint function (e.g., the screw home mechanism of the knee), and this may also be indicative of stress concentrations in the AC and joint distraction, leading to focal damage and stretching of ligaments. A joint’s ROM is defined by its form and function. The joint may provide musculoskeletal stability during motion and act as a fulcrum between two lever arms (e.g., the knee between the femoral and tibial long bones). It allows mobility in terms of joint rotations and translations and can be a contributor to conservation of momentum of ADLs (e.g., the knee flexes and extends to limit the up and down movement of a person’s center of mass during walking). Range of motion can be described in engineering terms with respect to the degree of freedom (DOF) of movement of a joint. The DOF in the context of whole-joint movement refers to the translations and rotations of a rigid body in anatomic planes. Generally, the relative motion of one human body segment (e.g., bone) with regard to an adjacent one can involve translation, rotation, or both. For example, a hip joint is a ball and socket joint that is inherently stable and has three rotational DOF; alternatively, the tibiofemoral joint of the knee is much more complex and unstable with three rotational and three translational DOF (6DOF in total) (Fig. 5.1). However, if the object of the study is gross human motion, such as walking or exercise, the translations can often be disregarded because of their small magnitude (which can be difficult to quantify accurately) compared with rotations, thus allowing joint motion to be analyzed as pure rotation. In describing joint ROM, it is important to understand the joint configuration. Simplifying assumptions can be made when joint motions are considered as pure rotations around fixed axes; that is, the axes of rotation intersect at one point (if the joint exhibits rotation around more than one axis), coinciding with a joint reference coordinate system that usually matches the anatomic axes (e.g., for the knee, the flexion–extension axis should coincide with the frontal axis passing through joint center2,3). Methods used to measure and quantify joint configuration differ primarily in the manner in which the local reference frame is fixed within a body segment. All local reference systems are classified as either technical or somatic.6,7 ■ Technical reference systems are fixed with technical devices (i.e., goniometer, inertial movement sensor, or accelerometer), located externally on the body surface rather than fixed directly at the origin of the body segment local reference frame. ■ Somatic reference systems can be defined in three ways (Fig. 5.2). Also, a movement pattern that is considered as a pure rotation around one reference axis in one frame may be expressed as a complex general motion in another reference system.8 The Clinical Reference System (CRS) is most often used by practitioners and is defined as the sagittal, frontal, and transverse planes defined in the anatomic position. Segmental motion can be defined as (1) motion in the sagittal plan (flexion–extension), (2) motion away from or toward the midsagittal plane (abduction–adduction), (3) rotation about the long axis (internal–external rotation or supination–pronation depending on the joint), or (4) a combination of flexion–extension and abduction–adduction resulting in circumduction.9

CHAPTER 5  Biomechanics of peripheral joints and spine DEGREES OF FREEDOM OF MOVEMENT OF THE KNEE AND HIP

39

INCLUDED ANGLE 0°

30°

150°

FIG. 5.3  The included angle is located between the longitudinal axis of two segments defining a joint—150 degrees—and the anatomic angle is the angle through which the joint would have to be moved to take it from anatomic position to the position of interest. (From Zatsiorsky VM. Kinetics of human motion. Human Kinetics; 1998, p. 97.)

FIG. 5.1  (a) Six degrees of freedom (DOF) of movement of the tibiofemoral joint of the knee involves three translations and three rotations. (b) The more constrained and therefore more stable hip joint is a ball and socket joint with only three rotational DOFs; however, hip distraction is a translational DOF and is not present in healthy hip function but has been measured in total hip arthroplasty using fluoroscopy4,5 and occurs in hip dislocation. a

SOMATIC REFERENCE SYSTEM FOR A KNEE JOINT Center of femoral head ZF

Posterior points on femoral condyles ZT XT a

YF YT Center of tibial intercondylar notch

90° flexion

Center of femoral head

ZF

XF

b

Dependent posture

XF XT

ZT

ZF Most distal points on femoral condyles YF YT

b

Transepicondylar line XF ZT XT

YF YT

c

FIG. 5.2  Somatic reference system for a knee joint: mechanical-based system (a),10,11 system based on anatomic axes of the tibia and femur12 (b), and system based on the transepicondylar line and the tibial mechanical axis (c).13 Experimentally measured differences of abduction and adduction at maximum flexion in leg swing during the gait cycle are 4 degrees between a and c and 7 degrees between b and c. (From Zatsiorsky VM. Kinetics of human motion. Human Kinetics; 1998, p. 83.)

90° abduction c

Adduction d

FIG. 5.4 A subject performs three shoulder joint motions in succession: (a) starting from a dependent posture with arms by the side and the palms of the hand facing medially, (b) flexion of 90 degrees, and (c) horizontal extension (abduction) of 90  degrees. (d) Adduction. The hand is now in a pronated position (anatomic posture), although pronation was not performed. This phenomenon, known as the Codman’s paradox,14 occurs because rotations in a clinical system are not defined in accordance with the requirements of kinematics.

mechanism allows the quadriceps tendons to absorb energy when the knees are flexed to soften the landing from a jump.

SPINAL MOVEMENTS Geometrically included angles can be viewed as internal joint angles and anatomic angles can be viewed as external, to designate joint configuration (Fig. 5.3). The advantages of using the CRS are that it provides anatomically meaningful definitions of the main segmental movements and is convenient when a joint moves from a standard anatomic or neutral position. The disadvantages are that it is not suitable when a joint rotation commences from a non neutral configuration and is not appropriate to describe complex movement patterns (Fig. 5.4).

MECHANICAL FUNCTION OF THE SPINE When considering spinal curvature, cervical lordosis appears when infants first lift their heads up, and lumbar lordosis develops when walking begins. Thoracic kyphosis appears to be a compensatory mechanism to maintain a level line of sight and to increase the volume of the thoracic cavity. Spinal curves (Fig. 5.5) probably play a shock-absorbing role during locomotion because the natural tendency for the curves to flatten and accentuate as the body rises and falls is resisted by the muscles of the trunk. The tendons of these muscles have a great capacity to store energy so that they can act as shock absorbers and minimize vertical accelerations of the head. A similar

Intervertebral movements in living people combine angular rotations with small gliding movements (translations) in the plane of the disk. Angular rotations stretch and compress the disk anulus in such a manner that the center of rotation moves around within the disk nucleus. The oblique surfaces of the apophyseal and uncovertebral joints ensure that certain movements are mechanically “coupled”; for example, attempted lateral bending normally creates a small axial rotation as well. The cervical spine is the most mobile region because cervical intervertebral disks are relatively thick in comparison to the height of adjacent vertebral bodies. Conversely, the thoracic spine is the least mobile because its disks are narrow, and thoracic movements are inhibited by the ribs and dipping spinous processes. Mobility of the lumbar spine declines by approximately 50% between the ages of 16 and 85 years.15 This is partly due to disk narrowing, which brings the neural arches of adjacent vertebrae closer together and causes the center of rotation for flexion and extension to migrate posteriorly toward the apophyseal joints.16

STATICS AND DYNAMICS Whole-joint force analyses are commonly performed to estimate the force and moments that a diarthrodial joint may experience during ADLs.

SECTION 1  Scientific Basis of Rheumatic Disease

40

ANALYSIS OF FORCES IN THE SHOULDER JOINT

SPINAL CURVATURE

Deltoid muscle Humerus

Scapula

Cervical lordosis

Radius

Weight in hand

Ulna

a

y

FJ

Fm θJ

x

θm a WA

WB

b b

Lumbar lordosis

FIG. 5.5 The S-shaped curves of the spine can assist in shock absorption during locomotion. When the center of gravity of the body descends at “heel strike,” the cervical and lumbar lordosis both increase, and they decrease again as the body rises at “toe-off.” This enables energy to be stored and then released by deformed intervertebral disks, tendons, and ligaments.

However, most activities are dynamic (even standing still!). The main forces that must be considered during this type of analysis are due to body weight, muscle forces, other forces related to soft tissues constraints, and other externally applied loads (e.g., carrying the weight of an object). Friction forces also exist within a joint when two articulating surfaces interact; however, for a healthy joint, these are negligible and can be ignored for a dynamic analysis. A static analysis examines the forces and moments (torques) acting on a body in equilibrium (i.e., at rest or constant speed). An example of a static analysis is the evaluation of forces in the knee during standing. In vector notation, if the system is in   equilibrium, the sum Σ of all of the forces F and moments (torques) M acting on the body should be equal to   zero; this is written as ∑ F = 0 , ∑ M = 0 . A dynamic analysis examines the forces and moments acting on a body in motion (i.e., accelerating or decelerating) and includes descriptions of the inertial properties of the body   being analyzed. In vector notation, this is written as ∑ F = ma and ΣM = Iα, 

where a and α are the linear and angular accelerations, respectively, of the b o d y ; m is the mass of the body; and I represents the inertial properties (mass distribution) of the body.

Example of static analysis An example of a static force analysis is that performed for the shoulder joint (Fig. 5.6, a). Although this is performed in two dimensions, for ease of analysis, important generalized biomechanical characteristics of whole joints are evident from the results. The goal of this analysis is to calculate the static in vivo muscular forces and contact force between the proximal humerus

c

FIG. 5.6  (a) Person holding a ball in the hand at 90 degrees of shoulder abduction. Relative positions of the bones in the arm are indicated. (b) Free-body diagram of the arm in 90 degrees of shoulder abduction. (The humerus, radius, and ulna are grouped together for simplification of analysis.) a, b, c, Distances from the glenohumeral joint center to forces acting on the limb; FJ, Joint contact force; FM, deltoid muscle force; θJ, angle of joint contact force; θM, angle of deltoid muscle force; WA, weight of arm; WB, weight of ball. The z axis is acting out of the page. and glenoid fossa of the glenohumeral joint. We examine a shoulder at 90 degrees of abduction with a ball held in the hand. To perform a force analysis (static or dynamic), it is necessary to construct a free-body diagram (FBD), which displays all intrinsic forces and moments acting on a body or segment of interest. An FBD of a simplified shoulder joint and the key muscle group acting to maintain the joint in its current posture is shown in Fig. 5.6, b. For ease of analysis, a single rigid body is used to represent a combined radius, ulna, humerus, and hand. All forces and moments acting on the selected body segment must be included in the FBD. Forces included may be separated into four classes: 1. Contact force from the humerus acting on the glenoid fossa. 2. Muscle forces from muscle groups that flex, extend, or rotate the shoulder joint; only the deltoid is modeled here. 3. Intrinsic weight of the arm. 4. External forces, such as the weight of the ball. In the FBD, it is important to record the lines of action of the forces and moments plus the point of application, direction (orientation), and magnitude of each force (as it is a vector). The vector (arrow), representing the contact force, is placed at the proximal end of the humerus, representing the contact region in the joint between the humeral head and the glenoid; however, its direction (θJ) and magnitude (FJ) are unknown. The vector (arrow), representing the deltoid muscle force, is placed at its point of attachment to the humerus at a distance “a” from the glenohumeral joint rotation center, which in this case is assumed to coincide with the glenohumeral joint contact location, for simplicity. The magnitude of the muscle force (FM) is unknown. Lines of action of muscle forces (θM) are assumed on the basis of detailed anatomic dissections of joints. The force vector representing the arm weight (WA) is assumed to be known and is placed at the center of mass of the arm at a distance “b” from the joint center. The force vector representing the arm weight is acting downward, in the direction of gravity. The same is true for the ball of known weight held in the hand (WB and distance c). The unknown variables are the magnitude of the contact force (FJ), the direction of the contact force (θJ), and the magnitude of the muscle force (FM). These are calculated using static force analysis. A body is considered to be in static equilibrium when all forces and all moments acting on the body sum to zero. This summation may be performed around any point on the FBD. For this two-dimensional model, static equilibrium vector equations may be written in terms of their individual x, y, and z components:

∑F

x

= 0, ∑FY = 0, ∑Mz = 0

CHAPTER 5  Biomechanics of peripheral joints and spine BOX 5.1  STATIC FORCE ANALYSIS OF A FREE-BODY DIAGRAM

∑F



= 0 → FJ ⋅ cos(θ J ) − FM ⋅ cos( θM ) = 0

[Eqn. 1]

= 0 ↑ FM ⋅ sin(θM ) − FJ ⋅ sin(θ J ) + WA + WB = 0

[Eqn. 2]

x

∑F

y

In a static analysis, the sum of moments (ΣMz) may be taken at any coordinate location. In the current analysis, the sum of moments was taken about the point of application of the contact force on the humerus. The sum of moments was taken at this point to preclude the presence of the articulating surface contact force in the moment equation, yielding:



∑M

Z

= 0 FM ⋅ sin(θM ) ⋅ a − WA ⋅ b − WB ⋅ c = 0

The preceding equations can be solved: From Eq. 3: W ⋅ b + Wb ⋅ c FM = a sin(θM ) ⋅ a

[Eqn. 3]

[Eqn. 4]

From Eq. 1: FJ ⋅ cos(θ J ) = FM ⋅ cos(θM )





[Eqn. 5]

From Eq. 2:

FJ ⋅ sin(θ J ) = FM ⋅ sin(θM ) − Wa − Wb



[Eqn. 6]

Divide Eq. 6 by Eq. 5: tan(θ J ) =

FM ⋅ sin(θM ) − Wa − Wb FM ⋅ cos(θM )

F ⋅ sin(θM ) − Wa − Wb   θ J = tan−1  M   FM ⋅ cos(θM )



The resultant FJ is found by the following equation (using a known trigonometric identity):

FJ2 = (FM ⋅ cos(θM ))2 + (FM ⋅ sin(θM ) − Wa − Wb )2 FJ =

(FM ⋅ cos(θM ))2 + (FM ⋅ sin(θM ) − WA − WB )2

We now substitute values for known variables from anthropometric measurements17,18 a = 15 cm, b = 30 cm, c = 60 cm, θM = 15 degrees, WA = 40 N, and WB = 60 N to solve for the unknown variables FM, FJ, and NJ, calculated as FM = 1236.4 N, FJ = 1214.4 N, and θJ = 10.4 degrees.

The force equilibrium equations are applied to the FBD in Fig. 5.6, b and the result is displayed in Box 5.1. This simple analysis shows characteristics common to diarthrodial joints throughout the human body: (1) muscle force is the main contributor to the force acting through the joint and (2) poor mechanical advantage is shown for the shoulder when the weight of the ball in the hand is compared with the muscle force required to maintain the ball position (the calculated muscle force is more than 20 times the weight of the ball!). Altering three factors of the analysis may increase the mechanical advantage of the system by decreasing the muscle force required to hold the ball: (1) An increase of θM would increase the component of FM that resists the downward force of the combined weight of the arm and ball. (2) Increase the moment arm of FM, distance “a,” but this is often not practical. (3) Flex the elbow and bring the effect of the combined weight of the arm and ball closer to the center of rotation of the shoulder. This would change the resulting value from the moment equation and reduce the effective muscle force and resulting contact force.

Limitations of static analysis A number of limitations to the static analysis exist because of the number of unknown variables. The number of static equilibrium equations available for use prevents the inclusion of additional muscle or ligamentous forces. That is, for a two-dimensional problem, we could only use two force equations (ΣFx = 0, ΣFy = 0) and one moment equation (ΣMz = 0) to solve the unknown variables (i.e., only three unknown variables may be determined in a two-dimensional analysis). If the analysis were performed in three dimensions, it would be possible to solve nine unknown variables. Owing to complex human anatomy and numerous muscle forces, we often have a greater number of unknown variables to solve than we have equations to use in the analysis. This results in an indeterminate problem.

41

Several computational methods have been developed to increase the number of variables that may be solved. One is the exclusion of selected forces. For example, in the previous analysis, the teres minor muscle, an adducting muscle of the shoulder, was excluded because the shoulder was in pure abduction. A second is to reduce the number of unknown forces by assuming a force relationship between the different muscle units. For example, the supraspinatus muscle is also active during shoulder abduction, but it was excluded to limit the number of unknown variables. We may have assumed a relationship between the deltoid and supraspinatus, such as F2 = A • F1, where F2 is the muscle force of the supraspinatus, F1 is the muscle force of the deltoid, and A is a constant. The relationship between different muscular units not included in the analysis may be formatted in a linear or nonlinear manner. A third method to decrease the number of unknown variables would be to incorporate representations of muscle electromyographic (EMG) measurements into the analysis. (Note: EMG does not equate directly to muscle force.) A fourth method to increase the number of unknown variables is to use numerical optimization. Using state-of-the-art techniques in clinical movement analysis, joint moments can be reliably estimated from recorded movement and external force data. Optimization is performed by minimizing a mathematical function that is defined as the “cost” of performing an ADL. Various cost functions that have been used include minimization of muscular forces, muscle stress, and muscle energy. These cost functions have been successful in evaluating muscle forces during various ADLs. Static optimization methods that transform joint moments into estimates of individual muscle forces using musculoskeletal models have been used for several decades.19 Examples include OpenSim, an open source software that allows the user to input limb movement, joint DOF, kinematics, and lines of action and force-generating parameters of the muscle. This allows the function of each muscle to be analyzed.20 The AnyBody Modeling system is another example of this type of software to analyze the musculoskeletal system of humans or other creatures as rigid body systems.21

JOINT LUBRICATION Human joints are exposed to great variation in loading conditions and movement; thus they are expected to respond dynamically at all times to allow for ADLs, sports, and functional alterations (e.g., caused by pain, deformity, or muscle weakness). There can be high-impact, short-duration loads such as in running; moderately low loads with a prolonged loading time such as standing; and low loads with rapid motion such as in the swing phase of walking. Over a lifetime there is relatively little wear of the joint articulating surfaces, which indicates a highly effective lubricating system. The coefficient of friction between AC lubricated by synovial fluid in healthy joint is 0.005, where friction is the resistance to movement between two surfaces in contact. This is lower than found in highly polished machine bearings (0.01) and the interaction of steel on ice (i.e., ice skating). Much of the experimental research into understanding the role of synovial fluid and AC in human joints was undertaken in the early days of biotribology research. The following information is based on these early studies, which still provide the basis of our understanding of human and artificial joint tribology today.

Modes of lubrication Two types of lubrication exist: boundary lubrication and fluid film lubrication. Boundary lubrication is caused by a single layer (monolayer) of lubricant adsorbed on each bearing surface. In a joint, boundary lubrication is achieved by a macromolecular monolayer attached to each articular surface. These layers carry loads and are effective in reducing friction. Fluid film lubrication is caused by a thin film of lubricant that is entrained into, or retained in, the contact between the joint surfaces during their motion and impact. This produces a greater bearing–surface separation. The pressure developed in the lubricating fluid carries the loads applied to the joint (Fig. 5.7) and shearing in the fluid takes place. The lubricating characteristics depend on the lubricant properties (e.g., viscosity), the shape of the gap between the two bearing surfaces, and the relative velocity of the surfaces. In a human joint, the bearing materials (i.e., the AC) are not rigid and stiff, which results in elastohydrodynamic lubrication. As the joint surfaces move relative to each other and entrain a layer of lubricant (i.e., synovial fluid) into the contact, the fluid pressure that develops causes surface deformation (i.e., AC flattening) (Fig. 5.8). This changes the film geometry by increasing the surface area (and thus the area over which the joint contact force is transmitted), reducing the escape of lubricant from between the bearing surfaces and generating a longer lasting film. These factors produce a lower stress concentration within the joint surfaces.22

SECTION 1  Scientific Basis of Rheumatic Disease

42

ARTICULAR CARTILAGE LUBRICATION

HYDRODYNAMIC LUBRICATION Adsorbed boundary lubricant

Weight

Pressurized fluid

Macromolecular monolayer

Velocity

Pressure distribution

Fluid pressure

~0.3 mm

FIG. 5.7  Fluid film lubrication. During motion at sufficiently high velocities, the weight

Cartilage

tilts and forms a wedge shape of lubricant entrained into the contact. Because of the viscous properties of the fluid, a pressure will be created within the fluid to support the weight.

Boundary lubricated asperity contact

Articular surface

FIG. 5.9  Mixed lubrication operates in articular cartilage bearings: boundary lubrication in which the lubricating film is as thick as the roughness of the bearing surfaces (order = 0.3 mm19) and fluid film lubrication in which surfaces are more widely separated in the troughs between the surface asperities.

COMPARISON OF LUBRICATION Rigid bearings 1

Load

Rolling

Pressure distribution Rolling

2

VARIOUS LOADING MODES IN TISSUES THROUGHOUT THE BODY

Load Squeeze film

Squeeze film

Deformable bearings 3 Rolling

Load

4 Rolling

Squeeze film

Load Squeeze film Unloaded

Tension

Compression

Bending

FIG. 5.8  Load carrying by lubricated bearings. A comparison of hydrodynamic lubrication (1) and squeeze film lubrication (2) of rigid surfaces and elastohydrodynamic lubrication of deformable bearing surfaces under a hydrodynamic (sliding) action (3) and a squeeze film action (4). Surface deformation of elastohydrodynamically lubricated bearings increases the contact area, thus increasing the load-carrying capacity of these bearings and spreading the load over a larger contact area. Shearing takes place between the layers of the lubricant.

Lubrication in diarthrodial joints In diarthrodial joints, a mixed mode of lubrication can occur, with the joint surface loads being sustained by fluid film pressures in areas of noncontact and by boundary lubrication in areas of contact (Fig. 5.9). Articular cartilage can be treated as a biphasic material with an interstitial fluid phase and porous-permeable solid phase. The material properties and porosity of the solid matrix define the interstitial fluid pressure, which supports load bearing and lubrication and contributes to the protection of AC from wear. The surfaces can exude and imbibe a lubricating fluid. As the joint moves and the surfaces slide, fluid is exuded in front of and beneath the leading half of the load. When the peak stresses decrease, fluid is reabsorbed back into the AC and it returns to its original dimensions.22–26 The viscosity of a lubricating fluid is important. Synovial fluid undergoes large changes in viscosity with changes in both temperature and velocity gradient. For very low velocities, a thinner lubricating film is desirable. Because synovial fluid is thixotropic, which means it can become fluid when agitated and then settle when left at rest, it can meet these requirements. If a joint effusion is present, the velocity-dependent properties may be lost, resulting in reduced lubrication and subsequent joint surface damage. Hyaluronan, lubricin, and phospholipid molecules exist in synovial joints and more recently have been suggested to act as lubricants. However, they

Shear

Torsion

Combined loading

FIG. 5.10  Schematic representation of various loading modes. cannot alone explain the extremely low friction. Each may play a different role, acting together; hyaluronan is attached at the AC surface by lubricin molecules and phospholipid complexes to provide lubrication.27

BIOMECHANICS OF TISSUES Understanding how the various tissues in the joint respond to the loads that they experience during ADLs, overload, and traumatic events provides insight into the progression and treatment of musculoskeletal diseases. When a force is applied to a tissue, the tissue will deform in response to the applied load. If a displacement is applied to the tissue (i.e., by applying a force), it will produce a resistive force as a reaction to the applied displacement and deform. The amount of deformation is proportional to a combination of the stiffness of the tissue, which is in turn related to its composition, its shape and size, and the properties of the surrounding, supporting tissues. These material and structural properties vary for all tissues within a joint. A structure can be loaded in various ways; Fig. 5.10 provides a simplified approach to understanding them, and they may be experienced, often in combination, by all tissues.

CHAPTER 5  Biomechanics of peripheral joints and spine

STRUCTURAL AND MATERIAL PROPERTIES Tissues can be tested as isolated individual samples (mechanical testing), to understand the material properties, or within an entire structural complex (structural testing). The structural properties of a tissue incorporate not only the material composition of the tissue but also its geometric configuration and mechanical environment.28 Output from structural testing, which involves measuring the deformation of the tissue in response to an applied load is shown as a force–displacement curve (Fig. 5.11). The units of force, F, are Newtons (N) or pounds force (lbf), and the units of displacement, D, are typically millimeters (mm). Stiffness, a structural property, is calculated as the slope of the linear elastic region of the force–displacement curve. The material properties of a tissue encompass its inherent material (chemical and physical) composition (e.g., contribution of collagen fibrils in a tendon).28 Output from mechanical testing of a tissue sample is shown as a stress–strain curve. The units of stress are Pascals or Newtons/meter2 (Pa, N/m2); strain, as a ratio, has no units. The mechanical property, modulus of elasticity (Young’s modulus), is calculated from the linear section of

43

the stress–strain curve. Stress and strain are normalized values of load and displacement, respectively, based on test sample geometry (Fig. 5.12).

STRESS AND STRAIN Stress (σ) is calculated as the applied force divided by the initial cross-­ sectional area of the tissue sample: σ = F/Ao. Strain (ε) is calculated as change of length of the tissue sample divided by the initial length of the sample: ε = ΔL/Lo. Stress, strain, force, and displacement may be positive or negative values (i.e., putting the structure or sample in tension invokes a tensile force; conversely, compressing the sample invokes a compressive force, and this requires ± representation). Additional information about the tissue may be extracted from the stress–strain curve (Fig. 5.13). For example, amount of plastic deformation of a sample when it reaches failure (ductility) and the ability of a material to absorb energy when deformed elastically and to release the energy when unloaded (resilience), as shown in Fig. 5.14 where stress–strain qualities of cortical and cancellous bone with different bone densities are tested under similar conditions. The stress distribution in a body is a quantitative description of the distribution of the internal forces as a result of the external forces acting at its

FORCE–DISPLACEMENT CURVE ADDITIONAL MECHANICAL PARAMETERS FROM STRESS–STRAIN CURVE Yield point

D

C

Fracture point

B Force (Newtons)

Brittle material Ductile material

Stiffness Stress

∆F ∆D Elastic region

Plastic region

E

A

Displacement (millimeters)

FIG. 5.11  Force–displacement curve for a structure composed of a pliable material. If a load is applied within the elastic region (A–B) and removed, no permanent deformation occurs. If loading continues past the yield point (B) and into the plastic region (B–D) and is then released, permanent deformation results. The amount of permanent deformation that occurs if the structure is loaded to point C in the plastic region and then unloaded is represented by the distance between A and E. Structural stiffness is calculated as the slope of the linear portion of the elastic region (i.e., ΔF/ΔD).

Strain

FIG. 5.13  Ductility is a measure of the amount of plastic deformation at failure and is shown in this figure. Resilience is the ability of a material to absorb energy when deformed elastically and to release the energy when unloaded. Resilience is calculated as the area under the stress–strain curve line. The presence of shear strain in a structure loaded in tension and in compression is indicated by angular deformation.

COMPARISON OF FORCE–DISPLACEMENT CURVES WITH STRESS–STRAIN CURVE

A2

T1, T2, T3 F F Ai ∆L Ei = i Li i = 1, 2, 3

Force

L2 A1

F

Ti =

F

L1 A3

F

FIG. 5.12 Different continuous structures composed

Stress

F

of the same pliable material but with different geometries are tested. When individual forces are converted to stress and displacements are converted to strains, all loading curves are superimposed onto one another.

F

L3 Displacement L3 > L1 = L2 A2 > A 1 = A 3

Strain E1, E2, E3

SECTION 1  Scientific Basis of Rheumatic Disease

44

TYPICAL COMPRESSIVE STRESS–STRAIN BEHAVIOR OF TRABECULAR AND CORTICAL BONE

STATE OF STRAIN UNDER TENSION AND COMPRESSION LOADING Unloaded

200

Apparent density

Under compressive loading

0.30 g/cc

150 Stress (MPa)

Under tensile loading

Cortical bone

0.90 g/cc 1.85 g/cc

100 50 Trabecular bone 0

0

5

10 15 Strain (%)

20

25

θ

θ

θ

FIG. 5.14  Examples of typical compressive stress–strain behavior of trabecular and cortical bone for different apparent demises. (Adapted from Keaveny TM, Hayes WC. Mechanical properties of cortical and trabecular bone. In: Bone, vol. VII: Bone Growth-B. Boca Raton, FL: CRC Press; 1992, p. 285–344.)

θ = 90

θ > 90

θ < 90

FIG. 5.16  Tension and compression strain are indicated by longitudinal elongation STRESS IN DIFFERENT LOADING MODES Tensile loading

Compressive loading

Shear loading

or compression of the body. When considering the unloaded shape, the square will elongate under tension or flatten out under compression. In three dimensions, six independent strain components are required to describe the state of strain at each point in a body. Three of the strain components represent longitudinal elongation or compression of the body; the other three represent shear. Whenever a structure is subjected to tensile or compressive loading, shear stress is produced. In response to shear loading, the diamond in the unloaded body deforms in an angular manner with the angle changing depending on compression or tension (i.e., more acute or more obtuse).

ANISOTROPY AND INHOMOGENEITY OF CARTILAGE D

FIG. 5.15  Stress distribution within a material with tensile loading, compressive loading, and shear loading. In three dimensions, six independent stress components are required to describe the state of stress at each point in a body. Three of the stress components are normal stresses (tension–compression, which act perpendicular to the cross-sectional plane), and three stress components are shear stresses that act along the plane of the cross-sectional area.

Surface zone

Articular surface A

Collagen fibrils

B

Middle zone

Subchondral bone

C

D A

Deep zone a

B

= Tissue sample

Cancellous bone D C Stress

surfaces (Fig. 5.15). Strain is the deformation of a body when it is resisting an applied external force (Fig. 5.16). For a given tissue we must apply a stress–strain relationship to calculate the stress based on measured experimental strain. The stress in a body is related to the strain by the modulus of the body’s material. This relationship may be complex and may consist of numerous modulus values. The exact number of modulus values depends on the homogeneity and isotropy of the test sample.29 If a tissue is homogeneous, the mechanical properties of the tissue do not differ depending on the source location of the tested tissue sample. If a tissue is isotropic, the mechanical properties of the tissue do not change as the orientation of the tissue sample is changed. Most tissues in the body are inhomogeneous and anisotropic. Stress–strain plots of tissue samples from an inhomogeneous and anisotropic tissue (AC) are shown in Fig. 5.17. Because of this variation, the orientation and source location of the tissue sample significantly influence the stiffness of the tissue. An example of this is well understood for AC samples.30 AC samples that are aligned with the preferred direction of collagen fibrils are stiffer than samples that are oriented perpendicular to the preferred direction. In addition, tissue samples from the articular surface are stiffer than tissue samples from deep within the tissue. Researchers often assume a tissue to be homogeneous and isotropic. This results in a requirement for only two variables to fully describe the force–displacement response of a tissue to mechanical loading: Young’s modulus (Ey) and Poisson’s ratio (ν). In one dimension, Young’s modulus is calculated as the slope of the linear (elastic) portion of the stress–strain curve. Poisson’s ratio relates the longitudinal elongation (εy) of the material to the lateral contraction (εx) of the material (Fig. 5.18). This varies depending on the internal structure of the material; also, soft tissues have a viscoelastic component response.

C

b

B A

Strain

FIG. 5.17  (a) Schematic diagram of collagen fiber orientation through the depth of articular cartilage. Superficial fibers are tangent to the articular surface. Fibers in the middle zone have no preferred orientation. Fibers in the deep zone are oriented radially to the subchondral surface. (b) Stress–strain diagram of cartilage testing in tension. Tissue sample A is from the same region as tissue sample B but is oriented 90 degrees to tissue sample B. Tissue sample C is from the same region as tissue sample D but is oriented 90 degrees to tissue sample D. Differences in stress–strain response indicate the anisotropic and inhomogeneous material nature of cartilage.

VISCOELASTICITY For a viscoelastic tissue, the stress–strain response depends not only on the magnitude of the applied stress or strain but also on the rate of the applied stress or strain. Viscoelastic tissues have three characteristic stress–strain responses: creep, stress–relaxation, and hysteresis, as seen in Box 5.2.31

CHAPTER 5  Biomechanics of peripheral joints and spine CREEP TESTING

POISSON‘S RATIO EXPRESSES LATERAL STRAINS y Stress

F

x

σ

Ey = ∆L = Li – Lo Lo Lo Li

0

Ex = ∆W = Wi – Wo Wo Wo

Lo

Time Fluid-like material

ν= Ex = (Wi – Wo) Lo Ey (Li – Lo) Wo

Wo

Solid-like material

Strain

Wi

45

= Initial configuration = Final configuration

FIG. 5.18 Poisson’s ratio relates the longitudinal elongation of the material to the

lateral contraction of the material. In an ideal incompressible material, ν = 0.5.

Time

0

F

FIG. 5.19  In creep testing, an instantaneous stress (σo) is applied to a tissue sample at time t0 and maintained while the resulting tissue strain is recorded. Whereas solid-like materials exhibit an equilibrium deformation in response to the applied load, fluid-like materials elongate continuously.

BOX 5.2  STRESS–STRAIN RESPONSES IN VISCOELASTIC TISSUE Creep: the deformation response of a tissue sample under a constant applied load (see Fig. 5.19) Stress–relaxation: the stress response of a tissue sample under a constant applied displacement (see Fig. 5.20) Hysteresis: the difference in the response curve between loading and unloading of the tissue sample on a stress–strain diagram (see Fig. 5.21) Strain

STRESS–RELAXATION TESTING

0

Time

Stress

These responses can be shown diagrammatically on a ligament sample. We assume a ligament has been removed from a joint as a bone–ligament– bone (BLB) segment. One end of the BLB has been anchored to the mechanical testing apparatus through a load cell to measure applied force, and the other end of the BLB has been attached to the cross-head of the testing system, which can be moved to apply a tensile load (pulling the two ends of the test segment away from each other), which induces a tensile stress distribution within the test segment along its test length, or compressive load (bringing the two ends of the test segment toward each other), which induces a compressive stress distribution within the test segment along its test length. The viscoelastic responses of a ligament are due to the interaction of fluid and solid components of the ligament: water and collagen, respectively. This can be described as biphasic. In a relaxed state before loading the ligament is approximately 60% to 80% water and contains collagen bundles that have a wavy appearance.32 When a tensile force or displacement is applied to the ligament, the fluid is exuded through pores in the tissue and the collagen fibers begin to straighten and align in the direction of the applied load. In a creep test, an instantaneous step or ramp load is applied to the tissue sample and held constant for an extended period of time (Fig. 5.19). This is considered a load control test, and the resulting tissue displacement is measured. The majority of the fluid is exuded from the tissue, and the applied load is balanced by the straightened collagen bundles. The displacement shows an initial elastic response of the tissue followed by a gradual increase of lengthening of the tissue. As the test proceeds, fluid continues to exude from the tissue, and the solid components of the tissue support the applied load. The “solid-like” material will be distracted to a point at which the solid components of the tissue will balance the applied load and will not elongate further. The modulus of the tissue is calculated as the stress of the tissue divided by its end displacement. The “fluid-like” material will not be able to balance the applied load and will continue to elongate. In a stress–relaxation test, an instantaneous step or ramp displacement is held constant for an extended period (Fig. 5.20).33 This is considered a displacement control test; the resulting tissue force is measured. The collagen bundles are straightened by the imposed displacement, and fluid is initially exuded in response to the rapid increase in interstitial fluid pressure. With

ε0

Solid-like material Fluid-like material 0

Time

FIG. 5.20  In stress–relaxation testing, an instantaneous deformation (εo) is applied to a tissue sample at time t0 and maintained while the resulting tissue stress is recorded. Tissues in the body have a solid component that resists the applied deformation after interstitial fluid has been exuded from the tissue.

time, the interstitial fluid pressure comes to equilibrium and fluid is no longer exuded. An initial increase in force measured by the load cell is followed by a gradual reduction. The force eventually approaches equilibrium; the magnitude depends on the solid or fluid nature of the tissue. Solid-like materials have a non zero final stress, whereas for fluid-like materials, it is close or equal to zero. Finally, hysteresis of a soft tissue is displayed while the tissue is cycled to a known force or displacement and back to its initial position (Fig. 5.21).34 A combination of the fluid–solid effects is seen in a hysteresis loop. As shown in the figure, the loading portion of the force–displacement curve is always higher than the unloading portion of the curve. The area between the loading and unloading curves represents nonrecoverable energy that is lost during testing.

SECTION 1  Scientific Basis of Rheumatic Disease

46

HYSTERESIS CURVE FOR A LIGAMENT

= Energy loss

TOTAL COMPRESSIVE FORCE ON THE LUMBAR SPINE

Spinal load (N)

= Direction of loading

2500 2000

Stress

1500 A

1000

B

500 0 0

4

6

8

10 12 14 16 18 20 22 24 Angle of motion segment

Strain

FIG. 5.23  The compressive force acting on the lumbar spine increases to 2000 N

FIG. 5.21  The loading portion of the hysteresis curve (A) is always above the unloading portion of the curve (B). The area between the loading and unloading portions of the curve indicates relaxation of the collagen fibers within the ligament and the exuding of fluid from the ligament.

HIGH FORCES FROM BACK MUSCLES

(≈200 kg) with stooped, standing postures. Forces were calculated from pressure in the L4 to L5 intervertebral disk nucleus measured in vivo by a miniature pressure transducer. “Angle of motion segment” refers to the relative orientation of the upper and lower endplates of the L4 to L5 disk. Reproduced from Sato K, Kikuchi S, Yonezawa T. In vivo intradiscal pressure measurement in healthy individuals and in patients with ongoing back problems. Spine 1999;24:2468–74.

MUSCLE FORCES Contracting muscle tension compresses the bones between the muscle’s tendinous insertions. Muscle forces often reach high levels for the reason illustrated in Fig. 5.22. Muscles act on short internal lever arms and consequently must exert forces that are several times greater than the external loads that often act on much greater lever arms. Typically, the external load is dominated by the weight of the upper body, which is why lifting a small object from the floor can generate a peak tensile force in the back muscles of greater than 200 kg.35 Forces peak when they accelerate or decelerate body segments during jerky movements; for example, a stumble. Muscle forces can rise even higher during eccentric (lengthening) contractions when the collagenous tissue within is severely stretched. The need to stabilize the upper body during dynamic activities often requires high co-contraction of paraspinal and abdominal muscles. High muscle forces have several implications; for example, epileptic fits can cause the back muscles to crush vertebrae even when no falls are involved.36

D dw α

F

2

O d

w

INTRAABDOMINAL PRESSURE

W

EM = F × d = W × D + w × dw C = F + (W + w) × cos α

FIG. 5.22  During manual handling, high tensile force (F) must be created by the back muscles to generate an extensor moment (EM) large enough to lift up an external weight (W) and the weight of the upper part of the body (w). The back muscles act on a short internal lever arm (d) as opposed to the long lever arms (D, dw) of the objects being lifted. In practice, muscle force F is often much greater than the weight being lifted, so the compressive force acting on the spine (C) rises to approximately 500 kg when a weight of 20 kg is lifted. (Reproduced from Adams MA, Bogduk N, Burton K, Dolan P. The biomechanics of back pain. 3rd ed. Edinburgh: Churchill Livingstone; 2013.)

FORCES ACTING ON THE SPINE This section provides an example of the complex loading and movement mechanisms in the spine and how seemingly innocuous activities can lead to high forces acting in the spine.

People struggling to lift a heavy weight often hold their breath, a strategy to stabilize the spine. Contracting trunk muscles generate high pressure in the abdominal cavity, transmitting a compressive force directly from the thoracic spine and ribs to the pelvis, bypassing the lumbar spine. The mechanism is difficult to quantify because tension in longitudinal abdominal muscles acts to compress the spine further. However, raising intraabdominal pressure is most beneficial when the spine is flexed, when a thick belt provides lateral support to the abdomen, or when pressure is raised by contraction of transversus abdominis, which does not compress the spine.15

DIURNAL VARIATION In the early morning, intervertebral disks are swollen with water, so the already-stretched anulus and intervertebral ligaments provide strong resistance to bending and are vulnerable to injury.15 As the day progresses, disks lose 20% of their water and height, so the spine becomes more supple but the neural arches then resist more of the compressive force. These changes explain why backache often increases after several hours of standing and why recurrent back pain can be reduced by avoiding flexion movements during the early morning.37

MEASUREMENT OF SPINAL LOADING IN VIVO The total compressive force acting on the spine of a living volunteer can be measured by inserting a pressure-sensitive needle into an intervertebral disk. The compressive force on the L4 to L5 disk of healthy subjects ranges from 14 kg when lying prone to more than 200 kg in the stooped, standing position,38 as shown in Fig. 5.23. Relaxed sitting increases disk compression

CHAPTER 5  Biomechanics of peripheral joints and spine more than standing does because sitting flexes the lower lumbar spine and generates additional tension in the posterior ligaments, but a lordotic standing posture causes some of the compressive force to be resisted by the neural arch.39 Direct measurements of spinal loading are unsafe when the spine is moved forcefully. An alternative approach is to quantify spinal compression from electromyographic (EMG) signals recorded from the skin surface overlying the back muscles.35 Peak compressive forces on the lumbar spine vary between 250 and 500 kg when lifting objects weighing up to 30 kg from the floor. Rapid lifting increases peak loading more than 60% compared with slow lifting, and forces of this magnitude can cause fatigue damage to accumulate in some spines. Similar peak forces are reported when mathematical models are used to calculate spinal loading from optical measurements of the movement and acceleration of various body parts.40 Shear forces and torques have not been measured reliably in vivo, but mathematical models show that peak anterior shear forces reach 150 to 200 kg in the lower lumbar spine when heavy weights are lifted.40 The peak bending moments acting on the spine of a living person have been estimated by measuring the moment required to bend a cadaveric spine to the same angle to rise to 10 to 25 Nm during heavy lifting.35 Cadaveric spines can be flexed more than this before they are damaged, so in life, back muscles must normally protect the spine from excessive flexion. However, protective muscle reflexes can be impaired if the spine is flexed repeatedly or for periods of an hour or more.41 This could explain why activities such as gardening and long-distance driving are often associated with back pain.

INTERVERTEBRAL DISK MECHANICS The central nucleus pulposus of an intervertebral disk normally has such a high water content that it behaves like a pressurized fluid, with compressive load being spread evenly on the adjacent vertebral bodies even when the vertebrae are angled in flexion or extension.38,42 The layers (lamellae)

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of the anulus fibrosus act in tension to retain this pressurized nucleus, but the adult human anulus is sufficiently fibrous and stiff to resist direct compressive loading as well. The internal mechanical functioning of loaded cadaveric disks has been investigated by pulling a needle-mounted pressure transducer along their midsagittal diameter. The resulting “pressure profiles” (Fig. 5.24) show the extent of the fluid-like region and the pressure within it. Both decrease with age, but the compressive stress (force per unit area) resisted by the anulus increases.42 Cervical disks behave in essentially the same way.43

RESISTANCE TO COMPRESSION, SHEAR, TORSION, AND BENDING Compressive spine loading is resisted mostly by the disks and vertebral bodies. As it increases, the disk anulus bulges radially outward and the vertebral endplates bulge vertically into the vertebral bodies. The relatively high stiffness of the disks and vertebral endplates ensures that they absorb little energy and so are poor shock absorbers. A small proportion of the compressive force is normally resisted by the neural arch.39 The apophyseal joints resist the forward shearing movements of adjacent vertebrae (see Fig. 5.5). The more frontal plane orientation of the lower lumbar joints prevents forward slip of the overlying vertebra. Similarly, these joints are orientated to resist axial rotation. In the lumbar spine, only 1 to 2 degrees of rotation is permitted before the articular surfaces make firm contact, but considerably more movement is allowed in the cervical spine.15 Stretching of the joint capsule and ligaments on the tension side and deformation of the disk anulus also contribute to the spine’s resistance to torsion. Loss of articular cartilage, as in osteoarthritis,44 allows more laxity and increases the range of axial rotation. The first two cervical vertebrae provide negligible resistance to torsion. Neural arch ligaments reorientate when the spine moves into flexion. They then resist end-range movement, with the interspinous and supraspinous ligaments being the first to be damaged in hyperflexion. The strong

NONDEGENERATED vs. DEGENERATED HUMAN INTERVERTEBRAL DISK

Compressive stress (MPa)

3 2.5

1.5

2 1.5

1

“Functional nucleus” (hydrostatic)

1

0.5

0.5 0

P 0 Posterior anulus

a

10

20

30

Distance across disk (mm) Vertical

Horizontal

40

0 0

Anterior anulus

10

20

30

40

Distance across disk (mm) b

FIG. 5.24  (a) Photograph showing a mature nondegenerated human intervertebral disk cut through in the midsagittal plane. The graph below it shows how the horizontal and vertical components of compressive stress vary within such a disk. There is a central region of hydrostatic pressure (the “functional nucleus”) and a small concentration of compressive stress in the posterior anulus. (b) Internal disruption of the anulus lamellae and the damaged endplate indicate that this young adult disk is degenerated. Stress distributions in such a disk show a decompressed nucleus and high stress concentrations (arrows) in the anulus. The generally low disk stress suggests that some compression has been transferred to the neural arch. Approximately 1 MPa = 10 kg/cm2. (Adapted from Adams MA, Bogduk N, Burton K, Dolan P. The biomechanics of back pain. 3rd ed. Edinburgh: Churchill Livingstone; 2013.)

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SECTION 1  Scientific Basis of Rheumatic Disease

capsular ligaments of the apophyseal joints resist flexion the most, followed by the disk.41 The ligamentum flavum has such a high content of elastin that it can be stretched by up to 100% in full flexion even though it is the only intervertebral ligament to be prestressed in the upright position. The posterior longitudinal ligament is weaker than the anulus to which it adheres and therefore offers little protection from hyperflexion. Backward bending (spinal extension) is resisted by the neural arch bony surfaces, with most resistance from the facet joints or the spinous processes, depending on individual variations in anatomy.41 The fact that most disks are wider from side to side than from front to back suggests that they resist lateral bending strongly, together with the apophyseal joint on the side that is being compressed. Lateral bending is often combined with flexion when individuals bend awkwardly to pick something up as it involves extra stretching of one posterolateral corner of the disk.

ACKNOWLEDGMENT The authors acknowledge the contributions of Matthew F. Koff, Michael A. Adams, and Patricia Dolan, who were the authors of chapters in previous editions.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 1. 1 12. 13. 14. 15. 16. 17.

Nordin M, Frankel V. Basic biomechanics of the musculoskeletal system. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001. Kinzel GL, Hall AS, Hillberry BM. Measurement of the total motion between two body segments. I. Analytical development. J Biomech. 1972;5(1):93–105. Woltring HJ. Representation and calculation of 3-D joint movement. Hum Mov Sci. 1991;10(5):603–616. Dennis DA, Komistek RD, Northcut EJ, et al. “In vivo” determination of hip joint separation and the forces generated due to impact loading conditions. J Biomech. 2001;34(5):623–629. Reference deleted during page review. Cappozzo A, Gazzani F, Macellari V. Skin marker artifacts in gait analysis. Abstracts of the Sixth Biannual Meeting of the European Society of Biomechanics; 1990. Soderkvist I, Wedin P-A. Determining the movements of the skeleton using well-configured markers. J Biomech. 1993;26(12):1473–1477. Zatsiorsky V. Kinematics of human motion. Champaign, IL: Human Kinetics; 1998. American Academy of Orthopaedic Surgeons Joint motion: method of measuring and recording. Chicago: American Academy of Orthopaedic Surgeons; 1965. Grood ES, Suntay WJ. A joint coordinate system for the clinical description of three-­ dimensional motions: application to the knee. J Biomech Eng. 1983;105(2):136–144. Reference deleted during page review. Lafortune MA, Cavanagh PR, Sommer HJ, et al. Three-dimensional kinematics of the human knee during walking. J Biomech. 1992;25(4):347–357. Pennock GR, Clark KJ. An anatomy-based coordinate system for the description of the kinematic displacements in the human knee. J Biomech. 1990;23(12):1209–1218. Codman E. The shoulder: rupture of the supraspinatus tendon and other lesions in or about the subacromial bursa. Boston: Thomas Todd Company; 1934. Adams M, Bogduk N, Burton K, et al. The biomechanics of back pain. 3rd ed. Edinburgh: Churchill Livingstone; 2013. Zhao F, Pollintine P, Hole BD, et al. Discogenic origins of spinal instability. Spine. 2005;30:2621–2630. Winter DA. Biomechanics and motor control of human movement. New York: John Wiley & Sons; 2009.

8. Reference deleted during page review. 1 19. Erdemir A, McLean S, Herzog W, et al. Model-based estimation of muscle forces exerted during movements. Clin Biomech (Bristol, Avon). 2007;22(2):131–154. 20. Delp SL, Loan JP. A graphics-based software system to develop and analyze models of musculoskeletal structures. Comput Biol Med. 1995;25(1):21–34. 21. Damsgaard M, Rasmussen J, Christensen ST, et al. Analysis of musculoskeletal systems in the AnyBody Modeling System. Simul Model Pract Theory. 2006;14(8):1100–1111. 22. Unsworth A, Dowson D, Wright V. Some new evidence on human joint lubrication. Ann Rheum Dis. 1973;32(6):587–588. 23. Radin EL, Paul IL. A consolidated concept of joint lubrication. J Bone Joint Surg Am. 1972;54(3):607–616. 24. Katta J, Jin Z, Ingham E, et al. Biotribology of articular cartilage—a review of the recent advances. Med Eng Phys. 2008;30(10):1349–1363. 25. Walker PS, Dowson D, Longfield MD, et al. “Boosted lubrication” in synovial joints by fluid entrapment and enrichment. Ann Rheum Dis. 1968;27(6):512–520. 26. McCutchen CW. The frictional properties of animal joints. Wear. 1962;5(1):1–17. 27. Seror J, Zhu L, Goldberg R, et al. Supramolecular synergy in the boundary lubrication of synovial joints. Nat Commun. 2015;6:6497. 28. Mow V, Gu W, Chen F. Structure and function of articular cartilage. In: Mow V, Huiskes R, eds. Basic orthopedic biomechanics and mechano-biology. Philadelphia: Lippincott Williams & Wilkins; 2005:181–258. 29. Lai W, Rubin D, Krempl E. Introduction to continuum mechanics. 3rd ed. Oxford: Pergamon Press; 1993. 30. Mow VC, Ratcliffe A, Poole AR. Cartilage and diarthrodial joints as paradigms for hierarchical materials and structures. Biomaterials. 1992;13(2):67–97. 31. Callister WD, Rethwisch DG. Materials science and engineering: an introduction. New York: John Wiley & Sons; 2007. 32. Weiss JA, Gardiner JC. Computational modeling of ligament mechanics. Crit Rev Biomed Eng. 2001;29(3):303–371. 33. Kennedy JC, Hawkins RJ, Willis RB, et al. Tension studies of human knee ligaments. Yield point, ultimate failure, and disruption of the cruciate and tibial collateral ligaments. J Bone Joint Surg Am. 1976;58(3):350–355. 34. Fung Y. Biomechanics: Mechanical properties of living tissues, Springer Science & Business Media; Berlin; 1993. 35. Dolan P, Earley M, Adams MA. Bending and compressive stresses acting on the lumbar spine during lifting activities. J Biomech. 1994;27:1237–1248. 36. Vascancelos D. Compression fractures of the vertebra during major epileptic seizures. Epilepsia. 1973;14:323–328. 37. Snook SH, Webster BS, McGorry RW, et al. The reduction of chronic nonspecific low back pain through the control of early morning lumbar flexion. A randomized controlled trial. Spine. 1998;23:2601–2607. 38. Sato K, Kikuchi S, Yonezawa T. In vivo intradiscal pressure measurement in healthy individuals and in patients with ongoing back problems. Spine. 1999;24:2468–2474. 39. Pollintine P, Przybyla AS, Dolan P, et al. Neural arch load-bearing in old and degenerated spines. J Biomech. 2004;37:197–204. 40. Bazrgari B, Shirazi-Adl A, Arjmand N. Analysis of squat and stoop dynamic liftings: muscle forces and internal spinal loads. Eur Spine J. 2007;16:687–699. 41. Sanchez-Zuriaga D, Adams MA, Dolan P. Is activation of the back muscles impaired by creep or muscle fatigue? Spine. 2010;35:517–525. 42. Adams MA, McNally DS, Dolan P. “Stress” distributions inside intervertebral discs. The effects of age and degeneration. J Bone Joint Surg Br. 1996;78:965–972. 43. Skrzypiec DM, Pollintine P, Przybyla A, et al. The internal mechanical properties of cervical intervertebral discs as revealed by stress profilometry. Eur Spine J. 2007;16:1701–1709. 44. Tischer T, Aktas T, Milz S, et al. Detailed pathological changes of human lumbar facet joints L1–L5 in elderly individuals. Eur Spine J. 2006;15:308–315.

Scientific basis of pain Hans-Georg Schaible

Key Points ■ Nociception is the encoding and processing of noxious stimuli in the nervous system, and the conscious subjective experience of nociception is the sensation of pain. ■ Clinically relevant pain is classified as nociceptive, when tissue is inflamed or damaged, or as neuropathic, when nerve fibers or nerve cells are affected. ■ Peripheral nociceptors are slowly conducting, thinly myelinated, or unmyelinated nerve fibers that respond to tissue-damaging mechanical, thermal, and chemical stimuli. ■ The central nociceptive system consists of neurons in the spinal cord, brain stem, thalamus, and cortical areas that process noxious stimuli. The conscious sensation of pain, with its sensory-discriminative and affective components, is generated at the thalamocortical level. ■ During inflammation, peripheral nociceptors are sensitized to mechanical or thermal stimuli, or both, by inflammatory mediators via peripheral sensitization. ■ Damaged nerve fibers may show action potentials that are evoked at the site of the lesion and in the neuronal cell bodies (ectopic discharges). ■ Peripheral sensitization and ectopic discharges may induce a state of hyperexcitability in the central nociceptive system (central sensitization) that increases the gain of central nociceptive processing. ■ The brain areas involved in pain processing may show atrophy or reorganization. ■ Nerve fibers originating in the brain stem can enhance or inhibit the spinal nociceptive processing (descending facilitation or inhibition). ■ Both inflammatory and destructive processes contribute to pain generation. ■ Pain intensity may be increased by systemic/general factors such as diabetes mellitus and other comorbidities and genetic, psychological, and social factors.

NOCICEPTION AND PAIN Pain is an unpleasant sensory and emotional experience that is evoked by actual or potential noxious (i.e., tissue damaging) stimuli or by tissue injury. Because pain is a subjective experience, it cannot be measured objectively. Nociception is the encoding and processing of noxious stimuli in the nervous system and can be measured objectively (e.g., with electrophysiologic recordings). Under normal conditions, the relationship between nociception and pain is relatively precise and predictable. A stimulus that is noxious will usually evoke a subjective pain response. However, under clinically relevant conditions, the relationship between nociception and pain may not be strict, particularly when the pain is chronic (see next section). Neurons in the peripheral and central nociceptive systems that encode noxious stimuli form the nociceptive system. A simplified scheme of the nociceptive system is shown in Fig. 6.1. Peripheral nociceptive neurons (nociceptors) innervate the skin, deep tissue, and most visceral organs. They encode noxious stimuli applied to the tissue. The central nociceptive system consists of sensory nociceptive neurons in the spinal cord, spinal reflex pathways, and ascending tracts that activate the brain stem and supraspinal structures in the thalamus and cortex. Corticothalamic networks produce the conscious pain response.1,2

TYPES OF PAIN Application of a noxious stimulus to normal tissue elicits acute physiologic nociceptive pain. This pain protects tissue from being further damaged because withdrawal reflexes are usually elicited. Inflammation or injury causes pathophysiologic nociceptive pain. It may appear as spontaneous (resting) pain, hyperalgesia, allodynia, or any combination of these types of pain. Hyperalgesia is a higher pain intensity felt on noxious heat stimulation (thermal hyperalgesia) or noxious mechanical stimulation (mechanical hyperalgesia). Allodynia is pain that is elicited by stimuli that are normally below the pain threshold.1 Whereas nociceptive pain is elicited by noxious stimulation of sensory endings of nociceptors in the tissue, neuropathic pain is caused by injury or

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disease of nociceptive neurons in the peripheral or central nervous system. This pain does not primarily signal tissue damage. It often has an abnormal burning or electrical character and can be persistent or episodic (e.g., trigeminal neuralgia). It may be combined with hyperalgesia and allodynia. Thus, even touching the skin with a soft brush can cause intense pain. Causes of neuropathic pain include nerve or plexus damage, metabolic diseases such as diabetes mellitus, herpes zoster, and others. Damage to central pain processing neurons (e.g., in the thalamus) can cause central pain.1,3 Usually pain is called “chronic” when it lasts longer than 6 months. Chronic pain may result from persistent nociception (with a chronic disease), but it is often significantly influenced by psychological and social factors. It can be accompanied by neuroendocrine dysregulation, fatigue, dysphoria, and impaired physical and even mental performance.4

THE PERIPHERAL BASIS OF PAIN STRUCTURE AND DUAL FUNCTION OF PERIPHERAL NOCICEPTORS Nociceptors are sensory neurons with thinly myelinated Aδ or unmyelinated C fiber axons. The cell bodies of nociceptors are located in the dorsal root ganglia. Their peripheral branches form sensory endings (“free nerve endings”) in the innervated tissue, and their central branches terminate in the dorsal horn of the spinal cord or in the brain stem, where they activate nociceptive dorsal horn neurons (see Fig. 6.1).5 Many nociceptors have a dual function. They encode noxious stimuli and transmit this information to the spinal cord (sensory function). In addition, they transport neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) from the cell body to the periphery and release these mediators in the tissue on stimulation. There, these neuropeptides induce vasodilatation, plasma extravasation, attraction of macrophages or degranulation of mast cells, or other processes that elicit a neurogenic inflammation. Such neurogenic components contribute significantly to many inflammatory diseases.6

SENSORY FUNCTION OF NOCICEPTORS Most nociceptors respond to noxious mechanical stimuli (e.g., painful pressure, squeezing, or cutting the tissue), noxious thermal stimuli (e.g., heat or extreme cold), and chemical stimuli and are therefore called polymodal. Noxious stimuli evoke a sensor potential in the sensory ending termed transduction. When the depolarization is sufficiently strong, action potentials are triggered and conducted by the axon to the spinal cord or the brain stem (Fig. 6.2).5 In joints, nociceptors innervate mainly the fibrous capsule, ligaments, adipose tissue, menisci, and the synovial layer. The cartilage is normally not innervated. A typical joint nociceptor is activated by strong pressure to the joint (e.g., hitting the joint) and by noxious movements (i.e., painful rotation against the resistance of the tissue). It is not usually activated by movements and positions in the working range.7 Nociceptors in the muscle are located in the muscle belly, tendon, and fascia. They respond to noxious compression of the muscle and they may be activated by muscle contraction under ischemic conditions. Normally, they do not respond to innocuous pressure and to contractions of the muscle.5 Some nociceptors are activated by noxious thermal stimuli. Cutaneous nociceptors respond to noxious heat (in the range of 42°C to higher than 50°C), and they encode noxious mechanical stimuli such as squeezing.5 Visceral nociceptors respond to a variety of mechanical, thermal, and chemical stimuli.5 Notably, not all nociceptors are polymodal. An important group of nociceptors is relatively mechanoinsensitive and, in the skin, heat insensitive. Because these nociceptors do not respond to noxious stimuli applied to normal tissue, they are called initially mechanoinsensitive or silent nociceptors.1,7 These nociceptors are “recruited” during inflammation (see next section).

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SECTION 1  Scientific Basis of Rheumatic Disease

THE NOCICEPTIVE SYSTEM WITH NOCICEPTIVE FREE NERVE ENDINGS IN THE PERIPHERAL TISSUE, AFFERENT NERVE FIBERS AND THEIR SYNAPSES IN THE DORSAL HORN OF THE SPINAL CORD, AND ASCENDING TRACTS WITH TARGETS IN THE BRAIN Anterior cingulate cortex (ACC) Insula Prefrontal cortex Cortical areas SI, SII in somatosensory cortex

Medial thalamus Lateral thalamus

Peripheral tissue

Medial Lateral

Spinothalamic tract

C fiber A fiber

Sympathetic axon

Motor axon

FIG. 6.1  The neural pathway of the nociceptive system. Nociceptive fibers with free nerve endings in the tissue project to spinal cord neurons that form the medial and lateral spinothalamic tracts ascending to the medial and lateral thalamus and to spinal cord interneurons that form motor and sympathetic reflex pathways. Thalamic relay neurons project to SI and SII, the primary and secondary somatosensory cortices. Note: Other ascending pathways such as the spinoreticular tract and dorsal column pathways are not displayed.

SENSITIZATION OF NOCICEPTORS (PERIPHERAL SENSITIZATION) With repetitive or strong noxious stimulation of the tissue, and, in particular, during inflammation, nociceptors are sensitized to stimuli such that they are hyperexcitable. The excitation threshold of polymodal nociceptors decreases such that light, normally innocuous stimuli activate the fibers and silent nociceptors become excitable by innocuous and noxious stimuli.1,7 This peripheral sensitization produces enhanced input to the spinal cord and induces central sensitization (Fig. 6.3). Both peripheral and central sensitization (see section “Central Sensitization”) cause primary hyperalgesia and allodynia at the site of inflammation. In addition, central sensitization causes secondary hyperalgesia, enhanced pain sensitivity in healthy tissue surrounding the site of inflammation (Fig. 6.4). Peripheral sensitization is a hallmark of many painful diseases of the musculoskeletal system. It is a major pathophysiological pain mechanism of primary inflammatory joint diseases such as rheumatoid arthritis (RA), and it is also involved in osteoarthritic pain, various forms of myositis, and many others. Because of the peripheral and central sensitization, movements in the working range and palpation of the joints are painful, and patients may even experience pain in the absence of stimulation.

MOLECULAR MECHANISMS OF PERIPHERAL STIMULUS TRANSDUCTION AND PERIPHERAL SENSITIZATION The sensory endings of nociceptors express ion channels and membrane receptors that transduce the mechanical, thermal, and chemical stimuli into a sensor potential (see Fig. 6.2). Some sensor molecules have been identified.8 The best known is transient receptor potential vanilloid 1 (TRPV1), a ligand-gated ion channel that is expressed in nociceptors but not in other peripheral neurons. Upon opening, cations, in particular Ca2+, flow into the

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Chemokines and chemokine receptors in lymphoid tissue dynamics. Annu Rev Immunol. 2016;34:203–242. 59. Eash KJ, Greenbaum AM, Gopalan PK, Link DC. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J Clin Invest. 2010;120:2423–2431. 60. Heusinkveld LE, Majumdar S, Gao JL, McDermott DH, Murphy PM. WHIM syndrome: from pathogenesis towards personalized medicine and cure. J Clin Immunol. 2019;39:532–556. 61. Baekkevold ES, Yamanaka T, Palframan RT, et al. The CCR7 ligand elc (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment. J Exp Med. 2001;193:1105–1112. 62. Forster R, Schubel A, Breitfeld D, et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999;99:23–33. 63. Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci U S A. 1998;95:258–263. 64. Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt’s lymphoma receptor-1. Nature. 1998;391:799–803. 65. Crotty S. T follicular helper cell biology: a decade of discovery and diseases. Immunity. 2019;50:1132–1148. 66. Forster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell. 1996;87:1037–1047. 67. Pereira JP, Kelly LM, Cyster JG. Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses. Int Immunol. 2010;22:413–419. 68. Gatto D, Brink R. B cell localization: regulation by EBI2 and its oxysterol ligand. Trends Immunol. 2013;34:336–341. 69. Lu E, Cyster JG. G-protein coupled receptors and ligands that organize humoral immune responses. Immunol. Rev. 2019;289:158–172. 70. Proia RL, Hla T. Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest. 2015;125:1379–1387. 71. Cyster J.G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. 2005. 72. Goodman AD, Anadani N, Gerwitz L. Siponimod in the treatment of multiple sclerosis. Expert Opin Investig Drugs. 2019;28:1051–1057. 73. Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545–556. 74. Daniel C, Sartory N, Zahn N, Geisslinger G, Radeke HH, Stein JM. FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells. J Immunol. 2007;178:2458–2468. 75. Liao JJ, Huang MC, Goetzl EJ. Cutting edge: Alternative signaling of Th17 cell development by sphingosine 1-phosphate. J Immunol. 2007;178:5425–5428. 76. Johansson-Lindbom B, Agace WW. Generation of gut-homing T cells and their localization to the small intestinal mucosa. Immunol Rev. 2007;215:226–242. 77. Feagan BG, Sandborn WJ, D’Haens G, et al. Randomised clinical trial: vercirnon, an oral CCR9 antagonist, vs placebo as induction therapy in active Crohn’s disease. Aliment Pharmacol Ther. 2015;42:1170–1181. 78. Boppana NB, Devarajan A, Gopal K, et al. Blockade of CXCR2 signalling: a potential therapeutic target for preventing neutrophil-mediated inflammatory diseases. Exp Biol Med (Maywood). 2014;239:509–518. 79. Rennard SI, Dale DC, Donohue JF, et al. CXCR2 Antagonist MK-7123. A phase 2 proofof-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191:1001–1011. 80. Lazaar AL, Miller BE, Tabberer M, et al. Effect of the CXCR2 antagonist danirixin on symptoms and health status in COPD. Eur Respir J. 2018:52. 81. Zimmermann HW, Sterzer V, Sahin H. CCR1 and CCR2 antagonists. Curr Top Med Chem. 2014;14:1539–1552.

CHAPTER 10 Cytokines 82. Haringman JJ, Kraan MC, Smeets TJ, Zwinderman KH, Tak PP. Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62:715–721. 83. Isozaki T, Arbab AS, Haas CS, et al. Evidence that CXCL16 is a potent mediator of angiogenesis and is involved in endothelial progenitor cell chemotaxis: studies in mice with K/BxN serum-induced arthritis. Arthritis Rheum. 2013;65:1736–1746. 84. Szekanecz Z, Koch AE. Successes and failures of chemokine-pathway targeting in rheumatoid arthritis. Nat Rev Rheumatol. 2016;12:5–13. 85. Vergunst CE, Gerlag DM, Lopatinskaya L, et al. Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum. 2008;58:1931–1939. 86. Haringman JJ, Gerlag DM, Smeets TJ, et al. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:2387–2392. 87. Ble A, Mosca M, Di Loreto G, et al. Antiproteinuric effect of chemokine C-C motif ligand 2 inhibition in subjects with acute proliferative lupus nephritis. Am J Nephrol. 2011;34:367–372. 88. Tanaka Y, Takeuchi T, Umehara H, et al. Safety, pharmacokinetics, and efficacy of E6011, an antifractalkine monoclonal antibody, in a first-in-patient phase 1/2 study on rheumatoid arthritis. Mod Rheumatol. 2018;28:58–65. 89. Yellin M, Paliienko I, Balanescu A, et al. A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-1100, a fully human anti-CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64:1730–1739. 90. Lee MC, Saleh R, Achuthan A, et al. CCL17 blockade as a therapy for osteoarthritis pain and disease. Arthritis Res Ther. 2018;20:62. 91. Tobinai K, Takahashi T, Akinaga S. Targeting chemokine receptor CCR4 in adult T-cell leukemia-lymphoma and other T-cell lymphomas. Curr Hematol Malig Rep. 2012;7:235–240. 92. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 2007;8:345–350. 93. Campbell JJ, Ebsworth K, Ertl LS, et al. IL-17-secreting gammadelta T cells are completely dependent upon CCR6 for homing to inflamed skin. J Immunol. 2017;199:3129–3136. 94. Robert R, Ang C, Sun G, et al. Essential role for CCR6 in certain inflammatory diseases demonstrated using specific antagonist and knockin mice. JCI Insight. 2017:2. 95. Bouma G, Zamuner S, Hicks K, et al. CCL20 neutralization by a monoclonal antibody in healthy subjects selectively inhibits recruitment of CCR6(+) cells in an experimental suction blister. Br J Clin Pharmacol. 2017;83:1976–1990.

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96. Duhen T, Duhen R, Lanzavecchia A, Sallusto F, Campbell DJ. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood. 2012;119:4430–4440. 97. Mailloux AW, Young MR. Regulatory T-cell trafficking: from thymic development to tumor-induced immune suppression. Crit Rev Immunol. 2010;30:435–447. 98. Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu. Rev. Immunol. 1999;17:657–700. 99. Woollard SM, Kanmogne GD. Maraviroc: a review of its use in HIV infection and beyond. Drug Des Devel Ther. 2015;9:5447–5468. 100. Choi SW, Reddy P. Current and emerging strategies for the prevention of graft-versus-host disease. Nat Rev Clin Oncol. 2014;11:536–547. 101. Martin-Blondel G, Brassat D, Bauer J, Lassmann H, Liblau RS. CCR5 blockade for neuroinflammatory diseases—beyond control of HIV. Nat Rev Neurol. 2016;12:95–105. 102. Joy MT, Ben Assayag E, Shabashov-Stone D, et al. CCR5 is a therapeutic target for recovery after stroke and traumatic brain injury. Cell. 2019;176(1143–57):e13. 103. Fantuzzi L, Tagliamonte M, Gauzzi MC, Lopalco L. Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders. Cell Mol Life Sci. 2019;76:4869–4886. 104. Lim JK, Louie CY, Glaser C, et al. Genetic deficiency of chemokine receptor CCR5 is a strong risk factor for symptomatic West Nile virus infection: a meta-analysis of 4 cohorts in the US epidemic. J Infect Dis. 2008;197:262–265. 105. Rot A, von Andrian UH. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol. 2004;22:891–928. 106. Xu J, Fei W, Van Keymeulen A, et al. Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils. Cell. 2003;114:201–214. 107. Kehrl JH. The impact of RGS and other G-protein regulatory proteins on Gα-mediated signaling in immunity. Biochem Pharmacol. 2016;114:40–52. 108. Reiter E, Lefkowitz RJ. GRKs and beta-arrestins: roles in receptor silencing, trafficking and signaling. Trends Endocrinol Metab. 2006;17:159–165. 109. Steen A, Larsen O, Thiele S, Rosenkilde MM. Biased and G protein-independent signaling of chemokine receptors. Front Immunol. 2014;5:277. 110. Anderson CA, Solari R, Pease JE. Biased agonism at chemokine receptors: obstacles or opportunities for drug discovery? J Leukoc Biol. 2016;99:901–909.

11

Inflammation and its chemical mediators Ruth Fernandez-Ruiz • Michael Toprover • Michael H. Pillinger

Key Points ■ Inflammation is the primary process through which the body attacks and destroys microbial invaders, heals wounds, and damages its own tissues. ■ The acute phase of inflammation is characterized by microvascular changes and activation of granulocytic cells (neutrophils, mast cells, eosinophils). Monocytic cell lineages predominate in the mature or chronic inflammatory response. ■ Platelet and endothelial cell activation is an essential element of the inflammatory response. ■ Soluble mediators released from activated cells promote inflammation and provoke tissue injury. These include histamine and serotonin, prostaglandins and leukotrienes, superoxide anion, and nitric oxide.

Inflammatory responses can be either acute or chronic. Whereas the acute, or early, phase of inflammation is characterized by microvascular changes and neutrophilic infiltration, cells from the monocytic lineage predominate in the chronic inflammatory response. These distinctions are somewhat arbitrary, however, and have many exceptions. For example, monocytic lineage cells may dominate from the beginning of an inflammatory response (as in tuberculosis), and neutrophils may persist in some forms of chronic inflammation (as in polyarteritis nodosa). This chapter summarizes the major cellular participants in inflammation and provides an overview of the mediators that drive—and limit—inflammatory responses.

■ The inflammatory response involves a complex interaction between the nervous system and inflammatory cells.

THE CELLS OF INFLAMMATION

■ The resolution of inflammation is an active process critical to preventing undesirable tissue damage.

ENDOTHELIAL CELL ACTIVATION AND LEUKOCYTE ADHESION

INTRODUCTION Inflammatory processes are necessary for survival. Best recognized as a localized response to injury from a variety of insults, inflammation is also important in tissue remodeling during development and in the clearance of cell debris during tissue turnover. Acute inflammation is characterized by microvascular changes and activation of granulocytes (neutrophils, mast cells, eosinophils), whereas monocytic cell lineages predominate in chronic inflammatory responses. Platelets and endothelial cells are also key in modulating inflammation. Many disease states are associated with inappropriately triggered, exaggerated, or persistent inflammation, resulting in an undesirable and potentially destructive process. Inflammatory responses (and their resolution) are driven, in a complex and integrated manner, by a wide range of molecular mediators, which represent potential or well-established therapeutic targets. This chapter summarizes the major cellular participants in inflammation and provides an overview of the mediators that drive—and limit—inflammatory responses. For two millennia, inflammation has been clinically identified by the four cardinal signs of Celsus: calor (heat), rubor (redness), dolor (pain), and tumor (swelling). A fifth sign, functio laesa (loss of function), was proposed by the 19th-century pathologist Virchow to underscore inflammation’s potential for tissue damage. At the cellular level, inflammation involves a series of events beginning with vasodilation and increased permeability of the microcirculation that lead leukocytes, the foot soldiers of inflammation, to transmigrate into injured tissue.1 Inflammation involves the interplay of the innate and adaptive immune responses, the nervous system, and the coagulative and fibrinolytic cascades. Inflammatory responses are driven in a complex and integrated manner by a wide range of molecular mediators that can be loosely grouped into several categories: (1) growth factors and cytokines, (2) the complement system, (3) lipid mediators, (4) vasoactive amines, (5) reactive oxygen species, and (6) neuropeptides. In health, inflammation is a self-limited response to a specific injury. On occasion, however, the inflammatory response is triggered inappropriately, is excessive for the problem at hand, or fails to resolve after the trigger is removed. Excessive inflammation may result from a persistent host antigen being mistaken as foreign (as in rheumatic fever or poststreptococcal glomerulonephritis) or from a decreased ability to clear immune system stimulants such as apoptotic cells or immune complexes (as in systemic lupus erythematosus [SLE]). In the so-called autoinflammatory syndromes (familial Mediterranean fever, tumor necrosis factor [TNF] receptor–associated periodic fever syndrome [TRAPS], and others), intrinsic defects lead to a persistent or recurrent undesirable inflammatory response with no appreciable stimulus.2 Despite ongoing advances, we still do not fully understand what causes inflammation. 96

Vascular endothelial cells play a critical role in inflammatory processes. To localize to the tissues, leukocytes must exit the vasculature (diapedesis) and migrate to the extravascular space (chemotaxis). These processes require a complex sequence of events, beginning with the microvascular response to injury. Arterioles vasodilate and endothelial cells contract, exposing the basement membrane; blood flow slows, and plasma extravasates. In turn, leukocytes slow and increase their contact with the endothelium.3 In response to bacteria or other affronts, resident tissue immune cells (macrophages, dendritic cells, and fibroblasts) generate proinflammatory mediators such as interleukin-1β (IL-1β) and TNF. These cytokines (Greek, “cell movers”) induce local vascular endothelial cells to express surface molecules that contact and bind leukocytes, eventually promoting their egress from the vasculature. Diverse pairs of adhesion molecules sequentially mediate leukocyte margination and rolling, tight adhesion, and diapedesis (Fig. 11.1). The first step, leukocyte margination and rolling, occurs mainly via the interactions of adhesion molecules of the selectin class (E-selectin on endothelial cells and L-selectin on leukocytes) with mucin-like sialylated glycoproteins that serve as selectin counter ligands (also on both leukocytes and endothelial cells). Selectins are expressed constitutively, but their interactions are short-lived; at all times, a percentage of leukocytes adhere intermittently to the endothelium (margination), rolling along in a tumbleweed-like progression. At sites of inflammation, after exposure to stimuli such as IL-1β and TNF, E-selectin expression on endothelial cells increases markedly, promoting increased leukocyte margination and rolling. The next step, leukocyte tight adhesion, results from the interaction of leukocyte adhesion molecules known as integrins (e.g., CD11a/CD18–also known as LFA-1–on lymphocytes; CD11a/CD18 and CD11b/CD18—also known as Mac-1 or CR3 [complement receptor 3]—on neutrophils; and VLA-4 on monocytes) with endothelial cell counter-ligands (e.g., intercellular adhesion molecule 1 [ICAM-1] and vascular cell adhesion molecule 1 [VCAM-1]). Tight adhesion requires de novo expression of the cellular adhesion molecules (CAMs) on endothelium and activation of preexisting integrins on leukocytes, which is driven by inflammatory mediators. Specific integrin–CAM pairings establish cell–cell adhesion events that contribute to the distribution and homing of leukocytes; common integrin–CAM pairs include CD11a–CD18/ ICAM-1 (lymphocytes–endothelium), CD11b–CD18/ICAM-1 (neutrophils– endothelium), and VLA-4/VCAM-1 (monocytes–endothelium). Importantly, many of these adhesion molecules are not simply inert binders; for example, CD11b–CD18 (also known as CR3, or complement receptor 3) functions both as an adhesion molecule and as a receptor for the “inactive” form of the C3b complement component (iC3b). Finally, transmigration of leukocytes through the endothelium and basement membrane is driven by chemokines such as monocyte chemoattractant protein 1 (MCP-1), C5a, and IL-8.1 Endothelial cells also respond to stress by upregulating Toll-like receptors (TLRs), members of the pattern recognition receptor family. Although TLRs are most commonly considered as innate immune receptors on leukocytes, their presence and engagement on endothelial cells may contribute to additional vascular activation.4

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LEUKOCYTE MIGRATION FROM THE VASCULATURE

Basement membrane

Rolling

L-selectin (shed)

Tight adhesion

Diapedesis

Sialyl-Lewisx Sialyl-Lewisx L-selectin Sialyl-Lewisx

E-selectin

β2 integrins (active)

Basement membrane

ICAM-1

Endothelial cells

Upregulation of ICAM-1 Activation of β2 integrins Cytokines (IL-1, TNF-α)

Macrophages

Chemoattraction

Chemoattractants (MCP-1, fMLP, C5a, LTB4, IL-8)

FIG. 11.1  Leukocyte migration from the vasculature. Leukocytes exit the vasculature through a sequence of interactions with the vascular endothelium. The first step, rolling, guarantees leukocyte–endothelial contact through transient interactions between selectins and sialylated glycoproteins (Sialyl-Lewisx) on cognate cells. Leukocyte tight adhesion results from the interaction of leukocyte adhesion molecules known as integrins with counter-ligands on endothelial cells, such as intercellular adhesion molecule 1 (ICAM-1). In contrast to selectin/glycoprotein interactions, integrin/ICAM interactions are activation and expression dependent. Once tightly adherent to the endothelium, leukocytes transmigrate through the vasculature and into the tissues. Activation of leukocytes, and their transmigration through the endothelium and basement membrane, is mediated by chemoattractants such as monocyte chemoattractant protein 1 (MCP-1), C5a, N-formyl-methionyl-leucyl-phenylalanine (fMLP), leukotriene B4 (LTB4), and interleukin-8 (IL-8). Proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin-1β (IL-1β), upregulate ICAM-1 in endothelial cells, allowing leukocytes to form tight adhesions.

GRANULOCYTES Neutrophils, eosinophils, and basophils comprise the group of leukocytes known as granulocytes, so named for the highly visible vacuolar structures (granules) in their cytoplasm (Fig. 11.2). Mast cells are similarly equipped with specialized granules but derive from a different lineage and are classified separately. Granulocytes, also called polymorphonuclear leukocytes because of their multilobed nuclei, are crucial to acute inflammatory responses.

Neutrophils Polymorphonuclear neutrophils (PMNs) are among the body’s first-line defense against foreign invaders and constitute the major cell type in most acute and some chronic inflammatory diseases.3 The importance of neutrophils in bacterial defense is demonstrated by patients who have hereditary defects in neutrophil function and are prone to repeated and often life-threatening infections. Neutrophils are the most prevalent leukocyte in the bloodstream, accounting for more than 50% of all circulating white blood cells and increasing to over 80% in acute inflammatory conditions (e.g., bacterial infection). Unlike most other leukocytes, neutrophils are normally sparse in extravascular spaces. Neutrophil granules contain a remarkable arsenal of microbicidal weaponry (Figs. 11.3 and 11.4). Under routine staining, neutrophil granules consist of two classes: primary (or azurophilic) granules and secondary (or specific) granules. Azurophilic granules are functionally similar to the lysosomes of other cells and contain a variety of proteases, including elastase, matrix metalloproteinase (MMP)-3, MMP-8, MMP-9, cathepsins, and lysozyme (Table 11.1). Azurophilic granules also contain myeloperoxidase (MPO), a key enzyme for both microbicidal activity and for mediating tissue injury in inflammatory disease. In response to phagocytosis of a bacterium

or other foreign body, azurophilic granules fuse with the phagosome (now phagolysosome) to direct their contents at the ingested target. In addition, a membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is assembled and activated, resulting in rapid oxygen consumption (the “respiratory burst”) and the generation of highly reactive oxygen species (ROS) within the phagolysosome. MPO catalyzes the reaction of ROS and chloride to form hypochlorous acid (HOCl, or chlorine bleach), a potent oxidizing agent that can disrupt bacterial electron-transport chains and disturb DNA synthesis.5 Azurophilic granules thus provide effective mechanisms through which microorganisms are destroyed, but when inappropriately released into the extracellular environment, the content of these granules can cause significant tissue injury. In contrast to azurophilic granules, specific granules possess an extensive array of membrane-associated proteins, including cytochromes, signaling molecules, and receptors. Specific granules constitute a reservoir of proteins destined for the membranes of phagolysosomes. They additionally contain proteins such as lactoferrin and β2-microglobulin, along with proteases such as collagenase (MMP-1) and plasminogen activator.3 Ultrastructural studies have identified two additional neutrophil granules. Gelatinase granules have a high content of gelatinase, a latent enzyme with the capacity for tissue destruction. Secretory vesicles are the smallest granules and lack proteolytic enzymes. In contrast to the other granules, which typically fuse with phagolysosomes, secretory granules fuse with the cell membrane and serve as a reservoir of surface membrane–associated lipids and proteins. Because neutrophils have such destructive capacity, their localization and activation must be carefully regulated. Chemoattractants for neutrophils include leukotriene B4 (LTB4), platelet-activating factor (PAF), IL-8, formylated peptides, and the complement split product C5a. At low concentrations

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98

b

a

c

d

FIG. 11.2  Leukocyte micrographs (light microscopy, hematoxylin and eosin staining). (a) A neutrophil, or polymorphonuclear leukocyte. Note that the cytoplasm stains bluish and appears granular secondary to the staining properties of the azurophilic granules. Neutrophils typically have nuclei with three to five lobes; four lobes are seen here. (b) An immature neutrophil, known as a band cell because of the distinctive nuclear shape. Such cells are frequently released prematurely from the bone marrow during acute inflammatory events. (c) An eosinophil, with pink (eosinophilic) granules and a nucleus with two lobes. Eosinophils have multiple lobes but typically fewer than are seen in neutrophils. (d) A monocyte. Note the lack of obvious cytoplasmic granules, the unilobular nucleus, and the monomorphic nucleus and irregular shape. (Figure produced with the kind permission of Harold Ballard, MD.)

b

a

c

d

FIG. 11.3  Electron micrographs of neutrophils at rest and after stimulation with N-formyl-methionyl-leucyl-phenylalanine (fMLP). These electron micrographs highlight the active process of neutrophil disgorgement. When activated, the neutrophil cell surface ruffles as granules and lysosomes merge with the cell surface to release their contents into the extracellular environment. (a) and (b) Scanning electron micrographs of a resting neutrophil and activated neutrophil, respectively. (c) and (d) Transmission electron micrographs of the same. Note the numerous empty spaces within the activated neutrophil’s cytoplasm; these are indicative of emptied-out granules and resultant expanded surface membrane. (Figures produced with the kind permission of Gerald Weissmann, MD.)

NEUTROPHIL ACTIVATION

C3b, iC3b, ICAM-1

in a gradient, these molecules direct neutrophils to migrate toward higher concentrations. When high concentration regions are reached (e.g., at the bacterial source of the gradient), these same molecules cause neutrophils to cease migration and become activated. Receptors for soluble ligands other than chemoattractants have also been identified on neutrophils, including receptors for growth factors, colony-stimulating factors, and cytokines (Fig. 11.4); pretreatment of neutrophils with either insulin or granulocyte-macrophage colony-stimulating factor (GM-CSF) results in amplification (priming) of subsequent neutrophil responses to chemoattractants.3 When localized to its target tissue and activated, the neutrophil is intrinsically inefficient at phagocytosing unmodified targets. Optimal neutrophil phagocytosis depends on opsonization (Greek, “to prepare for eating”), which is the adornment of pathogens with immunoglobulins, complement components, or both. Neutrophils express complement receptors (CR1 and CR3) that promote phagocytosis by binding the target-adhering complement components C3b and iC3b, respectively.3 In addition, neutrophils express two families of receptors for the Fc tail of bound or aggregated IgG: low-affinity FcγRIIa and high-affinity FcγRIIIb. Binding of Fc immunoglobulin tails to Fc receptors stimulates phagocytosis (for an overview of leukocyte receptors, see Table 11.2).

CR1 (CD35), CR3 (CD11b/CD18)

Neutrophil extracellular traps

O2-, H2O2, HOCl Metalloproteinases

Lysosome, defensins, BPI LTB4

LTB4

LPS

BLT1,2

TLR4

IgG FcR

fMLP FPR

C5a IL-8 CXCR-1

FIG. 11.4 Neutrophil activation. Various signals stimulate neutrophil activation via ligation of cell-surface receptors. On activation, neutrophils both degranulate and produce a number of inflammatory mediators. See text for details. BLT1,2, Leukotriene B4 receptors 1 and 2; CXCR-1, CXC motif chemokine receptor 1; FcR, Fc receptor; fMLP, N-formyl-methionyl-leucyl-phenylalanine; FPR, formyl peptide receptor; ICAM-1, intercellular adhesion molecule 1; IgG, immunoglobulin G; IL-8, interleukin-8; LPS, lipopolysaccharide; LTB4, leukotriene B4; TLR4, Toll-like receptor 4.

In some instances, neutrophils confronted with microbial invasion release networks of decondensed chromatin associated with antimicrobial proteins and other granular components. These structures are known as neutrophil extracellular traps (NETs). NETs function as both a physical structure to contain microorganisms and an antimicrobial delivery system to kill bacteria, fungi, and viruses. Sterile stimuli such as monosodium urate (MSU) and calcium pyrophosphate dehydrate crystals are also able to induce NET formation. In the classical model, neutrophils release NETs through a specialized form of cell death called NETosis. However, neutrophils may remain functional after NET extrusion, particularly when the NETs are composed of

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Table 11.1

Products of Neutrophils, Macrophages, and Eosinophils Cell

Granule Contents

Cytokines Produced

Other Inflammatory Mediators

Neutrophil

Primary (azurophilic) granules:

IL-1, IL-6, IL-8, TNF and GM-CSF

Macrophage

Elastase MMP-3, -8, -9; cathepsins; defensins; bactericidal/permeability increasing protein; proteinase 3; lysozyme; myeloperoxidase Secondary (specific) granules: Collagenase, plasminogen activator, lysozyme, lactoferrin, β2-microglobulin Gelatinase granules: Gelatinase Lysozyme (and others mentioned in the text)

Reactive oxygen species (ROS), PAF, PGE2, LTB4

IL-1β, TNF, IL-6, IL-8, IL-12, MCP-1, MCP-2, RANTES, PDGF, TGF-β, IFN-γ

Eosinophil

Specific granules:

Complement components, ROS, iNOS, PGE2, TxA2, PGI2, LTB4, LTC4, PAF, MMP-1, tissue factor, plasmin inhibitor LTB4, LTC4, PAF, PGE2, ROS, collagenase

IL-4, IL-5, IL-8, IL-10, IL-12, GM-CSF, TNF, TGF-β, PDGF, VEGF, MCP-1

Charcot-Leyden crystal protein, major basic protein, eosinophil peroxidase, eosinophil cationic protein, eosinophil-derived neurotoxin, secretory PLA2 Small granules: Arylsulfatase B Table 11.2

Leukocyte Receptors, Ligands, and Their Functions Receptor Type

Examples

Examples of Ligands

Functions

FcγR

FcγRI, FcγRlla, FcγRlllb

Immunoglobulins

Toll-like receptors

TLR-1 to TLR-11

Formyl peptide receptors

Formyl peptide receptor 1

Pathogen-associated molecular patterns (PAMPS; e.g., LPS) Bacterial N-formyl-methionyl peptides

Scavenger receptors

Scavenger receptor A

Mannose receptor

Mannose receptor C type 1

Numerous targets on bacteria, apoptotic cell structures Mannose (on pathogens)

Complement receptors

CR1, CR2, CR3, CR4 C5aR Mac-1 (CD11b/CD18),

Complement components C5a ICAM-1

Recognize and bind Fc portions of immunoglobulins Recognize pathogens and activate immune responses Mediate chemotaxis and activation of neutrophils and monocytes/macrophages Stimulate phagocytosis of bacteria and apoptotic cells, adhesion Mediates the endocytosis of glycoproteins by phagocytes Aid in opsonization and phagocytosis Activates inflammatory cells Bind to cell-adhesion molecules and extracellular matrix, resulting in strong adhesion

LFA-1 (CD11a/CD18) CCR: CCR1 CCR3, CCR5

CC:MCP-1, RANTES, MlP-1a

CXCR: CXCR1, CXCR2

CXC: IL-8

Integrins

Chemokine receptors (CR, CCR, CXCR, CXXXCR classes)

mitochondrial, rather than nuclear, DNA. NET formation requires several well-orchestrated events, including production of ROS, disintegration of intracellular granules and nuclear or mitochondrial membranes, relocation of neutrophil elastase and MPO into the nucleus, histone citrullination, chromatin decompensation, and eventual rupture of the plasma membrane.6 In contrast to its protective roles, dysregulated NET formation has been linked to many inflammatory and autoimmune diseases, including lupus, rheumatoid arthritis (RA), vasculitis, and the autoinflammatory syndromes.7,8 Impaired degradation of NETs, exposure of oxidized DNA, and altered autoantigens may promote autoreactivity and unrestrained tissue injury. Furthermore, the type of molecules that decorate NETs may account for their different contribution to various disease phenotypes.

Eosinophils and basophils Similar to neutrophils, eosinophils and basophils contain a variety of lipid and peptide mediators (see Table 11.1). These cells are less abundant in the bloodstream than neutrophils but are found in greater numbers in extravascular tissue. Eosinophils typically do not phagocytose their targets but instead discharge their contents against target surfaces. Eosinophils are important in combating parasitic infection and are also involved in the inflammatory response generated by allergic and immediate hypersensitivity reactions. Aberrant eosinophil activity is implicated in several inflammatory diseases, including asthma, eosinophilic pneumonia, eosinophilic

Recognize chemoattractants, mobilize and activate leukocytes

granulomatosis with polyangiitis, and the hypereosinophilic syndromes.9 Basophils also play an important role in allergic reactions.

Mast cells Mast cells are most commonly localized to perivascular sites within tissues. Their granular contents resemble basophils, except for the mast cell–­specific proteases tryptase and chymase. Mast cells act as a tissue’s first line of defense against invading pathogens and also play a role in allergic reactions. Activated mast cells amplify tissue inflammation through several mechanisms, including increased vascular permeability, recruitment of immune cells, activation of synovial fibroblasts, increased angiogenesis, and cartilage breakdown. Mast cell hyperplasia is a hallmark of multiple autoimmune diseases, and data from animal models suggest that mast cells are important in the pathogenesis of RA.10

MACROPHAGES Macrophages play multiple roles in inflammation and immunity. Macrophages are highly heterogeneous cells and exhibit distinct phenotypic and functional characteristics depending on their anatomical location and the local microenvironment. For instance, macrophages have different identities in the skin (Langerhans cells), liver (Kupffer cells), and brain (microglial cells). Additionally, two well-defined phenotypes of macrophages have been described: whereas M1 macrophages synthesize numerous proinflammatory

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SECTION 1  Scientific Basis of Rheumatic Disease

mediators and mediate antimicrobial and antitumoral defense, M2 macrophages have antiinflammatory, wound-healing, and fibrotic properties. Despite this nomenclature, macrophages represent a spectrum of activated phenotypes rather than discrete stable subpopulations.11 One of the earliest steps in many inflammatory responses is activation of resident-tissue macrophages.12 Macrophages may be activated by phagocytosing targets or through the engagement of their receptors with interferon (IFN)-γ, complement components, immune complexes, lipopolysaccharide (LPS), and cytokines such as IL-1β, TNF, and IL-6. Upon activation, macrophages secrete a dazzling variety of proinflammatory products (see Table 11.1), including proteases (e.g., lysozyme, elastase, and collagenase), inflammatory cytokines (IL-1β, TNF, IL-6, IL-12, and others), chemokines (IL-8, MCP-1, MCP-2, RANTES, and others), and several complement cascade proteins (C1, C2, C3, and C4). A vigorous acute-phase response, driven by cytokine production and characterized by high serum levels of acute-phase reactants and erythrocyte sedimentation rate, is typical of diseases characterized by extensive macrophage involvement. Activated macrophages also produce multiple lipid mediators (e.g., prostaglandin E2 [PGE2], thromboxane A2 [TXA2], prostacyclin [PGI2], LTB4, and PAF; see later discussion) that can contribute to the propagation of inflammation. In addition, activated macrophages produce procoagulant factors such as tissue factor and plasmin inhibitor, linking the inflammatory and clotting responses. Local intravascular coagulation triggered by microbial invasion is thought to play a role in limiting the spread of infection, but when unchecked it can lead to disseminated intravascular coagulation, a potentially life-threatening condition. Infiltrating macrophages derive from circulating mononuclear phagocytes that differentiate upon entering peripheral tissues. Although the process of mononuclear phagocyte adhesion to, and diapedesis through, blood vessels is similar in many respects to that of neutrophils, the mononuclear phagocyte responds to a different set of chemotactic factors, including the chemokines RANTES (regulated on activation, normal T cell expressed and secreted), MCP-1, and macrophage inflammatory protein (MIP)-1α and MIP-1β, and the growth factors transforming growth factor (TGF)-β and platelet-­derived growth factor (PDGF) (Table 11.1). Once in the tissues, infiltrating macrophages typically live for months. As actors in the innate immune system, macrophages phagocytose nonencapsulated bacteria by recognizing evolutionarily conserved motifs on bacterial surfaces using surface receptors for pathogen-associated molecular patterns (PAMPs). PAMP-directed (or pattern recognition) receptors include TLRs, formyl peptide receptors, and scavenger receptors, some of which are also found on neutrophils (Table 11.2). After phagocytosis, macrophages destroy microbes through mechanisms similar to those of neutrophils: lysosomal enzymes, reactive oxygen and nitrogen intermediates, toxic radicals, and chloramines. As with neutrophils, macrophage phagocytosis and killing are greatly enhanced by pathogen opsonization. Macrophages have surface receptors for multiple opsonins, including the mannose receptor (that directly recognizes microbial surface glycoproteins), CR1, CR3, CR4, FcγRI, FcγRII, and FcγRIII (Table 11.2).13 Although the majority of macrophage products augment inflammation and repel external threats, macrophages also have the capacity to damage host tissue via release of their digestive and degradative contents. Macrophages differ from neutrophils in their capacity to serve as “professional” antigen-presenting cells (APCs). After phagocytosis, APCs degrade foreign antigens in protease-containing phagolysosomes; vesicles containing major histocompatibility complex (MHC) class II molecules then fuse with the phagolysosomes, allowing MHC class II complexes to become loaded with antigenic peptide fragments. The MHC class II–peptide complexes are then delivered to the cell surface, where they present antigen to T cells to stimulate the highly specific responses of adaptive immunity. Thus, the actions of macrophages can provide a bridge from inflammation to immune processes.

Inflammasomes Macrophage production of the proinflammatory cytokines IL-1β and IL-18 is a tightly regulated process, requiring two signals. The initial trigger consists of macrophage priming by extracellular inflammatory stimuli (“Signal 1”), leading to synthesis of pro-IL-1β and pro-IL-18 (the inactive forms of IL-1β and IL-18, respectively). Secondary stimuli, such as MSU crystals, silica, asbestos, extracellular ATP, RNA-DNA hybrids, and multiple microbial pathogens (“Signal 2”), are recognized by pattern-recognition receptors and induce the oligomerization of intracellular multiprotein complexes known as inflammasomes into wheel-shaped structures (Fig. 11.5). Once assembled, inflammasomes canonically activate cysteine-dependent aspartate-directed protease (caspase) 1, which converts pro-IL-1β and pro-IL-18 to their bioactive forms. In some cases, inflammasome activation induces a lytic form of cell death known as pyroptosis, triggered by the cleavage and activation of gasdermin D.14 There are five receptor proteins that assemble the canonical inflammasomes, with different ligands and activation mechanisms.14 These include the nucleotide-binding oligomerization domain, leucine-rich

repeat-­containing (NLR) protein 1 (NLRP1), NLRP3, NLR family apoptosis inhibitory proteins (NAIPs)-NLRC4, absent in melanoma 2 (AIM2), and pyrin (marenostrin or TRIM 20). Noncanonical inflammasome pathways target caspase-4 and caspase-5 (in humans) and caspase-11 (in mice), in response to lipopolysaccharide (LPS). Although the main downstream effect of noncanonical inflammasomes is pyroptosis, activation of these caspases also triggers the NLRP3 inflammasome, leading to release of IL-1β and IL-18. Other less-well characterized pathways include NLRP6, NLRP7, NLRP12, retinoic acid–inducible gene I (RIG-I), and IFN-γ-inducible protein 16 (IFI16), all of which activate caspase 1.14,15 In addition to a linkage to autoinflammatory syndromes such as familial Mediterranean fever (FMF), dysregulated inflammasome activation has been linked to autoimmune disorders (RA, systemic sclerosis, and SLE), various malignancies, metabolic diseases, and neurodegenerative diseases.16

PLATELETS Platelets are small, anucleate, circulating cellular fragments that primarily function to maintain vascular integrity. In response to vascular injury, platelets adhere to the subendothelial matrix of the vascular wall, rapidly aggregating and driving thrombus formation. The brisk nature of thrombotic events is primarily due to platelet degranulation, wherein platelets disgorge preformed factors from α-granules and dense granules into the surrounding microvasculature. In addition to procoagulant factors, platelet granules contain inflammatory mediators, including chemokines (e.g., RANTES, MCP-3, MIP-1α, and platelet factor 4), growth factors (e.g., PDGF and TGF-β), histamine, and serotonin. Further underscoring the link between inflammation and coagulation, platelets are activated on exposure to inflammatory mediators such as platelet-activating factor (PAF). Activated platelets also participate in inflammatory processes by expressing plasma membrane proteins. Signaling molecules upregulated on the activated platelet include P-selectin, which activates neutrophils, and CD40L, which induces inflammatory responses in many cell types, including endothelium. On activation, platelets rapidly produce eicosanoids such as TXA2 and PAF (see below). Platelets both participate in cell–cell interactions and release microparticles that contribute to leukocyte–leukocyte and leukocyte–endothelial cell interactions. Platelet–leukocyte interactions, also known as thromboinflammation, occur in a broad range of conditions including sepsis, ischemia-reperfusion injury, organ transplant rejection, preeclampsia, sickle cell disease, and antiphospholipid syndrome, among others. A central event associated with thromboinflammation is the loss of the normal antithrombotic and antiinflammatory functions of endothelial cells, leading to dysregulation of coagulation, complement and platelet activation, and leukocyte recruitment in the microvasculature.17

REGULATION AND MODULATION OF INFLAMMATORY CELLS METABOLIC REGULATION OF INFLAMMATION The initial phases of an inflammatory process are energy intensive. In the presence of microbes or other triggers of acute inflammation, macrophages rapidly go from a resting basal to a highly active state. Immune cells in this phase depend on glucose as fuel, producing a surge of ATP via the utilization of glucose in the glycolytic pathway with reduced mitochondrial oxidation despite normoxic conditions, a process known as the Warburg effect, or aerobic glycolysis. Glucose is also metabolized in the pentose shunt to generate NADPH, which is required by the NADPH oxidase for ROS formation. The ratios of AMP/ATP and NAD+/NADH are thought to regulate signaling pathways that control the transition from aerobic glycolysis to a mainly oxidative metabolism in immune cells.18 The role of metabolism in inflammation is supported by findings concerning the role of AMP-activated protein kinase (AMPK) in inflammation and immunity. AMPK is a cellular biosensor with antiinflammatory activities, acting at least partly through downregulation of NF-κB signaling. AMPK is activated by stressors that increase AMP : ATP ratio, including nutrient deprivation, hypoxia, and exercise. Several antiinflammatory drugs are indirect activators of AMPK, including colchicine, methotrexate, and high-dose aspirin. Conversely, MSU crystals, alcohol, and fructose inhibit AMPK, and its activity is diminished in type 2 diabetes and obesity. In patients with gout, activation of AMPK has been shown to decrease MSU crystal–induced inflammation. Thus, promoting AMPK activation could be a novel therapeutic focus for management of gouty arthritis and other inflammatory diseases.19 Sanchez-Lopez and collaborators recently reported that inhibition of choline uptake and phosphorylation in activated macrophages prevents NLRP3 inflammasome activation and IL-1β/IL-18 production. This antiinflammatory effect seems to be mediated by disruption of mitochondrial

CHAPTER 11  Inflammation and its chemical mediators

101

ACTIVATION OF THE NLRP3 INFLAMMASOME

Stimulus “signal 2”

“signal 1”

ASC Pro-Caspase-1

NLRP3 stimulated assembly Active inflammasome

Pro-IL-1 gene

Transcription/ translation

Pro-IL-1 (inactive)

Caspase-1 action

IL-1 (active)

FIG. 11.5  Activation of the NLRP3 inflammasome. The action of the inflammasome typically involves at least two separate stimuli. The first, “Signal 1,” results in the synthesis of inactive pro-interleukin-1β (pro-IL-1β). Subsequently, a second stimulus (“Signal 2”) induces the assembly of multiple copies of three separate proteins—apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC); nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3); and procaspase-1—leading to the activation of caspase-1, which then converts pro-IL-1β into active IL-1β and is secreted to affect other cells. IL-18 is activated by the inflammasome in a similar manner. Table 11.3

Differences Between Innate and Adaptive Immune Memory Cells Recognition and effector molecules Secondary immune response Duration Mechanism

Innate Immune Memory

Adaptive Immune Memory

Monocytes, macrophages, dendritic cells, natural killer and innate lymphoid cells Pattern recognition receptors and cytokines Nonspecific as it provides cross-protection against other potential pathogens Weeks to months after the elimination of the initial trigger Metabolic and epigenetic reprogramming via histone modification and changes in DNA methylation patterns

B and T lymphocytes

ATP synthesis, which triggers AMPK activation and subsequent mitophagy (selective degradation of mitochondria by autophagy). Mitophagy inhibits IL-1β production by decreasing the number of damaged mitochondria that produce oxidized mitochondrial DNA, a potent NLRP3 activator.20 Furthermore, activation of AMPK increases expression of genes involved in mitochondrial oxidative metabolism, which is associated with antiinflammatory M2 macrophages.21 These findings highlight the key role of AMPK in the transition from proinflammatory to proresolution pathways.

TRAINED IMMUNITY, OR INNATE IMMUNE MEMORY Recent studies have shown that the innate immune system mounts a stronger response when re-exposed to microbes or other danger signals weeks to months after a prior initial exposure. This novel finding, designated trained immunity or innate immune memory, has challenged the assumption that only lymphocytes can develop immunologic memory. In fact, trained immunity has several unique features compared to classical adaptive immunity (see Table 11.3). The mechanisms by which the innate immune system is “trained” involve epigenetic reprogramming, mostly via histone modification and changes in methylation patterns but without gene rearrangement or mutations.22 For instance, it has been suggested that the bacillus Calmette-Guerin (BCG) vaccine alters DNA methylation patterns in macrophages, including reduced methylation of the IFN-γ promoter, which leads to persistently enhanced antimycobacterial responses.23 Studies on dendritic cells have shown that the enhanced cytokine response after re-exposure to pathogens can be abolished by using inhibitors of histone modifications.24 Trained immunity also involves alterations in key cellular metabolic pathways, including glycolysis, oxidative phosphorylation, fatty acid metabolism, cholesterol metabolism, and amino acid metabolism.25 Despite its apparent role in protecting from recurrent infections, development of innate immune memory can sometimes be detrimental. Trained

T-cell receptor and immunoglobulins Antigen specific Many years after the elimination of the initial stimulus Clonal expansion and generation of long-lasting memory cells that are antigen-specific. Changes are due to gene rearrangement or mutations and clonal selection

immunity has been associated with chronic inflammatory conditions such as atherosclerosis, diabetes, neurodegenerative and autoimmune disorders, and gout. Hence, modulation of trained immunity may be considered as a new therapeutic target for many of these diseases.

INFLAMMATORY MEDIATORS A myriad of soluble mediators coordinate the inflammatory process. These molecules derive from various sources, including the inflammatory cells described earlier, plasma proteins, and resident tissue cells such as nerves and endothelium.

THE COMPLEMENT SYSTEM Complement was described by Bordet in 1899 as a heat-labile component of fresh plasma that “complemented” the ability of specific antibodies to lyse red blood cells and bacteria. Notably, complement factor C3b coats and opsonizes cell membranes and soluble antigens for recognition and digestion by phagocytic cells. C5a is a potent chemoattractant for neutrophils and can stimulate neutrophil adhesion, degranulation, and the respiratory burst as well as inducing vasodilation and increasing capillary permeability.26 The complement system also functions to lyse unencapsulated gram-negative bacteria via the generation of a membrane attack complex. For a more detailed description of the complement system, please see Chapter 12.

LIPID MEDIATORS OF INFLAMMATION In addition to their roles as part of membrane structure, membrane lipids serve as substrates for the generation of both pro- and antiinflammatory mediators.

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SECTION 1  Scientific Basis of Rheumatic Disease

Arachidonic acid derivatives Many bioactive lipid mediators are produced through the oxidation of arachidonic acid (AA), including prostaglandins, leukotrienes (LTs), and the antiinflammatory lipoxins (Fig. 11.6). AA is a polyunsaturated fatty acid covalently associated with membrane phospholipids. The enzyme cytosolic phospholipase A2 (cPLA2) catalyzes the release of AA from nuclear membrane lipids by hydrolysis of the sn-2 ester bond. In any given cell, the products formed from AA will be determined by factors such as cytokine milieu and local expression of AA-modifying enzymes.

Cyclooxygenase products Prostaglandins (PGs), so named because they were originally identified in seminal fluid (i.e., from the prostate gland), result from the action of cyclooxygenases (COX-1 or COX-2) on AA. COX enzymes are heterobifunctional: they first incorporate oxygen into AA, producing the unstable molecule PGG2. A second COX reaction then reduces PGG2 to PGH2 (hence the alternate designation of COXs as PGH synthases). PGH2 is subsequently converted into stable prostanoids by a variety of so-called terminal synthases, which are expressed with some tissue specificity; differentiated cells tend to produce only one PG type in abundance. COX-1 and COX-2 are structurally similar and perform identical enzymatic functions but are differentially expressed in tissues. COX-1 is expressed abundantly in many tissues and cell types, including renal collecting tubules, gastric epithelial cells, endothelial cells, macrophages, and platelets. COX-1 products typically participate in organism homeostasis and basic physiologic processes (e.g., protection of the gastric mucosa). In contrast, COX-2 is inducible and expressed primarily in cells involved in inflammation (e.g., macrophages, fibroblasts, and endothelial cells) in response to

stimuli such as IL-1β, TNF, PDGF, and EGF.27 COX-2 products contribute to the inflammatory processes that drive further COX-2 expression. Moreover, COX-2 expression is elevated in many pathologic conditions, including inflammatory arthritis and neoplasms such as prostate and colon cancer. On this basis, selective COX-2 inhibitors were developed and shown to be just as antiinflammatory as nonselective COX inhibitors but with less gastrotoxicity. However, additional research revealed that COX-2 expression is less selective than initially hoped and that COX-2 also generates PGs that play roles in homeostasis. Thus, COX-2 inhibitors have some advantages over traditional nonsteroidal antiinflammatory drugs (NSAIDs) but are not unequivocally benign. In particular, selective COX-2 inhibition appears to convey an increased risk of myocardial infarction, possibly by disturbing the balance between COX-1- and COX-2-mediated products in the vasculature (see Chapter 61 for further discussion of selective COX-2 inhibitors). PGs are short-lived and generally act in an autocrine or paracrine manner. PG effects are primarily mediated through specific G protein-coupled, seven-transmembrane-domain receptors, which have been classified into five types according to their responsiveness to selective agonists and antagonists.28 PGE2 is the most critical prostanoid to inflammation. PGE2 mediates fever and pain, induces smooth muscle contraction, spurs T-cell migration, and contributes to the vasodilation and vascular hyperpermeability of early inflammation. Elevated PGE2 levels are found in patients with RA and osteoarthritis (OA) and likely contribute to joint damage by promoting osteoclastic bone resorption and inhibiting proteoglycan synthesis. In addition to its proinflammatory effects, PGE2 exerts multiple modulatory and antiinflammatory effects, including inhibiting T-cell activation and proliferation, downregulating antibody production, and reducing proinflammatory cytokine release by macrophages and dendritic cells. PGE2 has also

ARACHIDONIC ACID DERIVATIVES THAT MEDIATE INFLAMMATION

Membrane phospholipids

Phospholipase A2 5-Lipoxygenase (5-LO), FLAP

5-HPETE

12-Lipoxygenase (platelets)

LTA4 synthase

15-Lipoxygenase

Arachidonic acid

15-S-HETE 5-LO (neutrophils)

LXA4

LTA4

5,6-Epoxytetraene

PGG2

Cyclooxygenase -1 and -2

LXB4

Epoxide hydrolase (neutrophils)

PGH2 LTB4 synthase

LTC4 synthase LTB4

LTC4

Terminal synthases TXA2

PGF2α

PGE2

PGD2

PGI2

LXA4

LXB4

Transpeptidase LTD4

H2O Dipeptidase

LTE4

PGJ2

FIG. 11.6  Arachidonic acid derivatives that mediate inflammation. Arachidonic acid (AA) is liberated from cell membrane phospholipids via phospholipase A2 (PLA2) activity. Three distinct classes of products—prostanoids, leukotrienes, and lipoxins—may be subsequently generated by the action of distinct enzyme systems. Prostanoid formation: cyclooxygenase (COX)-1 and COX-2 convert AA sequentially into PGG2 and PGH2. Specific terminal synthases generate all other prostanoid products from PGH2, with the exception of PGJ2, which forms from PGD2 through a dehydration reaction. Leukotriene formation: 5-lipoxygenase (5-LO) in concert with 5-lipoxygenase-activating protein (FLAP) act on AA to generate 5-hydroxyeicosapentaenoic acid (5-HPETE) and, subsequently, leukotriene A4 (LTA4). LTB4 is formed from LTA4 via LTA4 hydrolase. In contrast, LTC4 synthase converts LTA4 into LTQ. Subsequently, transpeptidase and dipeptidase convert LTC4 into LTD4 and LTD4 into LTE4, respectively. Lipoxin formation: Lipoxins (LX) form through cell–cell interactions during inflammation; two of the several pathways leading to lipoxin formation are shown here. Cells such as airway epithelium produce and release AA-derived 15-S-HETE. 15-S-HETE then diffuses into leukocytes, where it is first converted into 5,6-epoxytetraene by 5-LO and then into LXA4 or LXB4 by the action of epoxide hydrolase. Alternatively, when adherent platelets interact with activated leukocytes in the vascular lumen, LTA4 released from leukocytes diffuses into platelets, where it is converted to LXA4 and LXB4 by 12-LO. In contrast to prostanoids and leukotrienes, lipoxins appear to have largely antiinflammatory effects. Not shown are the aspirin-triggered lipoxins, which form when acted upon by aspirin-acetylated COX-2.

CHAPTER 11  Inflammation and its chemical mediators been shown to prevent the development of allergic airway inflammation in murine models of airway disease.29,30 PGE2 is generated from PGH2 by at least three different isoforms of PGE synthase (PGES)—cytoplasmic PGES (cPGES) and microsomal PGES (mPGES)-1 and mPGES-2. Like COX-1, with which it is functionally coupled, cPGES is constitutively and ubiquitously expressed. In contrast, mPGES-1 is upregulated by proinflammatory stimuli and is functionally coupled with COX-2. mPGES-2 has a less clearly defined role.31 COX-2 and mPGES-1 tend to increase in tandem and to co-localize to the same subcellular fraction. In human rheumatoid synovial fibroblasts, mPGES-1 expression is induced by IL-1β and TNF and inhibited by dexamethasone32; mPGES-1–null mice are resistant to both adjuvant- and collagen-induced arthritis.33 Given the possibility that it may regulate the inflammatory but not constitutive production of PGE2, mPGES-1 is an attractive target for drug development.34 Whereas PGE2 predominates at inflammatory sites, activated cells produce a spectrum of additional prostaglandins with distinctive biologic activities. PGI2, or prostacyclin, is synthesized by endothelial cells and induces vasodilation while inhibiting platelet aggregation, qualities that have been exploited in the treatment of pulmonary hypertension.35 PGD2, released in large amounts by mast cells, is a vasodilator and activates group 2 innate lymphocytes, promoting chemotaxis, cytokine production, survival, and recruitment of basophils, eosinophils, and Th2 cells into tissues.36 PGD2 plays an important role in allergic inflammation and asthma but has also been shown to inhibit granulocyte trafficking.37 PGF2 is a potent uterine constrictor; the related molecule 8-iso-PGF2α is associated with oxidative injury in RA and other types of inflammatory arthritis.38 PGJ2 exerts a number of antiinflammatory effects. Unlike conventional PGs, which signal via cell surface receptors, PGJ2 is actively transported into cells to activate the intranuclear peroxisome proliferator activating receptor (PPAR)-γ. PPAR-γ then inhibits NF-κB, an important driver of the transcription of proinflammatory genes. In an animal model of arthritis, intraperitoneal administration of PGJ2 suppressed inflammation and pannus formation.28 However, PGJ2 may also mediate proinflammatory effects through PPARγ-independent pathways, including upregulation of COX-2 expression, increase of IL-8 production, and activation of mitogen-activated protein kinases (MAPK).39 Thromboxane A2 is formed from PGH2 via the action of thromboxane synthase. TXA2 is a platelet activator and a potent vasoconstrictor. Platelet TXA2 production is COX-1-dependent and unaffected by COX-2 inhibitors. Although TXA2 is conventionally thought of as a platelet product, thromboxane synthase can be upregulated in other cell types, and thromboxane production has been implicated in both asthma and the pathogenesis of murine lupus nephritis.40,41

Lipoxygenase products Leukotrienes (LTs) are created when 5-lipoxygenase (5-LO) oxygenates AA to generate 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which in turn is converted to LTA4 (Fig. 11.6). LTA4 can then be converted to either LTB4 or, via an alternative pathway, to LTC4, LTD4, and LTE4, the so-called cysteinyl LTs (Cys LTs). Leukotriene B4 is the most important LT in acute inflammatory responses; it activates leukocytes and prolongs their survival. Additionally, LTB4 is a powerful chemoattractant for neutrophils and macrophages and stimulates leukocyte adhesion to vascular endothelium by upregulating leukocyte integrin expression.42 LTB4 is present in high levels in the synovial fluid and sera of RA patients, and LTB4 antagonism inhibits inflammatory arthritis in animal models. In a phase 2 clinical trial, however, an LTB4 receptor antagonist was not efficacious for RA.43 Cys LTs are produced by eosinophils, basophils, macrophages, and mast cells. Cys LTs induce vasodilation and increase vascular permeability; increase bronchoconstriction, wheezing, and mucus secretion; and decrease mucociliary clearance.44 The 5-LO inhibitor zileuton and the Cys LT receptor antagonists montelukast and zafirlukast are currently available for treating asthma.

Platelet-activating factor Like the AA derivatives, PAF can be generated from membrane lipids. It is synthesized by activated neutrophils, eosinophils, monocytes, platelets, endothelial cells, mast cells, and fibroblasts. In addition to activating platelets, PAF is a chemoattractant and stimulant for neutrophils, macrophages, and eosinophils. It induces bronchoconstriction, increased vascular permeability, and vasodilation and has been implicated in inflammatory arthritis. Although a PAF receptor antagonist reduces arthritis in animal models, a randomized controlled trial in human patients with RA demonstrated no reduction in RA disease activity.45,46

103

VASOACTIVE AMINES Histamine Histamine is the decarboxylation product of the amino acid histidine. It is released from mast cell and basophil granules during cell activation, most notably after cross-linking of cell surface Fcε receptors in response to IgE binding. Histamine promotes immediate-type hypersensitivity reactions, including vasodilation and enhanced permeability of postcapillary venules. In the respiratory system, histamine promotes bronchoconstriction and increased flow of bronchial mucus.

Serotonin In addition to its well-recognized neurotransmitter function, serotonin is stored in the dense granules of platelets and promotes both vasoconstriction and microvascular permeability. Serotonin also promotes fibrosis via enhancing fibroblast collagen synthesis and may therefore play a role in periaortitis-associated retroperitoneal fibrosis.

REACTIVE OXYGEN SPECIES AND NITRIC OXIDE Reactive oxygen species and nitric oxide (NO) are small molecules containing unpaired electrons that are highly reactive with cellular components. ROS and reactive nitrogen species function beneficially as specific intracellular signaling molecules. In inflammatory diseases, these unstable intermediates may be overproduced and released by activated immune cells. The subsequent nonspecific oxidative reactions that occur between the radicals and biologic targets lead to cell death and tissue damage.

Reactive oxygen species Activation of macrophages and neutrophils during inflammation can lead to the release of ROS into the extracellular milieu, resulting in oxidative stress and damage of extracellular and cellular components, including nucleic acids, lipids, carbohydrates, proteins, and matrix components. ROS are continuously generated in low concentrations in all aerobic cells, which protect themselves through the presence of antioxidant enzymes (e.g., catalases, peroxidases, and superoxide dismutases). However, when ROS are produced at extremely high levels by activated neutrophils and macrophages, the defensive machinery is overwhelmed and tissue damage can occur. The major ROS formed by cells are, in descending order of stability, superoxide, hydrogen peroxide, and the hydroxyl radical (which is responsible for much of the havoc wreaked by oxidative intermediates) (Fig. 11.7).47 NADPH oxidases are ubiquitous enzymes with multiple variants. NADPH oxidases are termed PHOX (for phagocytic oxidase) in phagocytic cells and NOX (nonphagocytic oxidases) in other cells. ROS produced by NOX influence a number of cellular events, including cell proliferation and apoptosis.48 The proinflammatory transcription factors, activator protein (AP)-1 and NF-κB, were among the first intracellular components discovered to be responsive to ROS signaling.49 These two transcription factors spur the production of dozens of proinflammatory mediators, including collagenase, IL-1β, and TNF. ROS have also been demonstrated to upregulate adhesion molecule expression on endothelium and increase both cytokine and chemokine production by leukocytes.

Nitric oxide Nitric oxide (NO) is synthesized via oxidation of arginine by three distinct NO synthase (NOS) isoforms (Fig. 11.7). The neuronal (nNOS) and endothelial (eNOS) isoforms are constitutively expressed, with activity regulated by intracellular calcium levels and the calcium-binding protein calmodulin. In contrast, the iNOS isoform is induced by stimuli that include LPS, IL-1β, TNF, and IFN-α and leads to sustained generation of NO.50 NO helps downregulate inflammation but can also cause vasodilation, edema, cytotoxicity, and the mediation of cytokine-dependent processes that can lead to tissue destruction. Given the short half-life of NO gas, the biologic activity of NO is usually determined by its reactivity with target molecules. Binding of NO to the heme group of soluble guanylate cyclase activates this enzyme, raising intracellular levels of cyclic guanosine monophosphate (cGMP) and promoting smooth muscle relaxation.51 The reaction of NO with superoxide anion yields peroxynitrite, a highly toxic free radical that nitrosylates proteins, leading to the accumulation of injurious intracellular oxidants and DNA damage (Fig. 11.7).52 NO and its derivatives play complex roles in immune regulation. Whereas low NO levels promote lymphocyte activation and proliferation, high concentrations suppress APC activity and T-cell proliferation.53,54 NO exerts divergent effects on subpopulations of T cells, inhibiting secretion of IL-2 by Th1 cells while increasing IL-4 secretion by Th2 cells. At high concentrations, NO promotes apoptosis in macrophages, CD4+/CD8+ thymocytes, and chondrocytes.55 At lower concentrations, NO inhibits apoptosis

104

SECTION 1  Scientific Basis of Rheumatic Disease GENERATION OF REACTIVE OXYGEN AND NITROGEN SPECIES O2 (molecular oxygen)

Arginine iNOS

NADPH oxidase O2 (superoxide)

NO (nitric oxide)

Superoxide dismutase ONOO(peroxynitrite)

H2O2 (hydrogen peroxide)

Myeloperoxidase

Fe2+

HOCI (hypochlorous acid)

Cl-

Fe3+ Nitrosylated proteins

OH(hydroxyl radical)

of hepatocytes, B lymphocytes, and eosinophils.56 Although excessive NO production is associated with tissue injury, NO constitutively produced by the endothelium is believed to play a protective role in the microvasculature, by inhibiting platelet and neutrophil adhesion and reducing leukocyte superoxide anion production.57,58 NO has been implicated in the pathogenesis of lupus and RA.59–61 IFNα, a key cytokine in SLE, represses endothelial NOS and inhibits NO generation, promoting endothelial dysfunction.62 In OA, NO is spontaneously produced by chondrocytes and is implicated in cartilage deterioration. Deleterious NO effects on cartilage include inhibition of collagen and proteoglycan synthesis, activation of MMPs, increased susceptibility to oxidant injury, and apoptosis.63

THE NERVOUS SYSTEM IN INFLAMMATION The immune and nervous systems are in constant communication, such that they constitute a unified defense against internal and external threats.64 The nervous system registers inflammation in the periphery and directs the immune system through a variety of messengers, ranging from autonomic neurotransmitters (e.g., acetylcholine [Ach]) to peripherally synthesized neuropeptides such as substance P. The CNS additionally controls inflammatory responses by releasing neuroendocrine hormones that dampen inflammation. Conversely, the immune system regulates the CNS by releasing cytokines, growth factors, and other mediators; cytokine generation in the periphery, for instance, can induce the hypothalamic–pituitary–adrenal axis to release glucocorticoids. Both clinical and experimental evidence support that the peripheral nervous system (PNS) modulates inflammatory arthritis. Joint denervation attenuates distal joint inflammation in murine models.65 Peripheral sensory nerves, upon stimulation from noxious stimuli such as bradykinin and histamine, inflammatory cytokines such as IL-1β, and pathogen-derived factors acting via TLR receptors, transmit pain signals and secrete inflammatory mediators known as neuropeptides.66 Neuropeptides mediate neuron-to-neuron communication but also act on macrophages, dendritic cells, and lymphocytes to both promote and help resolve inflammation (Table 11.4).

AUTONOMIC INFLUENCE ON INFLAMMATION In the autonomic nervous system (ANS), both parasympathetic branches from the vagus nerve and sympathetic nerve fibers synapse upon the major organs of immunity, including the spleen, lymph nodes, thymus, bone marrow, and the gut’s mucosa-associated lymphoid tissue. Thus, a dense neuronal network affords direct lines of communication between the immune and autonomic nervous systems, permitting rapid and robust responses to stimuli.

The parasympathetic nervous system: a largely antiinflammatory pathway In response to stimuli, the parasympathetic nervous system primarily plays an antiinflammatory role. TNF, IL-1β, and other inflammatory mediators activate afferent parasympathetic sensory nerve fibers that ascend in the vagus nerve to the brainstem and supratentorial regions of the CNS.64 Efferent signals then travel back down the vagus to terminate in the celiac ganglia where stimulated adrenergic neurons residing in the celiac ganglia

FIG. 11.7 Generation of reactive oxygen and nitrogen species. As shown on the right side of the figure, molecular oxygen is converted to superoxide (O2−) by the action of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Superoxide dismutase subsequently converts superoxide to hydrogen peroxide (H2O2). In the presence of molecular iron, H2O2 is spontaneously converted to hydroxyl radical (OH−), an extremely unstable and reactive oxygen product. Alternatively, reaction of H2O2 with molecular chloride is catalyzed by myeloperoxidase in phagolysosomes of macrophages and neutrophils; the product, hypochlorous acid (HOCl), is an extremely potent antibacterial agent. As shown on the left side of the figure, inducible nitric oxide synthase (iNOS) liberates nitric oxide (NO) from the side chain of arginine. Interaction of NO and superoxide results in the formation of highly reactive peroxynitrites, which can modify, and potentially alter, the function of a wide range of proteins.

continue to the spleen. Norepinephrine released from splenic neurons engages β2-adrenergic receptors on a subset of T cells capable of releasing Ach, which exerts a potent antiinflammatory effect, including by engaging α-7 nicotinic (α7nACh) receptors on macrophages.67,68 This mechanism is sometimes termed the “inflammatory reflex”—a misnomer as its function is primarily antiinflammatory (Fig. 11.8).

The sympathetic nervous system The effects of the sympathetic nervous system on immunity and inflammation are complex and vary with the cell and clinical context. Distinct pro- and antiinflammatory effects of norepinephrine may relate to dose, with higher concentrations required to activate β-adrenergic receptors. On macrophages and dendritic cells, high concentrations of norepinephrine activate β2-adrenoreceptors, inhibiting release of the proinflammatory cytokines and increasing the production of antiinflammatory IL-10. Activated β-adrenergic receptors also inhibit neutrophil and NK cell function. Stimulation of β2-adrenoreceptors reduces the emigration of lymphocytes from lymph nodes to the lymph and bloodstream.64,69,70 In contrast, activation of α-adrenoreceptors by low-dose norepinephrine promotes inflammation.

NEUROENDOCRINE MECHANISMS The hypothalamus continuously receives data about the body’s environment and, in response to stress signals such as IL-1β, releases corticotrophin-releasing hormone (CRF). CRF activates the pituitary to secrete adrenocorticotropic hormone (ACTH), in turn stimulating the adrenal glands to produce and secrete glucocorticoids, potent endogenous antiinflammatory immunomodulators. Melanocyte-stimulating hormone (MSH), which derives from the same precursor, pro-opiomelanocortin (POMC), as ACTH is also secreted by the pituitary gland and can suppress inflammation.71 Systemic administration of MSH improves inflammatory arthritis, experimental colitis, and experimental allergic encephalomyelitis.72 Studies suggest that the antiinflammatory effects of MSH are mediated through engagement of a specific receptor, MSH-R3, and that ACTH can also engage this receptor, indicating a direct antiinflammatory effect in addition to its ability to drive cortisol synthesis.73 The proposed mechanism for this effect is a cAMP-­dependent reduction in the production of proinflammatory cytokines.74

NEUROPEPTIDES Substance P Substance P, aka neurokinin, is widely distributed in the peripheral and central nervous systems and functions as a transmitter of pain signaling. Additionally, substance P ligation of the NK-1 receptor on postcapillary endothelium causes edema by inducing vasodilation and increases microvascular permeability and neutrophil infiltration. However, substance P can also suppress neutrophil extravasation at later time points.75 Substance P attracts and activates macrophages, lymphocytes, and mast cells76; mast cells degranulate in response to substance P, releasing histamine, tryptases, leukotrienes, and serotonin. Increased substance P levels are found in a number of human inflammatory diseases, including RA, inflammatory bowel disease, and asthma.77 Depletion of substance P from presynaptic vesicles is the mechanism of action of capsaicin, a topical analgesic used in osteoarthritis.

CHAPTER 11  Inflammation and its chemical mediators

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Table 11.4

Inflammatroy Effects of Select Neuropeptides Neuropeptide

Where Produced (Outside the CNS)

Effects on Inflammation

Evidence for Involvement in Arthritis

Substance P (neurokinin)

C-type nerve fibers

Arteriole vasodilation

Lymphocytes

Increased microvascular permeability

Macrophages

Chemoattracts and activates macrophages, polymorphonuclear neutrophils, lymphocytes, and eosinophils Mast cell degranulation Potent arteriole and venous vasodilator

Elevated SP in synovial fluid of RA joints RA synovial fibroblasts (RASF) overexpress SP receptor (NK-1R) Stimulates RASF to proliferate and secrete inflammatory products

Calcitonin-gene-related peptide (CGRP)

Eosinophils C-type nerve fibers

Neuropeptide Y

Sympathetic nerve fibers

Vasoactive intestinal peptide

Peripheral nerves

May favor Th2 response: Inhibits IFN-γ and stimulates IL-4 production in lymphocytes Antiinflammatory peptide

Mast cells

Inhibits chemotaxis and activation of macrophages and T cells

Lymphocytes Polymorphonuclear neutrophils Macrophages

Stimulates production of IL-4, IL-10, and IL-1ra

is highly expressed in osteoarthritis synovium.80 However, CGRP also has multiple antiinflammatory roles, including upregulation of IL-10, decreased production of proinflammatory cytokines, decreased neutrophil recruitment, and phagocytosis. CGRP may also promote T-cell differentiation into a Th2 phenotype by inducing dendritic cell polarization and increasing IL-4 production.75

THE INFLAMMATORY REFLEX Celiac ganglion

Efferent vagus nerve Infection Injury Macrophage TNF-α IL-10

Neuropeptide Y Splenic nerve

Afferent vagus nerve

CNS

Norepinephrine release

Inflammatory cytokines

CGRP overexpressed in entheses of animals with adjuvant arthritis Elevated CGRP levels in synovial tissue from OA joints RA synovium has paucity of NPYcontaining nerve fibers Therapeutic in collagen-induced arthritis

Macrophage TNF-α IL-10

β2AR

T cell (ACh producing) Acetylcholine α7nAChR release Spleen

FIG. 11.8  The inflammatory reflex. Local damage or generalized inflammation in the periphery drives inflammatory cytokine production by macrophages and other cell types, which cause sensory signals to travel to the central nervous system (CNS) via the afferent vagus nerve, where they stimulate a parasympathetic response. Reactive impulses travel down the efferent vagus nerve to synapses in the celiac ganglion. Secondary signals are delivered to the spleen via the splenic nerve, where norepinephrine is released and engages β2-adrenergic receptors (β2AR) on specialized choline acetyltransferase-expressing T cells. Release of acetylcholine by these cells activates α7-nicotinic acetylcholine receptors (α7nAChR) on macrophages, leading to an antiinflammatory macrophage phenotype including suppression of TNF as well as expression of the antiinflammatory cytokine interleukin-10 (IL-10), among others. See text for details.

Calcitonin gene-related protein CGRP, an alternative splice product of calcitonin, is primarily released from small peripheral sensory nerves and acts on CGRP receptors on smooth muscle, endothelial cells, macrophages, and lymphocytes. CGRP is coreleased with substance P and is a potent arterial and venous vasodilator.78 CGRP is overexpressed in adjuvant and collagen-induced arthritis79 and

Neuropeptide Y (NPY) is released from sympathetic nerve endings, alone or in combination with catecholamines, and exerts both pro- and antiinflammatory effects. NPY can activate macrophages, leading to production of proinflammatory cytokines such as IL-12 and TNF, while also inhibiting IFN-γ and stimulating IL-4 production.81 RA synovium has a paucity of NPYcontaining nerve fibers, which may suggest a loss of suppressive function. However, elevated levels of NPY have been reported in rheumatoid synovial fluid, suggesting a complex role for this peptide.82 Furthermore, NPY plays a crucial role in the regulation of inflammatory processes and crosstalk between the enteric nerves and the immune system.83

Vasoactive intestinal peptide Vasoactive intestinal peptide (VIP) is released by immune cells as well as by nerve endings that synapse on central and peripheral lymphoid organs. VIP is an antiinflammatory peptide that inhibits chemotaxis and activation of macrophages and T cells. It inhibits the production of NO, TNF, IFN-γ, IL-6, and IL-12 and stimulates the synthesis of the antiinflammatory cytokines IL-10 and IL-1RA. VIP may additionally promote the expansion of Treg cells, favor Th2 differentiation, and enhance the production of IL-5 and IL-13 by a group of innate lymphoid cells. VIP has been shown to be therapeutic in several neurodegenerative and inflammatory models (Table 11.4).83,84

THE RESOLUTION OF INFLAMMATION To maintain homeostasis, organisms must both activate inflammatory processes and terminate them when they are no longer needed. As seen most prominently in monogenic autoinflammatory syndromes but also in uncontrolled autoimmune conditions such as RA, dysregulated or persistent inflammation contributes to tissue damage and dysfunction. Incomplete resolution of inflammation results in a chronic inflammatory phenotype, leading to tissue damage and, in some cases, autoimmunity, through the continuous exposure to self-antigens. Thus endogenous antiinflammatory mechanisms are as important as proinflammatory ones in the maintenance of life. The appropriate resolution of inflammation constitutes a cascade of active and tightly regulated events that starts as soon as the inflammatory process begins. In an elegant piece of evolutionary engineering, it is often the same cells that define inflammation that, in a late phase of activation, contribute to its resolution.

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ELIMINATION OF THE INCITING STIMULUS AND PROINFLAMMATORY SIGNALS For effective resolution of inflammation, the triggering stimulus must be eliminated. For instance, in the case of an infection, removal of the pathogen is crucial for adequate resolution of inflammation. Failure to remove the inciting stimulus may lead to chronic inflammatory processes and tissue injury. The resolution of inflammation must also include the abrogation of leukocyte recruitment into the inflammatory site. Because leukocyte ingress is driven in large part by chemokine gradients, the depletion of proinflammatory chemokines is an active process. For instance, leucine-rich repeat-containing 33 (LRRC33), a TLR homolog, negatively regulates TLR signaling and subsequently inhibits NF-κB activation and proinflammatory cytokine production.85 Chemokine proteolysis, along with prostaglandin catabolism, is necessary to reduce the leukocyte infiltration. Dampening of leukocyte recruitment is also mediated by a family of silent or decoy (nonsignaling) chemokine receptors that prevent chemoattraction by competing with active chemokine receptor signals. This group includes D6, Duffy antigen receptor for chemokines (DARC), and CCX-CKR. NETs, which are normally associated with proinflammatory responses, can also serve as a scaffold for the interaction of catalytic enzymes and cytokines, promoting enzymatic degradation of the latter and limiting inflammation.86

REMOVAL OF INFLAMMATORY CELLS Effective resolution of inflammation also requires active removal of inflammatory cells from the tissue to limit their harmful effects. Neutrophils and eosinophils may be eliminated by several pathways, including reverse migration, lymphatic drainage, exudation to the external environment, or local cell death, followed by efferocytosis. Efferocytosis is the process by which apoptotic cells are taken up by phagocytes for clearance. This process depends on the cell surface expression of signals by apoptotic cells, most prominently phosphatidylserine.87,88 Defective efferocytosis has been proposed as a mechanism of autoantibody production in systemic lupus erythematosus, due to a failure to clear apoptotic bodies. The efferocytosis of neutrophils by macrophages induces an antiinflammatory program and transition to the M2 phenotype, which is dominated by the release of antiinflammatory cytokines IL-10, TGF-β, and antiinflammatory lipid mediators, as well as upregulation of coinhibitory molecules such as programmed death ligand-1 (PDL1) and inducible costimulatory (ICOS) ligand. Late in inflammation, neutrophils themselves produce more antiinflammatory mediators, switching from prostaglandins and leukotrienes to lipoxins, resolvins, maresins, and protectins (described below). In addition, late-inflammation neutrophils can extrude antiinflammatory molecules from their secretory granules. In this way, for example, late-inflammation neutrophils can express annexin A1, a potent antiinflammatory protein that inhibits neutrophil diapedesis, among its other effects. Changes in cellular polarity secondary to the redistribution of molecules such as glycogen synthase kinase-3β, Akt, and protein kinase C also modulate inflammatory processes, including chemotaxis.87

LIPOXINS, RESOLVINS, AND OTHER ANTIINFLAMMATORY MEDIATORS In addition to proinflammatory mediators, humans produce antiinflammatory molecules that reduce inflammation and enhance proresolution pathways. Among this group of mediators are AA-derived lipids known as lipoxins (LXs). LXs are formed during cell–cell interactions that occur during inflammation (see Fig. 11.6). When adherent platelets interact with activated leukocytes in the vascular lumen, LTA4 released from the leukocytes diffuses into the platelets, where it is converted to LXA4 and LXB4. LXs can also form when monocytes or epithelial cells release the AA derivative 15S-HETE, which is then converted to LXs by neutrophils. The requirement for two different inflammatory cells for LX formation may delay LX production until inflammation has already been established, consistent with a role for LX in the resolution. LXs exert multiple antiinflammatory effects, including inhibiting cytokine expression, neutrophil chemotaxis and interaction with endothelial and epithelial cells, monocyte activation, and inflammatory cell proliferation. LXs also promote macrophage clearance of apoptotic leukocytes.89 LXs inhibit animal models of inflammation, including experimental colitis, asthma, and peritonitis.90 Their actual role in human inflammation is less well established, including the extent to which aspirin’s effects are mediated via ATL production. Resolvins, protectins, and maresins are derived from the omega-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic

acid (DHA). These lipid molecules are potent endogenous antiinflammatory mediators. Similar to the lipoxins, they are produced during the later phases of inflammation and hasten its resolution. Resolvins D1 and E1 promote antiinflammatory macrophage polarization, inhibit the production of proinflammatory cytokines by neutrophils and macrophages, prevent granulocyte trafficking, and stimulate noninflammatory efferocytosis of apoptotic cells. Resolvin E1 has been shown to inhibit leukocyte infiltration in murine models of inflammation and protect against the development of colitis.91–93 Protectin D1 (PD1) is synthesized by neutrophils, macrophages, and eosinophils. PD1 is also found in the brain, where it is called neuroprotectin D1.94 PD1 is a potent antiinflammatory and proresolving agent in mouse models of peritonitis and colitis and promotes resolution of neuroinflammation.95 Maresins, or macrophage mediators in resolving inflammation, are also DHA derived and enhance resolution of inflammation by inhibiting neutrophil influx, as well as by promoting the noninflammatory efferocytosis of dead neutrophils by macrophages.96 The role and potential therapeutic effect of the specialized proresolving mediators have been studied in multiple inflammatory diseases, including cystic fibrosis, atherosclerosis, asthma, obesity, and rheumatologic conditions. Resolvins, LXA4, and maresins have been identified in synovial fluid from patients with RA; however, their exact roles in RA remain to be determined.97,98 Increased synthesis of these molecules may explain the modest beneficial effect of EPA and DHA supplementation in patients with RA. Additionally, aspirin and statins are thought to modulate the biosynthesis of several of the proresolving mediators.99

IMMUNE ACTIVITY AFTER RESOLUTION OF INFLAMMATION The classic final stage of the resolution of inflammation is the tissue return to homeostasis. This is orchestrated in part by TGF-β-driven fibroblast differentiation into myofibroblasts, which promote remodeling. Where tissue damage has occurred, reparative programs are activated that, when effective, limit the adverse consequences of the postinflammatory state. The resolution process seems to be a critical step in maintaining immune tolerance and preventing chronic inflammation and autoimmunity. Like inflammation, the resolution process itself must be carefully controlled; for example, excessive myofibroblast activity can lead to collagen deposition and excessive tissue fibrosis.100

THE AGING INFLAMMATORY SYSTEM: IMMUNOSENESCENCE AND INFLAMMAGING Broadly, the term immunosenescence describes the overall decline in immune function in older individuals compared with young, healthy ones. In contrast, inflammaging is a phenomenon of low-grade persistent inflammation and increased cytokine production by leukocytes, which is a common feature in older individuals. Although counterintuitive, immunosenescence and inflammaging are related processes reflecting immune/inflammatory dysregulation. Immunosenescence and inflammaging can have detrimental consequences, including increased susceptibility to infections and cancer, along with diabetes, cardiovascular and neurodegenerative disorders, and other chronic inflammatory conditions. Immunosenescent cells are not quiescent and in fact secrete proinflammatory mediators and growth factors, a phenotype referred to as senescence-associated secretory phenotype (SASP).101 The mechanisms underlying immunosenescence and inflammaging are yet to be fully understood. The prevailing model involves multiple mechanisms, including cell senescence (increased cell cycle arrest associated with aging), mitochondrial dysfunction, oxidative stress, defective autophagy/ mitophagy, persistent inflammasome activation, and dysbiosis (i.e., changes of microbiota). Additionally, trained immunity or innate immune memory (described earlier) has been proposed to partially explain the sustained state of activation of some immune cells in aging.102

ACKNOWLEDGMENTS The authors acknowledge the contributions of Drs. Sabina Sandigursky, Aryeh Abeles, and Steven Abramson, who were authors of this chapter in previous editions.

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79. O’Connor TM, O’Connell J, O’Brien DI, et al. The role of substance P in inflammatory disease. J Cell Physiol. 2004;201(2):167–180. 80. Saito T, Koshino T. Distribution of neuropeptides in synovium of the knee with osteoarthritis. Clin Orthop Relat Res. 2000;376:172–182. 81. Wheway J, Herzog H, Mackay F. The Y1 receptor for NPY: a key modulator of the adaptive immune system. Peptides. 2007;28(2):453–458. 82. Buljevic S, Detel D, Pucar LB, et al. Levels of dipeptidyl peptidase IV/CD26 substrates neuropeptide Y and vasoactive intestinal peptide in rheumatoid arthritis patients. Rheumatol Int. 2013;33(11):2867–2874. 83. Chandrasekharan B, Nezami BG, Srinivasan S. Emerging neuropeptide targets in inflammation: NPY and VIP. Am J Physiol Gastrointest Liver Physiol. 2013;304(11):G949–G957. 84. Chen G, Hao J, Xi Y, et al. The therapeutic effect of vasoactive intestinal peptide on experimental arthritis is associated with CD4+CD25+ T regulatory cells. Scand J Immunol. 2008;68(6):572–578. 85. Liu J, Zhang Z, Chai L, et al. Identification and characterization of a unique leucine-rich repeat protein (LRRC33) that inhibits Toll-like receptor-mediated NF-κB activation. Biochem Biophys Res Commun. 2013;434(1):28–34. 86. Schauer C, Janko C, Munoz LE, et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med. 2014;20(5):511–517. 87. Cartwright JA, Lucas CD, Rossi AG. Inflammation resolution and the induction of granulocyte apoptosis by cyclin-dependent kinase inhibitor drugs. Front Pharmacol. 2019;10:55. 88. Gilroy D, De Maeyer R. New insights into the resolution of inflammation. Semin Immunol. 2015;27(3):161–168. 89. Serhan CN. A search for endogenous mechanisms of anti-inflammation uncovers novel chemical mediators: missing links to resolution. Histochem Cell Biol. 2004;122(4):305–321. 90. McMahon B, Godson C. Lipoxins: endogenous regulators of inflammation. Am J Physiol Renal Physiol. 2004;286(2):F189–F201. 91. Chiang N, Dalli J, Colas RA, et al. Identification of resolvin D2 receptor mediating resolution of infections and organ protection. J Exp Med. 2015;212(8):1203–1217.

92. Bannenberg GL, Chiang N, Ariel A, et al. Molecular circuits of resolution: formation and actions of resolvins and protectins. J Immunol. 2005;174(7):4345–4355. 93. Arita M, Yoshida M, Hong S, et al. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc Natl Acad Sci U S A. 2005;102(21):7671–7676. 94. Hansen TV, Vik A, Serhan CN. The protectin family of specialized pro-resolving mediators: potent immunoresolvents enabling innovative approaches to target obesity and diabetes. Front Pharmacol. 2019;9:1582. 95. Frigerio F, Pasqualini G, Craparotta I, et al. n-3 Docosapentaenoic acid–derived protectin D1 promotes resolution of neuroinflammation and arrests epileptogenesis. Brain. 2018;141(11):3130–3143. 96. Serhan CN, Yang R, Martinod K, et al. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J Exp Med. 2009;206(1):15–23. 97. Perretti M, Cooper D, Dalli J, et al. Immune resolution mechanisms in inflammatory arthritis. Nat Rev Rheumatol. 2017;13(2):87–99. 98. Norling LV, Headland SE, Dalli J, et al. Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis. JCI Insight. 2016;1(5):e85922. 99. Miles EA, Calder PC. Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. Br J Nutr. 2012;107(suppl 2):S171–S184. 100. Feehan K, Gilroy D. Is resolution the end of inflammation? Trends Mol Med. 2019;25(3):198–213. 101. Latz E, Duewell P. NLRP3 inflammasome activation in inflammaging. Sem Immunol. 2018;40:61–73. 102. Fulop T, Larbi A, Dupuis G, et al. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol. 2018;8:1960.

The complement system William H. Robinson

Key Points ■ The complement system is a key component of innate immunity that serves as a first line of defense against pathogens. ■ The complement system is involved in diverse processes, including defense against infection by microbes, interface between innate and adaptive immunity, disposal of potentially damaging immune complexes and products of inflammatory injury, and others. ■ The complement proteins are organized into three distinct proteolytic cascades: the classical, alternative, and mannose-binding lectin pathways. Although they differ in their modes of activation and target recognition, these pathways all converge on the formation of C3 and C5 convertases. ■ In health, the complement system is tightly regulated, such that it can be rapidly activated in response to infection without targeting the body’s own cells and tissues. ■ Aberrant complement activity contributes to the pathogenesis of multiple rheumatic and related diseases, including various autoimmune and chronic inflammatory diseases. ■ Multiple approaches are being developed to therapeutically supplement or target the complement system, including complement supplementation in diseases characterized by deficiencies in complement components and complement inhibition in diseases characterized by overproduction and/or excessive activation of complement.

The complement system is an essential component of innate immunity that serves as a first line of defense against pathogens. It was discovered by Jules Bordet in 1896 as a heat-labile component of fresh plasma that “complemented” the ability of antibodies to lyse red blood cells and bacteria. Today, a network of more than 30 proteins in plasma and on cell surfaces is recognized as the complement system. These proteins can be divided into three functional groups: proteins involved in complement activation, regulatory proteins for complement activation, and cell membrane–associated proteins (receptors) that interact with fragments of complement components formed during complement activation. The majority of the circulating complement proteins are produced by hepatocytes in the liver, although extrahepatic complement biosynthesis also occurs, for example, in the brain, kidney, and adipose tissue.1 Many complement plasma proteins are zymogens (proteases that become active after proteolytic cleavage) and generally circulate in a dormant state. Once activated, a complement enzyme generated by cleavage of its zymogen precursor then cleaves its substrate, another complement zymogen, to its active enzymatic form. This in turn cleaves and activates the next zymogen in the complement pathway. In this way, the activation of a small number of complement proteins at the start of the pathway is greatly amplified by each successive enzymatic reaction, resulting in the rapid generation of a disproportionately large complement response. Because of this potential for explosive activation, complement regulatory molecules exist to keep the complement cascades in check. In a healthy individual, the complement system functions to defend against infection, bridge innate and adaptive immunity, and dispose of potentially damaging immune complexes (ICs) and products of inflammatory injury.2–4 Evidence from more recent studies indicates that complement participates in such diverse processes as synapse maturation, angiogenesis, mobilization of hematopoietic stem/progenitor cells, tissue regeneration, and lipid metabolism.5 To protect the host from infection, the complement proteins, once activated by binding to pathogenic surfaces, opsonize cell membranes and soluble antigens for recognition and digestion by phagocytic cells. Other components generated during complement activation­ —that is, anaphylatoxins (C3a and C5aa)—independently generate an inflammatory response by rapidly inducing vasodilation, leukocyte activation, and chemotaxis. Further, the terminal complement components directly lyse By convention, cleaved components are designated with the letter “a” for the smaller, soluble fragment and “b” for the larger, enzymatically active fragment. a

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unencapsulated, gram-negative bacteria by creating pores in the bacterial membrane. The complement proteins are organized into three distinct proteolytic cascades, namely, the classical, alternative, and mannose-binding lectin (MBL) pathways, which differ in their mechanisms of target recognition and initial activation but converge at the cleavage of C3 and the activation of C5 (Fig. 12.1).

CLASSICAL PATHWAY The first of the three complement pathways to be discovered, the classical pathway was in fact the last to evolve and largely depends on a humoral immune response for its activity. The classical pathway is activated when the C1q component of the multimeric complement 1 complex (C1) binds to the Fc tails of multiple IgG or IgM immunoglobulins complexed to antigen in ICs. When at least two of the six C1q globular heads are bound, the remaining components of the C1 complex (two molecules each of C1r and C1s) undergo conformational changes that unleash the autocatalytic enzyme activity in C1r. Active C1r cleaves C1s to its active form.b C1s in turn cleaves soluble C4, generating C4a and C4b, and then soluble C2, generating C2a and C2b.6 C4b and C2b combine to form C4b2b, known as the C3 convertase of the classical pathway because it cleaves and thereby converts the central C3 component to C3a and C3b. C3b combines with C4b2b to form C4b2b3b (the C5 convertase of the classical pathway), which in turn cleaves and converts C5 to C5b and C5a. Subsequent assembly of C5b, C6, C7, C8, and C9 forms the membrane attack complex (MAC), creating membrane-penetrating pores in pathogens that result in cell death (note that at sublytic levels, the MAC can instead induce inflammatory signaling7). Although a portion of C3b joins with C4b2b to form the C5 convertase, the majority of C3b (as C3b or C3bi as a result of C3b fragmentation due the actions of regulatory proteins factor I and factor H) serves as an opsonin: minutes after activation of the complement cascade, hundreds to thousands of C3b molecules covalently attach to the surface of a single pathogen, thereby facilitating its phagocytosis by macrophages and neutrophils.

MANNOSE-BINDING LECTIN PATHWAY The MBL pathway evolved before the classical pathway and appears to have given rise to the latter. In contrast to the classical pathway, the MBL pathway does not require immunoglobulin for its activation; rather, it is activated through contact with mannose residues on the surface of microbes. These residues are normally inaccessible on vertebrate cells, except that in apoptotic or necrotic cells, as part of senescence, the terminal sugars on the cell surface glycoproteins can be altered and exposed as potential ligands for MBL.8,9 When a C1q-like component of the MBL complex engages mannose on a pathogen, it activates the mannose-associated serine proteases MASP-1 and MASP-2 (analogous to C1r and C1s in the classical pathway); thereafter, the MBL complex functions in an identical fashion to activated C1, cleaving C4 and C2 to form the classical C3 convertase.10

ALTERNATIVE PATHWAY The alternative pathway is unique in that its activation is not initiated by binding of recognition proteins to specific targets; instead, it continuously undergoes activation via the spontaneous hydrolysis of C3 in plasma, a phenomenon termed “tickover.” This hydrolysis is greatly accelerated by contact of C3 with various surfaces.11 Components of the complement system that are unique to the alternative pathway are factor B, factor D, and properdin.12 Tickover generates a conformationally altered C3, designated C3(H2O). Once b Complement molecules in the classical pathway are numbered in the order in which they were discovered, which in almost all cases corresponds to their place in the complement sequence, except that C4 acts before C2 but was discovered after C3.

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OVERVIEW OF COMPLEMENT CASCADE Bacterial cell

Mannose-binding lectin pathway

Classical pathway

Bacterial cell

Alternative pathway

C4

C3b Factor B

Mannose C4b C1s C4a

MASP2

MASP1

Properdin

C3b

C1r C1q C4b

Mannosebinding lectin

C2 C4b

C3b

C3 convertase

C3b

C2a Bacterial cell

Bb

Factor D C3

Ba

C2b

C3 convertase C3b

C3b C3a

C3b

C5 C5a

C1s

C5 convertase

C5b

C1r C1q C7 C3b

C3b

C6

C3b Bb

Late steps of complement activation C8

C3b C3b C6 C5b

C3b C5 convertase

C4b C2a

C6 C5b

Membrane attack complex

C7 C8 C7 C8

C3b

FIG. 12.1  Three distinct complement cascades. These include the classical, alternative, and mannose-binding lectin (MBL) pathways, which differ in their mechanisms of target recognition and initial activation but converge at the cleavage of C3 and the activation of C5. Activation of the classical pathway occurs when the C1q component of C1 (which consists of C1q, two molecules of C1r, and two molecules of C1s) binds to multiple Fc portions of IgG or IgM antibodies complexed to antigen. Binding of C1q activates C1r, which in turn cleaves C1s to its active form. C1s then cleaves soluble C4 to C4a and C4b and C2 to C2a and C2b. C4b and C2b combine to form C4b2b (the C3 convertase of the classical pathway), which cleaves C3 to C3a and C3b. C3b combines with C4b2b to form C4b2b3b (C5 convertase), which then cleaves C5 to C5b and C5a. Subsequent assembly of the C5b, C6, C7, C8, and C9 results in formation of the membrane attack complex (MAC). The MBL pathway is a primitive version of the classical pathway. When the MBL component of the MBL complex (analogous in form and function to the C1 complex) binds mannose residues on the surface of a pathogen, it activates the mannose-associated serine proteases MASP-1 and MASP-2 (akin to C1r and C1s); thereafter, the MBL complex functions as activated C1 does by cleaving C4 and C2 to form C3 convertase. The alternative pathway is initiated by the spontaneous hydrolysis of fluid-phase C3, and this spontaneous hydrolysis is greatly accelerated by contact of C3 with various surfaces. C3(H2O) binds the alternative pathway component factor B, which is then converted by the associated factor D into Ba and Bb. The C3(H2O)-Bb complex that results in an alternate C3 convertase and converts fluid-phase C3 into C3a and C3b, the latter of which is quickly inactivated by hydrolysis unless it is deposited onto a cell surface. If bound to a cell surface, however, C3b can bind factor B; factor D then cleaves factor B, thereby resulting in formation of the C3 convertase C3bBb, which is equivalent to the C3 convertase (C4b2b) of the classical and MBL pathways. (From Abeles AM, Pillinger MH, Abramson SB: Inflammation and its mediators. In: Hochberg MC, Smolen JS, Weisman MH, et al [eds]: Rheumatology, 6th Ed. Philadelphia: Elsevier, 2015, pp. 169–182; adapted from Walport MJ. Complement. First of two parts. N Engl J Med 344, 1058–1066, doi:10.1056/NEJM200104053441406 [2001].)

CHAPTER 12  The complement system factor B associates with C3(H2O), factor B itself changes conformation and can then be cleaved by the constitutively active serum protease factor D, generating Ba and Bb. The C3(H2O)-Bb complex, an alternative pathway “initiation C3 convertase,” converts fluid-phase C3 into C3a and C3b, the latter of which is quickly inactivated by hydrolysis unless it is deposited on a cell surface. Once covalently bound to a cell surface, however, C3b binds factor B; cleavage of factor B by factor D then results in formation of the membrane-associated C3bBb “amplification C3 convertase,” which is functionally equivalent to the classical C3 convertase (C4b2b). This overall series of successive proteolytic steps is enhanced by the serum protein properdin, which stabilizes protein– protein interactions during the process. Because this primitive pathway fails to distinguish “self” from “other,” its specificity resides not in any intrinsic property of foreign particles but in the ability of host cells (but not microorganisms) to defend themselves against indiscriminate complement activation (see the later section on complement regulation).

ANAPHYLATOXINS The anaphylatoxins are soluble fragments (C3a, C4a, and C5a) released during complement activation. They act on specific receptors to accelerate local inflammatory response. When produced in large amounts or injected systemically, anaphylatoxins induce a generalized circulatory collapse, producing an anaphylactic shock similar to that in a systemic allergic reaction involving IgE antibodies. Of the three anaphylatoxins, C5a is the most stable and has the highest specific biological activity. All three induce smooth muscle contraction and increase vascular permeability, but C5a and C3a also upregulate the expression of adhesion molecules on leukocytes and endothelium. The increase in vessel diameter and permeability leads to the accumulation of fluid and protein in the body. Fluid accumulation increases lymphatic drainage, bringing pathogens and their antigenic components to nearby lymph nodes. In addition, anaphylatoxins recruit immune cells to sites of complement activation and elicit oxidative bursts in macrophages, eosinophils, and neutrophils.13 C5a also activates mast cells to release mediators such as histamine and TNF that contribute to the inflammatory response.

REGULATION OF THE COMPLEMENT SYSTEM The complement system needs to be tightly regulated so that it is activated only to target pathogenic microorganisms with minimal deposition of complement proteins on the body’s healthy cells and tissues. Two features of the complement system prevent its uncontrolled activation: the activation of complement zymogens is confined to pathogen surfaces and the activated complement fragments that are produced in the ensuing cascade of reactions usually bind adjacent molecules or are rapidly inactivated by hydrolysis. In addition, regulatory proteins have evolved not only to keep in check the spontaneous “tickover” but also to constrain the activity of pathogen-activated complement cascades at different points. Interestingly, many pathogens interact with human complement regulators to evade attack by the host immune system.14 The activation of C1 is regulated by a plasma serine proteinase inhibitor or serpin, the C1 inhibitor (C1Inh). C1Ihn binds the active enzyme C1r:C1s and causes it to dissociate from C1q, which remains bound to the pathogen, thereby limiting the time during which active C1s cleaves C4 and C2. By similar means, C1Inh limits the spontaneous activation of C1 in plasma. Other complement regulatory proteins mediate protective mechanisms to minimize the formation of C3 convertase and amplification of complement activation after the binding of a small number of C3 or C4 to host cell membranes. Factor I, a plasma serine protease, circulates in active form and cleaves C3b or C4b into inactive forms when they are bound to cofactors such as CR1 or the membrane cofactor of proteolysis (MCP). Regulatory proteins such as CR1 and decay-accelerating factor (DAF) also augment the dissociation of C4b2b and C3bBb convertases in addition to their cofactor activities. In contrast to host cells, microbial surfaces lack these regulatory proteins and are vulnerable to attack by complement. Another cofactor protein for factor I is factor H, which distinguishes C3b bound to host cells or to a pathogen by the carbohydrate content of their cell membranes. Factor H has a high affinity for the terminal sialic acids of glycoproteins on the host cell membranes and binds preferentially the C3b deposited on these cells. The bound C3b is catabolized by factor I to iC3b and C3dg and complement activation is inhibited. In contrast, factor H has a much lower affinity for C3b deposited on the pathogen cell walls, and factor B binds in preference, resulting in amplification of complement activation on these cell surfaces.

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Additional regulatory proteins exist to prevent the inappropriate insertion of newly formed MACs diffused from the site of complement activation into adjacent host cell membranes. In addition to the C8β protein, which is a part of the C8 complex, a glycolipid CD59 (protectin) inhibits the binding of C9 to the C5b,6,7,8 complex and thereby its random insertion into cell membranes.

COMPLEMENT IN DISEASE A spectrum of aberrant activity of the complement system, resulting from deficiency, overproduction, or inappropriate activation of complement components or their regulators, is associated with increased susceptibility to infections, as well as with autoimmunity, chronic inflammation, thrombotic microangiopathy, graft rejection, and cancer.13 In this chapter, we focus our discussion on the roles of the complement system in rheumatic and related diseases.

COMPLEMENT IN AUTOIMMUNITY The complement system is involved in the pathogenesis of several autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), vasculitides, Sjögren’s syndrome, antiphospholipid antibody syndrome, systemic sclerosis, and dermatomyositis (Table 12.1). The relationship between the complement system and autoimmunity, however, is paradoxical. On the one hand, activation of the complement system contributes to tissue damage in autoimmune diseases; on the other hand, deficiencies in complement proteins are associated with susceptibility to autoimmunity.15 In RA, for instance, excessive complement activation is associated with the disease onset and/or augmentation of inflammation, but so are deficiencies in complement components C1q and C2.15,16 Likewise, complement activation contributes to IC-mediated inflammation and tissue damage in SLE, with histopathological findings of complement deposits correlating with clinical symptoms of the disease. Yet individuals with hereditary deficiencies in complement are prone to SLE, which develops in approximately 93% of individuals who lack C1q, 75% of those who lack C4, and up to 30% of those who lack C2. Acquired complement deficiencies, such as a reduction in C1q levels caused by autoantibody targeting of C1q or a reduction in C3 or C4 levels, are also frequently observed in SLE and thought to contribute to its pathogenesis.17 The paradoxical role of complement in autoimmune diseases may reflect the distinct functions of the different complement components.3 Factors derived from C3, or components downstream of C3, in the complement cascade may trigger or promote cell and tissue damage, whereas initial development of the disease is likely influenced by deficiencies in the initiating components of the classical pathway. How aberrant complement activity contributes to autoimmune disease is not entirely clear, but this process may involve impaired scavenging of autoantigens, abnormal tolerance induction, inefficient clearance of ICs and apoptotic cells, as well as changes in cytokine regulation (Fig. 12.2).3,49,50

COMPLEMENT IN INFLAMMATORY DISEASES The complement system has been associated with inflammatory diseases. For example, hereditary or acquired deficiencies in complement regulatory proteins result in inflammatory conditions: deficiency of the C1q inhibitor protein leads to undue complement activity under metabolic stress and the development of intermittent and potentially life-threatening angioedema. In OA, a multifactorial disorder that involves low-grade, chronic inflammation, multiple lines of evidence from human and murine studies indicate a central role for complement in disease pathogenesis.7 Complement and immunoglobulin deposits are present in the cartilage and synovium of individuals with OA.51,52 This complement deposition may result from local overproduction or hyperactivation of complement or both. Chondrocytes can produce complement components,53 and human OA synovium expresses abnormally high levels of complement effectors and abnormally low levels of complement inhibitors.7 Additionally, damage-associated molecular patterns present in OA joints, such as cartilage extracellular matrix proteins, calcium crystals, and components of apoptotic debris, have been shown to bind and activate complement.54–59 Complement activity in the joint has an important role in OA pathology, as suggested by findings from mouse studies: deficiency in complement components C5 or C6 attenuated a mouse model of OA, whereas deficiency in CD59a (a protein that inhibits the formation and hence activity of MAC60) worsened it.7 Further, evidence suggests that cartilage breakdown products such as fibromodulin can induce activation of the complement system in OA joints.7

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SECTION 1  Scientific Basis of Rheumatic Disease

Table 12.1

Associations Between Complement Components and Rheumatic (and Related) Diseases Disease

Complement Components Associated With Disease

Rheumatic and other diseases

Atypical hemolytic-uremic syndrome (aHUS) ANCA-associated vasculitis Antiphospholipid syndrome Autoimmune hemolytic anemia (AIHA) Behçet disease C3 glomerulopathy and membranoproliferative glomerulonephritis (MPGN) Dermatomyositis and polymyositis Hypocomplementemic urticarial vasculitis syndrome (HUVS) IgA nephropathy Osteoarthritis Paroxysmal nocturnal hemoglobinuria (PNH) Psoriatic arthropathy Rheumatoid arthritis Sjögren’s syndrome Systemic lupus erythematosus (SLE) and lupus nephritis Shiga toxin-producing Escherichia coli associated HUS (STEC-HUS) Thrombotic microangiopathy (TMA) Thrombotic thrombocytopenic purpura (TTP)

C3, factor H, MCP, factor I, factor B, complement factor H-related proteins, thrombomodulin18 Alternative pathway C3, C4, C5 C3a, C4a, MAC19,20 Complement-mediated mechanism varies depending on the type of AIHA21 C3, C43,22 C3, alternative pathway23,24 C3b, C4b, MAC3 C1q3 Alternative and MBL pathways25 Classical pathway, alternative pathway, MAC7 Alternative pathway, CD55, CD5926 C3, C427 C1q, C3, C4, C1Inh-C1r-C1s complexes, C2a, C3a, C3d, C3dg, C5a, C3aR, C5aR, MAC3 C4A, C4BP3 C1q, C1r, C1s, C2, C3, C4, MBL, factor D3 Alternative pathway through C5b-9 assembly28 See aHUS, STEC-HUS, and TTP C3, C5b-9 complex28

Related diseases

Anaphylaxis Asthma Atherosclerosis Chronic obstructive pulmonary disease (COPD) Crohn’s disease and ulcerative colitis Dementia Diabetic angiopathy Glaucoma Guillain-Barré syndrome Hereditary angioedema Macular degeneration Mood disorders Multiple sclerosis Myasthenia gravis Neuromyelitis optica Pemphigus and pemphigoid Sepsis and acute respiratory distress syndrome (ARDS) Transplant rejection Uveitis

C3a29 C3a, C5a30,31 C332 C5a33 MBL pathway34 C1q, C3, C4, C5b-935 MBL pathway, C3, C4, C5, MAC36 C1qa, C537 Complement-fixing antibodies38 C1Inh39 Factor H, Factor I40 Classical and MBL pathways41 Alternative pathway42 Classical pathway43 Classical pathway44 Classical and alternative pathways45 All three pathways46 C3, C547 C448

ANCA, Antineutrophil cytoplasmic antibody; MAC, membrane attack complex; MBL, mannose-binding lectin.

STRATEGIES FOR THERAPEUTICALLY TARGETING COMPLEMENT With important roles in the pathogenesis of rheumatic and related diseases, the complement system is an attractive therapeutic target. Currently, only a few complement-targeting therapies are approved, but many more are being developed.3,61 The main goals of such therapies are to reconstitute complement function in complement-deficient states and to inhibit complement activation in diseases with overproduction and/or excess activation, as well as to strengthen the defense against certain infections and improve antibody responses to vaccines.3 Several characteristics make the complement system amenable to therapeutic targeting at many levels: its proteolytic cascades involve specific proteases, unique multimolecular activation and lytic complexes, a plethora of natural inhibitors, and numerous receptors that bind to activation fragments.61 Supplementation of complement components has been attempted in various deficiency syndromes.3 C1Inh concentrate is now licensed in many countries to correct deficiency of this protein. Plasma-derived or recombinant MBL may be beneficial in patients deficient in MBL.62 Clinical improvements have been reported in individuals with C1q or C2 deficiency who were treated with regular infusions of plasma. Another possible method for complement supplementation in C1q deficiency is stem cell transplantation,63 as C1q is mainly produced by bone marrow–derived mononuclear cells.

A large number of anticomplement drugs have also been developed, such as antibodies that target complement components. However, inhibiting complement components runs the risk of blocking important physiological functions of the complement system, such as defending against infections. To minimize these risks, strategies that specifically target late complement componentsc or deliver the drug locally or transiently have led to the successful development of pharmacologic complement inhibitors such as eculizumab, a humanized monoclonal anti-C5 antibody approved for paroxysmal nocturnal hemoglobinuria. Nevertheless, several hurdles to development of new complement therapeutics remain, such as risk for infections and autoimmunity, cost, and routes of administration, particularly in the use of anticomplement drugs in chronic conditions. Additionally, for patients with complement deficiencies (e.g., SLE) who are at risk for infections, immunization has been an effective approach to the prevention of infections.3,64 Conversely, vaccination against complement components may be an option in preventing inflammatory rheumatic disorders that are dependent on aberrant complement activation, such as those involving the anaphylatoxin C5a and its receptor C5aR.65 c The only infection risk of targeting late complement components would be from Neisseria species (bacteria that cause the sexually transmitted disease gonorrhea and a common form of bacterial meningitis), as deficiencies in complement components C5–C9 have been associated with susceptibility only to these species.

CHAPTER 12  The complement system MECHANISMS BY WHICH BOTH OVERPRODUCTION OR EXCESSIVE ACTIVATION AND DEFICIENCY OF THE COMPLEMENT SYSTEM CAN CONTRIBUTE TO THE PATHOGENESIS OF SLE Environmental factors (e.g., UV light, virus)

Apoptosis Impaired scavenging Autoantigens

I

SLE Activation of classical pathway Amplification of alternative pathway

gu sre

d

ire

a mp

n

ce

ran

a cle

Dy

Autoantibodies ICs

to

lati o

Impaired

Aberrant complement activities

lerance

Cytokines

Complement consumption

Tissue damage

FIG. 12.2 Mechanisms by which both overproduction or excessive activation and deficiency of the complement system can contribute to the pathogenesis of SLE. Apoptosis of cells, caused by environmental insults such as UV exposure or viral infections, results in the extracellular release of components that are normally intracellular and thus hidden from the body’s immune system. In genetically predisposed individuals, some of these newly exposed components are recognized as foreign by the immune system, serving as autoantigens that elicit the generation of autoantibodies and ICs. The ensuing sustained autoimmune reaction results in SLE, characterized by inflammation and tissue damage in multiple organs. The classical and alternative complement pathways are critical mediators of this inflammation and tissue damage, including the glomerulonephritis characteristic of SLE. Aberrant complement activity, caused by either genetic deficiencies or excessive activation and consumption of complement, can contribute to SLE pathogenesis on multiple levels. It can impair several protective processes that normally dampen autoimmune responses—for example, the scavenging of autoantigens, immune tolerance to autoantigens, and clearance of autoantibodies and ICs—as well as trigger the production of cytokines, such as interferon, that have been implicated in the pathogenesis of SLE. The tissue damage provokes further inflammation, additional complement aberrations, and possibly the generation of additional autoantigens, establishing a vicious cycle that prevents termination of the disease process. IC, Immune complex; SLE, systemic lupus erythematosus; UV, ultraviolet. (Adapted from Sturfelt, G, Truedsson, L. Complement in the immunopathogenesis of rheumatic disease. Nat Rev Rheumatol 8, 458–468, doi:10.1038/nrrheum.2012.75 [2012].3.)

CONCLUSIONS The complement system is a key component of the innate immune systems defense against invading microbes and altered host cells. The complement system is crucial to the health of the host, with both deficiencies and overproduction or excess activation of complement proteins contributing to the pathogenesis of many diseases. Our increasing understanding of the complex roles of complement in health and disease is leading to the development of therapeutic interventions that target the complement system and that are anticipated to provide new approaches for the treatment of rheumatic diseases.

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5. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785–797. 6. Arlaud GJ, et al. Structural biology of the C1 complex of complement unveils the mechanisms of its activation and proteolytic activity. Mol Immunol. 2002;39:383–394. 7. Wang Q, et al. Identification of a central role for complement in osteoarthritis. Nat Med. 2011 8. Nauta AJ, et al. Mannose-binding lectin engagement with late apoptotic and necrotic cells. Eur J Immunol. 2003;33:2853–2863. 9. Ip WK, Takahashi K, Ezekowitz RA, Stuart LM. Mannose-binding lectin and innate immunity. Immunol Rev. 2009;230:9–21. 10. Fujita T, Matsushita M, Endo Y. The lectin-complement pathway—its role in innate immunity and evolution. Immunol Rev. 2004;198:185–202. 11. Nilsson B, Nilsson Ekdahl K. The tick-over theory revisited: is C3 a contact-activated protein? Immunobiology. 2012;217:1106–1110. 12. Thurman JM, Holers VM. The central role of the alternative complement pathway in human disease. J Immunol. 2006;176:1305–1310. 13. Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement system part I— molecular mechanisms of activation and regulation. Front Immunol. 2015;6:262. 14. Lindahl G, Sjobring U, Johnsson E. Human complement regulators: a major target for pathogenic microorganisms. Curr Opin Immunol. 2000;12:44–51. 15. Ballanti E, et al. Complement and autoimmunity. Immunol Res. 2013;56:477–491. 16. Mizuno M. A review of current knowledge of the complement system and the therapeutic opportunities in inflammatory arthritis. Curr Med Chem. 2006;13:1707–1717. 17. Bajic G, Degn SE, Thiel S, Andersen GR. Complement activation, regulation, and molecular basis for complement-related diseases. EMBO J. 2015;34:2735–2757. 18. Waters AM, Licht C. aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol. 2011;26:41–57. 19. Lim W. Complement and the antiphospholipid syndrome. Curr Opin Hematol. 2011;18:361–365. 20. Samarkos M, Mylona E, Kapsimali V. The role of complement in the antiphospholipid syndrome: a novel mechanism for pregnancy morbidity. Semin Arthritis Rheum. 2012;42:66–69. 21. Berentsen S. Role of complement in autoimmune hemolytic anemia. Transfus Med Hemother. 2015;42:303–310. 22. Kose AA. Direct immunofluorescence in Behcet’s disease: a controlled study with 108 cases. Yonsei Med J. 2009;50:505–511. 23. Bomback AS, Appel GB. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat Rev Nephrol. 2012;8:634–642. 24. Cook HT, Pickering MC. Histopathology of MPGN and C3 glomerulopathies. Nat Rev Nephrol. 2015;11:14–22. 25. Maillard N, et al. Current understanding of the role of complement in IgA nephropathy. J Am Soc Nephrol. 2015;26:1503–1512. 26. DeZern AE, Brodsky RA. Paroxysmal nocturnal hemoglobinuria: a complement-mediated hemolytic anemia. Hematol Oncol Clin North Am. 2015;29:479–494. 27. Chimenti MS, et al. Immunomodulation in psoriatic arthritis: focus on cellular and molecular pathways. Autoimmun Rev. 2013;12:599–606. 28. Noris M, Mescia F. Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol. 2012;8:622–633. 2 9. Munoz-Cano R, Picado C, Valero A, Bartra J. Mechanisms of anaphylaxis beyond IgE. J Investig Allergol Clin Immunol. 2016;26:73–82. quiz 72p following 83. 30. Khan MA, Nicolls MR, Surguladze B, Saadoun I. Complement components as potential therapeutic targets for asthma treatment. Respir Med. 2014;108:543–549. 31. Zhang X, Kohl J. A complex role for complement in allergic asthma. Expert Rev Clin Immunol. 2010;6:269–277. 32. Hertle E, Stehouwer CD, van Greevenbroek MM. The complement system in human cardiometabolic disease. Mol Immunol. 2014;61:135–148. 33. Marc MM, et al. Complement factors c3a, c4a, and c5a in chronic obstructive pulmonary disease and asthma. Am J Respir Cell Mol Biol. 2004;31:216–219. 34. Reichhardt MP, Meri S. SALSA: A Regulator of the early steps of complement activation on mucosal surfaces. Front Immunol. 2016;7:85. 35. Sardi F, et al. Alzheimer’s disease, autoimmunity and inflammation. The good, the bad and the ugly. Autoimmun Rev, 2011;11:149–153. 36. Flyvbjerg A. Diabetic angiopathy, the complement system and the tumor necrosis factor superfamily. Nat Rev Endocrinol. 2010;6:94–101. 37. Soto I, Howell GR. The complex role of neuroinflammation in glaucoma. Cold Spring Harb Perspect Med. 2014;4 38. Winer JB. An update in guillain-barre syndrome. Autoimmune Dis. 2014;2014(793024). 39. Triggianese P, et al. The autoimmune side of hereditary angioedema: insights on the pathogenesis. Autoimmun Rev. 2015;14:665–669. 40. van Lookeren Campagne M, Strauss EC, Yaspan BL. Age-related macular degeneration: complement in action. Immunobiology. 2016;221:733–739. 41. Mayilyan KR, Weinberger DR, Sim RB. The complement system in schizophrenia. Drug News Perspect. 2008;21:200–210. 42. Ingram G, Hakobyan S, Robertson NP, Morgan BP. Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin Exp Immunol. 2009;155:128–139. 43. Huda R, Tuzun E, Christadoss P. Targeting complement system to treat myasthenia gravis. Rev Neurosci. 2014;25:575–583. 44. Papadopoulos MC, Bennett JL, Verkman AS. Treatment of neuromyelitis optica: state-of-theart and emerging therapies. Nat Rev Neurol. 2014;10:493–506. 45. Lessey E, Li N, Diaz L, Liu Z. Complement and cutaneous autoimmune blistering diseases. Immunol Res. 2008;41:223–232. 46. Rittirsch D, Redl H, Huber-Lang M. Role of complement in multiorgan failure. Clin Dev Immunol. 2012;2012(962927). 47. Sacks SH, Zhou W. The role of complement in the early immune response to transplantation. Nat Rev Immunol. 2012;12:431–442.

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48. Hou S, Kijlstra A, Yang P. Molecular genetic advances in uveitis. Prog Mol Biol Transl Sci. 2015;134:283–298. 49. Barilla-LaBarca ML, Atkinson JP. Rheumatic syndromes associated with complement deficiency. Curr Opin Rheumatol. 2003;15:55–60. 50. Truedsson L, Bengtsson AA, Sturfelt G. Complement deficiencies and systemic lupus erythematosus. Autoimmunity. 2007;40:560–566. 51. Cooke TD, Bennett EL, Ohno O. The deposition of immunoglobulins and complement in osteoarthritic cartilage. Int Orthop. 1980;4:211–217. 52. Corvetta A, et al. Terminal complement complex in synovial tissue from patients affected by rheumatoid arthritis, osteoarthritis and acute joint trauma. Clin Exp Rheumatol. 1992;10:433–438. 53. Bradley K, et al. Synthesis of classical pathway complement components by chondrocytes. Immunology. 1996;88:648–656. 54. Happonen KE, et al., Regulation of complement by COMP allows for a novel molecular diagnostic principle in rheumatoid arthritis. Arthritis Rheum, doi:10.1002/art.27720 55. Sjoberg A, Onnerfjord P, Morgelin M, Heinegard D, Blom AM. The extracellular matrix and inflammation: fibromodulin activates the classical pathway of complement by directly binding C1q. J Biol Chem. 2005;280:32301–32308. 56. Sjoberg AP, et al. Short leucine-rich glycoproteins of the extracellular matrix display diverse patterns of complement interaction and activation. Mol Immunol. 2009;46:830–839.

57. 58. 59. 60. 61. 62. 63. 64. 65.

Moreth K, Iozzo RV, Schaefer L. Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation. Cell Cycle. 2012;11:2084–2091. Rosenthal AK. Crystals, inflammation, and osteoarthritis. Curr Opin Rheumatol. 2011;23:170–173. Sofat N. Analysing the role of endogenous matrix molecules in the development of osteoarthritis. Int J Exp Pathol. 2009;90:463–479. Kemper C, Atkinson JP. T-cell regulation: with complements from innate immunity. Nat Rev Immunol. 2007;7:9–18. Morgan BP, Harris CL. Complement, a target for therapy in inflammatory and degenerative diseases. Nat Rev Drug Discov. 2015;14:857–877. Garred P, et al. Mannose-binding lectin (MBL) therapy in an MBL-deficient patient with severe cystic fibrosis lung disease. Pediatr Pulmonol. 2002;33:201–207. Olsson RF, et al. Allogeneic hematopoietic stem cell transplantation in the treatment of human C1q deficiency: the Karolinska experience. Transplantation. 2016;100:1356–1362. Barber C, Gold WL, Fortin PR. Infections in the lupus patient: perspectives on prevention. Curr Opin Rheumatol. 2011;23:358–365. Nandakumar KS, et al. A recombinant vaccine effectively induces c5a-specific neutralizing antibodies and prevents arthritis. PLoS One. 2010;5:e13511.

Osteoimmunology Georg Schett • Aline Bozec

Key Points ■ Osteoimmunology describes the impact of the immune system and inflammation on bone homeostasis. ■ Inflammatory cytokines trigger an imbalance of bone metabolism in favor of bone resorption. ■ Autoantibodies and immune complexes induce osteoclast differentiation. ■ Inflammatory arthritis is characterized by local and systemic bone loss associated with bone erosion and enhanced fracture risk. ■ The bone marrow microenvironment regulates immune cell differentiation, allowing for feedback from bone to the immune system.

INTRODUCTION Inflammatory rheumatic diseases typically develop through two major events. The first key event is immune activation, which is a central component of many forms of rheumatic disease. This robust and often chronic activation of both the innate and adaptive immune system is regarded as a central triggering factor for inflammatory rheumatic diseases and is sometimes also associated with the break of immune tolerance and autoantibody formation, as well as the accumulation of cells of the adaptive immune system at sites of inflammation. The second key event is that inflammation leads to disturbances that affect musculoskeletal tissue, the common target of rheumatic diseases. Indeed, progressive local and systemic damage to bone is an important determent of the functional impairment and high disease burden in rheumatic diseases. Thus, the combination of chronic immune system activation and bone damage is the hallmark of rheumatic diseases. Detailed understanding of the pathophysiologic processes of rheumatic diseases requires clarification of the mutual interactions between the immune and skeletal systems. These interactions are elucidated through studies in the field of osteoimmunology.

CURRENT CONCEPTS IN OSTEOIMMUNOLOGY Osteoimmunology is a field of research that focuses on the crosstalk between the immune and musculoskeletal systems.1 This field is particularly relevant for understanding rheumatic diseases, which are characterized by profound alterations in bone architecture as a consequence of activation of the immune system. The term osteoimmunology was created after landmark observations in the late 1990s demonstrating that T lymphocytes trigger bone loss by inducing the differentiation of the bone-resorbing cells, termed osteoclasts.2–4 These observations placed the immune system and bone as two closely interacting systems. Current concepts of osteoimmunology that are of relevance for rheumatology include (1) regulation of bone degradation by the immune system, (2) the interaction between inflammation and bone formation, and (3) the role of bone and bone marrow as a niche for immune cells. The first concept, immune-mediated regulation of bone loss, has been studied intensively in recent years and has become a well-developed concept that is instrumental in understanding the different forms of bone loss in the course of rheumatic diseases. In contrast, the second concept, interactions between inflammation and bone formation, is much less developed but is important for defining the mechanisms of repair of structural damage in the joint, as well as for explaining the pathophysiology of bony ankylosis. Similarly, the third concept, the role of the bone marrow niche, is actively being investigated and is particularly relevant to understand the dysregulation of immune cell trafficking during inflammatory diseases (i.e., the triggers for recruitment of immune cells from bone marrow into inflammatory sites) and to explain the formation of a stable microenvironment that allows longevity and antibody production by long-lived plasma cells. These three concepts are discussed in this chapter.

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OSTEOCLASTS AS TRIGGERS OF ARTHRITIC BONE EROSIONS Erosion of periarticular bone is a central feature of rheumatoid arthritis (RA) and psoriatic arthritis (PsA).5,6 Bone erosion reflects the damage triggered by chronic inflammation. Visualization of bone erosions by imaging techniques is important not only for the diagnosis of RA but also for defining the severity of disease and response to antirheumatic therapy.7 Osteoclasts are bone-specialized macrophages and are the only cell type capable of removing calcium from bone and, consequently, degrading bone matrix. Postnatal maintenance of osteoclasts is accomplished by iterative fusion of circulating blood monocytes with long-lived osteoclast syncytia.8 This bone-resorbing function is an essential component of the bone-remodeling process that allows not only normal bone development and skeletal growth but also bone maintenance and repair throughout life. Osteoclasts are also required for the bone erosions observed in rheumatic joints. Indeed, osteoclasts are localized at the interface of the inflamed synovial tissue and bone in human RA and PsA and are present in all major experimental models of arthritis. Preliminary evidence for the presence of osteoclasts in the synovial tissue of patients with RA was gathered in the 1980s.9 Gravallese and colleagues first described that mature osteoclasts are localized at the site of bone erosions in RA joints by using modern molecular tools for characterization of these cells.10 Later, the essential function of osteoclasts in triggering inflammatory bone erosions was shown by blocking molecules required for osteoclastogenesis or by using mice deficient in osteoclasts.11,12 In all of these models, despite the presence of synovial inflammation, bone erosions did not occur when either osteoclast differentiation was effectively blocked or osteoclasts were genetically depleted. These findings clearly identified osteoclasts as the effector cells for bone erosion and structural damage downstream of inflammation in affected joints.

MOLECULAR AND CELLULAR MECHANISMS OF INFLAMMATORY BONE EROSION What are the mechanisms leading to osteoclast formation in inflamed joints because these cells are not usually present in the joints? Two key mechanisms are essential to form osteoclasts in joints: (1) accumulation of osteoclast precursor cells in the synovium and (2) stimulation of their differentiation into osteoclasts. Osteoclast precursors are mononuclear cells belonging to the monocyte/macrophage lineage.13 Early monocytic precursor cells have the potential to differentiate into macrophages, dendritic cells, osteoclasts, and other organ-specific cell lineage types such as Kupffer cells in the liver or microglia in the brain. It is not fully clear whether some monocytes entering an inflamed joint are already committed to the osteoclast lineage or whether monocytes “decide” locally within the inflamed synovium to differentiate to the osteoclast lineage on receiving the appropriate signals. Nonetheless, experimental evidence supports the observation that the peripheral pool of monocytes changes during inflammation. For instance, the fraction of CD11b+ cells that serve as osteoclast precursors increases, thus suggesting that an increased number of cells entering the joint can differentiate into osteoclasts.14 This concept is in line with the aforementioned physiological maintenance of osteoclasts by circulating bone marrow-derived monocytes.8 Moreover, cytokines such as tumor necrosis factor (TNF) induce the expression of receptors on the monocyte surface, such as osteoclast-associated receptor (OSCAR), that are important for osteoclast differentiation.15 Much less is known about the mechanisms that negatively regulate the differentiation of monocytes into osteoclasts. One such mechanism is the binding of CTLA4, a negative regulator of T-cell costimulation to CD80 and Cd86 on the surface of monocytes, which effectively blocks osteoclast differentiation.16,17 This could link regulatory T cells that express high levels of CTLA4 on their surfaces to bone homeostasis because these cells can suppress osteoclast formation independent of receptor activator of nuclear factor κB (NF-κB) ligand (RANKL), which is one of the major regulators of osteoclast differentiation. 115

SECTION 1  Scientific Basis of Rheumatic Disease

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The second mechanism is that monocytic osteoclast precursors that have already entered the inflamed joints find the ideal environment there to further differentiate into osteoclasts because of the presence of RANKL and monocyte colony-stimulating factor (M-CSF/CSF-1), essential stimulating signals for osteoclastogenesis. Both factors are also involved in the activation of mature osteoclasts (Fig. 13.1). M-CSF, which binds to CSF-1R encoded by the proto-oncogene C-FMS, promotes both proliferation and survival of osteoclast precursors. RANKL binds the surface receptor RANK on precursor cells, inducing signaling essential for osteoclast differentiation via NF-κB and the activator protein 1 (AP-1) transcription factor family.2,3 In the joint, this process requires crosstalk with other cells, particularly fibroblast-like synoviocytes and activated T cells.18,19 Among T cells, both type 1 and type 17 helper subsets are of importance in this process. Indeed, both cell types can be induced to express RANKL.3,20 This essential osteoclastogenic cytokine is expressed in the synovium of patients with RA, thus suggesting that it actively contributes to formation of osteoclasts in the synovium.18,19 A high level of RANKL expression in the synovium is apparently not balanced by the expression of regulatory molecules such as osteoprotegerin (OPG), a decoy receptor of RANKL that blocks osteoclast formation,21 indicating that this imbalance is of importance in the process of articular erosion in RA. This concept is supported by data obtained from animal models of arthritis, showing effective protection from structural damage by blocking RANKL with OPG (despite clear synovial inflammation) and by recent clinical data showing that an antibody directed against RANKL (denosumab) protects against the progression of bony structural damage in patients with RA.22,23 In addition to RANKL, the osteoclastogenic properties of the inflamed synovial membrane are further enhanced by expression of M-CSF, which is essential for osteoclast formation as well.24 Moreover, proinflammatory cytokines such as TNF, interleukin-1 (IL-1), IL-6, IL-17, and vascular endothelial growth factor (VEGF) are all potent inducers of RANKL expression and thus enhance osteoclast differentiation. Some of these cytokines additionally exert direct effects on osteoclast precursors; in particular, TNF engages TNF receptor type I on the surface of osteoclast precursors, augmenting their differentiation into osteoclasts.25 This link between proinflammatory cytokines and osteoclast formation is likely the explanation for the observation that cytokine-targeted therapy, particularly blockade of TNF, is highly effective in retarding the structural damage in RA. Indeed, TNF-blocking agents virtually arrest the radiographic damage in RA and are considered excellent

OSTEOCLAST FORMATION IN THE JOINT

TH1 and TH17 TNF-α, IL-6 IL-1, IL-17

M-CSF RANKL

Osteoblast

Fibroblasts

Bone

Osteoclast precursors (monocytes) Osteoclast

T reg

Preosteoclast

FIG. 13.1  Monocytic cells in the synovium serve as osteoclast precursors. On exposure to monocyte colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL) synthesized by T cells and synovial fibroblasts, monocytes fuse to polykaryons, termed preosteoclasts, which then undergo further differentiation into mature osteoclasts and acquire specific features such as the ruffled membrane. Inflammatory cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, and IL-17, increase the expression of RANKL and thus support osteoclastogenesis in the joint while inhibiting systemic bone formation by the osteoblasts. In contrast, regulatory T cells (T regs) block osteoclast formation via CTLA4.

agents for achieving structural protection of joints.26–31 Apart from anti-TNF agents, a similar effect of IL-6 receptor inhibition has been observed in addition to its well-established antiinflammatory effect.32 These results are predictable, because IL-6, similar to TNF, drives RANKL expression and hence supports osteoclastogenesis.33,34 Aside from proinflammatory cytokines, anticitrullinated protein antibodies (ACPAs), as well as immune complexes, have been identified as important factors for osteoclast differentiation and bone loss. Importantly, immunoreceptor tyrosine-based activation motif (ITAM) stimulation through binding of antibodies to Fc receptors has been shown to cooperate with RANKL for osteoclast activation.35 ACPAs are among the strongest predictors of bone-erosive disease in RA, thus linking autoantibody response in RA to the ability of the disease to elicit structural bone damage. Recently, autoantibodies against citrullinated vimentin have been reported to bind to osteoclasts, induce their differentiation into bone-resorbing cells, and promote bone loss. This effect was based on the inducible release of TNF and IL-8 from osteoclast precursors upon stimulation by anticitrullinated vimentin antibodies.36,37 In addition, immune complexes including rheumatoid factor can trigger osteoclast differentiation upon binding to high-affinity Fc receptors and induce osteoclast formation via Syk activation. This process has been shown to depend on the sialylation profile of these immunoglobulins, which determines Fc-receptor binding.38,39 Low levels of sialylation of immunoglobulins, which result from a cytokine milieu driven by IL-23, enhance osteoclast formation and bone loss.40 Once osteoclasts are formed upon stimulation of cytokine receptors and Fc-receptors, these cells start to widen preexisting bone channels that cross the cortical bone. Such channels permit blood vessels to cross cortical bone (trans-cortical vessels, TCVs) and thereby grant the access of bloodborne osteoclasts to the inner part of cortical bone.41 The widening of such TCVs is the first step toward a radiographic bone erosion.42 While TCVs with a diameter of 20 microns cannot be visualized even with high-resolution computed tomography scanners in vivo, their widened forms, so-called cortical micro-channels (CoMiCs), can be seen as early as in patients with pre-RA and predict the onset of the disease.43

INTRAARTICULAR AND SYSTEMIC BONE LOSS IN RHEUMATIC DISEASE Intraarticular bone loss was formerly referred to as “periarticular bone loss” or “periarticular osteoporosis” and has been long known as an early radiographic sign of RA. This form of bone loss has been explained by the paracrine effects of inflammatory cytokines on the juxtaarticular bone. However, the mechanisms of “periarticular bone loss” have been poorly defined until recently. In fact, the term periarticular bone loss is incorrect because the juxtaarticular bone affected during arthritis is localized inside the joint capsule; hence, the term intraarticular bone loss more correctly describes the anatomical features of this form of skeletal pathology in arthritis.44 Because of its intraarticular localization, bone is directly exposed to the inflammatory milieu of arthritis. Intraarticular bone loss is caused by a substantial decrease in bone trabeculae along the metaphyses of bones close to inflamed joints, suggesting that the bone marrow cavity along inflamed joints is also part of the disease process of arthritis. This is supported by data from magnetic resonance imaging (MRI) studies in patients with RA that have indicated a high frequency of signal alteration in the juxtaarticular bone marrow in addition to synovitis outside the cortical bone barrier.45,46 These lesions are rich in water with a low fat content, suggesting that bone marrow fat is locally replaced by water-rich tissue. Histologic examination of bone marrow lesions has been carried out in joints of patients with advanced-stage RA undergoing joint replacement surgery. They have revealed that the bone marrow lesions visualized on MRI contain water-rich, vascularized inflammatory infiltrates that replace bone marrow fat and harbor aggregates of B cells and T cells. Importantly, very similar MRI changes are found early in the disease process of RA and have been shown to be a predictor of subsequent bone erosions in these same joints.47 Bone marrow lesions are often linked to cortical penetration of inflammatory tissue either by means of bone erosions or by small cortical bone channels that connect the synovium with the juxtaarticular bone marrow. Moreover, bone marrow lesions are associated with an endosteal bone response because they coincide with the accumulation of osteoblasts and deposition of bone matrix in the endosteum.48 These novel data have enhanced our view of arthritis as a disease that is confined not solely to the synovial membrane but also to bone marrow. It has long been known that inflammatory diseases, including RA, PsA, and ankylosing spondylitis (AS), lead to osteoporosis and increased fracture risk. Data obtained in recent years have supported this concept and have

CHAPTER 13 Osteoimmunology shed light on the mechanisms of osteoporosis and fracture risk in patients with RA. Architectural changes of cortical and trabecular bone resulting in osteopenia and osteoporosis are frequently observed in patients with RA49 and are even observed in rather high frequency before any disease-modifying antirheumatic drug or glucocorticoid therapy is initiated. Roughly 25% of patients with RA have osteopenic bone mineral density at the spine or hip before the onset of therapy in early RA, and 10% have osteoporosis, thus suggesting that this bone loss is an intrinsic component of the disease.50 Consequently, patients with RA are at high risk for the development of complications from systemic bone loss because of the increased prevalence of low bone mass at the onset of disease. This risk is compounded by the presence of standard risk factors for osteoporosis, including older age and female sex. In addition, there is the possibility that low-grade inflammation often long precedes the onset of clinical symptoms of RA. Indeed, independent population-based studies have shown that even a small elevation in C-reactive protein as a sign of low-grade inflammation in the normal healthy population dramatically increases the risk for fractures.51 Fracture risk is in fact higher in patients with RA, an observation that has been confirmed by a recent meta-analysis of nine prospective population-based cohorts in which it was shown that fracture risk doubles with the diagnosis of RA, independent of whether glucocorticoids are used.52 Similarly, a large case-control study based on the British General Practice Research Database has shown that RA doubles the risk for hip and vertebral facture, which clearly supports the concept that inflammation is an independent risk factor for osteoporosis.53

OSTEOIMMUNOLOGIC ASPECTS OF BONE FORMATION IN RHEUMATIC DISEASE To gain a balanced view of the interaction between the immune system and bone, it is important to better define how activation of the immune system controls bone formation. Inflammatory arthritis induces profound changes in joint architecture that cover the spectrum from an almost purely erosive disease (e.g., RA) to a disease with a mixed pattern of bone erosion and formation (e.g., PsA) to one with a prominent bone-forming pattern (AS). Regulation of bone formation thus becomes an important aspect of osteoimmunology in rheumatic diseases. In RA, there is little sign of repair of bone erosions, a fact that is astonishing considering that bone formation is usually coupled to bone resorption and that an increased rate of bone resorption should increase bone formation. This, however, is not the case in RA. Bone formation seems to be actively suppressed by inflammation. The suppressive role of inflammation on bone formation is embedded in immune responses to infection, as it has been shown that cytosolic DNA sensors, which detect microbial DNA and promote type I interferon (IFN) release, can regulate bone formation.54 Interestingly, TNF potently suppresses bone formation by enhancing the expression of Dickkopf-1 (DKK1), a protein that negatively regulates the wingless/int (Wnt) signal transduction pathway.55 Similarly, IL-6 has been shown to actively suppress bone formation. This notion is supported by repair of erosions of RA patients in the context of IL-6 receptor (IL-6R) inhibition by tocilizumab or IL-6R signaling by Janus kinase inhibitors.56,57 As effector molecules of bone formation, Wnt ligands enhance the differentiation of bone-forming osteoblasts from their mesenchymal precursors. Wnt proteins are also involved in the regulation of osteoclastogenesis because they enhance the expression of OPG, which blocks osteoclast formation.58 Thus, influencing the balance of Wnt proteins and their inhibitors is a very potent strategy for disturbing bone homeostasis: Whereas a low level of Wnt activity yields low bone formation and high bone resorption, a high level of Wnt activity increases bone formation and simultaneously blocks bone resorption. In RA, the former scenario appears to be at play because bone resorption is increased and bone formation is decreased. Inhibitors of the Wnt pathway, such as DKK1 and SFRP family members,55,59 are expressed in the synovial tissue in animal models of RA, and DKK1 has been shown to be expressed in patients with RA, thus suggesting a suppressive effect on bone formation. This concept is further supported by the paucity of fully differentiated osteoblasts within arthritic bone erosions and the lack of bone formation occurring in these lesions.60 Pure degradation of bone during arthritis is the exception rather than the rule in joint disease. PsA, AS, osteoarthritis, and metabolic arthropathies such as hemochromatotic arthropathy are partly or even predominantly characterized by bony spurs along joints and intervertebral spaces. These lesions result from new bone formation. We have recently reported that therapies blocking bone erosions, such as TNF inhibitors, do not influence the formation of osteophytes or syndesmophytes.61 Areas prone to osteophyte formation are (1) periarticular sites of the periosteum in the vicinity of the articular cartilage, (2) edges of vertebral bodies, and (3) the insertion

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sites of tendons. These sites are particularly rich in fibrocartilage, which is ­considered to be the tissue from which osteophyte formation emerges, given the interplay of local triggering factors.62 Triggers include mechanical factors because osteophytes often emerge at entheses along the insertion sites of the tendons.63 IL-17 and IL-23 have been identified as crucial mediators of enthesitis and hence may play a role in new bone formation around the entheses in diseases such as PsA and AS.64–66 In particular, the role of IL-17 on bone is interesting in this context: While IL-17 increases bone resorption66 and inhibits bone formation at the systemic level,67–69 potentially explaining the enhanced osteoporosis in PsA and AS, IL-17 also promotes local skeletal repair processes,70 which appear to be part of a response of tendons, ligaments, and bone to mechanical stress.71 As such, IL-17 combines the systemic features of a proinflammatory cytokine on the bone with local tissue repair processes associated with mesenchymal responses and local bone repair. Similarly, IL-17 also blocks bone formation by downregulating essential factors for osteoblast differentiation and activity. Usually, osteophytes develop through the process of endochondral ossification, which first leads to differentiation of hypertrophic chondrocytes from mesenchymal cells and abundant deposition of extracellular matrix, followed by remodeling into bone. This process requires invasion and resorption of mineralized cartilage by osteoclasts and subsequent differentiation of osteoblasts that deposit bone. The molecular signals involved in osteophyte formation have recently been defined and include transforming growth factor-β (TGF-β) and bone morphogenetic proteins (BMPs), with active BMP signaling through SMAD3 proteins, facilitating osteophyte formation.72 Moreover, noggin, an inhibitor of BMPs, effectively blocks osteophyte formation in animal models, thus suggesting that this protein family plays a key role in the formation of bony spurs by facilitating osteoblast differentiation.72 The Wnt protein family is also an essential protein family involved in osteophyte formation. Wnt proteins bind to receptors including low-density lipoprotein–related protein (LRP) 5/6 and frizzled proteins on the surface of mesenchymal cells, leading to signaling through β-catenin, which translocates to the nucleus and activates genes involved in bone formation. Nuclear translocation of β-catenin is observed at sites of bony spurs, suggesting activation by Wnt ligands. There appears to be tight crosstalk between Wnt and BMP proteins because these two protein families act synergistically on bone formation. Moreover, crosstalk with the RANKL–OPG system occurs as well because Wnt proteins induce the expression of OPG, shutting down bone resorption.58 It thus appears that the balance between bone-forming factors (Wnt and BMP proteins) and bone-resorbing factors (RANKL and TNF) is crucial to the result of joint remodeling in rheumatic diseases.

BONE MARROW AS A NICHE FOR B-CELL DIFFERENTIATION AND AUTOANTIBODY FORMATION Mechanisms that explain the influence of the immune system on bone homeostasis have thus far dominated osteoimmunology research; however, bone– immune system interactions also play an important role in other areas. Bone is a hematopoietic organ that provides the microenvironment, or “niche,” for the maintenance and mobilization of hematopoietic stem cells (HSCs), for early B-cell differentiation, and for the homing of long-lived plasma cells. Current concepts suggest that mesenchymal cells and HSCs form bone marrow niches that are regulated by the local surrounding environment and by remote signals such as hormones and energy metabolism.73,74 Aside from osteoclasts,75 two types of mesenchymal cells in the bone marrow are considered essential for maintaining HSC and B-cell and plasma cell niches: spindle-shaped N-cadherin+CD45− osteoblast (SNO) cells that express IL-7 and CXCL12– abundant reticular (CAR) cells. SNO cells provide a bone marrow niche function for HSCs,76–78 allow homing of memory B cells and plasma cells to bone marrow, and provide survival signals that allow longevity of these cells and prevent their apoptosis. CAR cells also provide a bone marrow niche function and are mesenchymal progenitors that have both adipogenic and osteogenic potential. CXCL12 is essential for bone marrow homing of C cells and plasma cells (Fig. 13.2). Long-lived memory B cells and plasma cells are dependent on an acquired ability to survive. Successful competition for survival niches therefore is likely a key factor explaining the longevity of these cells. Plasma cells appear to traffic into these survival niches in bone marrow through CXCL12-induced chemotaxis, where they produce antibodies and persist. Hence, the bone marrow composition and its niche function may determine the functional state of B cells and antibody production, thereby influencing the course of diseases such as RA that are characterized by B-cell stimulation and autoantibody production.

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SECTION 1  Scientific Basis of Rheumatic Disease BONE MARROW NICHE Plasma cells Pro-B cells IL-7 CXCL12 Pre-pro-B cells

Bone

CAR cells Bone SNO cells Osteoblast

Pro-B cells HSC

Osteoclast

FIG. 13.2  Bone marrow niche. Maintenance and renewal of hematopoietic stem cells (HSCs) depend on a subset of mesenchymal cells forming the HSC niche, which are defined as spindle-shaped N-cadherin+CD45− osteoblastic (SNO) cells. HSCs are mobilized by the activity of osteoclasts and differentiate. Pre-pro-B cells share a common niche with plasma cells, based on the expression of CXCL12 by bone marrow stromal cells, also known as CAR (CXCL12-abundant reticular) cells. On further differentiation into pro-B cells, the cells switch to a different niche that is based on bone marrow stromal cells that express interleukin-7 (IL-7). Further differentiation of B cells into pre-B cells makes them independent of bone marrow niches before leaving the bone marrow to secondary lymphatic organs. Plasma cells reentering the bone marrow share the CXCL12-triggered bone marrow niche with pre-pro-B cells.

CONCLUSION Osteoimmunology has considerably refined our insights into the pathogenesis of rheumatic diseases, particularly those that manifest with arthritis. It appears that one of the reasons for the preferential targeting of bone by inflammatory arthritis is a disturbance in the natural interaction of the bone and immune systems. This idea gives credence to the old concept of bone remodeling as a controlled inflammatory response.79 Through studies in the field of osteoimmunology, we are beginning to understand the molecular interactions between immune activation and the skeletal system, linking inflammatory diseases with bone loss. Knowledge of these pathways will allow tailoring of drug therapies to target skeletal damage more specifically and thus more effectively. In addition, further insight into the roles that bone and bone marrow play in shaping the immune responses, particularly in maintaining plasma cells in the bone marrow niche, will open a new perspective in autoimmune diseases.

REFERENCES 1. Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007;7:292–304. 2. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165–176. 3. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397:315–323. 4. Horwood NJ, Kartsogiannis V, Quinn JM, et al. Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun. 1999;265:144–150. 5. McInnes I, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Immunol. 2007;7:429–442. 6. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–361. 7. Van der Heijde DM. Joint erosions and patients with early rheumatoid arthritis. Br J Rheumatol. 1995;34:74–78. 8. Jacome-Galarza CE, Percin GI, Muller JT, et al. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature. 2019;568:541–545. 9. Bromley M, Woolley DE. Chondroclasts and osteoclasts at subchondral sites of erosion in the rheumatoid joint. Arthritis Rheum. 1984;27:968–975. 10. Gravallese EM, Harada Y, Wang JT, et al. Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol. 1998;152:943–951. 11. Pettit AR, Ji H, von Stechow D, et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol. 2001;159:1689–1699.

12. Redlich K, Hayer S, Ricci R, et al. Osteoclasts are essential for TNF-alpha-mediated joint destruction. J Clin Invest. 2002;110:1419–1427. 13. Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289:1504–1508. 14. Ritchlin CT, Haas-Smith SA, Li P, et al. Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest. 2003;111:821–831. 15. Herman S, Mueller R, Kronke G, et al. OSCAR, a key co-stimulation molecule for osteoclasts, is induced in patients with rheumatoid arthritis. Arthritis Rheum. 2008;58:3041–3050. 16. Zaiss MM, Axmann R, Zwerina J, et al. Treg cells suppress osteoclast formation: a new link between the immune system and bone. Arthritis Rheum. 2007;56:4104–4112. 17. Axmann R, Herman S, Zaiss M, et al. CTLA-4 directly inhibits osteoclast formation. Ann Rheum Dis. 2008;67:1603–1609. 18. Gravallese EM, Manning C, Tsay A, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 2000;43:250–258. 19. Shigeyama Y, Pap T, Kunzler P, et al. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum. 2000;43:2523–2530. 20. Sato K, Suematsu A, Okamoto K, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203:2673–2682. 21. Stolina M, Adamu S, Ominsky M, et al. RANKL is a marker and mediator of local and systemic bone loss in two rat models of inflammatory arthritis. J Bone Miner Res. 2005;20:1756–1765. 22. Cohen SB, Dore RK, Lane NE, et al. Denosumab treatment effects on structural damage, bone mineral density and bone turnover in rheumatoid arthritis. Arthritis Rheum. 2008;58:1299–1309. 23. Takeuchi T, Tanaka Y, Ishiguro N, et al. Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose−response study of AMG 162 (denosumab) in patients with rheumatoId arthritis on methotrexate to validate inhibitory effect on bone erosion (DRIVE)—a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial. Ann Rheum Dis. 2016;75:983–990. 24. Firestein GS, Xu WD, Townsend K, et al. Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J Exp Med. 1988;168(5):1573–1586. 25. Lam J, Takeshita S, Barker JE, et al. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 2000;106:1481–1488. 26. Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004;363:675–681. 27. Smolen JS, Van Der Heijde St. DM, Clair EW, et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum. 2006;54:702–710. 28. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical and functional outcomes of treatment with adalimumab (a human anti–tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized placebo-controlled 52-week trial. Arthritis Rheum. 2004;50:1400–1411. 29. Lipsky PE, van der Heijde St DM, Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy Study Group. N Engl J Med. 2000;343:1594–1602. 30. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti–tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:35–45. 31. Maini St. R, Clair EW, Breedveld F, et al. Infliximab (chimeric anti–tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet. 1999;354:1932–1939. 32. Smolen JS, Avila JC, Aletaha D. Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: disassociation of the link between inflammation and destruction. Ann Rheum Dis. 2012;71:687–693. 33. Axmann R, Böhm C, Krönke G, et al. Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum. 2009;60:2747–2756. 34. Wong PK, Quinn JM, Sims NA, et al. Interleukin-6 modulates production of T lymphocyte– derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum. 2006;54:158–168. 35. Koga T, et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature. 2004;428:758–763. 36. Harre U, Georgess D, Bang H, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest. 2012;122:1791–1802. 37. Krishnamurthy A, Joshua V, Haj Hensvold A, et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann Rheum Dis. 2016;75:721–729. 38. Harre U, Lang SC, Pfeifle R, et al. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat Commun. 2015;6:6651. 39. Negishi-Koga T, Gober HJ, Sumiya E, et al. Immune complexes regulate bone metabolism through FcRβ signalling. Nat Commun. 2015;6:6637. 40. Pfeifle R, Rothe T, Scherer HU, et al. The IL-23/Th17 axis unlocks autoantibody activity and times onset of autoimmune disease. Nat Immunol. 2016;Nov 7 41. Grüneboom A, Hawwari I, Weidner D, et al. A network of trans-cortical capillaries as mainstay for blood circulation in long bones. Nat Metab. 2019;1:236–250. 42. Werner D, Simon D, Englbrecht M, et al. Early changes of the cortical micro-channel system in the bare area of the joints of patients with rheumatoid arthritis. Arthritis Rheumatol. 2017;69:1580–1587. 43. Simon D, Kleyer A, Bui CD, et al. Micro-structural bone changes are associated with broad-spectrum autoimmunity and predict the onset of rheumatoid arthritis. 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CHAPTER 13 Osteoimmunology 44. Simon D, Kleyer A, Stemmler F, et al. Age- and sex-dependent changes of intra-articular cortical and trabecular bone structure and the effects of rheumatoid arthritis. J Bone Miner Res. 2016;Oct 27 45. McQueen FM, Gao A, Østergaard M, et al. High-grade MRI bone oedema is common within the surgical field in rheumatoid arthritis patients undergoing joint replacement and is associated with osteitis in subchondral bone. Ann Rheum Dis. 2007;66:1581–1587. 46. Conaghan P, Bird P, Ejbjerg B, et al. The EULAR-OMERACT rheumatoid arthritis MRI reference image atlas: the metacarpophalangeal joints. Ann Rheum Dis. 2005;64:i11–i21. 47. McQueen FM, Benton N, Perry D, et al. Bone edema scored on magnetic resonance imaging scans of the dominant carpus at presentation predicts radiographic joint damage of the hands and feet six years later in patients with rheumatoid arthritis. Arthritis Rheum. 2003;48:1814–1827. 48. Jimenez-Boj E, Redlich K, Turk B, et al. Interaction between synovial inflammatory tissue and bone marrow in rheumatoid arthritis. J Immunol. 2005;175:2579–2588. 49. Kocijan R, Finzel S, Englbrecht M, et al. Differences in bone structure between rheumatoid arthritis and psoriatic arthritis patients relative to autoantibody positivity. Ann Rheum Dis. 2014;73:2022–2028. 50. Güler-Yüksel M, Bijsterbosch J, Goekoop-Ruiterman YP, et al. Bone mineral den sity in patients with recently diagnosed, active rheumatoid arthritis. Ann Rheum Dis. 2007;66:1508–1512. 51. Schett G, Kiechl S, Weger S, et al. High-sensitivity C-reactive protein and risk of nontraumatic fractures in the Bruneck study. Arch Intern Med. 2006;166:2495–2501. 52. Kanis JA, Johnell O, Oden A, et al. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385–397. 53. van Staa TP, Geusens P, Bijlsma JW, et al. Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:3104–3121. 54. Baum R, Sharma S, Organ JM, et al. STING contributes to abnormal bone formation induced by deficiency of DNase II in mice. Arthritis Rheumatol. 2017;69:460–471. 55. Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13:156–163. 56. Finzel S, Kraus S, Figueiredo CP, et al. Comparison of the effects of tocilizumab monotherapy and adalimumab in combination with methotrexate on bone erosion repair in rheumatoid arthritis. Ann Rheum Dis. 2019;78:1186–1191. 57. Adam S, Simon N, Steffen U, et al. JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function. Sci Transl Med. 2020;12 eaay4447. 58. Glass DA, Bialek P, Ahn JD, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 2005;8:751–764. 59. Walsh NC, Reinwald S, Manning CA, et al. Osteoblast function is comprised at sites of focal bone erosion in inflammatory arthritis. J Bone Miner Res. 2009;24(9):1572–1585. 60. Matzelle MM, Galant MA, Condon KW, et al. Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis Rheum. 2012;64(5):1540–1550.

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14

Joint tissue destruction and proteolysis David J. Wilkinson • David A. Young

Key Points ■ Cartilage is made up of collagens, proteoglycans, and minor glycoproteins. Bone consists of a mineralized collagen matrix. Both tissues can be degraded by active proteinases. ■ Different classes of proteinases play a part in connective tissue turnover, but the proteinase that predominates varies with different tissues and the resorptive situation. ■ Matrix metalloproteinases (MMPs) are produced in proforms and, when activated, can degrade connective tissue. A disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS) proteinases are also upregulated in diseased joints and some cleave proteoglycans. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of many metalloproteinases, especially MMPs, and the balance between active metalloproteinases and TIMPs determines the extent of degradation. Pro-MMPs can be activated by metalloproteinases as well as serine proteinases, which have likewise been implicated in cartilage breakdown, and cysteine proteinases promote collagen breakdown in cartilage and bone. ■ Various cytokines and growth factors, alone or in combination, inhibit matrix synthesis and stimulate proteinase production and matrix destruction. Tissue destruction occurs in both rheumatoid arthritis and osteoarthritis. ■ Some growth factors increase the synthesis of matrix and proteinase inhibitors. Growth factor combinations can be used in conjunction with stem cells and chondrocytes within artificial matrices to promote the repair of small cartilage defects in large joints.

INTRODUCTION Arthritis is a disease of the whole joint—involving the cartilage, synovium, and bone—with each tissue considered as having varying levels of importance in different forms of the disease. In all forms of arthritic disease, cartilage and the underlying subchondral bone are destroyed in severe cases, reducing normal joint function. Indeed, there are multiple potential intervention points in different parts of the joint to limit unwanted breakdown of the joint connective tissue (Fig. 14.1). Cartilage contains different types of collagen, which are composed of rod-shaped molecules that aggregate in staggered arrays to form cross-linked fibers that give connective tissue strength and rigidity.1 Entrapped within these collagen fibers are proteoglycans,2 predominantly aggrecan, which consists of three globular domains interspersed with heavily glycosylated and sulfated polypeptide. In the presence of hyaluronic acid, these form highly charged aggregates, attract water into the tissue, and allow cartilage to resist compression. Chondrocytes in normal adult cartilage maintain a steady state in which the extent of matrix synthesis equals that of degradation. During growth and development, synthesis of matrix components exceeds degradation. In pathology, this balance is perturbed, resulting in an increase in the rate of degradation that is often associated with a reduction in matrix synthesis (Fig. 14.2). The primary cause of cartilage destruction in the arthritides is elevated levels of active proteinases, secreted from a variety of cells, which degrade collagen and aggrecan. The source(s) of these proteinases depends on the disease such that in osteoarthritis (OA), proteinases produced by chondrocytes play a major role. In contrast, in a highly inflamed rheumatoid joint, chondrocytes, synovial cells, osteoclasts, and inflammatory cells all contribute to the proteolytic loss of tissue matrix and an invasive hyperplastic synovial “pannus” invades, depositing destructive proteinases in the joint space. Joint tissues are capable of repair; although aggrecan can be readily resynthesized, replacement of collagen after its destruction is more difficult.3 A variety of growth factors and cytokines present in the joint are able to promote matrix synthesis, and these factors have been studied to determine whether cartilage and bone defects can be repaired in vivo. 120

PROTEOLYTIC PATHWAYS OF CONNECTIVE TISSUE BREAKDOWN Extracellular matrix (ECM) proteins are broken down by different proteolytic pathways. The five main classes of proteinases4 are grouped according to the chemical group that participates in the hydrolysis of peptide bonds. Cysteine and aspartic proteinases are predominantly active at acidic pH and act intracellularly; threonine proteinases, the proteasome being the most characterized, also act intracellularly at nearly neutral pH; and the serine proteinases and metalloproteinases, active at neutral pH, mostly act extracellularly. Other enzymes, such as elastase, are stored and released when neutrophils are stimulated. Some enzymes, such as furin, may not participate directly in the proteolysis of matrix proteins but can activate proenzymes that subsequently degrade the matrix. Membrane-bound proteinases are associated with cytokine processing, receptor shedding, and removal of proteins that are responsible for cell–cell or cell–matrix interactions. The complete repertoire of human proteases (defined as the degradome)5 comprises approximately 588 proteinases, and all classes of proteinases have roles in the turnover of connective tissues. One proteinase pathway may act in concert with or precede another, and the pathway that predominates varies with different resorptive situations. ECM turnover often involves complex interactions among different types of cells. The osteoid layer in bone is removed by osteoblast-derived metalloproteinases before the attachment of osteoclasts, which secrete predominantly cysteine proteinases such as cathepsin K. These proteinases degrade bone matrix after removal of the mineral. An intricate series of interactions among T cells, macrophages, synovial fibroblasts, and chondrocytes occur in the rheumatoid joint. In septic arthritis, both serine proteinases and metalloproteinases released from neutrophils exceed the local concentration of inhibitors, which results in rapid removal of the cartilage matrix from the joint cavity. In OA, inflammation is typically less marked but nevertheless is thought to contribute to pathology.6 Other mechanisms also contribute to joint tissue destruction, especially in OA, including abnormal mechanical loads inducing mechanosensitive genes7 and age-related changes to the cartilage ECM,8 altering cellular responses by engaging alternative receptors (e.g., Toll-like receptors) and resulting in the expression of different genes.

EXTRACELLULAR PROTEOLYSIS MATRIX METALLOPROTEINASES The matrix metalloproteinase (MMP) family, when activated and acting collectively, can degrade all components of the cartilage ECM. MMPs are zinc-dependent endopeptidases containing common domains (Fig. 14.3),9,10 and all are produced as latent (inactive) proenzymes with proteolytic cleavage and loss of the propeptide leading to activation. The membrane-type MMPs (MT-MMPs) and stromelysin-3 (MMP-11) have a short peptide insert between the propeptide and the N-terminal domain, a sequence recognized by furin, a serine proteinase located in the Golgi apparatus; these MMPs therefore reach the cell surface as active enzymes. Zinc is present at the catalytic center within the N-terminal catalytic domain, which is joined to the C-terminal hemopexin domain by a flexible linking peptide. For efficient catalysis, cooperation between the catalytic domain and an exosite in the hemopexin domain is critical for conferring substrate specificity for individual MMPs.11 Whereas MMP-8 and MMP-9 are found stored within the specific granules of the neutrophil, most other MMPs are produced by different connective tissue cells after stimulation with a variety of mediators. The MMPs are divided into four main groups called the stromelysins, collagenases, gelatinases, and MT-MMPs.9,10 The stromelysins have broad substrate specificity, and the natural substrates of these enzymes are probably proteoglycans, fibronectin, and laminin.12 Stromelysin-1 (MMP-3) is not normally widely expressed but can readily be induced by growth factors and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF). The

CHAPTER 14  Joint tissue destruction and proteolysis THERAPEUTIC INTERVENTION POINTS

(b)

Synovial Synovial Cartilage Bone membrane fluid

Proenzymes 5 Enzymes

4

6

Chondrocyte

(b)

Cytokines

(a)

(c)

Blood vessel

4 Chondrocytes Cytokines 3

1 2 (a)

implicated in the pathologic destruction of joint tissues and are involved in the normal turnover of connective tissue matrix that occurs during growth and development. In OA, rates of both ECM synthesis and breakdown are increased, which lead to the formation of excess matrix in some regions (osteophytes) with focal lesions (loss of matrix) in other areas. The regulation of MMPs therefore needs to be carefully controlled.12 This is accomplished at a number of critical steps (Fig. 14.5, a), including transcription, epigenetics, activation of the proenzymes, and inhibition or modulation of enzyme activity.

MMP regulation—from transcription to inhibition Regulation of MMP transcription

Cartilage destruction

3

121

4

5

Enzymes Fibroblasts

Enzymes

6

Tissue damage Enzymes 4

Cytokines 3 (c)

Osteoclasts

FIG. 14.1  Arthritis is a disease of the whole joint resulting in connective tissue turnover. Therapeutic intervention points for preventing destruction and cellular mechanisms involved in tissue damage. The destructive cycle of events can be broken down in a number of ways, including (a) (1) blocking the entry of harmful cells, (2) removal of harmful cells from the joint, (b and c) (3) blocking or mimicking the action of a cytokine or growth factor or other ligands, (4) blocking the intracellular signaling pathways involved in the production of proteinases, (5) preventing the activation of proteinases, and (6) direct inhibition of the destructive proteinases degrading bone or cartilage. (c) Within the joint, mixtures of cytokines or other ligands stimulate chondrocytes to release and activate enzymes that damage the cartilage matrix. Within the synovium, fibroblasts, macrophages, and T cells interact to produce tissue damage in bone and cartilage. The cytokines released also activate osteoclasts, which leads to the destruction of the underlying subchondral bone. three stromelysins have similar substrate specificities, but their expression patterns are often quite distinct. There are three mammalian collagenases: MMP-1, MMP-8, and MMP-13. These enzymes, when activated, cleave fibrillar collagens at a single site to produce fragments three quarters and one quarter the original size. The enzymes differ in their specificity for different collagens, with MMP-13 having much broader substrate specificity than the other collagenases. Both MMP-1 and MMP-13 are synthesized by macrophages, fibroblasts, and chondrocytes when these cells are stimulated by inflammatory mediators. MMP-8 is predominantly released from neutrophils on stimulation of these cells, but this MMP can also be produced by chondrocytes, and all three collagenases are present in diseased cartilage (Fig. 14.4). MMP-13 is often controlled in a different way from MMP-1; for example, retinoic acid, which downregulates MMP-1, is known to upregulate MMP-13 in some cell types. The two gelatinases cleave denatured collagens, type IV and V collagen, and elastin. Expression of MMP-2 is the most widespread of all the MMPs; MMP-9 is expressed in a wide variety of transformed and tumor-derived cells. Both MMP-2 and MT1-MMP (MMP-14) have also been shown to have collagenolytic activity, and the cell-surface location of MT1-MMP ideally situates it for the pericellular proteolysis that is often evident in cartilage affected by OA. Levels of several MMPs are increased in rheumatoid synovial fluid, in conditioned culture media from rheumatoid synovial tissues and cells, in synovial tissue at the cartilage–pannus junction in rheumatoid joints, in OA cartilage, and in animal models of arthritis.13,14 These proteinases are

Interleukin-1, TNF, and IL-17 stimulate numerous cell types to produce proinflammatory and degradative molecules. For example, the synthesis and secretion of MMP-1, MMP-3, and other MMPs are stimulated by such mediators.15 Arthritic joints have large numbers of different cell types that produce specific cytokines and growth factors that often differ in their action on individual cell types. It is also likely that multiple cytokines will be present within such an inflammatory milieu, thus making it difficult to predict the outcome of blocking the action of an individual cytokine to prevent tissue destruction. TNF blockade in some patients with rheumatoid arthritis (RA) successfully reduces inflammation and joint destruction, but some studies suggest that blocking other cytokines such as IL-6 may confer similar benefit, especially in patients unresponsive to a given biologic agent.16 Cytokines and growth factors mediate their effects on cells by binding to specific cell-surface receptors. A “signal” is transduced to the nucleus via specific intracellular signal transduction pathways that culminate in the activation or repression of target genes. Signaling in inflammation is complex, and multiple signaling cascades are often activated by a given cytokine in different cell types. A further level of complexity is that interactions, or “cross-talk,” between different signaling pathways can occur to effect the gene expression of degradative molecules.12 The key components of signaling pathways are an attractive therapeutic target because they allow small molecules to be used as drugs. For example, specific inhibitors of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway have been tested successfully in trials17,18 and are in use clinically.

Epigenetic regulation Other studies suggest metalloproteinases are regulated epigenetically (Fig. 14.5, b), at both the transcriptional level and posttranscriptional level.19 DNA methylation at specific CpG sites within promoters is a further mode of regulation of MMPs, by affecting the binding of transcription factors. Significant differences in DNA methylation between tissue in human OA and nondiseased tissue have been observed, which include differences in MMP promoters.20,21 Histone deacetylases (HDAC) are a class of enzymes responsible for regulating the interaction of histone proteins with chromatin, thereby regulating gene expression. HDAC inhibitors repress metalloproteinase expression in cytokine-stimulated cartilage, notably the expression of MMP-1 and MMP-13,22 and a general HDAC inhibitor is protective in an OA animal model.23 MicroRNAs are short noncoding RNAs that posttranscriptionally regulate gene expression. With regard to cartilage development and disease, the most convincing experimental data involve the role of the cartilage-specific microRNA, miR-140. Deletion of this microRNA in mice leads to mild dwarfism and craniofacial abnormalities,24 a very similar phenotype to that reported in patients with heterozygous mutation in the miRNA.25 miR-140 indirectly targets MMP-13 expression,26 but several other microRNA (e.g., miR-127-5p and miR-27b) can directly regulate the MMP13 gene27 or MMPs in general.28

Regulation by activation Activation of latent pro-MMPs is an important and understudied control point in connective tissue breakdown. The propeptide of an MMP is removed proteolytically, which disrupts a disulfide bridge between a cysteine and active site zinc, an interaction that is critical for MMP latency, in a mechanism referred to as the “cysteine switch.”29 MMP activators are likely to differ in different physiological circumstances. Plasmin, matriptase, hepsin, and other serine proteinases activate some members of the MMP family, and in vitro studies have demonstrated that inhibitors of furin or plasmin can block cartilage breakdown.30–33 MMPs are themselves activators of other MMPs. For example, active MMP-3 activates procollagenases and other pro-MMPs.

Regulation by inhibition All active MMPs are inhibited by tissue inhibitors of metalloproteinases (TIMPs),34 which are a family of four highly stable proteins that bind tightly to active MMPs in a 1 : 1 ratio. TIMPs play an important role in controlling

SECTION 1  Scientific Basis of Rheumatic Disease

122

CONTROL OF COLLAGEN SYNTHESIS AND DEGRADATION

IL-1 TNF

Active collagenase

Procollagenase

Collagen degradation

Other ligands OSM bFGF PDGF IL-17

TIMPs Intracellular route

TGF-β IL-4 IGF-1 IFN-γ OSM IL-13

Collagen synthesis Procollagen peptidases

Collagen assembly

FIG. 14.2  Interleukin-1 (IL-1) and tumor necrosis factor (TNF) increase the production of proteinases and can reduce collagen synthesis. Other ligands (e.g., alarmins), as well as oncostatin M (OSM), interleukin-17 (IL-17), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF), can further influence these processes. Conversely, many growth factors (e.g., transforming growth factor β [TGF-β], interferon-γ [IFN-γ], insulin-like growth factor-1 [IGF-1], IL-4, IL-13) increase the synthesis of collagen, increase proteinase inhibitors (e.g., tissue inhibitors of metalloproteinases [TIMPs]) and often reduce the production of proteinases.

THE DOMAIN STRUCTURE OF THE MATRIX METALLOPROTEINASES (MMPs) Function

Maintains MMP in inactive form

Zn2+ is involved in cleavage of matrix protein

Propeptide

Catalytic domain

QPRC92GVP

H218ELGHSLGLSH

Flexible linking peptide Hinge

Protein binding to confer substrate specificity C-terminal domain

C278

C466

Zn2+

Additional domains

RXKR

Function

Sequence recognized Gelatin-binding by furin domains

MMP

MMP-11, MT-MMPs

MMP-2, -9

Collagen-like homology

Transmembrane domain and cytoplasmic tail

MMP-9

MT-MMPs

connective tissue breakdown by blocking activated MMPs (see Figs. 14.2 and 14.5). When TIMP levels exceed those of active enzymes, connective tissue turnover is prevented. TIMP-3 is bound by the ECM after secretion and inhibits members of the ADAM and ADAMTS families (see the next section). TIMP-4 is predominantly localized in heart tissue but can be produced by joint tissues. TIMP-1 and TIMP-3 are upregulated by growth factors such as transforming growth factor-β (TGF-β), insulin-like growth factor 1 (IGF1), and oncostatin M (OSM); these agents also upregulate ECM synthesis.

Endocytic regulation Although many metalloproteinases are secreted as soluble enzymes, recent evidence also suggests that they can bind to specific cell surface receptors, membrane-anchored proteins, or cell-associated ECM molecules to function pericellularly at discrete locations within the matrix.35 Indeed, endocytosis of metalloproteinases and their inhibitors via binding to low-density lipoprotein-related protein 1 (LRP-1) on the chondrocyte cell surface represents yet another mechanism that serves to control their extracellular activity35 as illustrated in Fig. 14.5. ADAMTS-5, ADAMTS-4, MMP-13, and TIMP-3 have all been shown to be endocytosed by chondrocytes.36–39 Shedding of this endocytic receptor therefore represents an additional level of complexity in regulating the proteolytic burden in the extracellular space.40

FIG. 14.3 All matrix metalloproteinases (MMPs) contain a similar domain structure with a zinc-binding domain that contains the catalytic HEXXH motif (yellow/orange). Most contain a C-terminal hemopexin domain (blue), which is involved in protein binding and substrate specificity. A flexible hinge region (red) separates the catalytic and hemopexin domains. All are secreted with a propeptide (purple) that maintains the latency of the MMP via a conserved cysteine binding to the active site zinc. Other groups of MMPs build on this core structure. The gelatinases have additional domains inserted (green), and membrane-type MMPs (MT-MMPs) have a transmembrane domain (pink) that locates the MMP at the cell surface. The MT-MMPs and stromelysin-3 (MMP-11) have a sequence of basic amino acids (RXXR) inserted between the pro- and catalytic domains that are specifically recognized by furin, a serine proteinase that activates these enzymes intracellularly.

REGULATION OF MMPS AND THEIR INHIBITORS BY THE ECM Cartilage ECM acts not as an inert framework but as dynamic, regulated system. MMPs and TIMPs are known to be regulated by the ECM, perhaps most notably through interaction with glycosaminoglycan (GAG) chains of proteoglycans. The sequestration of TIMP3 is well described in the literature,41,42 a process that has recently been demonstrated to be regulated by changes in GAG sulfation pattern. Indeed, binding of TIMP3 to GAG chains competes with binding to the endocytic receptor LRP-1.43 Some MMPs have also been shown to bind to GAGs,44 and specific interactions with the ECM may promote pro-MMP activation.45

OTHER PROTEINASES INVOLVED IN PATHOLOGICAL JOINT DESTRUCTION ADAM and ADAMTS proteinase families Two additional families of metalloproteinases, both closely related to MMPs, are also implicated in cartilage biology, particularly in relation to proteoglycan turnover. ADAMs are usually membrane-anchored proteinases with diverse functions conferred by the addition of different protein domains. The disintegrin domain can bind to integrins and prevent cell–cell interactions; cysteine-rich, epithelial growth factor (EGF)–like, transmembrane,

CHAPTER 14  Joint tissue destruction and proteolysis COLLAGENASES AND JOINT DESTRUCTION Neutrophil

Synovial fluid

MMP-8 MMP-9 Elastase

MMP-TIMP complexes

Cartilage destruction

Cartilage TIMP 1–4

Protease-2M complexes

Inhibition

Inhibition

MMP-1, -8, -13

TIMP 2-4

MMP-14

Chondrocyte

Pannus

T cells, fibroblasts, macrophages

FIG. 14.4  Cell–cell interactions among T cells, synovial fibroblasts, and macrophages within the pannus tissue give rise to a mixture of cytokines, growth factors, and other ligands that act on these cells and the chondrocytes to synthesize proforms of the collagenases matrix metalloproteinase 1 (MMP-1), MMP-8, MMP-13, or membrane type 1 (MT1)-MMP (MMP-14). After activation, if local levels exceed the available tissue inhibitors of metalloproteinases (TIMPs), collagen destruction ensues. MMP14, located at the cell surface, can initiate activation cascades, as can serine proteinases (e.g., plasmin, elastase) that activate procollagenases. Within the joint cavity, neutrophils can also release MMP-8, gelatinase B (MMP-9), or elastase at or close to the cartilage surface, where degradation will occur unless α2-macroglobulin (α2M) or TIMPs bind and inactivate the enzymes.

and cytoplasmic tail domains are also found. Some members are associated with the cleavage and release of cell-surface proteins. For example, ADAM17 is known to release TNF-α from the cell surface. Other ADAMs have also been described in cartilage, including ADAM10, ADAM12, and ADAM15. ADAMTS family members are distinguished from the ADAMs in that they lack the EGF-like, transmembrane, and cytoplasmic domains but have additional thrombospondin-like domains (which can number up to 13 and are located predominantly at the C-terminus). They are thought to mediate ECM interactions.46 Some ADAMTS proteinases can, under certain circumstances, be produced as alternatively spliced forms that differ primarily in the number of thrombospondin repeats and may give rise to differences in their substrate specificity or localization (or both) within the ECM. Some members of this family are recognized as “aggrecanases,” cleaving aggrecan at a specific site distinct from that effected by MMPs,46 and, most notably, ADAMTS-4 and ADAMTS-547 are thought to be responsible for the cleavage of cartilage proteoglycan, aggrecan (Fig. 14.6). Interestingly, many of the ADAM and ADAMTS family members (including ADAM17, ADAMTS-4, and ADAMTS-5) are inhibited by TIMP-3, which, in in vitro studies, effectively blocks aggrecan release from cartilage. A role for ADAMTS-5 in pathological aggrecan destruction is further supported by studies using in vivo models of OA (see “Proteinase-Deficiency in Murine Models of Arthritis”).

123

SERINE PROTEINASES There are almost as many serine proteinases (31%) in the human degradome as there are metalloproteinases (33%),5 which makes this proteinase class, which is somewhat understudied in terms of joint destruction, of increasing interest. Indeed, both direct and indirect roles for serine proteinases have been described, including regulation of cell signaling and modulation of the biologic activity of growth factors; these events can significantly alter inflammatory responses. The complement cascade may have an important role in arthritis.30 Indeed, the complement serine proteinase C1s can degrade IGFbinding protein-5 (IGFBP-5) to release active IGF-1, a growth factor integral in controlling cartilage damage. Complement activation components are elevated in the synovial fluid, in the synovium, and in cartilage of patients with arthritis. Interactions between TNF and the complement system may contribute to disease pathogenesis, and several complement proteinases have now been implicated in OA progression and protection.48 In addition to its role as a pro-MMP activator, plasmin can activate TGF-β, release IGF-1 from IGFBPs, and activate the complement cascade. The serine proteinases neutrophil elastase and cathepsin G are stored in azurophilic granules and released after exposure of the neutrophil to inflammatory stimuli. In mice deficient in both neutrophil elastase and cathepsin G, experimental arthritis is less severe,49 with reduced inflammatory cell infiltration, suggesting that these neutrophil serine proteinases are important in promoting the inflammatory process by establishing chemotactic gradients that recruit immune cells and enhance inflammation. Modulation of the biological activity of chemokines is another important function,50 and it is now apparent that serine proteinase activators of protease-activated receptor-2 (PAR2), such as mast cell β-tryptase and chondrocyte matriptase, contribute to joint swelling and synovial vasodilation, as well as MMP expression and activation.32,51,52 Moreover, the protective phenotypes of PAR2-deficient mice in experimental RA and OA52,53 strongly suggest that these proteolytic activators could be therapeutic targets. Conversely, some serine proteinases are thought to be protective, such as fibroblast activation protein α (FAP-α) and dipeptidyl peptidase IV (DPPIV). These transmembrane enzymes have unusual catalytic activities in that they hydrolyze after proline residues located two or more amino acids from the N-terminus of target substrates, which makes them important regulators of biologically active peptides or neuropeptides and chemokines. Inhibition of FAP-α and DPPIV increases cartilage invasion by RA synovial fibroblasts,54 and because FAP-α is elevated during inflammation as well as in OA cartilage and α2-antiplasmin is a physiologic substrate of FAP-α, these findings suggest an important protective feedback mechanism for these enzymes in maintaining cartilage homeostasis. Interestingly, recent evidence suggests that expression of FAP-α may define a distinct fibroblast subset within the rheumatoid synovium, deletion of which suppressed inflammation and bone erosions in murine RA.55 Indeed, mice that are globally deficient in FAP-α have also been shown to be resistant to cartilage damage in a mouse model of inflammatory arthritis.56

INTRACELLULAR PATHWAYS Levels of cathepsin D (an aspartic proteinase) and cathepsin B (cysteine proteinase) are increased in OA cartilage, and increased levels of cathepsins B, H, and L (cysteine proteinases) are reported in antigen-induced rat arthritis models and within rheumatoid joints.57 Incubation of resorbing cartilage with specific cathepsin B inhibitors blocked the release of proteoglycan fragments, an action suggesting the involvement of an intracellular route for cartilage proteoglycan breakdown. Cathepsin K can also cleave collagen, albeit at different sites from the MMPs, and the presence of chondroitin sulfate increases the activity and stability of this enzyme. A correlation of cathepsin K–generated collagen fragments with increasing age in OA cartilage has been reported.58 Cathepsin K is now a drug target for the treatment of osteoporosis in which bone resorption is excessive (see later). The relative contribution of intracellular and extracellular pathways to collagen breakdown is controversial. Tissues with high matrix turnover (e.g., periodontal ligament) or that have been stimulated to resorb have increased numbers of collagen-containing vacuoles, which suggests that these vacuoles are linked to resorption. Some work suggests that the intracellular pathway predominates in normal turnover, but the extracellular route is prevalent only in pathologic conditions.59

OSTEOCLASTIC BONE RESORPTION Inflammation mediates bone destruction in RA,60,61 a process involving both MMPs and cysteine proteinases62 as well as inhibition of bone formation/ repair.63 For details, see Chapter 13.

124

SECTION 1  Scientific Basis of Rheumatic Disease CONTROL OF MP ACTIVITY 1. Synthesis and sectretion

2. Activation

Catabolic stimulation (e.g., cytokines)

3. Inhibition or modulation

LRP-1

Activating enzymes 2 2

1

2

3

3 Matrix destruction

Active MP (e.g., MMPs)

Pro-MP

3 TIMPs

1 a

Chondrocyte or synovial fibroblast

EPIGENETIC REGULATION OF GENES INCLUDING MMPS VIA HISTONE MODIFICATIONS, DNA METHYLATION AND MICRORNAS

microRNA HATs Chromosome

HDACs Ac

Histones

Histones tails

TF AAAAAA A

Me

AAAAAA A

CG

AAAAAAA

gene CG

Histone modification

b

A combination of different molecules can attach to the‘tails’ of proteins called histones.These after the activity of the DNA wrapped around them.

FIG. 14.5  (a) The matrix metalloproteinases (MMPs) are controlled by mechanisms that include (1) upregulation and secretion after external stimuli such as cytokines and growth factors as well as a wide variety of other ligands (including alarmins, nucleic acids [dsDNA and RNA], Indian hedgehog [IHH], Wnt, advanced glycation end-products [AGEs], and bioactive fragments from degraded extracellular matrix [ECM] components such as fibronectin and aggrecan). Synthesis of MMPs also depends on several epigenetic regulatory mechanisms (for detail see (b)); (2) activation of the pro-MMPs both intracellularly and extracellularly, which also applies to various ADAMTS enzymes; (3) removal of MMP activity either by inhibition with tissue inhibitors of metalloproteinases (TIMPs) or active endocytosis of active MMPs (and A disintegrin and metalloproteinase with thrombospondin motifs [ADAMTSs]) via low-density lipoprotein–related protein-1 (LRP-1). (b) Epigenetic regulation of genes including MMPs via histone modifications, DNA methylation, and microRNAs. DNA is wrapped around core histone proteins to form nucleosomes. N-terminal tail of histones are heavily posttranslationally modified with various combinations of modifications controlling transcription of the encompassed DNA. Depicted is an acetylation modification (Ac) added and removed (generally to lysines) by histone acetyl transfersase (HATs) and histone deacetylase (HDACs) enzyme family members, respectively. DNA methylation comprises the addition of a methyl group to the cytosine of CpG dinucleotides. This modification is added by DNA methyltransferases and either removed passively during mitosis or by the ten-eleven translocation (TET) methylcytosine dioxygenase family of enzymes. Methylation of CpGs is generally considered repressive to transcription since the binding of numerous transcription factors (TFs) can be hindered by the modification, although this is not always the case. microRNAs (miRNAs) are short (~22 nt) noncoding RNAs that posttranscriptionally regulate gene expression. miRNAs (red) generally bind to the 3′ UTR of target mRNAs through sequence complementarity. This binding causes mRNA cleavage or represses translation, either way reducing protein expression. A single miRNA can in theory target many mRNAs and an mRNA can be targeted by many miRNAs.

Osteoblasts respond to parathyroid hormone and other agents that induce bone resorption, such as IL-1 and TNF, by increasing the secretion of MMPs to remove the osteoid layer on the bone’s surface. Osteoclast precursors then adhere to the exposed bone surface, differentiate, and form a low-pH microenvironment beneath their lower surface. This removes mineral, and lysosomal proteinases then resorb the exposed matrix. Cathepsins B and L cleave collagen types II, IX, and XI and destroy cross-linked collagen matrix at low pH. Osteoclasts produce cathepsin K, which cleaves type I collagen at the N-terminal end of the triple helix. This enzyme plays a key role in the degradation of bone collagen, and its expression correlates with bone resorption. It is also produced by synovial fibroblasts64 and is thought to contribute to synovium-initiated bone destruction in the rheumatoid joint.65 Bone resorption is impaired in situations in which cathepsin K is deficient, evidence that has made cathepsin K a drug target for the treatment of osteoporosis in which bone resorption is excessive.

There is clear evidence for a central role of receptor activator of nuclear factor-κB ligand (RANKL) in the bone destruction seen in RA.66 This member of the TNF ligand family of cytokines is abundantly produced by T cells and synovial fibroblasts in RA synovial membrane, and it stimulates the formation of multinucleated osteoclasts.67 It is upregulated by a variety of cytokines, including IL-1, TNF, IL-11, OSM, parathyroid hormone–related peptide (PTHrP), macrophage colony-stimulating factor (M-CSF), and IL-17. It binds to a specific receptor, receptor activator of nuclear factor-κB (RANK), on the surface of osteoclast precursors. Increased levels of RANK and RANKL, as well as multinucleated cells, are evident in arthritis models associated with bone erosions. The potent activity of IL-17 in osteoclastogenesis is mediated by the upregulation of RANKL. RANKL is antagonized by the decoy receptor osteoprotegerin (OPG),68 which is effective in blocking bone resorption.63 In rat adjuvant-induced arthritis and the arthritis of TNF transgenic mice,69 OPG protects against the development of bone and cartilage destruction.

CHAPTER 14  Joint tissue destruction and proteolysis

125

AGGRECANASES AND CARTILAGE AGGRECAN TURNOVER Structure of aggrecan Interglobular domain G2 G1

G3

Keratan sulfate–rich region Link protein Chondroitin sulfate–rich region

a Hyaluronan

Proteinases that cleave the interglobular domain 340 V D I

P

E

360 W T

N F

MMPs F G V G Cathepsin B G E b

P D

V T Q V T E D

I

I

M E L P L P R N

350

I

380

440

L

E

FIG. 14.6  (a) Structure of aggrecan. The major pro-

V D Elastase S L urokinase G V Plasmin R V A Q ADAMTS-4 E V ADAMTS-5 Matrilysin G T MMP-8 E A MMP-1 V P T 370

450

Cleavage of aggrecan by aggrecanases and MMPs

MMP neoepitope Subsequent cleavage by MMPs Soluble aggrecanase

Membrane-bound aggrecanase

V D I

Hyaluronic acid Initial cleavages by aggrecanase C-terminal cleavage

P E N COOH

teoglycan in human cartilage is aggrecan, a protein with three globular domains: G1 to G3. Between G2 and G3, there is a linear region of polypeptide to which glycosaminoglycans (GAGs) of both keratan sulfate (blue) and chondroitin sulfate (purple) are attached that attract water and cause the aggrecan to swell. (b) Proteinases that cleave the interglobular domain. Both A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) and (ADAMTS-5) (aggrecanases) and matrix metalloproteinases (MMPs) can cleave aggrecan at specific amino acid sequences between the G1 and G2 domains. Cleavage in this region by ADAMTS-4 and ADAMTS-5 is thought to be key to the pathologic loss of aggrecan from cartilage, and the combined action of aggrecanases and MMPs releases a soluble 32-amino acid bioactive peptide (highlighted in yellow) that further promotes cartilage breakdown. (c) Cleavage of aggrecan by aggrecanases and MMPs. Aggrecanases are either associated with the chondrocyte membrane or released into the extracellular space where aggrecan is cleaved between the G1 and G2 domains, as well as at several sites close to the G3 domain. A specific neoepitope is released and is found in diseased synovial fluids. The G1 domain, which remains bound to hyaluronic acid, can be subsequently cleaved by MMPs, with a specific MMP neoepitope being left that can be detected in arthritic cartilage in late-stage disease. These two cleavages release a bioactive peptide.

NH2 A R G S V

c

Lysosomal digestion of hyaluronan

Aggrecanase neoepitope

MODEL SYSTEMS OF JOINT DESTRUCTION A large number of in vitro and in vivo models are used to study the mechanisms of arthritic disease. Initiation of cartilage breakdown can be induced with IL-1, TNF, IL-17, retinoic acid, or other proinflammatory cytokine combinations in model systems.70 Specific proteoglycan fragments are released first from resorbing cartilage (see Fig. 14.6). TIMP-3 blocks such release of proteoglycans, thus supporting a role for ADAMTS enzymes, particularly ADAMTS-5. Cysteine proteinase inhibitors can also block the release of

proteoglycans from cartilage, thus indicating that they could be involved in upstream activation pathways.57 The loss of collagen from cartilage is viewed as the final phase of tissue destruction and is essentially irreversible; attempts at repair do not lead to restoration of normal cartilage. Before the loss of collagen, many of the minor components of the ECM are first degraded, including molecules that are closely associated with the collagen fibrils, such as cartilage oligomeric matrix protein (COMP), decorin, and type IX collagen. It is not known whether ECM disassembly occurs in a defined sequence, but it is evident that a matrix as

126

SECTION 1  Scientific Basis of Rheumatic Disease

complex as articular cartilage requires numerous proteolytic activities to effect complete tissue destruction. Aged and diseased cartilages, however, appear to be more resistant to such degradative stimuli for reasons that remain poorly understood, but factors involved with matrix component modifications, such as advanced glycation end products (AGEs) and collagen cross-links, may have “protective” roles. Interestingly, addition of the serine proteinase matriptase alone to human OA, but not to healthy cartilage, promotes significant levels of collagen release.32 Although IL-1 and TNF alone are sometimes able to initiate limited cartilage collagen resorption, when these cytokines are combined with OSM, rapid and reproducible release of collagen is found in bovine, porcine, and healthy human cartilages. Synthetic MMP inhibitors and TIMP-1 are able to prevent this release,70 a finding that strongly implicates the collagenolytic MMPs in this process. In vivo models of arthritis provide a crucial understanding of arthritic disease at the level of the whole organism. Indeed, both OA and RA are now considered diseases of multiple tissues within the joint, and a holistic approach to understanding disease pathology is therefore required.71 Implantation of RA synovial fibroblasts with normal articular cartilage under the renal capsule of mice with severe combined immunodeficiency leads to maintenance of the aggressive phenotype of the synovial fibroblasts that invade the cartilage, but implantation of OA synovial fibroblasts does not.72 Adenoviral delivery of proinflammatory cytokines intraarticularly can also lead to RA-like tissue destruction with concomitant synovial hyperplasia.73 These models emphasize the role that synovial fibroblasts play in destroying cartilage in RA, and methods have also been developed in which synovium and cartilage can be co-cultured in vitro. A role for inflammation and factors such as IL-1 in the progression of OA is broadly accepted but remains controversial.74 Although spontaneous OA animal models are available, surgical instability models are most common in laboratory animals, including dogs, guinea pigs, rabbit, rats, mice, sheep, and goats.75 Advantages of surgical models over spontaneous models include a significantly faster onset of disease with a decrease in both variability and dependence of genetic background.76 The two most common models are generated via either anterior

cruciate ligament transection or destabilization of the medial meniscus (DMM), with DMM being the model of choice in the mouse.76 These models in the mouse have allowed for the use of transgenic knockout (KO) or knock-in (insertion of a genetic alteration to a gene) animals to provide insight into the mechanisms that regulate OA pathology.6,76,77 Despite these developments, no single model fully replicates human disease, and it is unclear how well any of these models resemble idiopathic OA in the older human population.6,75

PROTEINASE DEFICIENCY IN MURINE MODELS OF ARTHRITIS Targeted gene disruption or KO experiments in mice have allowed investigation of the contribution of individual proteinases to many physiologic and pathologic processes, including arthritis. The phenotypes of various genetically modified (proteinase-relevant) mice are presented in Table 14.1. Of note, all MMP KO mice are embryonically viable, although some have developmental abnormalities (see Table 14.1). The deficiency of a given proteinase may sometimes have apparently opposing effects in different models, which is a reflection on where the deleted proteinase acts, the extent of compensation by the remaining proteinase repertoire, and the complexity of the proteolytic pathway(s) it acts in during disease. Data from the ADAMTS-4, ADAMTS-5, and double-KO mice suggest ADAMTS-5 to be most strongly implicated in pathologic cartilage turnover.47,78,79 Studies using knock-in mice have also proved insightful when studying how aggrecan is degraded. When the wildtype cleavage site was altered so that it was impervious to MMP activity, mice had no developmental problems, which implies that MMP-mediated aggrecanolysis is not important in growth plate remodeling. In addition, lack of a growth plate phenotype in KOs for ADAMTS-1, ADAMTS-4, or ADAMTS-5, as well as a knock-in mouse engineered to resist aggrecanase-mediated aggrecanolysis, supports nonproteolytic mechanisms of aggrecan remodeling in the growth plate.80 MMP-13 remains a major focus of interest and is regarded

Table 14.1

Phenotypic Consequences of Gene Deficiency in Murine Models of Arthritisa Gene

Joint Phenotype

Reference

MMP-2 MMP-3

Exacerbates AIA, rescued by injection of wild-type fibroblasts No difference in proteoglycan depletion or inflammation compared with wild type after AIA, CIA, collagenase-induced instability, or MCL/PM models of OA. MMP aggrecan neoepitope VDIPEN detection minimal in AIA and AIA but similar to wild type in other models Reduced damage in AIA. Less severe arthritis in K/BxN serum–induced arthritis. Increased frequency and severity of Staphylococcus aureus–induced septic arthritis but not more destructive No difference to wild type in AIA but with less cartilage erosions even in severely arthritic mice Transient abnormalities in cartilage remodeling during bone growth and fracture healing. No cartilage erosion after induction of arthritis by DMM Severe skeletal defect, abnormal tooth development, arthritis development, premature death Abnormal tooth development No observed protection against cartilage damage after induction of OA by DMM Ablation of cartilage damage after DMM surgery compared with wild-type mice As above Mice lacking ADAM-17 in chondrocytes display an enhanced zone of hypertrophic chondrocytes and growth retardation of long bones Accelerated OA caused by increased periarticular vascularization Mild transient OA, with increased staining of the MMP-specific aggrecan neoepitope VDIPEN. Increased cartilage damage compared with wild type with aging. Transiently enhanced antibody induced arthritis but similar cartilage damage to wild type Significantly reduced cartilage erosion compared with wild type when crossed onto mice with an hTNFtg background, which spontaneously develop arthritis Significantly reduced cartilage erosion compared with wild type in AIA model

83

Protection against joint destruction after induction of OA by DMM. Protection observed up to 1 year after surgery. Reduced osteophyte formation, osteosclerosis, and pain perception

53,95

MMP-9

MMP-2/MMP-9 MMP-13 MMP-14 MMP-20 ADAMTS-4 ADAMTS-5 ADAMTS-4/5 ADAM-17 TIMP-2 TIMP-3

FAP-α Neutrophil serine proteases (neutrophil elastase and cathepsin G) PAR-2

84,85

83,86

83

82

87,88

89 90 47,78 79 91

92 93,94

56

49

A selection of proteinase-related genes is listed with the major joint phenotype presented.

a

ADAM, A disintegrin and metalloproteinase; AIA, antibody-induced arthritis; CIA, collagen-induced arthritis; DMM, destabilization of the medial meniscus; FAP, fibroblast activator protein; hTNFtg, mice overexpressing human tumor necrosis factor α; K/BxN, mice expressing the KRN T-cell receptor transgene and the MHC class II molecule Ag7 that spontaneously develop RA-like joint inflammation; MCL, medial collateral ligament; MMP, matrix metalloproteinase; OA, osteoarthritis; PAR-2, PAR-2, protease-activated receptor-2; PM, partial medial meniscotomy; TIMP, tissue inhibitors of metalloproteinases; VDIPEN, MMP-generated neoepitope of aggrecan; see Fig. 14.6.

CHAPTER 14  Joint tissue destruction and proteolysis as the major collagenase in OA.81 MMP-13 KO mice show only transient abnormalities in cartilage resorption during long-bone growth and fracture healing; however, when subjected to a surgical model of OA (DMM), cartilage erosion is inhibited in these mice even in the presence of aggrecan depletion, supporting the potential for therapeutic intervention in established OA with MMP-13 inhibitors. Furthermore, MMP-13 expression correlates with elevated hypertrophy-associated genes. The recapitulation of growth plate–like hypertrophic differentiation of chondrocytes indicates an important role in the pathogenesis of OA. However, in the MMP-13 KO DMM animals, hypertrophy markers were still detected in noneroded cartilage, suggesting that it is not the hypertrophic differentiation of chondrocytes per se that results in cartilage degradation but rather the hypertrophy-associated expression of MMP13. Of further interest was the observation that osteophytes still formed in the MMP-13 KO mice subjected to DMM, thus implying that osteophyte formation is not linked to MMP13-driven articular cartilage destruction but to other factors, potentially joint instability.82 Mice deficient in TIMP-1 exhibit no major phenotype, but TIMP-2 deficiency accelerates OA-like changes. In TIMP-3 KO mice, there is a mild but transient OA with increased proteoglycan loss and increased generation of the VDIPEN neoepitope indicating MMP-mediated cleavage of aggrecan. As TIMP-3 KO mice age, there is evidence of increased cartilage catabolism; lack of TIMP-3 will lead to an altered metalloproteinase–TIMP balance, and the higher levels of TNF could also be due to lack of inhibition of the metalloproteinase TNF–converting enzyme (TACE or ADAM-17).93 Recently it has been demonstrated that mice overexpressing a mutant form of TIMP-3, which inhibits only aggrecanases (not MMPs), is able to protect against cartilage degradation in the STR/Ort mouse model of spontaneous OA,96 further demonstrating the importance of cartilage proteoglycan loss, prior to that of collagen. Studies in KO mice are a powerful approach for defining protein function, and application of these KO experiments in mouse models of diseases has shown that MMPs serve specific roles in a variety of pathologic processes. These data need to be interpreted carefully because of significant differences between mice and humans in MMP expression (e.g., MMP-1), gene redundancy, and the distribution of load across joints. However, these models remain an important platform to investigate novel targets as therapeutic interventions.

THERAPEUTIC INHIBITION OF PROTEINASES Notwithstanding the strong evidence, use of synthetic proteinase inhibitors as drugs to prevent joint destruction in the arthritides has been disappointingly unsuccessful to date. Compounds that inhibit MMPs are the most studied,12 with the aim of treatment being to shift the balance away from matrix degradation to prevent further loss of connective tissue matrix without leading to excess synthesis. Initial problems with the oral availability of MMP inhibitors have been overcome, but despite favorable results in the treatment of some cancers, trials of compounds that inhibit the collagenases in patients with RA have not been successful. It may be that the compounds used were unsuitable or that collagenases are not the best target. It is not known whether sufficient penetration of cartilage by these compounds was achieved or whether their specificity was altered during absorption. The antibiotic doxycycline and derivatives with no antibiotic activity weakly inhibit MMPs, and these compounds have been licensed for the treatment of periodontal disease. They are also effective in animal models of arthritis and have therefore been proposed as a treatment to prevent cartilage damage. In a randomized placebo-controlled trial of women who were overweight and with unilateral radiographic knee OA, those randomized to doxycycline 100 mg twice daily had a 33% reduction in the mean amount of joint space narrowing over a period of 30 months.97 It is possible that specific TIMPs could be used successfully in the future to halt the progressive and chronic destruction of connective tissue seen in the arthritides. It may be necessary to combine different proteinase inhibitors, either in sequence or with other agents that target different but specific steps in the disease pathogenesis. This approach may include targeting families of proteinase other than metalloproteinases,30 before the chronic cycle of joint destruction can be broken (see Fig. 14.1). Recent interest has begun to focus on compounds that target events before the induction of these destructive genes. Some compounds that block specific signal transduction pathways have been shown to prevent cartilage destruction in vitro, and compounds are in development that specifically inhibit the Janus kinases as an oral disease–modifying therapy.98

REPAIR OF CONNECTIVE TISSUE MATRIX Cartilage metabolism may be altered by effects on cellular proliferation, migration, or differentiation and the control of individual genes. The effect of any

127

particular growth factor also depends on the differentiation state of the cell. Various types of cells in tissues may respond differently to particular cytokines and growth factors. Other local conditions, such as mechanical loading, oxygen tension, and the presence of other factors, also affect these responses. Similarly, cartilage homeostasis is regulated by the circadian clock. Diseased joints have areas of cartilage in which new matrix synthesis occurs, as well as net loss of ECM. Growth factors play major roles in regulating normal matrix synthesis and in the processes that protect cartilage in disease. Growth factors such as TGF-β and bone morphogenic proteins (BMPs) have direct effects on chondrocytes and are known to be involved in matrix deposition in OA (e.g., osteophyte generation).99 However, TGF-β is also known to induce MMP-13 expression under some circumstances, and decreasing TGF-β responsiveness with increasing age may be an important caveat for effective tissue repair in disease. Other factors, such as hormones, corticosteroids, prostaglandins, peptides, or retinoids, may also influence cellular responses to these growth factors. Transforming growth factor β (TGF-β) and IGF-1 have profound effects on the synthesis of matrix components by chondrocytes.100 TGF-β can downregulate the production of several matrix-degrading proteinases and upregulate proteinase inhibitors such as TIMP-1 or plasminogen activator inhibitor-1 (PAI-1), thus suggesting that it may prevent cartilage destruction by both stimulating synthesis and blocking degradative pathways. TGF-β is locally synthesized by chondrocytes, affects protein synthesis, and potentiates the stimulation of DNA synthesis achieved with other growth factors rather than initiating this itself. IGF-1 mimics many of the actions of TGF-β and has a significant effect on matrix synthesis but does not have the same mitogenic properties or affect protein synthesis to the same extent. Within cartilage, TGF-β and IGF-1 are stored in considerable quantities bound to different matrix components. More recently, connective tissue growth factors and members of the BMP family have been shown to have anabolic effects on cartilage and bone. The source of growth factors varies: They can be produced by cells outside the cartilage and diffuse in or they can be produced locally by chondrocytes. The control mechanisms are complex and growth factors also exist in a latent form; other proteins, such as IGFBPs, may be present that sequester the factors and prevent them from binding to cellular receptors. The activity of some MMPs can cause the release of growth factors as matrix is degraded. This provides positive feedback mechanisms that redress the balance between degradation and synthesis of matrix components. Growth factors are recognized as being protective of cartilage, stimulating matrix synthesis, and blocking the effects of proinflammatory cytokines. Other factors also protect joint tissues. Interferon-γ inhibits cytokine-stimulated bone resorption and IL-1- or TNF-stimulated collagenase production by chondrocytes and reduces IL-1-stimulated release of prostaglandin from cartilage. IL-4, IL-13, and IL-10 have all been shown to oppose the effects of these proinflammatory cytokines by blocking MMP secretion or activation or increasing inhibitor production and matrix synthesis. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) can also affect cartilage homeostasis by inducing cells to migrate, differentiate, or proliferate. In addition, bFGF stimulates the production of plasminogen activator inhibitor and TIMP-1 in fibroblasts and endothelial cells. All of these growth factors are likely to stimulate cartilage repair, and many do not act alone but rather synergistically to promote the synthesis of new matrix. Recent research has demonstrated that connective tissue homeostasis is under partial control by the local circadian clock, disruption of which leads to mechanically dysfunctional tissue and potentially disease. Many genes in cartilage are rhythmically regulated (potentially because of growth factor circadian regulation), including many matrix genes. Disruption of the circadian rhythm in cartilage chondrocytes predisposes mice to OA-like pathological changes.101 Remarkable work focusing on the tendon tissue has demonstrated that although the majority of collagen (fibrils) persist unchanged throughout life, a pool of collagens is daily synthesized and removed, by cathepsin K, under the control of the circadian clock.102 These and other studies indicate that timing of administration should be a major consideration for potential connective tissue related therapeutics.103

ACKNOWLEDGMENTS The authors thank Professor Tim Cawston and Professor Drew Rowan, who were authors of previous editions of this chapter.

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3. Jubb RW, Fell HB. The breakdown of collagen by chondrocytes. J Pathol. 1980;130(3):159–167. 4. Rawlings ND, Barrett AJ, Finn R. Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 2016;44(D1):D343–350. 5. Perez-Silva JG, Espanol Y, Velasco G, Quesada V. The Degradome database: expanding roles of mammalian proteases in life and disease. Nucleic Acids Res. 2016;44(D1):D351–355. 6. Rahmati M, Mobasheri A, Mozafari M. Inflammatory mediators in osteoarthritis: a critical review of the state-of-the-art, current prospects, and future challenges. Bone. 2016;85:81–90. 7. Burleigh A, Chanalaris A, Gardiner MD, et al. Joint immobilization prevents murine osteoarthritis and reveals the highly mechanosensitive nature of protease expression in vivo. Arthritis Rheum. 2012;64(7):2278–2288. 8. Li Y, Wei X, Zhou J, Wei L. The age-related changes in cartilage and osteoarthritis. Biomed Res Int. 2013;2013:916530. 9. 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Serine proteinases in the turnover of the cartilage extracellular matrix in the joint: implications for therapeutics. Br J Pharmacol. 2019;176(1):38–51. 31. Wilkinson DJ, Desilets A, Lin H, et al. The serine proteinase hepsin is an activator of pro-matrix metalloproteinases: molecular mechanisms and implications for extracellular matrix turnover. Sci Rep. 2017;7(1):16693. 32. Milner JM, Patel A, Davidson RK, et al. Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arthritis Rheum. 2010;62(7):1955–1966. 33. Milner JM, Rowan AD, Elliott SF, Cawston TE. Inhibition of furin-like enzymes blocks interleukin-1alpha/oncostatin M-stimulated cartilage degradation. Arthritis Rheum. 2003;48(4):1057–1066. 34. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69(3):562–573. 35. Murphy G, Nagase H. Localizing matrix metalloproteinase activities in the pericellular environment. FEBS J. 2011;278(1):2–15. 36. Yamamoto K, Troeberg L, Scilabra SD, et al. LRP-1-mediated endocytosis regulates extracellular activity of ADAMTS-5 in articular cartilage. FASEB J. 2013;27(2):511–521. 37. Scilabra SD, Troeberg L, Yamamoto K, et al. Differential regulation of extracellular tissue inhibitor of metalloproteinases-3 levels by cell membrane-bound and shed low density lipoprotein receptor-related protein 1. J Biol Chem. 2013;288(1):332–342.

38. Yamamoto K, Okano H, Miyagawa W, et al. MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1. Matrix Biol. 2016;56:57–73. 39. Yamamoto K, Owen K, Parker AE, et al. Low density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytic clearance of a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4): functional differences of non-­ catalytic domains of ADAMTS-4 and ADAMTS-5 in LRP1 binding. J Biol Chem. 2014;289(10):6462–6474. 40. Yamamoto K, Santamaria S, Botkjaer KA, et al. Inhibition of shedding of low-density lipoprotein receptor–related protein 1 reverses cartilage matrix degradation in osteoarthritis. Arthritis Rheumatol. 2017;69(6):1246–1256. 41. Yu WH, Yu S, Meng Q, Brew K, Woessner Jr. JF. TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix. J Biol Chem. 2000;275(40):31226–31232. 42. Lee MH, Atkinson S, Murphy G. Identification of the extracellular matrix (ECM) binding motifs of tissue inhibitor of metalloproteinases (TIMP)-3 and effective transfer to TIMP-1. J Biol Chem. 2007;282(9):6887–6898. 43. Troeberg L, Lazenbatt C, Anower EKMF, et al. Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3. Chem Biol. 2014;21(10):1300–1309. 44. Tocchi A, Parks WC. Functional interactions between matrix metalloproteinases and glycosaminoglycans. FEBS J. 2013;280(10):2332–2341. 45. Yamamoto K, Murphy G, Troeberg L. Extracellular regulation of metalloproteinases. Matrix Biol. 2015;44-46:255–263. 46. Kelwick R, Desanlis I, Wheeler GN, Edwards DR. The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family. Genome Biol. 2015;16:113. 47. Stanton H, Rogerson FM, East CJ, et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature. 2005;434(7033):648–652. 48. Wang Q, Rozelle AL, Lepus CM, et al. Identification of a central role for complement in osteoarthritis. Nat Med. 2011;17(12):1674–1679. 49. Adkison AM, Raptis SZ, Kelley DG, Pham CT. Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J Clin Invest. 2002;109(3):363–371. 50. Milner JM, Patel A, Rowan AD. Emerging roles of serine proteinases in tissue turnover in arthritis. Arthritis Rheum. 2008;58(12):3644–3656. 51. Palmer HS, Kelso EB, Lockhart JC, et al. Protease-activated receptor 2 mediates the proinflammatory effects of synovial mast cells. Arthritis Rheum. 2007;56(11):3532–3540. 52. Crilly A, Palmer H, Nickdel MB, et al. Immunomodulatory role of proteinase-activated receptor-2. Ann Rheum Dis. 2012;71(9):1559–1566. 53. Ferrell WR, Kelso EB, Lockhart JC, Plevin R, McInnes IB. Protease-activated recep tor 2: a novel pathogenic pathway in a murine model of osteoarthritis. Ann Rheum Dis. 2010;69(11):2051–2054. 54. Ospelt C, Mertens JC, Jungel A, et al. Inhibition of fibroblast activation protein and dipeptidylpeptidase 4 increases cartilage invasion by rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2010;62(5):1224–1235. 55. Croft AP, Campos J, Jansen K, et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature. 2019;570(7760):246–251. 56. Waldele S, Koers-Wunrau C, Beckmann D, et al. Deficiency of fibroblast activation protein alpha ameliorates cartilage destruction in inflammatory destructive arthritis. Arthritis Res Ther. 2015;17:12. 57. Vasiljeva O, Reinheckel T, Peters C, Turk D, Turk V, Turk B. Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr Pharm Des. 2007;13(4):387–403. 58. Mort JS, Beaudry F, Theroux K, et al. Early cathepsin K degradation of type II collagen in vitro and in vivo in articular cartilage. Osteoarthritis Cartilage. 2016 59. Everts V, van der Zee E, Creemers L, Beertsen W. Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling. Histochem J. 1996;28(4):229–245. 60. Matzelle MM, Gallant MA, Condon KW, et al. Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis Rheum. 2012;64(5):1540–1550. 61. Gravallese EM, Goldring SR. Cellular mechanisms and the role of cytokines in bone erosions in rheumatoid arthritis. Arthritis Rheum. 2000;43(10):2143–2151. 62. Svelander L, Erlandsson-Harris H, Astner L, et al. Inhibition of cathepsin K reduces bone erosion, cartilage degradation and inflammation evoked by collagen-induced arthritis in mice. Eur J Pharmacol. 2009;613(1–3):155–162. 63. Matzelle MM, Shaw AT, Baum R, et al. Inflammation in arthritis induces expression of BMP3, an inhibitor of bone formation. Scand J Rheumatol. 2016:1–5. 64. Hou WS, Li W, Keyszer G, et al. Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum. 2002;46(3):663–674. 65. Tanaka M, Yamada H, Nishikawa S, et al. Joint degradation in a monkey model of collagen-induced arthritis: role of cathepsin K based on biochemical markers and histological evaluation. Int J Rheumatol. 2016;2016:8938916. 66. Pettit AR, Ji H, von Stechow D, et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol. 2001;159(5):1689–1699. 67. Gravallese EM, Manning C, Tsay A, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 2000;43(2):250–258. 68. Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8(11):656–664. 69. Schett G, Redlich K, Hayer S, et al. Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice. Arthritis Rheum. 2003;48(7):2042–2051. 70. Koshy PJ, Henderson N, Logan C, Life PF, Cawston TE, Rowan AD. Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines. Ann Rheum Dis. 2002;61(8):704–713. 71. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697–1707. 72. Pierer M, Muller-Ladner U, Pap T, Neidhart M, Gay RE, Gay S. The SCID mouse model: novel therapeutic targets—lessons from gene transfer. Springer Semin Immunopathol. 2003;25(1):65–78.

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15

Principles of tissue engineering and cell- and gene-based therapy Lars Rackwitz • Ulrich Nöth • Andre F. Steinert • Rocky S. Tuan

Key Points ■ Tissue engineering is an interdisciplinary research approach that combines the principles and methods of engineering sciences, cell and molecular biology, and clinical medicine with the aim of replacing injured or degenerated human tissues. ■ The central dogma of tissue engineering states that a target tissue–specific template for replacing injured tissue relies on three principal components: cells, cell carriers (scaffolds), and external stimuli (e.g., growth factors or mechanobiologic stimuli). ■ Mesenchymal stem cells are the most promising cell candidate for musculoskeletal tissue engineering because they can easily be obtained from the bone marrow, adipose, muscle, bone, and other mesodermally derived tissues; possess high expansion capacity; are able to differentiate into a number of mesenchymal lineages; and exhibit immune suppressive effects. ■ Innovative production methods, including electrospinning, three-dimensional bioprinting, and others, allow the fabrication of biomimetic, target tissue–specific three-dimensional templates using synthetic or natural polymers (or from both). ■ Various gene products (e.g., interleukin-1 receptor antagonist [IL-1ra], IL-4, IL-10, IL-13, IL-27, IL-35, nuclear factor-κβ, and transforming growth factor-β) have been identified as potential therapeutic agents for treating rheumatic disorders; gene delivery can be realized via viral (transduction) and nonviral (transfection) gene therapy technologies, applied in situ or via exogenous means.

INTRODUCTION Tissue engineering and cell-based therapies are emerging disciplines that constitute the principal technologies in the field of regenerative medicine. These technologies are directed toward self-regeneration and involve the use of biomaterials or biologically active molecules, application of differentiated or undifferentiated cells, functional tissue engineering, organ transplantation, and process technologies, as well as the development of regulatory standards (Fig. 15.1). For example, in orthopedic surgery, the repair of focal articular cartilage defects in young adults using (matrix-based) autologous chondrocyte implantation ((m)ACI) has become an established procedure. On the other hand, the repair of degenerated cartilage lesions that arise from diseases such as osteoarthritis (OA) or rheumatoid arthritis (RA) remains an unmet orthopedic challenge. The key underlying cause of this challenge is the inflammatory environment that drives the competing anabolic and catabolic processes toward extensive joint and cell-transplant degeneration.1, 2 As a result of intensive research in the past 2 decades, adult mesenchymal stem cells (MSCs) have emerged as a promising candidate cell type for the treatment of arthritic joint diseases, principally owing to their well-characterized ability to differentiate along the chondrogenic pathway and their recently demonstrated antiinflammatory, antiapoptotic, and immunosuppressive properties through trophic mediators.3

TISSUE ENGINEERING Tissue engineering is an interdisciplinary research approach that aims for replacement of injured or degenerated human tissues to restore their form, structure, and function by combining principles and methods of engineering sciences, cell and molecular biology, and clinical medicine.4, 5 Since its beginning in the 1980s, “tissue engineering” has developed into its own scientific and clinical discipline, with potential application for almost every tissue of the human body. The central dogma of tissue engineering states that a target tissue–specific template for replacing injured or degenerated tissue relies on three principal components: cells, cell carriers (scaffolds), and external stimuli (e.g., bioactive molecules, including growth factors and genes, or mechanobiologic stimuli) (Fig. 15.2). In the context of tissue engineering, the basic function of the scaffold is to provide a temporary structure for the seeded cells or migrating host cells to adhere to and enable the subsequent production of new native extracellular matrix (ECM) in a shape and form guided by the scaffold. The main 130

criteria for scaffold design include controlled biodegradability, suitable mechanical strength, and appropriate surface chemistry, as well as the ability to regulate cellular activities, such as proliferation, cell–cell and cell–matrix interactions, and directed differentiation.5–8 Scaffolds can be manufactured from native or synthetic polymers, with native materials exhibiting optimal biocompatibility and biodegradability, but synthetic polymers have higher primary stability and are more accessible for macro- or microstructure formation.6 A key requirement for a tissue engineering scaffold is an optimal porosity to facilitate nutrition, proliferation, and migration of cells and to ensure cell colonization of the entire carrier. Scaffolds that are biomimetic in nature are particularly desirable to promote cellular activities critical for neotissue formation, such as signaling, proliferation, differentiation, matrix production, and cell–matrix interaction.8 Although primary, tissue-specific cells (i.e., chondrocytes) are inherently the most suitable cell source for cartilage tissue engineering; they have limitations in practice because of the shortage of supply, loss of phenotype during culture expansion, and potential donor-site morbidity after harvest.6, 9

AUTOLOGOUS CHONDROCYTE IMPLANTATION An established procedure for the treatment of symptomatic chondral or osteochondral defects of the knee joint guided by the principles of tissue engineering is the first generation of ACI, originally developed by Brittberg and coworkers more than 2 decades ago.10 In this procedure, chondrocytes are first enzymatically isolated from a cartilage biopsy and then culture-expanded in vitro. The second surgical procedure involves knee joint exposure via an arthrotomy, debridement of the cartilage defect, and suturing of a periosteal patch or collagen membrane over the defect to obtain a cavity into which the culture-expanded chondrocytes, suspended in a collagen solution, can be injected and secured by sealing with fibrin glue. The long-term results of this technique exhibit predominantly good to very good clinical results in more than 70% of patients11 and reveal superior results compared with a sole debridement or osteochondral cylinder transplantation.12 However, ACI exhibits several disadvantages that have to be addressed. The use of periosteum can result in hypertrophy, calcification, and delamination of the transplant,13 and the cell suspension has the potential to leak, thus compromising the development of sufficient neotissue at the defect site. Experimental and clinical research has been directed toward the development of matrix-associated procedures of ACI, whereby biocompatible scaffolds are used as a vehicle to achieve secure delivery of primary chondrocytes to the defect site. Today, clinical experience and promising clinical outcome data using collagen type I membranes or hydrogels,14 a copolymer of polylactic acid (PLA) and polyglycolic acid (PGA), polyglactin and Vicryl, polydioxanone, and hyaluronic acid have been reported.6 For example, the utilization of a collagen type I hydrogel, which minimizes potential chondrocyte dedifferentiation, as seen in monolayer, by providing a three-dimensional (3D) environment subsequent to enzymatic cell isolation, results in homogeneous cell distribution and promotes cartilage-specific cell differentiation and ECM deposition within the scaffold.14, 15 In contrast to the surgical treatment of focal articular cartilage lesions, which can result from acute injury or osteochondrosis dissecans, regenerative approaches for the treatment of OA or RA must take into consideration that cartilage damage arises from an underlying disease process. It is noteworthy that acute cartilage injury and osteochondrosis dissecans often take place in an otherwise healthy joint. The patient may be young and thus a localized treatment may be sufficient to repair the focal defect. On the other hand, in OA and RA, the patient is likely to be older and thus requires the treatment of at least one compartment or the entire articulating tissue complex. In addition, the inflammatory conditions in the joint will likely lead to degradation of any engineered cartilage.16 Consequently, unless the underlying disease is treated effectively and technologies are available to restore whole compartments, any cell-based treatment in OA and RA is unlikely to be of long-term benefit.

CHAPTER 15  Principles of tissue engineering and cell- and gene-based therapy

131

SYNOPSIS OF REGENERATIVE MEDICINE Regenerative medicine Transplantation medicine Activated self-regeneration

Somatic cell therapy

Biomaterials

Bioactive molecules

Tissue engineering

Gene therapy

Cells • Undifferentiated

Cells • Undifferentiated • Differentiated

Process technology • Cell culture • Bioreactors • Operation monitoring • Logistics

Cells • Differentiated

Biomaterials

Regulatory affairs • FDA/EMA • Preclinical trials • Clinical trials

Bioactive stimuli • Growth factors • Mechanical

FIG. 15.1  Principal technologies of regenerative medicine targeting the reconstruction of damaged or diseased human tissue and organ function. EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration.

THE CLASSIC TISSUE ENGINEERING TRIAD AND THEIR FUNCTIONAL COMPONENTS Cells • Differentiated, progenitor/stem cells • Autologous, allogeneic • Genetically modified

Biomaterials • Natural, synthetic polymers • Sponges, meshes, nanofibers, hydrogels, etc.

been identified, an immunophenotype positive for STRO-1, CD73, CD146, and CD106 and negative for CD11b, CD45, CD34, CD31, and CD117 has been shown to most reliably characterize the MSC population based on activities such as colony formation, clonogenicity, extended expansion in vitro, and multilineage differentiation potential.7, 17–19 For the purpose of cartilage regeneration, extensive analyses of microenvironments that promote chondrogenesis in MSCs in vitro have been performed. Conditioning the culture medium with growth factors such as fibroblast growth factor-2 (FGF-2) or transforming growth factor-β (TGF-β) during monolayer expansion enhances positive selection for chondroprogenitor cells.20 The development of effective methods to maintain an articular cartilage phenotype without hypertrophy, ossification, or fibrinogenesis and a delivery system to localize the cells within a lesion without compromising their chondrogenic differentiation or the integrity of the repair tissue are additional requirements for the use of MSCs in articular cartilage regeneration.6, 7, 9, 21, 22

INTRAARTICULAR INJECTION OF MESENCHYMAL STEM CELLS

Bioactive stimuli • Factors: TGFs, BMPs, IGFs, VEGF, etc. • Mechanical: compression, tension, hydrostatic pressure, perfusion, etc.

FIG. 15.2  Functional components of the classic tissue engineering triad. BMP, Bone morphogenetic proteins; IGF, insulin-like growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

MESENCHYMAL STEM CELLS The advantage of adult MSCs, potentially overcoming the shortcomings of chondrocytes, is that they can be readily obtained from a bone marrow aspirate or other mesodermally derived tissues, possess high expansion capacity, and are able to differentiate into a number of mesenchymal lineages.7, 17, 18 In particular, MSCs have been shown to undergo efficient chondrogenic differentiation in vitro and in vivo.7, 15, 18 MSCs are commonly isolated from adult tissue-derived cell mixtures by virtue of their avid adherence to cell culture plastic substrate or by density-gradient fractionation and are intrinsically a heterogeneous cell population. Although no definitive MSC marker(s) have

Intraarticular injection of MSCs into the joint space is, at least conceptually, the simplest approach for their application in rheumatic diseases (Fig. 15.3, a). Because the synovium lines all of the internal surfaces of the joint space, except for cartilage and meniscus, and is highly cellular, it is likely to be a primary tissue for interaction with MSCs. Murphy and associates delivered autologous MSCs via a dilute solution of sodium hyaluronan (HA) in knee joints using a goat OA model, induced by a total medial meniscectomy and resection of the anterior cruciate ligament.23 In cell-treated joints, there was evidence of marked regeneration of the medial meniscus, and implanted cells were detected in the newly formed tissue. Articular cartilage degeneration, osteophytic remodeling, and subchondral sclerosis also were reduced. Whether the changes observed in the MSC-treated joints resulted from repair tissue formation by the transplanted cells or the interaction of MSCs with host synovial fibroblasts at the site of injury remains unclear.23 Thus far, only a limited number of clinical trials on the direct intraarticular injection of MSCs have been performed.24–26 In a phase I/II clinical trial, 30 patients with OA of the knee joint were treated by intraarticular injection of either 10 or 100 × 106 autologous bmMSC in HA or HA without cells (placebo). Twelve months after the injection, both cell groups revealed superior functional scores (WOMAC) and pain reduction (VAS) compared to the placebo group. However, only the application of 100 × 106 bmMSCs delayed progression of the OA as evidenced by magnetic resonance imaging T2 mapping quantification and standard x-ray views.24 These encouraging results are supported by the work of Jo and coworkers.25 OA knee joints of

132

SECTION 1  Scientific Basis of Rheumatic Disease DELIVERY OF CELLS TO DISEASED CARTILAGE IN PATIENTS WITH ARTHRITIC DISEASES

Vector

Cells

Cells +

Suspension

Selection

Growth factors

Bioreactor Genetically modified cells

Ex vivo

In vivo

Matrix

Suspension Intraarticular injection

Matrix

Matrix-guided repair

Joint

a

Intraarticular injection

b

Matrix-guided repair

Joint

FIG. 15.3  (a) Cell-based therapy for cartilage tissue engineering. Cells in suspension (i.e., ex vivo-expanded mesenchymal stem cells, cell concentrates from bone marrow aspirate or adipose tissue) can be injected directly into the joint cavity, where they encounter all intraarticular tissues and might function via trophic mediators and exhibit chondroprotective or regenerative effects. Otherwise, cells (i.e., mesenchymal stem cells, chondrocytes) can be implanted in a matrix-guided manner into the cartilage defect after ex vivo conditioning with biochemical or biomechanical stimulation (or both biochemical and biomechanical stimulation). (b) Gene therapy approach for cartilage tissue engineering. Vectors can be directly injected in an intraarticular mode for in vivo gene delivery, or primary cells can be used as vehicles for ex vivo gene delivery. In the latter, successfully transduced cells can be applied to the joint cavity either by intraarticular injection as a suspension or seeded within a matrix that can be implanted into a cartilage defect. Depending on which delivery approach is chosen, ubiquitous or local transgene expression is induced by the ex vivo genetically modified cells or by resident cells that are transduced via intraarticular vector application. 18 patients were treated by intraarticular delivery of 10, 50, or 100 × 106 autologous MSCs derived from adipose tissue. An improvement in functional scores (WOMAC, KOOS) and reduction in knee pain was detected for all cell doses at 12 months, whereby only the high cell dose led to an prolonged improvement at 24 months after cell injection.25 In another clinical trial (ADIPOA) conducted in France and Germany, 18 patients with severe knee OA were treated with a single intraarticular injection of autologous adipose-derived MSCs.26 The trial design consisted of three cohorts, six patients each; the first cohort received a low dose (2 × 106 cells), the second a medium dose (10 × 106 cells), and the third a high dose (50 × 106 cells). A remarkable improvement in knee pain, function, and mobility regardless of the injected dose was observed at the 6-month follow-up time point. Interestingly, the improvement was statistically significant only in the low-dose cohort. Based on the OARSI/OMERACT criteria, the low-dose group revealed the highest responder rate (80%), thus outperforming the medium- and high-dose groups with a responder rate of 60%, respectively.26 Overall, the intraarticular delivery of MSCs can be considered a safe procedure, and so far no cell-related serious adverse events have been observed in the reported trials.24–26

CELL CONCENTRATES Treatment strategies utilizing ex vivo expanded autologous MSCs have most commonly employed two-stage surgical procedures involving tissue harvest, cell isolation, MSC expansion, and subsequent implantation.

Although two-stage procedures can yield millions of autologous MSCs through ex vivo culture expansion, the associated economic, regulatory, and logistical challenges limit clinical translation.27 To overcome these challenges, single-stage procedures in which cells are harvested and implanted intraoperatively have been developed, and the results showed stimulation of regeneration comparable to that with two-stage MSC-based therapies. In particular, bone marrow aspirate concentrates (BMACs)28 derived from bone marrow aspirate by centrifugation or the stromal vascular fraction (SVF)29 obtained from adipose tissue by collagenase digestion and/or mechanical centrifugation, both consisting of a heterogeneous cell population with varying percentages being MSCs,28, 29 have been reported to stimulate cartilage formation.27, 28

Bone marrow aspirate concentrate Red blood cells, granulocytes, immature myeloic progenitor cells, and thrombocytes are eliminated from the bone marrow aspirate by centrifugation. The resulting BMAC consists of mesenchymal and hematopoietic stem cells as well as growth factors, such as PDGF, TGF-β, BMP-2/7, and interleukin 1 receptor antagonist (IL-1ra),2 at varying concentrations. The clinical efficacy of BMAC-laden scaffold material in the treatment of focal chondral defects was reviewed in a meta-analysis by Chahla and coworkers.30 All clinical trials (n = 8) reported a good to excellent functional outcome and significant reduction in knee pain up to 24 months after the intervention. Similarly, a significant reduction in knee pain and functional improvement was reported after intraarticular injection of BMAC into OA

CHAPTER 15  Principles of tissue engineering and cell- and gene-based therapy knee joints in three independent clinical trials. The results showed superior results with BMAC injection when applied to patients with mild to moderate OA (Kellgren–Lawrence II–III).31–33

Stromal vascular fraction In general, the SVF can be isolated from adipose tissue (e.g., abdominal adipose tissue, infrapatellar fat pad) by tissue dissection, enzymatic digestion, and/or centrifugation and consists of a heterogeneous cell population consisting of mesenchymal precursor cells, preadipocytes, endothelial cell, pericytes, macrophages, and T-cells, as well as different growth factors.27, 29, 34 The additive application of SVF in the treatment of degenerative cartilage lesions has shown promising clinical outcomes. Patients who underwent a microfracturing procedure with subsequent additional intraarticular injection of SVF revealed significantly higher functional outcome and pain reduction after 18 months when compared to patients receiving the microfracturing procedure alone.35 In general, the use of BMAC or SVF has been shown to be safe and have some short-term beneficial effects regarding the clinical efficacy in the treatment of knee cartilage pathologies.36 Currently, available data are undermined by the lack of high-quality studies, the varying clinical settings, and different treatment protocols reported in the few randomized clinical trials (RCTs) published so far, thus preventing a clear recommendation on the use of either product in clinical practice.34, 36

MATRIX-GUIDED APPLICATION OF MESENCHYMAL STEM CELLS A more controlled method of cell application to restore the eroded cartilage surface is via a scaffold (see Fig. 15.3, a). Seeding MSCs onto or into a scaffold, such as a biodegradable template, for proliferation and matrix production offers the advantage of providing an accessible, easy-to-manipulate, self-renewing source of otherwise spatially limited progenitor cells.

Synthetic scaffolds Synthetic scaffolds offer the advantage of design manipulation, such as fiber diameter, pore size, degradation time, and reproducible fabrication. Many commonly studied synthetic scaffolds in cartilage repair are fabricated using α-hydroxypolyesters, including PGA, PLA, their copolymer poly(lactic-co-glycolic acid) (PLGA), and poly-ε-caprolactone (PCL).6, 8, 21, 37–41

Natural scaffolds On the other hand, native biomaterials, including collagen type I, hyaluronic acid, chitosan, and alginate,6, 9, 14, 15, 21, 40, 41 offer the advantage of presenting a more natural microenvironment. These matrices are biodegradable; can be metabolized by the cells via the action of endogenous enzymes, such as collagenases, proteases, and glycohydrolases; elicit very limited, if any, inflammatory reaction; and offer a 3D microenvironment of biomaterials presenting molecular epitopes of the extracellular matrix. A recent approach is the application of decellularized tissue matrices from human or animal tissues. These offer the potential of preserving the biochemical composition and structural properties of native tissues. Decellularization can be achieved via chemical (e.g., sodium dodecyl sulfate, Triton X-100), physical (e.g., freezing in liquid nitrogen), and enzymatic (e.g., trypsin treatment) processes. After in vitro decellularization and prior to in vivo implantation, cells may be seeded into these matrices and cultured under various skeletogenic conditions to promote cell differentiation and new tissue formation. Common challenges associated with using decellularized matrix as scaffold include the risk of eliciting inflammatory responses.42 Another approach is the extraction of matrix-derived bioactive components via the preparation of a solubilized extract from decellularized tendon/ligament tissues, which have been found to promote tissue-specific differentiation of MSCs, including chondrogenesis.43–45

Fabrication methods Both synthetic and natural polymers may be fabricated into biomaterial scaffolds that take the forms of hydrogel, sponge, and micro- and nanofibrous mesh.6, 8, 37–41 Hydrogel formation may be carried out using thermal, ion-chelation, or chemical or photo-crosslinking, and fibers may be formed by extrusion, electrospinning, or 3D printing technologies.41–43 Mechanical properties, including elasticity and stiffness, porosity, and hydration efficiency, must also be considered and optimized. Finally, recently developed image-guided 3D printing technologies have greatly enhanced the capability of precision scaffold manufacturing.46, 47 For example, visible light– based projection stereolithography represents a convenient and cell-friendly approach to fabricate MSC-seeded hydrogel constructs to engineer chondral and biphasic osteochondral tissues.48–50 Several clinical studies on the transplantation of ex vivo-expanded MSCs alone or in association with a cell carrier for the repair of isolated full-thickness

133

cartilage defects have been reported.51–53 Based on the available early evidence, implantation of MSCs appears to be a successful treatment for focal traumatic chondral and osteochondral defects. Clinical outcomes improved with time over 24 months after implantation in the majority of patients with focal chondral and osteochondral lesions of the knee and ankle.51–53 It is noteworthy that these studies have been performed on isolated or focal articular cartilage defects in an otherwise healthy joint. A very different tissue microenvironment exists as a result of loss of joint homeostasis in OA or RA and thus influences MSC engraftment and differentiation.16, 22 Generally, cartilage lesions in OA and RA are large, unconfined, and often opposed (“kissing lesion”) and affect more than one location. Thus, it is important to point out that current biologic and technologic developments are as yet inadequate to indicate sufficient retention of cell-loaded scaffolds in OA or RA lesions.16

TROPHIC AND IMMUNOSUPPRESSIVE EFFECTS OF MESENCHYMAL STEM CELLS Although the exact mechanisms that guide homing of the implanted or mobilized cells are not known, it is clear that MSCs themselves secrete a broad spectrum of bioactive molecules that have immunoregulatory54, 55 or regenerative activities.56 The secreted bioactive factors have been shown to inhibit tissue scarring, suppress apoptosis, stimulate angiogenesis, and enhance mitosis of tissue-intrinsic stem or progenitor cells. Because of the complex, multifaceted secretory activity of MSCs, these cells also have been referred to as “medicinal signaling cells,” distinct from their differentiation capacity.57 MSCs are potent modulators of immune response, exhibiting antiproliferative capacities.58 They inhibit the proliferation of T lymphocytes induced by allergens, mitogens, or anti-CD3 and anti-CD28 antibodies. T-cell proliferation is inhibited through cell cycle arrest in the G0/G1 phase.59 They also modulate the function of major immune cell populations, including CD8+ cytotoxic T lymphocytes, B lymphocytes, and natural killer (NK) cells.60 The immunosuppressive activity of MSCs is induced by a combination of inflammatory cytokines present in the local environment, including interferon-γ (IFN-γ), TNF-α, and IL-1α or IL-1β.61 In addition, MSCs have significant effects on dendritic cell function by altering generation and maturation of dendritic cells and skewing their function toward a regulatory phenotype.62 Two other key mechanisms are based on the expression of the inducible nitric oxide (NO) synthase and indoleamine 2,3-dioxygenase (IDO) enzymes.63 Another important mediator of immunosuppression secreted by MSCs is HLA-G. HLA-G is a nonclassic HLA class 1 molecule, shown to suppress proliferation of CD4+ T cells, induce apoptosis of CD8+ T cells, and inhibit NK cells.64 MSCs can modulate B-cell responses depending on the ratio of both cell types. Indeed, at low ratio, MSCs inhibit the proliferation and activation of B cells, similar to their effect on T cells.65

GENE TRANSFER STRATEGIES Recent advances in cellular, molecular, and developmental biology have led to the identification of various gene products that might serve as therapeutic agents for treating rheumatic disorders, some of which are listed in Table 15.1. Because exogenous DNA is not spontaneously taken up and expressed by cells in an efficient manner, genes have to be transferred to cells with the aid of vehicles or vectors. These can be assigned to two broad categories: those that are derived from viruses and those that are not. Viral gene delivery is known as transduction, and viral vectors being used in human clinical trials include retrovirus, adenovirus, adeno-associated virus (AAV), and herpes simplex virus. Nonviral gene transfer is known as transfection and may be as simple as delivery of naked, plasmid DNA via polymers or lipid or by applying biophysical methods, such as electroporation. In general terms, nonviral vectors are less expensive, safer, and simpler than viral vectors but are considerably less efficient. Some of the specific advantages and disadvantages of each available vector system are listed in Table 15.2 and have been reviewed extensively elsewhere.66 Of note in this context is the occurrence of insertional mutagenesis during human gene therapy trials that has impeded the further use of oncoretroviruses in nonlethal and non-Mendelian diseases.67 Regardless of the vector, genes may be transferred to their targets by in vivo or ex vivo strategies, the principles of which are illustrated in Fig. 15.3, b.

RHEUMATOID ARTHRITIS Gene transfer to joints was first applied by Evans and coworkers as a means to treat arthritic disorders.68, 69 For the treatment of RA, therapies that use biologic disease-modifying antirheumatic drugs targeting TNF inhibition,

134

SECTION 1  Scientific Basis of Rheumatic Disease

Table 15.1

Gene Products for Cartilage Restoration and Protection in Arthritic and Rheumatic Diseases Therapeutic Target

Gene Product (Examples)

Chondrogenic induction

Growth factors (e.g., TGF-βs, BMPs, Wnts) Signal transduction molecules (e.g., Smads) Transcription factors (e.g., SOXs, brachyury) Osteogenic inhibitors (e.g., noggin, chordin) Inhibitors of chondrocyte terminal differentiation (e.g., PTHrP) Signal transduction molecules (e.g., Smad-6 and -7, mLAP-1) Caspase inhibitors (e.g., Bcl-2, Bcl-xL) FasL blockers (e.g., anti-FasL) NO-induced apoptosis inducers (e.g., Akt, PI-3-kinase) TNF-α, TRAIL-inhibitors (e.g., NF-κB) Inhibitors of telomere erosion (e.g., hTERT) Free radical antagonists (e.g., NO-antagonists, SOD) Growth factors (e.g., TGF-βs, BMPs, IGF-1) ECM component (e.g., collagen type II) Enzymes for GAG synthesis (e.g., GlcAT-1) Cytokine antagonists (e.g., IL-1ra, sIL-1R, sTNFR, anti-TNF-antibodies) Proteinase inhibitors (e.g., TIMP1, TIMP2) Antiinflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13) Inhibitors of IL-1β converting enzyme or caspase-1

Osteogenic inhibition

Apoptosis inhibition

Senescence inhibition

Cartilage matrix synthesis

Inflammation protection

akt, AKR mouse thymoma kinase; Bcl-2 and Bcl-xL, B-cell lymphoma 2 and Bcl extra-large; BMP, bone morphogenetic protein; ECM, extracellular matrix; FasL, first apoptotic signal ligand; GAG, glycosaminoglycan; GFAT, glutamine:fructose-6-phosphate aminotransferase; GlcAT-I, β1, 3-glucuronosyltransferase I; hTERT, human telomerase reverse transcriptase; IGF, insulin-like growth factor; IL-1ra, interleukin-1 receptor antagonist; mLAP-1, murine latency-associated peptide 1; NF-κB, nuclear factor κB; NO, nitric oxide; PI-3-kinase, phosphatidylinositol-3-kinase; PTHrP, parathyroid hormone–related peptide; sIL-1R, soluble IL-1 receptor; SOD, superoxide dismutase; TGF-β, transforming growth factor-β; TIMP, tissue inhibitor of matrix metalloproteinase; TNF-α, tumor necrosis factor-α; TRAIL, TNF-related apoptosis-inducing ligand.

Table 15.2

Vector Systems for Gene Delivery Applications for Arthritic and Rheumatic Diseases Vector

Characteristics

Nonviral

Overall weak efficiency, transient, many inflammatory High efficiency, transient, inflammatory Moderate efficiency, safe, clinical trial for RA

Adenovirus Adeno-associated virus Herpes simplex virus Retrovirus Lentivirus Spumavirus

High efficiency, cytotoxic, transient Long-term expression, clinical trial for RA, safety concerns High efficiency, safety concerns Moderate efficiency, no known disease in humans, used in joints experimentally

RA, Rheumatoid arthritis.

interleukin receptor inhibition, T-cell costimulation blockade, and B-cell depletion have shown efficacy. However, such therapies are expensive and require repeated administration, with many patients losing responsiveness over time, and the issue of side effects remains of concern.70, 71 So far, most attention on gene therapy has been focused on local, intraarticular administration using ex vivo and in vivo modes of gene delivery (see Fig. 15.3, b). The first clinical protocol selected an IL-1 blocker, IL-1ra, as the transgene,69 which was delivered in ex vivo fashion, using a retrovirus, to the metacarpophalangeal joints of nine individuals with severe RA. This phase I trial was successfully completed without incident, and the procedure was well tolerated by all nine patients included.68 A phase I protocol involving the direct intraarticular injection of a recombinant AAV2 vector into 15

individuals carrying a cDNA encoding a fusion protein comprising two TNF soluble receptors (sTNF-R) combined on an immunoglobulin molecule was closed and converted into a phase II clinical trial using the same vector.72 This was temporarily halted by the U.S. Food and Drug Administration (FDA) owing to the death of one individual enrolled in the study from a severe histoplasmosis infection.67 The FDA determined that the vector was not responsible for the outcome and has allowed the trial to continue.68 However, there has been no further activity from this clinical program.73

OSTEOARTHRITIS Because IL-1 is also an important mediator of cartilage breakdown in OA, its inhibitors have likewise been considered useful targets for gene interventions.73, 74 Several animal studies confirmed the promise of IL-1ra gene delivery in treating OA.73, 74 Ex vivo delivery of IL-1ra cDNA via retroviral vectors and direct delivery of IL-1ra via plasmid DNA to OA knee joints of dogs75 and rabbits, respectively, was shown to slow cartilage degeneration. Remarkably, in a similar study in horses exploring the effects of adenoviral-mediated gene delivery of IL-1ra in experimental OA, reduced lameness of the horses receiving gene therapy was observed.76 To support restoration of a cartilage-like matrix in OA, four clinical trials have been conducted in the United States and Korea using suspensions of allogeneic chondrocytes expressing TGF-β1 transgene (Invossa®) that were delivered into knee joints of patients in OA phase I–III trials.77 It is noteworthy that the Korean license for Invossa has been revoked and the Phase III United States trial has been suspended by the FDA, as it was uncovered that the genetically modified cells being injected intraarticularly were not chondrocytes but HEK293 cells.78 In summary, cell-based therapies and tissue engineering approaches have gained increasing public attention as a promising approach to improve the treatment of pathologies of the musculoskeletal system. To date, the efficacy of such treatment strategies remains unclear owing to a lack of high-quality controlled randomized trials, a broad spectrum of different cell isolation protocols with varying quality of cell product, and poor harmonization and absence of standardization of treatment modalities and outcome measurements. The promises and challenges of cell-based therapies for skeletal disorders and diseases were recently reviewed and presented by a multidisciplinary task force including scientists, physicians, and surgeons who are recognized experts in the development and use of cell-based therapies, organized by the American Society for Bone and Mineral Research (ASBMR) and the Orthopaedic Research Society (ORS). The report by the ASBMR/ORS Task Force was prepared to provide researchers and clinicians with a better understanding of the current state of the science and research needed to advance the study and use of cell-based therapies for skeletal tissues.79

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Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 2014;32:1254–1266. Pers YM, Rackwitz L, Ferreira R, et al. Adipose mesenchymal stromal cell–based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016;5:847–856. Rothrauff BB, Sasaki H, Kihara S, et al. Point-of-care procedure for enhancement of meniscal healing in a goat model utilizing infrapatellar fat pad–derived stromal vascular fraction cells seeded in photocrosslinkable hydrogel. Am J Sports Med. 2019;47:3396–3405. Holton J, Imam M, Ward J, et al. The basic science of bone marrow aspirate concentrate in chondral injuries. Orthop Rev. 2016;8(3):6659. Gentile P, Calabrese C, De Angelis B, et al. Impact of the different preparation methods to obtain human adipose-derived stromal vascular fraction cells (AD-SVFs) and human adipose-derived mesenchymal stem cells (AD-MSCs): enzymatic digestion versus mechanical centrifugation. Int J Mol Sci. 2019;2(21):20. Chahla J, Dean CS, Moatshe G, et al. Concentrated bone marrow aspirate for the treatment of chondral injuries and osteoarthritis of the knee: a systematic review of outcomes. Orthop J Sports Med. 2016;4. Centeno C, Pitts J, Al-Sayegh H, et al. Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft. Biomed Res Int. 2014;2014:370621. Kim JD, Lee GW, Jung GH, et al. Clinical outcome of autologous bone marrow aspirates concentrate (BMAC) injection in degenerative arthritis of the knee. Eur J Orthop Surg Traumatol. 2014;24:1505-1511. Hauser RA, Orlofsky A. Regenerative injection therapy with whole bone marrow aspirate for degenerative joint disease: a case series. Clin Med Insights Arthritis Musculoskelet Disord. 2013;6:65–72. Han S, Sun HM, Hwang KC, et al. Adipose-derived stromal vascular fraction cells: update on clinical utility and efficacy. Crit Rev Eukaryot Gene Expr. 2015;25:145–152. Nguyen PD, Tran TD, Nguyen HAT, et al. Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis. Stem Cells Transl Med. 2016;6:187–195. Di Matteo B, Vandenbulcke F, Vitale ND, et al. Minimally manipulated mesenchymal stem cells for the treatment of knee osteoarthritis: a systematic review of clinical evidence. Stem Cells Int. 2019;2019:1735242. Nöth U, Tuli R, Osyczka AM, et al. In-vitro engineered cartilage constructs produced by press-coating biodegradable polymer with human mesenchymal stem cells. Tissue Eng. 2002;8:131–144. Li WJ, Jiang YJ, Tuan RS. Chondrocyte phenotype in engineered fibrous matrix is regulated by fiber size. Tissue Eng. 2006;12:1775–1785. Li WJ, Tuli R, Huang X, et al. Multilineage differentiation of human mesenchymal stem cells in a three-dimensional nanofibrous scaffold. Biomaterials. 2005;26:5158–5166. Nesic D, Whiteside R, Brittberg M, et al. Cartilage tissue engineering for degenerative joint disease. Adv Drug Deliv Rev. 2006;58:300–322. Zheng MH, Chen J, Kirilak Y, et al. Porcine small intestine submucosa (SIS) is not an acellular collagenous matrix and contains porcine DNA: possible implications in human implantation. J Biomed Mater Res B. Biomater. 2005;73:61–67. Garg T, Goyal AK. Biomaterial-based scaffolds—current status and future directions. Expert Opin Drug Deliv. 2014;11:767–789. Rothrauff BB, Shimomura K, Gottardi R, et al. Anatomical region-dependent enhancement of 3-dimensional chondrogenic differentiation of human mesenchymal stem cells by soluble meniscus extracellular matrix. Acta Biomater. 2017;49:140–151. Rothrauff BB, Yang G, Tuan RS. Tissue-specific bioactivity of soluble tendon- and cartilage-derived extracellular matrices. Stem Cell Res Ther. 2017;8(1):133. Rothrauff BB, Coluccino L, Gottardi R, et al. Efficacy of thermoresponsive, photocrosslinkable hydrogels derived from decellularized tendon and cartilage extracellular matrix for cartilage tissue engineering. J Tissue Eng Regen Med. 2018;12:e159–e170.

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46. Jeong CG, Atala A. 3D printing and biofabrication for load bearing tissue engineering. Adv Exp Med Biol. 2015;881:3–14. 47. Lima MJ, Correlo VM, Reis RL. Micro/nano replication and 3D assembling techniques for scaffold fabrication. Mater Sci Eng C Mater Biol Appl. 2014;42:615–621. 48. Lin H, Zhang D, Alexander PG, et al. Application of visible light-based projection stereolithography for live cell-scaffold fabrication with designed architecture. Biomaterials. 2013;34:331–339. 49. Lin H, Cheng AWM, Alexander PG, et al. Cartilage tissue engineering application of injectable gelatin hydrogel with in situ visible light–activated gelation capability in both air and aqueous solution. Tissue Eng Part A. 2014;29:2402–2422. 50. Alexander PG, Gottardi R, Lin H, et al. Three dimensional osteogenic and chondrogenic systems to model osteochondral physiology and degenerative joint diseases. Exp Biol Med. 2014;239:1080–1095. 51. Wakitani S, Mitsuoka T, Nakamura N, et al. Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: two case reports. Cell Transplant. 2004;13:595–600. 52. Kuroda R, Ishida K, Matsumoto T, et al. Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. Osteoarthritis Cartilage. 2007;15:226–231. 53. Nejadnik H, Hui JH, Feng Choong EP, et al. Autologous bone marrow–derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med. 2010;38:1110–1116. 54. Chen X, Armstrong MA, Li G. Mesenchymal stem cells in immunoregulation. Immunol Cell Biol. 2006;84:413–421. 55. Uccelli A, Pistoia V, Moretta L. Mesenchymal stem cells: a new strategy for immunosuppression? Trends Immunol. 2007;28:219–226. 56. Kan I, Melamed E, Offen D. Autotransplantation of bone marrow–derived stem cells as a therapy for neurodegenerative diseases. Handb Exp Pharmacol. 2007;180:219–242. 57. Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011;9:11–15. 58. Petrie Aroni CE, Tuan RS. Therapeutic potential of the immunomodulatory activities of adult mesenchymal stem cells. Birth Defects Res C Embryo Today. 2010;90:67–74. 59. Jones S, Horwood N, Cope A, et al. The antiproliferative effect of mesenchymal stem cells is a fundamental property shared by all stromal cells. J Immunol. 2007;179:2824–2831. 60. Noël D, Djouad F, Bouffi C, et al. Multipotent mesenchymal stromal cells and immune tolerance. Leuk Lymphoma. 2007;48:1283–1289. 61. Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell–mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2:141–150. 62. Djouad F, Charbonnier LM, Bouffi C, et al. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells. 2007;25:2025–2032. 63. Alexander AM, Crawford M, Bertera S, et al. Indoleamine 2,3-dioxygenase expression in transplanted NOD islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. Diabetes. 2002;51:356–365. 64. Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells. 2008;26:212–222. 65. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107:367–372. 66. Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet. 2003;4:346–358. 67. Evans CH, Ghivizzani SC, Robbins PD. Arthritis gene therapy’s first death. Arthritis Res Ther. 2008;10:110. 68. Evans CH, Robbins PD, Ghivizzani SC, et al. Gene transfer to human joints: progress toward a gene therapy of arthritis. Proc Natl Acad Sci USA. 2005;102:8698–8703. 69. Evans CH, Robbins PD, Ghivizzani SC, et al. Clinical trial to assess the safety, feasibility, and efficacy of transferring a potentially anti-arthritic cytokine gene to human joints with rheumatoid arthritis. Hum Gene Ther. 1996;7:1261–1280. 70. Mateen S, Zafar A, Moin S, et al. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin Chim Acta. 2016;455:161–171. 71. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388:2023–2038. 72. Evans CH, Ghivizzani SC, Robbins PD. Gene therapy of the rheumatic diseases: 1998 to 2008. Arthritis Res Ther. 2009;11:209. 73. Evans CH. The vicissitudes of gene therapy. Bone Joint Res. 2019;8:469–471. 74. Evans CH, Huard J. Gene therapy approaches to regenerating the musculoskeletal system. Nat Rev Rheumatol. 2015;11:234–242. 75. Pelletier JP, Caron JP, Evans C, et al. In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis Rheum. 1997;40:1012–1019. 76. Frisbie DD, Ghivizzani SC, Robbins PD, et al. Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther. 2002;9:12–20. 77. Lee B, Parvizi J, Bramlet D, et al. Results of a phase II study to determine the efficacy and safety of genetically engineered allogeneic human chondrocytes expressing TGF-β1. Knee Surg. 2020;33:167–172. 78. Kim MK, Ha CW, In Y, et al. A multicenter, double-blind, phase III clinical trial to evaluate the efficacy and safety of a cell and gene therapy in knee osteoarthritis patients. Hum Gene Ther Clin Dev. 2018;29:48–59. 79. O’Keefe RJ, Tuan RS, Lane NE, et al. American Society for Bone and Mineral Research– Orthopaedic Research Society Joint Task Force report on cell-based therapies—secondary publication. J Orthop Res. 2020;38:485–502.

C.  Systems Biology Big Data analysis Paul Martin • Kimme Hyrich • Nophar Geifman

Key Points ■ With Big Data comes big responsibility in order to understand the potential pitfalls in the data, make appropriate assumptions, and choose the best analysis method. ■ The analysis of big biological data presents several challenges, due to its complexity and variety, but these are not insurmountable. ■ The development of better data integrative approaches will enhance our ability to understand and treat rheumatic diseases.

WHAT IS BIG DATA? The definition of the term “Big Data” has changed since its first conception, as much as Big Data itself has changed over time. The most fundamental way to describe it is by its most obvious characteristic of being large. However, what constitutes Big Data is evolving as the technologies that generate it are evolving and becoming more pervasive in everyday life. In addition to having large volume (as in there is a lot of it), other Vs are commonly used to define Big Data (Fig. 16.1), including variety, velocity, and veracity. Variety indicates that Big Data comes in many different forms and originates from difference sources. It can be numeric (represented by numbers, such as a patient’s age) or categorical (such as a patient’s ethnicity). The data may also consist of structured data that have been captured in a uniform way or unstructured data such as free text in a physician’s letters. Velocity refers to the speed at which Big Data are being generated, with more and more applications sometimes having to deal with a continuous real-time flow of large volumes of data, where a constant stream of information needs to be analyzed. Finally, veracity refers to the accuracy of Big Data. Big Data will inherently have a certain level of uncertainty. This means that we can expect Big Data to have some noise or bias in how the data were collected and captured.

SOURCES OF BIG DATA IN RHEUMATOLOGY Big Data in rheumatology can roughly be divided into two main types: clinical data and biological data. Each of these is considered in turn.

CLINICAL DATA Clinical data tend to be divided into two main types. The first is primary data, which researchers actively capture from patients or research participants for the purpose of research. This has historically been the main source of research data within rheumatology, and examples include data obtained within clinical trials and observational studies. The data can be derived from multiple sources and include patient and population surveys as well as clinical data captured directly from the patient by a medical doctor/research nurse or extracted from the medical record. Examples in rheumatology include the Norfolk Arthritis Register (NOAR), an inception cohort of adults with new onset inflammatory arthritis.1 Within NOAR, patient data, including demographic, clinical, radiographic, and patient-reported outcome data (using structured questionnaires), have been captured directly from more than 4000 patients or via the medical record by research nurses at regular intervals spanning over 20 years. More recently, we have seen the creation of large national treatment or biologic registers.2 For example, one of the largest of these, the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA), has collected data from patients via questionnaires or directly from the medical record (extracted by research nurses) at 6- to 12-month intervals since 2001 (https://www.bsrbr.org/). Over 30,000 patients have been recruited. Primary data collection creates large bespoke data sets designed for the purpose of research, such that relevant outcomes and information on potential confounders are readily available for analysis, but these data sets are expensive to develop and maintain. Therefore in more recent years we have seen a shift toward the use of secondary data. Secondary data is defined as data that are captured for reasons other than research but then made available for research. Examples here include

16

electronic heath record (EHR) data (initially collected to record and deliver health care), administrative claims data for health insurance companies, or national cancer or death registries (captured to record and monitor the health of a nation). Data sets such as the Clinical Practice Research Datalink (CPRD, previously the General Practice Research Database [GPRD]) (https://www.cprd.com/), which represents data captured through the UK National Health Service (NHS) primary care EHR, have been used to study the incidence and prevalence of disease as well as for pharmacoepidemiological research. Examples include the study of the risk of adverse outcomes associated with exposure to certain drugs.3,4 Similar large studies have been undertaken looking at the risk of biologic drug exposure with large US administrative data sets.5,6 We have also seen the creation and analysis of secondary data within health systems specifically developed for rheumatology, such as DANBIO, which is a rheumatology secondary care EHR used across Denmark.7 Secondary data have the advantages of lower costs for individual researchers, better sustainability, and large data volume but may be limited in the specificity of the data for rheumatology. Since the data are usually not obtained with the initial purpose of research, key variables or outcomes may not be available for analysis. Increasingly we have seen primary and secondary data sources linked together for research, which offers the advantage of both specific rheumatology data combined with details of other nonrheumatologic health conditions or other outcomes, which may not be immediately or easily captured in a rheumatology study, such as details of cancer or death8 or other nonmedical outcomes such as employment status and income support.9 Secondary data sources can also themselves be linked to create even larger and richer data sets, with a good example being the linked data sets across Scandinavia.10 Traditionally we have thought of Big Data for medical research as those types of sources already described, but increasingly we are seeing the secondary use of data collected outside of the medical research or health delivery environment. These may include data captured through personal mobile health apps, wearables such as activity trackers, and even large volumes of data being generated and collected with no immediate link to health, via applications such as Twitter, which bring new analytical challenges.11

CHALLENGES AND CONSIDERATIONS IN THE ANALYSIS OF BIG CLINICAL AND HEALTH DATA Traditional analytical approaches to Big Data Increasingly, as larger and more complex data sets are used for rheumatology and other medical research, further consideration must be given to the analytical approaches and opportunities. For many large data sets, traditional hypothesis-driven statistical approaches to data analysis are still valid, such as the use of multivariate regression models to model relative risk. Details of these approaches are well covered in many medical statistic textbooks and within training courses. Within this modern treatment era and with the advent of Big Data, there are a number of methodological considerations in the analysis of large realworld clinical data sets.12 Importantly, analytical design, especially when research is embedded within secondary data sets; handling of missing data; and minimization of bias are critical. Although relevant across all research questions, these issues are increasingly critical when these data sets are used for comparative effectiveness research; that is, research that aims to compare the risks and benefits between two or more therapies. With increasingly large data sets of exposed patients, the ability to compare between treatments for the risk of both common and rare outcomes is growing. Accurately defining exposure to therapies within large data sets is critical. For a fair comparison, the definition of treatment initiation within an analysis should start when a therapy is actually started and end of exposure should be clearly defined (new-user design). This may seem like a basic principle but can be challenging to implement in actual practice using large data sets. For example, it is important when comparing treatment outcomes to consider whether a new-user design has been used to avoid introducing 137

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SECTION 1  Scientific Basis of Rheumatic Disease THE FOUR V'S OF BIG DATA

Volume

Variety

Velocity

Veracity

Lots and lots of data

Data in many forms

Streaming data to enable fast decision making

Data uncertainty: imprecise data types

Clinical data:

Molecular data

Genetic variation

Wearables

Cohort studies Clinical trials Patient registries

FIG. 16.1  The four Vs of Big Data. Volume, variety, velocity, and veracity are the four main characteristics of Big Data. In the biomedical or health setting, these data can originate from many different sources, such as clinical trials, cohort studies, and patient registries, and include different forms of data, such as clinical information, molecular data, genetic variation, and geolocation and activity data collected through wearable devices. a prevalent user bias. This is especially critical if the aim is to compare the rates of adverse events that are likely to end in treatment discontinuation, such that patients who remain on a treatment (prevalent users) are less likely to experience the event of interest. A second bias, immortal-time bias, can be introduced if time prior to an exposure is misclassified as exposed time.13 This can occur if a researcher is interested in the effects of a treatment in reducing adverse outcomes, say, death, following another, possibly unrelated, intervention such as surgery. Unless time-varying exposure of the treatment of interest is considered, counting treatment-free time after surgery (prior to the start of the treatment of interest) as exposed can result in misclassification of exposure time and significant false observed reductions in risk. Missing data can also hamper statistical analysis using traditional approaches, as most computer software programs will drop or exclude patients who do not have complete data sets. Should these patients differ from those with complete data, in terms of either exposure, covariate data, or outcomes, analyses will be biased. The most widely used approach to handling missing data in rheumatology has been multiple imputation, whereby available information on both covariates, exposure, and the outcome within a data set are used to predict the value of the missing data such that a complete data set is available for analysis.14 As this is not exempt from error, imputation is repeated multiple times and multiple complete data sets are analyzed with results combined. Finally, it is important to consider confounding by indication when comparing outcomes between two (or more) different exposures. Confounding by indication can occur when certain patients are channeled toward specific treatments based on their patient characteristics. If these same characteristics are also risk factors for the outcome, biased analyses can result. Although the best approach is to consider the choice of comparator at the study design stage, confounding by indication is not always possible to avoid. For example, a comparison of cancer incidence as an outcome following either methotrexate or biologic therapy is likely to be confounded by disease severity, inherent in the fact that biologic drugs are usually reserved for more severe patients, which is an independent risk factor for lymphoma.15 An increasingly common approach to handling this confounding is the use of propensity score models as an alternative to multivariable regression models. In brief, a propensity score is a score between 0 and 1, generated using logistic regression, which represents a patient’s “propensity,” based on their characteristics, to receive an exposure of interest. It is then assumed that two patients (with and without exposure or with different exposures) with similar propensity scores are exchangeable and directly comparable with respect to the outcome. Propensity scores have the advantage of potentially better balance of covariates and, when outcomes are rare, reduce the number of covariates to be included in a multivariate regression model. They can be implemented in multiple different ways, depending on the research

question16; however, they are limited in their inability to control for unmeasured differences between treatment groups and therefore cannot replace randomization as performed during a clinical trial, which will balance both measured and unmeasured variables.

Machine learning approaches to Big Data The ever-increasing volume of health care data available for research has also meant that new data mining and analysis approaches are needed, as our traditional hypothesis-driven approaches are not always technically feasible and may limit our potential for scientific discovery. Machine leaning (ML) is any implementation of a task that a computer can carry out through the processing of data—data are fed to the algorithm and the program learns for itself, from examples present in the data. Another way to define machine learning is “the science of getting computers to act without being explicitly programmed” (https://www.coursera.org/learn/ machine-learning). Machine learning can help where we have a really difficult task and it is hard to program the computer to understand what we need it to do; for example, where it is very difficult to formulate rules and where a solution may change according to specific cases. Thus, it is useful for the computer to learn for itself from observations made in data. One of the useful applications of ML in health care is around diagnostics and therapeutics; for example, to make predictions about mortality and length of stay in hospital, make better diagnoses of rare diseases, and help make clinical decisions regarding the best approach for treatment. In precision medicine (which is the use of a patient’s individual characteristics such as genetic information, demographics, etc., to tailor better diagnosis and treatment), ML can help identify clinically meaningful and useful subgroups (or endophenotypes) and can help with the analysis of very large and diverse data often found, for example, in EHRs. Machine learning can broadly be split into two categories: The first is supervised learning, where we know in advance the correct labels in a set of data. This type is task driven and is often used for regression where a value is predicted from a set of observations (such as what a patient’s body mass index will be based on their age) or classification where we want to predict what group a patient will fall into based on some observations (for example, whether a patient presenting with acute febrile illness has Dengue fever).17 The second type is unsupervised learning, which is used when the correct classes or labels are not available and are data driven and includes clustering, where we try and identify meaningful groupings in the data that tell us something new.

Supervised machine learning Most supervised machine learning algorithms follow the same principle, starting with data that include labels such as sick/not sick. A subset of the

CHAPTER 16  Big Data analysis

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A SUPERVISED MACHINE LEARNING ALGORITHM PIPELINE Test data (no labels) Features + Labels

Training data

Machine learning algorithm

Predictive model

Test accuracy of model

Predictive labels

FIG. 16.2  A supervised machine learning algorithm pipeline. Starting with data that contain labels, a training set is used to train the ML algorithm. The model that is produced is then tested using the test data, presented to the model without the known labels. The performance of the model is then tested by comparing the predicted labels to the true labels in the test set.

data, called the training data, is fed to the ML algorithm, which generates a model. Next, a second subset of the data that was not used to train the algorithm, the testing set, is used to test the performance of the model by applying the model to these new data to get predicted labels. The performance of the algorithm is evaluated in terms of how well it makes predictions by comparing the predicted labels and the known labels (that were withheld from the model) (Fig. 16.2). One of the main advantages of these approaches is that they can detect complex nonlinear relationships between independent and dependent variables; they can perform complex processing with a large number of inputs and/or outputs and do it quickly. For example, deep neural networks, a form of ML, were applied to images of skin lesions to try and improve diagnosis and classification of a variety of skin cancers.18 To achieve this, the algorithm was trained on 129,450 clinical images, relying on only pixels and disease labels as inputs. When the performance of the algorithm was tested, it was on par with 21 board-certified dermatologists, demonstrating its ability to classify skin cancer as well as the clinical experts. Useful predictions from electronic patient records are also made possible with machine learning, allowing for the algorithm to choose which inputs are most important rather than relying on a priori, and sometimes misinformed, clinical understandings. Google took such an approach with the application of deep neural networks to a vast EPR data collection of 46,864,534,945 data points that included clinical notes. This generated models with high accuracy for predicting in-hospital mortality, 30-day unplanned readmission, prolonged length of stay, and patients’ final diagnoses, without requiring the labor-intensive process of extracting curated predictor variables from the data.19 Supervised machine learning approaches, however, do have their shortcomings. In addition to needing large data sets of labeled examples that are not always easy to come by, these algorithms have an element of “blackbox”-ness to them that may hinder uptake by clinical communities. The lack of transparency of what goes on within the algorithm (i.e., a black box), where the user can only see the inputs and outputs without any knowledge of the internal workings, means that justifiable caution is often taken when it comes to applying such models in clinical practice. Some machine learning algorithms, such as decision trees and random forests, are more intuitive and explainable in nature and, as such, have been used widely in clinical research.20 Interestingly, those machine learning methods that are often considered best performing (e.g., neural networks and deep learning) tend to be the least transparent. On the other hand, those methods that are more transparent and can provide a clearer explanation of the inner workings of the algorithm (e.g., decision trees) tend to be less accurate and less capable of handling vast data sets.21

the data and patterns within; it can help summarize information by identifying how data can be grouped and then, with the aid of some summary measure, describe each cluster. Other methods commonly used in biomedical research include latent variable models, often used for data preprocessing, such as reducing the number of features in a data set (dimensionality reduction) or decomposing the data set into multiple components. Latent class analysis (LCA) hypothesizes the existence of one or more unobserved (underlying, latent) variables to explain the relationships among a set of observed variables. There are many example applications for LCA in health care. In the analysis of emergency room patient data, two classes of patients (those with, and those without myocardial infarction) were identified using information from four clinical indicators.22 More recently, the analysis of longitudinal (time series) measurements of cognitive function among patients with three subtypes of Alzheimer’s disease with varying patterns of disease progression were identified.23 In rheumatoid arthritis, the same approach for trajectory-based subgroup discovery was applied and identified three groups of patients with varying patterns of response to treatment with biologics.24

Unsupervised machine learning

Big Data analytics often involves integrating diverse data from several sources, and these data may be diverse in terms of data type, format, data model, and semantics. Machine learning often requires some preprocessing and cleaning of the data to be suitable as input for a specific model or algorithm. However, data that emerge from different sources are likely to be formatted differently, making pooling of data more difficult. The data being fed to a machine learning algorithm may contain different types of information, such as images and categorical, discrete, and continuous data, all of which need to be processed together; however, machine learning algorithms are not designed to recognize and handle different types of representations at once and are not always capable of creating efficient unified generalizations.

Unsupervised machine learning algorithms “learn” and identify hidden patterns in data that do not contain known, or labeled, outcomes. Because there are no known labels, these approaches cannot be used for regression or classification problems but can instead be used for discovering the underlying structure of the data. In many cases in health-related research, this approach helps with hypothesis-free discovery as it is a data-driven approach—the data tell the story. Unsupervised machine learning includes techniques such as clustering, which is the organization of data into groups such that these groupings have a high level of similarity within the group but low similarity between groups (Fig. 16.3). Finding clusters in data can help us understand the structure of

“Garbage in, garbage out” One main advantage of using machine learning in health care is that these methods can help avoid and mitigate biases in diagnosis and treatment. If a computer algorithm is not biased, it will objectively synthesize, evaluate, and interpret the data presented to it and thus reach objective conclusions and recommendations. However, machine learning algorithms are only as good as the data they are fed.25,26 This is well known in computer sciences. If the data are bad, the resulting model or analysis will also be bad. Poorly labeled data—for example, using ambiguous or imprecise International Classification of Diseases, 10th Revision codes—will likely generate a flawed diagnostic classification model. To make matters worse, sometimes this will not be immediately obvious. Machine learning algorithms are not exempt from being subject to biases. Biases in how information about patients or a disease is captured in medical data sets can strongly influence any result from machine learning applications (or other analysis approaches). Many of these are similar to those encountered in more traditional analytic approaches and include those related to missing data, sample size and underestimation, and misclassification and measurement error.27 When an algorithm cannot observe and identify certain individuals, a machine learning model cannot make predictions about them. That would be the case, for example, where an algorithm is trained on data collected in a hospital that cater to one socioeconomic sector and then are used more widely.

Data heterogeneity and integration

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SECTION 1  Scientific Basis of Rheumatic Disease

Variable 2

Disease activity

IDENTIFICATION OF CLUSTERS OF DIFFERENT TYPES OF DATA

a

Variable 1

b

Time

FIG. 16.3  Identification of clusters of different types of data. (a) Where cross-sectional data are available, numeric or categorical variables (or a combination of these) can be used to identify subgroups, or clusters, of individuals. (b) Longitudinal patterns, such as the change in a disease measure over time, can also be used to identify clusters of individuals with varying time-dependent patterns.

Another source of heterogeneity comes from differences in meanings and interpretations; this becomes more evident where data sets developed by different parties are integrated.28 Different data sets from different sources are also likely to capture different clinical characteristics and outcomes, even if pertaining to the same disease. This is another source of heterogeneity that machine learning approaches are not well equipped to handle; often heterogeneity must be resolved before applying such approaches, using a common data model approach.29 Heterogeneity may also arise from differences in statistical properties among the different parts of an overall data set. This may be present in small data sets but is amplified in Big Data because data sets typically involve parts coming from different sources. This statistical heterogeneity may violate some of the assumptions made by common machine learning algorithms, compromising any arising results.

BIOLOGICAL DATA Alongside the expanding availability of clinical and health data, we have also seen a massive explosion of biological data. Biological data have always been represented by a diverse range of methods and experimental aims. From the initial draft of the human genome to the current “omics” era, Big Data plays a vital role in both research and health care. For rheumatic disease genetics, the focus from genome-wide association studies (GWAS) to the functional characterization of disease-associated loci has vastly increased the applications of Big Data, as well as the amount generated. The sources of the increase in Big Data have primarily come from large-scale epigenomics projects, such as the ENCODE project (www.encodeproject.org), the Roadmap Epigenomics Project (www.roadmapepigenomics.org), and the International Human Epigenome Consortium (IHEC, ihec-epigenomes. org). These projects aim to characterize the genome to determine a region’s potential function, accessibility, and gene expression, using several methods, such as ChIP-seq, ATAC-seq, and RNA-seq, respectively. Studies investigating the structure of DNA within the cell (chromatin), using chromosome conformation capture–based methods, particularly Hi-C and Capture Hi-C, have added to this vast amount of big biological data.30–35 Epigenomics data, in their simplest form, largely involve the production of sequence data and, indeed, the increase of epigenomic data is exemplified by the growth of those databases that are part of the sequence read archives of the International Nucleotide Sequence Database Collaboration (INSDC, www.insdc.org) (Fig. 16.4), showing a rapid growth post-2007 in the adoption of next generation sequencing (NGS). The majority of these data are publicly available and can therefore be utilized for other purposes, in some cases allowing wholly in silico projects to be conducted. This growth trend is set to continue as improvements in single-cell genomics over the last few years, particularly droplet-based single-cell

RNA-seq (scRNA-seq) and ATAC-seq (scATAC-seq) methods, promise not only to improve our knowledge and understanding of many complex systems and processes but also to add further to the already vast amount of publicly available data. Coupled with super high-resolution microscopy, imaging, and future applications of spatial transcriptomics, the analysis and sharing of big biological data presents several challenges that must be addressed to realize its full potential.

Challenges of generation and storage of big biological data As previously mentioned, the analysis and availability of big biological data pose several challenges. Firstly, current omics-based approaches, such as those previously mentioned, produce a large amount of data in a reasonably short space of time. Methodology and experimental aims aside, Illumina’s latest production-scale sequencer, the NovaSeq™ 6000, can produce over 3.5 terabytes (TB) of raw data in approximately 44 hours. It would therefore take five sequencers around 5 years to double the number of bases currently stored in the NCBI’s Sequence Read Archive (SRA) (>17 petabytes [PB]). Realistically this is unlikely to be the case, but it demonstrates that with an installed base of approximately 920 NovaSeq units at the end of 2019,36 the amount of data produced over the next decades will be vast. As daunting as this amount of data is, however, it is unlikely a single laboratory will have to manage much more than a single run at a time. Nevertheless, for even modest experiments, managing and storing this amount of data could be challenging, especially when also considering the amount of processed data generated during analysis. Fig. 16.5 shows the storage requirements of some of the methods discussed, and while a single sample seems manageable, the storage required for multiple samples quickly increases. More important for many laboratories, Big Data produced in the omics era surpasses previous Big Data (e.g., GWAS) by some margin, and while the long-term storage requirements may be lower, the short-term “processing space” requirements certainly are not. As such, laboratories wishing to conduct these experiments and analyze accordingly must be prepared for both short- and long-term requirements. Another important feature of this growth trend is represented by the lighter dashed lines in Fig. 16.4. These lines represent hypothetical growth based on Moore’s law, an observation that the number of transistors in an integrated circuit roughly doubles every 24 months.37 Prior to NGS, the generation of sequence data roughly followed Moore’s law. However, with the advent of NGS, the growth of data has rapidly exceeded Moore’s law, surpassing increases in computer power, and therefore has implications on the processing of big data. As data sets grow, it is becoming more important that these data sets can be analyzed efficiently, particularly important when utilized for health care applications, such as genetic screening. Historically, processors (central processing units) were single core and performance gains were mostly obtained by making them work faster; however, recently

CHAPTER 16  Big Data analysis

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this has not been the case and instead the number of cores has increased. To utilize these improvements, however, algorithms must be able to effectively use the extra cores available, as well as be optimized to carry out their tasks in the most efficient manner. Fortunately, high-performance computing (HPC) solutions, including cloud-based services, are now more accessible to many research institutes. The added benefit of these services is scalability, the ability to expand and renew resources as necessary in a modular fashion. For storage, scale-out network-attached storage (NAS), such as the Dell EMC Isilon (www.dellemc. com/en-us/storage/isilon/index.htm) or Huawei OceanStor 9000 (e.huawei. com/se/products/cloud-computing-dc/storage/cloud-storage/9000), has the potential to offer several petabytes (50–140) in a single file system. While this upper limit is far beyond the needs of individual laboratories, it does demonstrate that the level of storage needed is feasible. Furthermore these systems can facilitate the processing of these data in a highly distributable manner. HPC systems consist of several distinct processing systems or nodes, which share a common architecture, each made up of several processing cores. Each analysis can therefore be partitioned and distributed over multiple cores to improve processing time. Indeed, much of the software used for NGS analysis is designed to exploit the multiple cores now available to modern systems, further facilitating the efficient processing of big biological data. However, as experiments generate increasing amounts of data and require several analysis stages, further improvements are required to manage a pipeline and efficiently distribute analyses over several nodes and merge results accordingly. One such example, the Martian pipeline framework (martian-lang.org), was developed by 10×Genomics to handle the analysis of scRNA-seq data using a scatter–gather approach (Fig. 16.6). Martian partitions each stage of the analysis into hundreds of smaller jobs, distributes them over several nodes, tracks their completion, collects the results, and continues to the next stage. This approach reduces run time considerably compared to a single server approach, where only a limited number of jobs (4–56) can run at once. Therefore by utilizing either local HPC systems or cloud-based services, it is possible to access both sufficient scalable storage and distributed processing resources to store and analyze the big biological data now being generated. Further improvements in handling the analysis of Big Data come from efficient algorithm design and novel ways to store, process, and access data during analysis. While the cost of disk-based storage has fallen, random access memory (RAM), the type used to store working data or code, is still expensive in comparison. Computers, including HPCs, still have limited memory compared to storage and, furthermore, it is less scalable. Analyses that require working access to a large amount of data can therefore often be limited. This is particularly true of the high-dimensional data produced from modern single-cell experiments. Traditionally, these experiments have either examined few markers for thousands of cells or thousands of markers for few cells. However, with the advent of droplet-based single-cell methods,38–40 researchers now have the ability to generate data for thousands of cells for the whole transcriptome and this therefore poses a problem for analysis. For example, an experiment by Villani et al. tested 26,593 genes in 1244 cells producing approximately 33 million data points.41 In contrast, Dulken et al.

utilized a droplet-based approach and tested 27,998 genes in 14,685 cells, resulting in approximately 411 million data points, 12 times larger and consuming six times more memory.42 However, scRNA-seq suffers from a high degree of “drop-out,” a technical limitation that results in a high number of missing data that still need to be stored, wasting memory. Modern scRNAseq analysis therefore utilizes sparse matrices, an efficient way to store data when most elements are missing (or zero). The use of sparse matrices results in a 30% space reduction over nonsparse, or dense, matrices. This is coupled with efficient algorithms that identify the most variable, and therefore informative, features exploit principle component analysis (PCA) and reduce the computational and technical burden of analyzing this data. However, the size of Big Data also has implications when it comes to sharing between collaborators; data service providers, such as sequencing centers; and, ultimately, the wider scientific community. During the early days of NGS, it was often quicker and simpler to obtain and share data by physical media, such as USB hard drives, than to make them available online. However, due to the increased data volumes and stricter privacy concerns, this is no longer the case, and instead online alternatives, such as Secure File Transfer Protocol (SFTP) and IBM® Aspera® High-Speed Transfer Server (www.ibm.com/uk-en/marketplace/aspera-high-speed-file-transfer), or cloud resources, including Dropbox (www.dropbox.com) and Amazon Web Services (aws.amazon.com. AWS), are utilized. Indeed, in 2011, Illumina released BaseSpace (basespace.illumina.com), a cloud-based solution using the AWS, which allows users to store, analyze, and share sequence data with other users. However, while cloud-based services are a simple, secure, short-term solution for sharing data with collaborators, the storage requirements and lack of experimental metadata limit their long-term storage and sharing potential. Public functional genomics data repositories, such as Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo), dbGaP (www.ncbi.nlm.nih.gov/gap), and ArrayExpress (www.ebi.ac.uk/arrayexpress), offer solutions for sharing both processed and raw data following publication and offer straightforward and efficient platforms to provide restricted and unrestricted access to multiple data types. With each submission, extensive metadata is also collected, including information about the overall experimental design, species, and analysis protocols. Furthermore this metadata is fully searchable and linked to the parent publication, ensuring the openness and reproducibility of the analysis. While the growing size of big biological data is challenging, the scalable nature of modern computing architecture is able to mitigate this to an extent. However, the varied nature of biological data, coupled with distinct experimental aims, requires specific, often multidisciplinary knowledge and skills to effectively analyze and interpret these data. Obtaining this knowledge can be problematic. Indeed, a BBSRC and MRC review of vulnerable skills and capabilities performed in 2014 and updated in 201743 identified data analytics, especially bioinformatics, to be particularly vulnerable, highlighting both the importance and challenging nature in obtaining this skill set. Indeed, this has led to a number of commercial services and solutions, including Illumina’s BaseSpace, the Galaxy platform (usegalaxy.org/) and the BlueBee genomics platform (www.bluebee.com/bluebee-genomics-platform/), designed to help facilitate or bridge the gap between data analysis and the interpretation of

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CHAPTER 16  Big Data analysis results. While these solutions mask some of the complexities and work well for defined protocols and routine analyses, they have limited use when a novel, tailor-made solution is required. Furthermore laboratory development of new omics-based methods inevitably predates any analysis pipeline, sometimes with a significant lag until an accepted solution is developed. For example, the first Capture Hi-C study was published in 2015 and utilized approaches used in similar Hi-C based studies,31 but it was not until 2016, over a year later, that an analysis method designed specifically for Capture Hi-C was developed.44 Similarly, it took over a year before the first tool to analyze HiChIP data were published.45 The delay means that data generated utilizing novel techniques must be analyzed using methods designed for other purposes and therefore be interpreted accordingly. The knowledge to develop and implement these solutions is therefore key in the analysis of Big Data. The integration of the multiple data types that exist for biological data is particularly important, as no one data set is likely to tell the whole story. Particularly important for post-GWAS analysis is determining the functional impact of having the disease-associated variant. Perhaps the most straightforward approach is to assign genetic associations to genes, which can then be tested for enrichment in selected pathways46 to provide insight into processes important in disease. However, this approach can be improved by the addition of other experimental data. For example, Shchetynsky et al. took a candidate gene approach, informed by existing genetic associations, to investigate gene expression in seven patients with rheumatoid arthritis (RA) and 12 healthy controls and, following pathway analysis, found evidence to implicate three new candidate genes in the pathogenesis of RA.47 However, these approaches are limited by their selection of gene candidates, which is often difficult, as many GWAS associations do not directly affect proteins. Instead, by integrating publicly available ChIP-seq data from many cell types, several studies have shown that GWAS associations are enriched in regulatory elements.48–50 However, the integration of current omics Big Data is challenging, particularly as several Big Data experiments need to be integrated to fully determine the likely function or gene target of a region. For example, ATAC-seq determines if a region of the genome is accessible to other elements important in gene regulation, such as transcription factors, polymerases, and coactivators, but does not impart the function of the region or which elements are able to bind. In contrast, histone ChIP-seq can determine the presence of modifications indicative of function, but several modifications need to be tested to fully deduce its function. Further techniques, such as transcription factor ChIP-seq, Hi-C, and CHi-C, are then required to determine which elements can bind and how they may interact to control gene expression. Therefore to characterize a region and its possible function could require over ten different experiments that need to be analyzed individually and then integrated correctly and efficiently to allow further interpretation. To help address this challenge, several bioinformatics tools have been developed, such as ChromHMM,51 Segway,52 and Integrated Methods for Predicting Enhancer Targets (IM-PET),53 which predict the function or state of a region and how it regulates gene expression. Unlike traditional algorithms, which use explicit instructions based on predetermined criteria, these methods employ machine-learning approaches that rely on patterns to find shared similarity between features or regions and classify them accordingly. These approaches can be powerful as they utilize all characteristics of the data and do not require prior knowledge to classify states. However, they still require either prior biological knowledge or interpretation by a knowledgeable human to assign functions to the states they identify. Despite this limitation, machine-learning approaches are becoming an increasingly popular way to analyze Big Data in many areas of biology, including systems biology, evolution, and proteomics,54 and although their use in rheumatic diseases is only recent and focuses mainly on clinical data, machine learning has started to utilize big biological data in the rheumatic diseases. For example, Orange et al. used a support vector machine (SVM) learning algorithm to predict synovial tissue subtypes, based on RNA-seq data, using histologic features in patients with RA and osteoarthritis (OA).55 While the sample size was low (39 RA and 6 OA) and no independent validation was performed, it does demonstrate the applicability of machine learning approaches in the rheumatic diseases. As previously mentioned, the high dimensionality of single-cell genomics already poses several analysis challenges. However, while single-cell transcriptomics has provided tremendous insights into cellular heterogeneity and subtypes, to fully uncover the biological impact different cell subtypes have, particularly those elevated in disease, requires more than their identification alone. Therefore the integration of other modalities, such as scATAC-seq, would provide a necessary and improved understanding of both identity and function, although this presents a further analytical challenge that must be solved to realize this prospect. Stuart et al. turned to statistical learning to solve this challenge and developed a strategy to integrate data across technologies and techniques using canonical correlation analysis (CCA) to identify anchors between data sets.56 These anchors can then be

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used to correct for the differences between data sets, using methods based on batch correction, to fully integrate diverse single-cell data sets. This and similar approaches have also been used to address the technical noise present in scRNA-seq, particularly between samples, and provides an effective method to control for differences across samples and platforms, making a direct comparison possible. Indeed, a similar approach has been utilized by Zhang et al. to define inflammatory states in RA joint synovial tissue, using multiple experimental methods including histology, flow cytometry, and scRNA-seq.57 Using bulk RNA-seq as a reference, they integrated 5265 scRNA-seq profiles from patients with OA, RA, and leukocyte-rich RA and identified 18 unique cell populations. Furthermore several cellular subtypes of fibroblasts, monocytes, B-cells, and T-cells were identified that were expanded in RA synovia, by combining mass cytometry with transcriptomics. The development and application of these integration strategies shows that while integration is a challenging aspect of Big Data analysis, it is possible to combine data from a wide range of samples, technologies, and techniques, even when considering high-dimensional data sets. As more large-scale single-cell techniques become available, such as spatial transcriptomics and high-throughput single-cell ChIP-seq, our ability to integrate and interpret many forms of big biological data will improve our understanding of rheumatic diseases. This has the potential to identify which current therapies will be effective in which patient, develop new treatments, or identify exiting treatments that could be repositioned for use in the rheumatic diseases.

APPLICATION AND THE FUTURE OF BIG DATA The evolution of Big Data, both within rheumatology and beyond, is offering unprecedented opportunities for medical research. While there are considerable challenges covering generation, processing, and storage and analysis of Big Data, these are not insurmountable. One area in which Big Data will likely play a critical part within rheumatology is precision medicine. Our specialty has seen a massive and relatively fast expansion in choices of therapies for immune-mediated inflammatory diseases (IMIDs) such as rheumatoid arthritis, with an ever-increasing list of targeted biologic and synthetic disease-modifying antirheumatic drugs (DMARDs). Although these therapies have been revolutionary for many patients, they are prescribed stochastically, through trial and error, with low or absent response rates seen in 10% to 40% of patients, depending on the disease and drug used. Risk of serious adverse drug reactions also exists, with no way of predicting who will develop these currently. Collectively, these issues present an opportunity for stratified medicine approaches to make a real difference to patients’ lives. Big Data in rheumatology offers a tangible opportunity to change this approach. Precision medicine is “an emerging approach for disease treatment and prevention that takes into account individual variability in genes and other biomarkers, environment and lifestyle for each person.”58 The promise of precision, or stratified, medicine has emerged through advances and lowered costs of genetics and other omic information, combined with the availability of large-scale clinical data. However, achieving the full potential of precision medicine will only be possible by leveraging advanced machine learning and artificial intelligence (AI) technology that can rapidly handle and analyze large-scale data sets. Immune-mediated inflammatory diseases are phenotypically diverse but share underlying genetic susceptibility and inflammatory mechanisms. These diseases provide many opportunities and potential for precision or stratified medicine to make a significant impact on patient diagnosis, care, and disease management. In the United Kingdom and United States, as well as other countries, significant funding has been provided to support numerous large-scale projects, including many cross-institutional multidisciplinary consortia that focus on delivering stratified approaches across many disease areas. This is even truer for IMIDs, which are of national importance in the UK (demonstrated by United Kingdom Research and Innovation funding of over £25 million in this area over the last few years). In order to achieve the goals of stratified medicine, AI and advanced data analysis techniques applied to Big Data are needed. As a result, several interdisciplinary research groups, working together with pharmaceutical companies, are developing and applying data science techniques to large-scale data resources that include both clinical information as well as biological-level information such as genetics, proteomics, and other molecular data. The success of such programs is reliant on the integration of knowledge and experience for the clinical, computer sciences, epidemiology, and bioinformatics disciplines.

ETHICS Finally, as we increase our capture and use of Big Data, we must also consider the personal and societal ethical issues around the collection of and

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reuse of data for research. We are moving beyond the traditional approach of a patient being given an information leaflet and allowed time to consider participation in research before signing a consent form. Data are increasingly being used for research without direct consent or using an opt-out approach. In most cases, these data are completely anonymized or only a trusted third party has access to personal identifiable information. But knowing where to draw the line between anonymized and identifiable data is increasingly blurred, with the growing use of genetic data or in the case of analysis of very rare outcomes, such as certain rare IMIDs or cancers. The ethical issues around the reuse of data for commercial gain must also be considered. A framework for navigating the ethical landscape, with involvement of consumers and people living with disease, is critical. Recently, the European League Against Rheumatism (EULAR) has published the first-ever points to consider for the use of Big Data,59 which offers an important first step in navigating this new landscape.

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A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014;159(7):1665–1680. 31. Mifsud B, Tavares-Cadete F, Young AN, et al. Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat Genet. 2015;47(6):598–606. 32. Martin P, McGovern A, Orozco G, et al. Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci. Nat Commun. 2015;6(1):10069. 33. Javierre BM, Burren OS, Wilder SP, et al. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell. 2016;167(5):1369–1384. e19. 34. Dryden NH, Broome LR, Dudbridge F, et al. Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C. Genome Res. 2014;24(11):1854–1868. 35. Jäger R, Migliorini G, Henrion M, et al. Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci. Nat Commun. 2015;6(1):6178. 36. Illumina Source Book August 2020. 37. Wikipedia. Moore’s law—Wikipedia. 38. Macosko EZ, Basu A, Satija R, et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell. 2015;161(5):1202–1214. 39. Klein AM, Mazutis L, Akartuna I, et al. Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell. 2015;161(5):1187–1201. 40. Zheng GXY, Terry JM, Belgrader P, Ryvkin P, et al. Massively parallel digital transcriptional profiling of single cells. Nat Commun. 2017;8(1):14049. 41. Villani A-C, Satija R, Reynolds G, et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science. 2017;356(6335):eaah4573. 42. Dulken BW, Buckley MT, Navarro Negredo P, et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature. 2019;571(7764):205–210. 43. BBSRC, MRC. BBSRC and MRC Review of Vulnerable Skills and Capabilities Executive Summary. 2017. 44. Cairns J, Freire-Pritchett P, Wingett SW, Várnai C, Dimond A, Plagnol V, et al. CHiCAGO: robust detection of DNA looping interactions in Capture Hi-C data. Genome Biol. 2016 Oct;17(1):127. 45. Lareau CA, Aryee MJ. Hichipper: a preprocessing pipeline for calling DNA loops from HiChIP data. Nat Methods. 2018:155–156. 46. Cantor RM, Lange K, Sinsheimer JS. Prioritizing GWAS results: a review of statistical methods and recommendations for their application. Am J Hum Genet. 2010;86(1):6–22. 47. Shchetynsky K, Diaz-Gallo LM, Folkersen L, et al. Discovery of new candidate genes for rheumatoid arthritis through integration of genetic association data with expression pathway analysis. Arthritis Res Ther. 2017;19(1):19. 48. Farh KK-H, Marson A, Zhu J, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518(7539):337–343. 49. Trynka G, Sandor C, Han B, et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat Genet. 2013;45(2):124–130. 50. Trynka G, Westra H-J, Slowikowski K, et al. Disentangling the effects of colocalizing genomic annotations to functionally prioritize non-coding variants within complex-trait loci. Am J Hum Genet. 2015;97(1):139–152. 51. Ernst J, Kellis M. ChromHMM: automating chromatin-state discovery and characterization. Nat Methods. 2012;9(3):215–216. 52. Chan RCW, Libbrecht MW, Roberts EG, Bilmes JA, Noble WS, Hoffman MM. Segway 2.0: Gaussian mixture models and minibatch training. Bioinformatics, 34 (4), 2018, 669–671. 53. He B, Chen C, Teng LL, Tan K. Global view of enhancer–promoter interactome in human cells. Proc Natl Acad Sci. 2014;111(21):E2191–E2199. 54. Larrañaga P, Calvo B, Santana R, et al. Machine learning in bioinformatics. Brief Bioinform. 2006;7(1):86–112. 55. Orange DE, Agius P, DiCarlo EF, et al. Identification of three rheumatoid arthritis disease subtypes by machine learning integration of synovial histologic features and RNA sequencing data. Arthritis Rheumatol. 2018;70(5):690–701. 56. Stuart T, Butler A, Hoffman P, et al. Comprehensive integration of single-cell data. Cell. 2019;177(7):1888–1902. e21. 57. Zhang F, Wei K, Slowikowski K, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell tran­scriptomics and mass cytometry. Nat Immunol. 2019;20(7):928–942. 58. National Institutes of Health. Precision Medicine Initiative. Vol. 2017. 59. Gossec L, Kedra J, Servy H, et al. EULAR points to consider for the use of Big Data in rheumatic and musculoskeletal diseases. Ann Rheum Dis. 2019.

Principles and techniques in molecular biology Elaine F. Remmers • Michael J. Ombrello

Key Points ■ Restriction enzymes, DNA and RNA polymerases, DNA ligases, reverse transcriptases, phosphatases, kinases, and thermostable DNA polymerases are enzymes used to clone, modify, and amplify DNA in the laboratory. ■ Incorporation of exogenous DNA fragments into vectors that can replicate in bacteria, yeast, or insect cells permits large-scale production of the cloned gene or encoded protein. ■ Massively parallel high-throughput sequencing, which allows for the simultaneous analysis of nucleic acid sequence at billions of positions, is an extremely powerful tool that facilitates genomewide or transcriptome-wide investigations of both mendelian and complex genetic traits. ■ Whereas northern blot and real-time polymerase chain reaction are methods that quantitatively measure the expression of specific genes, microarray expression profiling and RNA sequencing simultaneously evaluate the expression of thousands of genes. ■ Electrophoretic mobility shift assays and chromatin immunoprecipitation assays detect DNA interactions with proteins, such as transcription factors and modified histones that are regulators of gene expression. ■ Transfection methods are biochemical, physical, or viral techniques for transferring exogenous DNA into cultured cells for expression. In a variant of the method, the expression vector directs transcription of short inhibitory RNAs that block the endogenous gene’s expression. ■ Transgenic mice are genetically modified animals into which an exogenous DNA construct has been transferred. In knockout mice, the endogenous gene has been disrupted, which thereby prevents its expression. ■ CRISPR-Cas9 and other genome editing methods introduce specific alterations into the genomes of cells or organisms. ■ Protein–protein interactions can be analyzed by coimmunoprecipitation and yeast two-hybrid screening. Fluorescence resonance energy transfer can be used to evaluate protein–protein interactions in living cells.

INTRODUCTION The past decade has witnessed rapid advancement in genomic medicine, driven initially by the Human Genome Project and subsequently by the 1000 Genomes Project and other large-scale, population-based genomic sequencing efforts. Together, these projects continue to reveal the scope and complexity of genetic and genomic variation in human beings, and they continue to afford scientists and physicians extraordinary opportunities to advance our understanding of physiology and pathology.1 Until just a few years ago, these possibilities were more science fiction than science. However, a number of critical technologic breakthroughs have truly revolutionized biomedical research. The opportunities for improving our understanding of rheumatic and autoimmune diseases are now astounding. Moreover, it is likely that recent advances will accelerate the pace at which disease susceptibility genes are identified and their functions analyzed. It is likely that this information will also improve treatment and propel the discovery of new therapeutic modalities. It is therefore intended in this chapter to review the basic tools that rheumatologists now see being used when they read the literature. Given the space constraints, the chapter does not review basic concepts in DNA replication, transcriptional control, or signal transduction. Several excellent textbooks cover these topics.2,3 Rather, the focus is on the methods used to study these processes; however, the intent is not for this to be a laboratory manual or “how to” guide. Again, there are ample sources that provide detailed protocols of this sort.4,5 Instead, the goal is to present the principles underlying important techniques with which astute rheumatologists should be familiar to comprehend studies that are pertinent to clinical work. Skimming through the rheumatologic literature, one sees references to a variety of techniques such as next-generation sequencing (NGS), RNA sequencing, chromatin immunoprecipitation sequencing, microarrays and gene expression profiling, gene editing with programmable nucleases, and

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tissue-specific knockouts using the cre/lox system. This chapter therefore discusses some of the major techniques and their modifications to facilitate comprehension of the literature.

THE HUMAN GENOME SEQUENCE AND BIOMEDICAL RESEARCH The human genome consists of about 3 billion adenine (A), guanine (G), cytosine (C), and thymine (T) bases (Fig. 17.1) arranged in 23 pairs of chromosomes. A great surprise was that the immense amount of potential genetic information encodes a relatively small number of genes, fewer than 30,000,6,7 which makes humans about twice as complex as model organisms such as yeast and Drosophila but less complex than rice. It is important to emphasize, however, that alternative splicing and protein modifications greatly increase the complexity of the polypeptides encoded by the human genome. The onslaught of information brought about by the Human Genome Project, the 1000 Genomes Project, and other similar large-scale sequencing projects has provided both new opportunities and new challenges to investigators. DNA and protein sequences, sequence variation, expression data, and structural data are among the information being deposited into a growing number of public and private databases. Savvy investigators mine these databases to obtain useful information with a variety of search and computational tools. Many publicly accessible databases and tools are available at the National Center for Biotechnology Information website (http://www.ncbi. nlm.nih.gov). Tools such as BLAST (Basic Local Alignment Search Tool), which facilitates sequence comparisons, can be used, for example, to find additional members of gene families that may have functions similar to one another. Comparisons of homologous genes of several species can identify regions that are conserved among species. These elements may be expressed parts of genes or unexpressed regions that may be conserved because they contain important regulatory elements. Managing and analyzing the data derived from genomewide approaches to expression profiling and disease– gene linkage and association studies can also require sophisticated computational and organizational approaches. The computational power, statistical sophistication, and computer programming skills required for development and implementation of tools applicable to biologic problems have resulted in rapid explosion of the field of bioinformatics, surely an area that will continue to grow for the foreseeable future.8,9 The molecular biology revolution, of course, began long before the Human Genome Project. Major steps in the revolution were the development of techniques that permitted the in vitro manipulation of DNA and advances in large-scale DNA sequencing. These advances permitted the identification, sequencing, isolation, and expression of genes, which allowed their functions to be discerned.

BASIC MANIPULATION OF DNA: CLONING VECTORS AND CUTTING AND PASTING DNA USING ENZYMES Vectors are engineered DNA molecules used to replicate, isolate, and express foreign DNA. There are several general types of commonly used vectors, which were derived from bacteria and bacteriophage. Plasmids are extrachromosomal, double-stranded circular DNA molecules. Often they are relatively small (3–5 kb), and they have three important features: a drug selection marker, convenient cloning sites, and a replicator that permits autonomous replication in cells (Fig. 17.2). Whereas some plasmids also have mammalian promoters that permit expression of the protein in mammalian cells, others are designed for expression in bacteria, yeast, or insect cells, the last being a very efficient means of generating large quantities of protein for crystallography studies. Sometimes plasmids are constructed to permit the production of fusion proteins. 145

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A commonly used vector permits cloning of a given gene in frame with glutathione S-transferase (GST). Glutathione-coupled agarose beads bind GST with high affinity and allow one to do “pull-down” experiments (see later). Another commonly used technique is to fuse the protein of interest to green fluorescent protein (GFP), a protein made by jellyfish, which can be easily visualized within cells (Fig. 17.3).10 Remarkably, most fusions to GFP retain the localization properties of the original protein molecule, provided that expression levels are not extremely high. As discussed later, this permits one to visualize trafficking of molecules in cells by live cell imaging. This is aided by the fact that fusion fluorescent proteins can now be engineered in a wide variety of colors from blue to far red, which permits simultaneous detection of multiple proteins and studies of protein–protein interaction by fluorescence resonance energy transfer.11 The bacteriophage λ has been a heavily used tool in molecular biology for many years. Its genome is about 50 kb, but the central portion of the viral genome is not essential for lytic growth and can be replaced by 10- to 20-kb inserts; for this reason, it is a commonly used vector to create libraries of genes. Cosmid vectors are hybrids between λ and plasmid vectors that can accommodate larger inserts of foreign DNA (35–50 kb). P1 vectors are derived from bacteriophage P1 and are large, circular DNA molecules that can contain 70 to 100 kb of eukaryotic DNA. P1-derived artificial chromosomes can accommodate even larger DNA inserts (up to 150 kb); bacterial artificial chromosomes have a still larger insert capacity (up to 200 kb) and have become the preferred vector for sequencing large DNA fragments and

THE HUMAN GENOME

POLYMERASE CHAIN REACTION

3 billion nucleotides ~30,000 genes 23 pairs of chromosomes

are used for multiple purposes, including generation of transgenic mice. Although yeast artificial chromosomes can accommodate even larger DNA inserts (≈ 1 Mb), these vectors are used less frequently because of problems with instability and chimerism. Finally, vectors derived from the M13 filamentous bacteriophage can accommodate small inserts (up to 1 kb) and can be used to produce single-stranded or double-stranded DNA. Libraries containing many different inserts representing different genes can be made using most of the aforementioned vectors. Libraries are made using genomic or complementary DNA (cDNA) and in some cases can permit expression of the gene encompassed by the insert. Many different enzymes are commercially available that permit replication and joining of DNA; such enzymes are termed DNA polymerases and ligases. Modifying enzymes such as phosphatases and kinases are also important in DNA ligation reactions. Exonucleases and endonucleases cut DNA, and restriction enzymes are bacterially derived enzymes that cut DNA at specific sites. These are among the most important tools in molecular biology. Hundreds of restriction enzymes are commercially available that allow one to cut DNA in a predictable manner. With the use of the enzymes just listed, pieces of DNA can be copied and spliced into vectors, which allows large-scale production of the gene or the encoded protein. An example of how these different enzymes can be used to move a piece of DNA from one vector to another is provided in Fig. 17.2. RNA also can be synthesized from DNA by DNA-dependent RNA polymerase, and the RNA, in turn, can be translated in vitro into protein. Conversely, reverse transcriptase, derived from retroviruses, synthesizes DNA from RNA. This enzyme is used to make cDNA and to make libraries from messenger RNA (mRNA) and can be the starting point in the polymerase chain reaction.

DNA

>3 x 104 to 1 x 105 proteins

FIG. 17.1  Although the human genome is less complex than initially thought in terms of the actual number of human genes, regulatory phenomena such as alternative splicing may considerably increase the diversity of proteins produced.

The polymerase chain reaction (PCR) is a rapid procedure for in vitro amplification of DNA; the development of this procedure was another landmark in molecular biology. There are a large number of applications of PCR, including the following: ■ Cloning of genomic DNA or cDNA ■ Mutagenesis or modification of DNA ■ Assays for the presence of pathogens, such as SARS-CoV-2 ■ Detection of mutations ■ Analysis of allelic sequence variations ■ Genetic fingerprinting of forensic samples ■ Nucleotide sequencing A schematic of PCR is shown in Fig. 17.4. The reaction includes the following components: a segment of double-stranded DNA to be amplified (template); two single-stranded oligonucleotide primers, each complementary to one of the two template strands; and deoxyribonucleoside triphosphates. Another critical component is a heat-stable DNA polymerase such as Taq polymerase. Its heat stability is an essential feature because the enzyme must withstand repeated cycles of heating and cooling to denature and replicate the target sequence many times. PCR takes place in a device termed a thermocycler, which can rapidly change the reaction temperature. First, the double-stranded DNA template is heated to generate single-stranded DNA. The primers, added in vast excess compared with the template DNA, anneal or hybridize to opposite strands of single-stranded DNA. The DNA polymerase then synthesizes new strands of DNA complementary

MANIPULATION OF DNA Plasmid 1

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FIG. 17.2  Abundant commercially available enzymes (ligases, polymerases, and restriction enzymes) and vectors make the in vitro manipulation of nucleic acids feasible. Ampr, Ampicillin resistance gene; GFP, green fluorescent protein; MCS, multiple cloning site; Ori, origin of replication; RE, restriction enzyme.

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to the template. After the first round of synthesis, the reaction mix is again heated, with subsequent denaturation of the double-stranded DNA, annealing of primers, and synthesis of DNA. These cycles permit a millionfold amplification of DNA. By designing particular primers, one can mutagenize DNA or add cloning sites. An important application of PCR is to detect RNA transcripts or to amplify their sequences to permit cloning or sequencing (or both). This requires first converting RNA templates to cDNA using reverse transcriptase (RT-PCR).

EXPRESSION OF A CHIMERIC FUSION PROTEIN

DNA SEQUENCING

FIG. 17.3 The ability to visualize the trafficking of cell proteins by tagging them with green fluorescent protein (GFP) has revolutionized cell biology and cell signaling. In this case, the Cybr gene is fused to GFP (green). Actin is visualized by binding of rhodamine-labeled phalloidin (red), and nuclei are stained with 4′,6-diamidino-2-phenylindole (blue). Courtesy of Dr. Massimo Gadina, National Institute of Arthritis, Musculoskeletal and Skin Disease, National Institutes of Health.

THE POLYMERASE CHAIN REACTION

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FIG. 17.4  The use of thermostable DNA polymerases and automated thermocyclers permits vast amplification of DNA and RNA templates through the polymerase chain reaction (PCR) method. Double-stranded DNA (template, light blue) is denatured by heat and, when cooled, primers (dark blue) anneal, which allows synthesis of new DNA (broken line, lavender). These cycles of denaturing, annealing, and synthesis are repeated with continued amplification of DNA (green). One can start with double-stranded DNA or with messenger RNA and use reverse transcriptase to generate the first complementary DNA strand, which is further amplified as earlier. PCR has many applications, ranging from diagnostics to mutagenesis, and has become an indispensable laboratory tool.

Manual techniques to sequence DNA were devised in the 1970s; however, sequencing the human genome was made possible by the development of automated sequencing technology. This technology continues to play an important role in rheumatology research laboratories and is beginning to be applied as a diagnostic tool. In the research setting, DNA sequencing is being used to refine the human genome sequence and to provide information regarding normal and disease-associated variation in the human genome. Sequencing cDNAs constructed by reverse transcription of mRNA can provide information regarding the structure of gene products. The DNA sequence is also obtained to confirm the structure of cloned DNA and manipulated DNA constructs used for expression, gene transfer, or gene-targeting experiments. In the clinical setting, several rheumatic diseases are now known to be genetic disorders for which mutations have been identified. These include several of the periodic fever syndromes, as well as some musculoskeletal disorders such as Marfan syndrome and familial osteochondral dysplasias causing early-onset osteoarthritis. For such disorders, sequencing can be used as a diagnostic tool; for example, to confirm the diagnosis of familial Mediterranean fever, which might be confused with a number of different inflammatory disorders. A definitive diagnosis permits the clinician to apply the most effective therapy as a treatment instead of using response to the therapy as a diagnostic tool. Sequencing by the Sanger method12 requires isolated DNA fragments specifically amplified by cloning or PCR. Complementary strands are synthesized by complementary base pairing on denatured DNA templates using enzymes (DNA polymerases) that normally perform this job in replicating cells. There are several variations on the strategy to obtain the sequence of the DNA fragment automatically. In the most common variant, four different fluorescent dye–labeled “terminator” analogs of the four deoxyribonucleotides, which incorporate into the growing strand but then terminate the reaction, are included in the replication mix (Fig. 17.5). The dye-labeled fragments are then separated by size through gel or capillary electrophoresis. The dye associated with each fragment identifies the last nucleotide analog incorporated. The sequence can then be automatically read by the succession of dyes detected as the fragments move through the separation medium. The initial sequencing of the human and mouse genomes was accomplished using these automated sequencing instruments. A landmark event in the evolution of nucleic acid sequencing was the emergence of massively parallel high-throughput sequencing methods, referred to in aggregate as next-generation sequencing. NGS approaches simultaneously generate sequence information at tens to hundreds of billions of base pair positions. Because of the substantial time and cost savings of NGS, compared with traditional sequencing methods, NGS has ushered in an era of genome-level sequencing projects that were previously unimaginable. Although there exist an ever-growing number of NGS platforms and techniques,13 they each share a central schema, which includes preparation of a library of DNA templates, sequencing and imaging of the template library, and, finally, analysis of the data. A general example of this process is depicted in Fig. 17.6. Creation of a library of DNA templates is the starting point for NGS, and a range of strategies may be used in library creation. Whole-genome sequencing uses DNA libraries created from whole genomic DNA, in contrast to target-enrichment strategies, which extract from the whole genomic DNA only those regions of interest. Target enrichment may be accomplished by a variety of methods, each of which effectively captures and separates the DNA segments of interest for library preparation. Exome sequencing, the most widely adopted target-enrichment strategy, seeks to capture and sequence the coding regions of the genome. In general, the DNA template library is generated by first breaking the genomic DNA into homogeneously sized fragments that are then ligated to adapter molecules on both ends. These adapter molecules facilitate the immobilization of DNA templates onto glass slides or beads, which produces a spatial distribution of DNA templates that allows for each of them to be imaged independently. In some cases, the immobilized DNA templates are amplified with universal primer

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AUTOMATED SEQUENCING OF DNA Template DNA

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sequence reads to place these otherwise multiply mapping reads into their correct genomic position. After the sequences have been assembled and aligned, one may generate a list of positions at which the experimental sample differs from the reference, and rapidly evolving bioinformatic tools can annotate sequence variants based on characteristics such as the type of variant, the depth of coverage or quality scores of a variant, the degree of conservation of that reference position across other organisms, and the predicted effect of the variant on its protein product. Even when sequencing is performed by the most experienced sequencing centers and bioinformaticians, errors are inescapably introduced at multiple steps of the NGS workflow, leading to an errant base call rate as high as 1%.14 Potential sources of error are widespread and may include the limited fidelity of polymerase enzymes during the whole-genome amplification or cluster amplification processes, the incorporation of degraded dye-labeled nucleotides or the misincorporation of dye-labeled nucleotides during cycle sequencing, the presence of optical interference that precludes proper identification of bases, and the false-positive and false-negative variant identification that may result from erroneously mapped sequence reads. In response to this problem, there is a rapid emergence of both experimental and bioinformatic approaches that promise to better identify erroneously called variants. At this point, validation of NGS findings by Sanger sequencing remains the gold standard.

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FIG. 17.5 Sequencing of DNA is performed by extending oligonucleotide-primed DNA templates with a thermostable DNA polymerase in the presence of dye-tagged dideoxy terminators that block further extension of the newly synthesized DNA strand and label the strand with one of four different fluorescent dyes identifying the last base incorporated. Automated methods for size fractionating the fragments, detecting the fluors, and reading the DNA sequence have made possible the largescale sequencing required for sequencing the human genome.

sequences contained within the adapters, which transforms each DNA template into a cluster of identical DNA molecules. In other cases, the signal intensity generated by a single DNA template molecule is adequate for detection and no DNA template amplification is required. Upon generation of a library of DNA templates, most NGS approaches use dye-labeled nucleotides that are specifically incorporated during cycle sequencing and are subsequently imaged. After the imaging step of each cycle, the labeled nucleotides are modified to remove the dye molecules and to allow progression of the next cycle of incorporation and imaging. Although the chemistry and experimental design vary among platforms, every NGS platform requires the sequential imaging of fluorescent signals at fixed locations to facilitate and assemble sequence reads from the DNA templates or clusters. The raw data generated by NGS consist of a very large number of sequence reads, the lengths and configuration of which are dictated by the platform and experimental design used for the sequencing. These sequence reads must be aligned to a known reference sequence to allow for identification of variant alleles. In some cases, it may be beneficial to first assemble the sequence reads with one another in the absence of the reference sequence, referred to as de novo assembly. In the case of structural variants, gene families with a high degree of homology, or regions rich in repetitive elements, sequence reads may align with multiple genomic locations in the reference sequence and, as a result, may be excluded from subsequent analysis. With de novo assembly, one attempts to harness the power of the overlapping

Insights into the physiologic and pathologic functions of a given gene may be gained by analyzing the expression of its mRNA in tissue and cells and delineating when, where, and how the gene is regulated. Northern blotting and quantitative real-time PCR are useful to measure the level of gene expression of one or a few genes, and in situ hybridization can be used to show the gene expression in tissue. RNA is often isolated using acid guanidinium-phenol-chloroform–based methods and in some cases is further purified by oligo-dT columns with immobilized short sequences of deoxythymine nucleotides, which bind the poly A tail of mRNA. In northern blotting, RNA is separated by size in an agarose gel, transferred to a membrane, and detected by a labeled probe using RNA–DNA hybridization. The amount of mRNA corresponds to the binding of the radioactive probe, which can be visualized by autoradiography. In real-time PCR, a quantitative method for measuring mRNA, mRNA is transcribed into cDNA by reverse transcriptase (Fig. 17.7). A probe with a fluorescent dye at its 5′ end and a quencher dye at the 3′ end is added to the reaction tube. During the PCR reaction, the reporter dye is separated from the quencher dye because DNA polymerase has 5′ nuclease activity, it degrades the hybridized probe as a new DNA strand is synthesized in its place. When the reporter dye is separated from the associated quencher dye, its fluorescence is detected and accumulates with each successive round of PCR. Generation of the fluorescence is quantitatively dependent on the number of transcript copies in the cDNA sample. A reference probe for a housekeeping gene is also included, which allows this to be a quantitative assay. Ribonuclease (RNAse) protection is another means of measuring mRNA and has the advantage that multiple genes can be analyzed simultaneously. In this method, labeled antisense riboprobes are hybridized to RNA in solution and then digested with RNAse, which digests single-stranded but not double-stranded RNA. The amount of riboprobe protected by the mRNA is therefore a measure of the gene expression. Another method to quantify multiple different mRNA molecules has recently been developed and is commercially available (NanoString Technologies, Seattle, WA). This method uses a two-probe barcoded detection system15 that can make direct measurements of the abundance of up to 800 RNA species in RNA from as few as 10,000 cells without enzymatic reactions or bias. In situ hybridization identifies which type of cell in a tissue expresses a particular gene. In this method, one hybridizes a specifically labeled nucleic acid probe to the cellular RNA in individual cells or tissue sections. In principle, this uses the same strategy as northern blotting (hybridization of RNA with labeled cDNA), but in this case, the hybridization is visualized within cells using microscopy. The gene’s protein product or other proteins can also be visualized by immunohistochemistry, which may be quite informative in the analysis of clinical samples or in assessing the role of the gene in development. The steady-state levels of mRNA are influenced by several factors, including the rate of its transcription as well as its stability, transport, and translation. The nuclear run-on assay measures the levels of primary transcript production without influence of other factors and thus can be used to distinguish whether a change in mRNA level is due to a difference in the rate of transcription per se or to other reasons such as altered mRNA stability.

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NEXT GENERATION SEQUENCING DNA Template Creation

Template Immobilization and Cluster Amplification

ds gDNA Shear/fragment DNA

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Two example amplified clusters

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FIG. 17.6  Next-generation sequencing permits simultaneous generation of sequence information at tens to hundreds of billions of base pair positions. (a) A library of DNA templates is created by fragmenting double-stranded genomic DNA (ds gDNA) into small, single-stranded pieces (ssDNA) to which adapter molecules are attached. (b) The DNA templates are immobilized to slide-bound adapter molecules, and through the use of oligonucleotides that recognize primer sites within the adapter molecules, cluster amplification transforms each immobilized DNA template molecule into a cluster of identical DNA templates. (c) Cycle sequencing begins with single-base-pair incorporation of dye-labeled nucleotides onto each DNA template molecule. The unbound dye-labeled nucleotides are thoroughly washed and removed, after which fluorescent images are captured for each cluster of DNA templates. The dyes are then cleaved from the incorporated nucleotides, and the subsequent cycle of sequencing begins again with the incorporation dye-labeled nucleotides at the next position of each DNA template.

GENE EXPRESSION PROFILING Although expression of genes can be evaluated by in situ hybridization, RNAse protection assay, northern blotting, or quantitative real-time PCR (see earlier), the selection of genes for study is limited by the extent of our prior knowledge. New technologies building on the identification of most expressed genes by the Human Genome Project and more recently using high-throughput sequencing permit expression profiling; that is, analysis of the expression of thousands of genes, including those with unknown function, in a tissue or cell population. Indeed, these newer methods permit evaluation of the expression of not just a few genes but potentially all genes. Several techniques have been developed for expression profiling. In serial analysis of gene expression, a small tag (short DNA fragment) is generated

from each transcript. The tags are concatenated, and these larger DNA fragments are sequenced to identify the transcripts as well as their frequency in the transcript pool derived from a tissue or cell population.16 Array-based methods of expression profiling use specific nucleic acid probes immobilized in an ordered array on a solid surface. Hybridization techniques in which labeled cDNA or complementary RNA (cRNA) fragments bind to the immobilized probes are then used to estimate the relative number of copies of each gene transcript in RNA extracted from a tissue or cell sample by the amount of label that binds to the immobilized probe. To achieve probe density sufficient to assay expression of tens of thousands of genes from relatively small tissue or cell samples, microarray technology was developed. The newest methods for expression profiling use NGS technologies to comprehensively characterize and quantify the transcriptome.

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Quencher Probe Primer

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MASSIVELY PARALLEL SEQUENCING OF RNA Massively parallel sequencing of RNA (RNA-Seq), which uses NGS to interrogate RNA sequence and abundance, is perhaps the most powerful tool for unbiased investigation of RNA species. RNA-Seq has been most widely used in the investigation of mRNA, in which case the polyadenylated RNA species are captured from a sample. The captured RNA is fragmented to a size of several hundred bases, either before or after producing cDNA by reverse transcription, and the cDNA fragments are concurrently sequenced using NGS technology. Each sequencing read is then assembled and aligned to the human genome and the prevalence of each RNA species may be determined. In addition to accurately quantifying genomewide expression, RNA-Seq may identify the presence of variant alleles, alternatively spliced transcripts, posttranscriptional mutations or RNA editing, and gene fusions. Furthermore using a variety of different RNA capture conditions, RNA-Seq may be modified to interrogate noncoding RNA, micro-RNA, or any other population of RNA. Because of the inherently error-prone nature of reverse transcriptase enzymes, the process of creating a cDNA library may introduce errors and bias to an RNA-Seq study. As a result, efforts are under way to develop protocols to perform RNA-Seq on RNA molecules themselves.

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SINGLE CELL RNA SEQUENCING

c

FIG. 17.7  In quantitative real-time polymerase chain reaction (PCR), oligonucleotide probes coupled to a reporter dye are synthesized along with ordinary primer pairs and used in the reaction. The intact probe in (a) does not fluoresce because a quencher is also coupled to the probe. However, the probe is cleaved by DNA polymerase during amplification in (b) and (c), which separates reporter dye from quencher dye and results in increased fluorescence. The amount of PCR products generated can therefore be measured by monitoring the intensity of fluorescence with each cycle because the amount of probe cleaved parallels the amount of PCR products produced. This is a reflection of the initial amount of complementary DNA (cDNA) generated from messenger RNA. This test can be further standardized by including probes and primers for housekeeping genes and can be made more quantitative by generating a standard curve using known amounts of cDNA encoding the gene of interest.

DNA CHIP MICROARRAYS DNA chip microarrays are manufactured by Affymetrix (Santa Clara, CA) and Illumina (San Diego, CA). Affymetrix uses a proprietary photolithographic process to synthesize 25-base oligonucleotides tethered to the chip surface; each is confined to an 11 × 11 μm square space. Each gene is represented by 22 squares with oligonucleotide probes covering various parts of the gene. Half of the probes are a perfect match and half are hybridization controls—that is, copies of the perfect-match oligonucleotides—each with a single nucleotide mismatch. Probes for up to 47,000 transcripts can be synthesized on a single chip that is less than 1 cm2. RNA is extracted from tissue or cells and cDNA is synthesized. The cDNA is used to produce biotin-labeled cRNA, which is fragmented and hybridized to the probes on the chip surface. The chips are washed and stained with a streptavidin-conjugated fluorescent dye, which binds to the hybridized biotinylated cRNA. The chips are scanned and the fluorescent signals are processed to determine the expression level of each gene. Normalized expression levels determined from different tissue or cell samples on different chips can then be compared. A variant of the DNA chip microarray is the Illumina BeadChip microarray. In this array, beads are coated with oligonucleotide probes (50-mers) attached to an address tag oligonucleotide (30-mers). The beads are randomly affixed to the surface of a slide-like solid support. About 30 beads of each type (representing a single transcript) are affixed to each BeadChip microarray, and their locations are determined by the address tags. Labeled cRNA is produced and hybridized to the BeadChip. The chips are scanned and the signal intensity for each probe type is measured. An advantage of DNA chip or bead microarrays is that, because the microarrays are mass produced under highly controlled conditions, reproducibility of the expression data obtained from them can be very high. A disadvantage is that production of the microarrays is inflexible (custom arrays are expensive). Furthermore only genes with sufficient sequence data to generate the probes can be represented on a DNA chip microarray.

In order to obtain sufficient material to evaluate mRNA abundance, the aforementioned methods all require extracting and analyzing mRNA from tissues or cells in bulk, making it impossible to know the variability in expression among specific cells or cell types comprising the analyzed sample. Newer methods are now permitting analysis of gene expression within single cells.17 These methods are growing in popularity because they allow identification of rare cell populations, they permit evaluation of gene expression within cells of selected populations, and they can highlight the heterogeneity in gene expression among cells in an apparently identical population that may have impact on their function or developmental potential.18 Although the methods vary, a general protocol is described in Fig. 17.8. The first step is to isolate single cells; for example, by using microfluidics, flow cytometry cell sorting, or droplet-based methods. Each cell is lysed and the mRNA is captured, reverse-transcribed, and PCR amplified. Adding a cell-specific barcode sequence allows the cDNAs from hundreds to thousands of cells to be processed and sequenced together by NGS methods. Using bioinformatic methods the transcripts are identified and their abundance in each cell determined. Important quality control measures are required to remove data from poor quality single cells identified by small library size or low number of detected genes or with a high fraction of reads mapping to mitochondrial genes. Other quality controls may include analysis of spiked-in control mRNAs or the use of unique molecular identifiers (UMIs) to remove PCR duplicates. After filtering low-quality cell data, bioinformatic tools such as principal component analysis and t-distributed stochastic neighbor embedding (t-SNE) are applied to reduce the multidimensional gene expression data, allowing the cells to be plotted in two dimensions, positioning cells with the most similar gene expression patterns closest to one another. Expression of specific genes can allow cell clusters to be identified as biologically meaningful populations or subpopulations within and among which gene expression can be characterized. Recent work has applied this methodology to synovial tissue cells from patients with rheumatoid or osteoarthritis, identifying and characterizing gene expression in 18 distinct cell populations.19

REGULATION OF GENE EXPRESSION AND PROTEIN–DNA INTERACTIONS Understanding what controls the expression of a given gene is of considerable interest in the pathogenesis of rheumatic diseases. Typically, the first step in the process involves the identification of the promoter and enhancers of the gene of interest. Generally, this is accomplished by identifying the transcriptional start site and the 5′ untranscribed regulatory portion of the gene. These regions of the gene are then subcloned into reporter systems, which are used as surrogates to measure transcriptional regulation and the interactions of cis- and trans-acting elements with promoters and enhancers. Typically, regulatory sequences are ligated to reporter genes, such as firefly luciferase, and these plasmids are transfected into cells of interest that are stimulated in various ways. In this manner, the luciferase gene is transcribed in the place of the native gene, and the level of transcription can be detected by light produced by the translated luciferase protein, which is regulated by stimuli that act on the heterologous promoter (Fig. 17.9). The fine structure of promoter/enhancer regions can be analyzed by introducing a series of

CHAPTER 17  Principles and techniques in molecular biology SINGLE CELL RNA SEQUENCING 1 Dissociate cells from tissue or purify a targeted cell population. 2 Isolate single cells.

3 Lyse single cells and capture mRNA. AAA AAA AAA

AAA AAA AAA

AAA AAA AAA

4 Reverse transcribe and prepare cDNA libraries adding cell-specific barcode sequences.

5 Combine cDNA libraries and sequence with NGS methods.

t-SNE 2

6 Use sequence reads to identify each transcript and its source cell, determining the transcript content and abundance in each cell.

t-SNE 2

t-SNE 1

Population 1 Population 2

Population 3 Population 4

7 Use bioinformatic tools such as t-distributed stochastic neighbor embedding (t-SNE) to cluster cells with similar gene expression patterns.

8 Use expression of specific genes to identify biologically relevant cell populations or sub-populations.

t-SNE 1

FIG. 17.8  In single cell RNA sequencing, individual cells are lysed and the mRNA of each cell is reverse-transcribed with the addition of a cell-specific barcode (shown by different colors in step 4). The barcoded cDNAs from hundreds to thousands of cells are combined and sequenced together by next-generation sequencing methodology, permitting the identification of the transcripts and their abundance in the individual cells. Bioinformatic tools are used to cluster cells with similar gene expression patterns, and specific cell populations or subpopulations can be identified by expression of cell-specific marker genes, allowing the gene expression profiles of these cell types to be elucidated.

mutations and examining the effects on reporter gene expression. The effect of patient-derived mutations or polymorphisms in promoters may also be examined to assess their influence on gene expression. Identifying transcription factors that bind promoter/enhancer sequences is another important aspect of understanding gene regulation. The electrophoretic mobility shift assay is a commonly used technique to detect specific DNA–protein interactions (Fig. 17.10). Nuclear proteins are incubated with radioactively labeled test oligonucleotides, which are subjected to electrophoresis on polyacrylamide gels and are visualized by autoradiography. DNA bound to protein “shifts” the oligonucleotide; that is, it migrates more slowly than the unbound radioactive oligonucleotide probe. Bound proteins can be identified by the use of specific antibodies that cause the protein–DNA complex to migrate even more slowly, a so-called supershift. The deoxyribonuclease (DNAse) footprinting assay is another assay used to look for transcription factors bound to DNA and to determine precisely which nucleotides are bound by transcription factors that protect them from degradation by DNAse treatment. The chromatin immunoprecipitation (ChIP) assay is a technique that detects protein–DNA interaction in cells (Fig. 17.11).20 In this procedure, nuclear DNA-bound proteins are cross-linked to DNA by formaldehyde. The DNA is sheared and the protein–DNA complexes are immunoprecipitated with antibodies against the proteins that putatively interact with the

151

DNA of interest, so that the DNA bound to these proteins is coprecipitated or captured. The cross-links are reversed, and PCR is used to amplify the regions of genes of interest. These products are then run out on agarose gels. Alternatively, real-time PCR can be used to detect the DNA that was bound by the immunoprecipitated protein. An extension of these principles allows the identification of virtually all the targets of the investigated DNA-binding protein in different cells under different circumstances. This can be accomplished by labeling the immunoprecipitated DNA fragments and hybridizing them to DNA sequences on a microarray slide (ChIP-on-chip) or by sequencing all of the immunoprecipitated DNA fragments using efficient NGS technologies (ChIP-Seq). When used in combination with other gene expression data, these techniques provide a powerful genomewide screening method to identify target genes of transcription factors. Recent evidence shows that modification of the histone tail (e.g., acetylation, methylation, phosphorylation) is of considerable importance in regulating chromatin structure and the accessibility of genetic loci to transcription factors.21 Alterations of histone modification are very important in explaining transcriptional on–off states. These changes can be assessed using ChIP with antibodies that specifically detect these modifications. The interaction of other transcription factors with promoters and enhancers can also be determined using ChIP in regions with altered histone modifications. Histone modifications are thought to affect the accessibility of genes and therefore their ability to be acted on by cis-acting transcription factors. Accessibility of genes to transcriptional machinery can also be assessed by their ability to be digested with DNAse; thus transcriptionally active, open chromatin displays DNAse hypersensitivity. A recently devised rapid method to accurately identify open chromatin regions in fewer cells is the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC–seq).22 This assay uses a hyperactive transposase to integrate high-throughput sequencing adaptors preferentially into accessible open chromatin. Through high-throughput sequencing, regions of open chromatin are identified by their high frequency of sequence reads. Furthermore, the sensitivity of this technique enables the identification of DNA-binding protein sites within the regions of open chromatin configuration, which can be recognized as “footprints” of reduced sequencing read depth within larger peaks of sequence reads. Recent work has illustrated that transcriptional regulation can also take place in the context of interactions between disparate genomic loci. Chromosome conformation capture assay (3 C assay) is designed to detect these interactions of genomic loci in vivo.23 In living cells, two loci that are seemingly far apart on the genome can move into close proximity by “looping out” of the chromosome and sharing DNA-binding proteins. A chemical cross-linker is used to stabilize these interactions. Subsequently, the captured DNA is digested and ligated to generate a novel junction between the two interacting DNA loci. PCR is then used to detect these novel ligation products, which are indicative of intrachromosomal interactions between a gene locus and a distant enhancer element and even interactions between two loci on different chromosomes. The 3 C assay has the potential to uncover coordinated regulation of genes that are not located close together on the genome yet become physically close together during regulatory remodeling of the chromatin. Many assays of gene regulatory elements are now being performed on a genomewide scale on a myriad of different cell types, and the results are being deposited into searchable databases such as the Encyclopedia of DNA Elements (ENCODE; http://www.nature.com/encode/#/threads)24 that allow investigators to query the locations of regulatory elements and to design experiments to evaluate their contributions to processes involved in normal as well as diseased states.

ANALYSIS OF GENE FUNCTION The transfer of genes into mammalian cells has been an essential tool to study gene function. These techniques allow examination of the consequence of expression of a new or altered gene and provide us with a great deal of our knowledge about the action of the encoded protein. The cDNAs corresponding to the genes of interest are cloned into expression vectors and are coupled to a strong promoter enabling high expression in cells. For instance, viral promoters are often used to allow high expression in various cell lines. Many different methods are used to transfect these constructs into mammalian cells. These include biochemical methods such as calcium phosphate, diethylaminoethyl–dextran, and liposome-based techniques. Alternatively, for cells that are difficult to transfect by these methods, physical methods such as electroporation and microinjection are used. A third way to transduce genes is by using viral vectors. Developed as tools for gene therapy, these are now widely used in many experiments. The vectors can infect various types of mammalian cells, including cells that are hard to

152

SECTION 1  Scientific Basis of Rheumatic Disease LUCIFERASE ASSAY Promoter of interest Luciferase

Luciferase Stimulate

Transfect

Cell

Luciferase + Lyse ATP

Light

Cell

FIG. 17.9  To determine if a segment of DNA has enhancer/promoter activity, it is cloned upstream of a reporter gene that, when transcribed, will produce the protein encoded by the reporter—such as the luciferase enzyme. The transcription of this gene and hence the production of the protein is measured by an in vitro assay that produces light, with the amount of light produced being proportional to the activation of the promoter. ATP, Adenosine 5′-triphosphate.

ELECTROPHORETIC MOBILITY SHIFT ASSAY

Synthesize + label oligonucleotide

* * Stimulate cells

Isolate nuclei

Incubated with or without Ab

Prepare nuclear protein Supershifted complex DNA–protein complex Labeled oligonucleotide

FIG. 17.10  When radiolabeled oligonucleotides are bound by nuclear proteins, their migration in acrylamide gels is retarded or slowed because of their larger molecular weight. This is also referred to as a shift in their mobility in the gel. If antibodies (Ab) against the putative DNA-binding proteins are also included, the complex is said to be supershifted, and this provides evidence that a particular transcription factor is bound to the oligonucleotide. Chemiluminescence methods can be used to detect biotinylated oligonucleotides to avoid the use of radionuclides.

transfect by the other two methods. Adenovirus and retroviruses are representative viruses used for gene transfer. Whereas adenovirus can infect most types of cells and allow transient but high protein expression, retroviruses infect only dividing cells and are characterized by moderate but long-term protein expression. These methods allow transient expression of genes, which are translated into protein; the effect on cell function can be determined over hours to days. Over time, the cells lose the introduced plasmid construct because of degradation and dilution, but in a few cells the gene is integrated stably into the genome and maintained in offspring cells. These rare cells can be selected by using drug-selection reagents to establish stable transfectants. They typically show lower expression of the gene than with transient expression but are of great use for various experiments. Recently, new methods have been devised for “knocking down” gene expression. This approach is based on RNA interference (RNAi) and is being heavily employed both in cells in tissue culture and more recently in animal

models. For determining the nonredundant function of a particular gene, reducing gene expression has clear advantages over introducing the gene exogenously with plasmid or viral vectors. It is also important for determining whether the functional effects of a treatment depend on a particular gene. RNAi has largely supplanted earlier techniques such as those using ribozymes or antisense oligonucleotides for reducing expression of specific genes. RNAi takes advantage of a recently discovered RNA silencing mechanism that is conserved from worms to mammals.25 Double-stranded RNA containing sequences complementary to the targeted gene are cut into 21- to 23-base-pair small interfering RNA (siRNA) fragments using a specialized RNAse III enzyme called Dicer. These fragments are then incorporated into the RNA-induced silencing complex (RISC), a multiprotein assembly that unwinds the double-stranded siRNA fragments, which bind to complementary sequences in an mRNA molecule. The RISC cleaves the target RNA at a single site in the middle of the complementary sequence, effectively inactivating further translation of the target mRNA. Because a single siRNA in the RISC can inactivate multiple target mRNAs, knockdown of gene expression through this mechanism can be potent (more than 90%) and long-lasting (up to 5 days from a single transfection of siRNA duplexes). The promise of this technique for basic research and therapeutic intervention is beginning to be realized.26 In most higher organisms, including humans and mice, transfection of long double-stranded RNA and even some shorter sequences can activate an antiviral gene response program that induces type I interferon induction and nonspecific RNA degradation by RNAse L, so siRNA oligonucleotides shorter than 23 base pairs are used. Synthetic siRNA can be delivered to a variety of cultured cells through conventional transfection methods. More recently, injection of siRNA with a fluid bolus was found to silence gene expression efficiently in mice, and coupling protamine-bound siRNA to a Fab antibody fragment specific for a cell surface molecule was able to target siRNA to specific cell subsets.27,28 For long-term silencing of target genes, expression of a “short-hairpin” RNA (shRNA) sequence containing the target siRNA connected by a loop region under the control of an RNA polymerase III promoter is preferred. Dicer cleaves the expressed shRNA into siRNA, which is incorporated into the RISC. Viral vectors have been engineered that can drive stable expression of shRNA and silence target RNA molecules in primary cells.29,30

GENETIC MANIPULATION OF MICE Another way investigators can learn about the function of a gene is to study its in vivo function in a genetic model organism in which its expression and structure can be experimentally manipulated. Mice are particularly amenable to such studies. Because mice are mammals, their genes and gene functions are very similar to those of humans, but it is possible to manipulate its genome by introducing or overexpressing genes in transgenic mice or by using targeted disruption to destroy a gene in knockout mice.31 Investigators can then study the effects of these genetic alterations in the animals, their tissues, or their cells.

TRANSGENIC MICE Transgenic animals are genetically modified animals in which foreign DNA has been experimentally inserted into the transgenic genome. This is accomplished by injecting a DNA construct into the pronucleus of a fertilized oocyte. Blastocysts that develop from these injected oocytes are transferred

CHAPTER 17  Principles and techniques in molecular biology

153

CHROMATIN IMMUNOPRECIPITATION ASSAY Cross-linking and shearing

Immunoprecipitation of protein–DNA complex

FIG. 17.11  Transcription factors, coactivators, and other Purification of DNA Input DNA PCR

Immunoprecipitated DNA

DNA-binding proteins can be analyzed by cross-linking these proteins to DNA, followed by DNA shearing and immunoprecipitation with antibodies directed against the proteins of interest. Then protein is digested and the DNA is amplified by polymerase chain reaction (PCR) with primer pairs for the DNA region of interest. A positive band indicates interaction of the protein with the DNA region (IP-stim) compared with what is seen in the absence of stimulation (IP-unstim). This is normalized to the amount of DNA present initially (input).

Agarose gel electrophoresis

C IP IP ut ontr -uns -stim ol tim

Inp

to pseudopregnant females, in which they develop, to produce potentially transgenic pups (Fig. 17.12). The pups are screened for the presence of the transgene and bred. If the transgene was integrated into the genome of its germline, the animal will then transmit the transgene to the next generation. The investigator can target expression of the transgene to specific tissues by using tissue-specific promoters or enhancers. The investigator can also control expression of a transgene by using an inducible promoter system such as a tetracycline-regulated system, in which a construct encoding a tetracycline-induced factor under the control of a tissue-specific promoter is introduced in one mouse line and the gene of interest, under the control of a promoter that is controlled by the factor, is introduced into a second line. The tetracycline-induced factor can be either an expression activator or an expression repressor. The lines are then crossbred to generate animals with both genetic alterations, in which expression of the transgene can be controlled in the target tissue by administering or withdrawing tetracycline. Transgenes typically integrate as a tandemly repeated unit within the recipient genome. It is not possible to control the integration site or the number of copies integrated.

KNOCKOUT MICE Another way to study the function of a gene is to determine in animals the effect of disrupting the gene so that its product is not produced. Spontaneous mutations that have this effect on genes have provided investigators with a great deal of information regarding the function of the affected genes. It is now possible for investigators to experimentally manipulate the genomes of mice by disrupting a gene in pluripotent embryonic stem cells and incorporating those cells into a developing blastocyst (Fig. 17.13). The technique used to disrupt a gene is to transfect the embryonic stem cells in vitro with a DNA construct in which a fragment of the gene sequence has been disrupted by incorporating a selectable marker gene, such as the neomycin resistance marker, that can also be used for positive selection of cells that have integrated the construct. Disruption of the endogenous gene occurs by the process of homologous recombination, whereby homologous sequences flanking the disruption facilitate the exchange of the disrupted gene fragment with the intact fragment of the endogenous gene. The construct may include a coding sequence deletion and/or a premature termination and polyadenylation signal, which, when incorporated within the endogenous gene, blocks its expression. The construct also contains, outside of the gene disruption cassette, a second marker, such as the thymidine

kinase marker, that can be used for negative selection to eliminate trans­ fectants in which nonhomologous recombination occurred. Cells in which homologous recombination occurred are injected into blastocysts and the blastocysts are transferred to foster mothers. Some of the pups produced may be chimeras, in which the genetically altered embryonic stem cells have expanded and contributed to the developing embryo. Through the use of blastocysts and stem cells from strains with different-colored coats, the chimeric pups can be recognized by the contribution of the stem cells to the coat color. As with transgenic mice, the chimeric offspring are then bred to determine whether the embryonic stem cells contributed to the development of germ cells and will therefore be transmitted to the next generation. Carriers of the chromosome with the disrupted gene can be interbred to produce knockout or gene-targeted mice in which both copies of the gene are disrupted. A variant of the knockout mouse, the knockin mouse, can be used to trace the temporal and spatial expression patterns of a gene and to study regulation of its expression. In this technique, the targeting construct includes a reporter gene, such as the β-galactosidase gene, as well as the selectable marker. The targeted animals produce a chimeric protein in which the reporter gene is fused to a portion of the gene under study. The chimeric gene is expected to be expressed in the same manner as the gene under study. Expression of the chimeric gene can be evaluated by analyzing expression of the reporter gene. Knockin technology can also be used to introduce a disease-associated or other mutation into the gene of interest.

MICE WITH CRE/LOX-DIRECTED TARGETED DISRUPTION If disruption of a gene interferes with embryonic development or is lethal, it is difficult to discern its function in knockout mice. Investigators may, however, examine the effect of eliminating the gene’s expression from specific tissues or at specific times. These experiments are made possible by the cre/ lox recombinase system in which a pair of locus of x-over, P1 (lox) sites, recognized by the cyclization recombinase of P1 bacteriophage (cre), is inserted in intron sequences flanking an essential portion of the targeted gene. This genetic alteration does not interfere with the gene’s expression. In the presence of the cre recombinase, however, the targeted region is excised from the gene, which leaves a nonfunctional remnant. The cre recombinase can be inserted into the genome as a transgene and an inducible or tissue-specific promoter can direct its expression. In this way, a gene can be disrupted in a

154

SECTION 1  Scientific Basis of Rheumatic Disease TRANSGENIC MICE Female pronucleus

KNOCKOUT MICE

Male pronucleus

Gene

Neo

DNA

Oocyte

Gene-targeting construct

TK

Disrupted gene Transgene integration

Transfect

Embryonic stem cells

Neo-positive selection TK-negative selection

Genomic DNA

Blastocyst

Genetically modified ES cells Transfer

Inject cells

Pseudopregnant female

Transgenic pups

Blastocyst

Transfer

FIG. 17.12  Overexpression of DNA constructs in transgenic animals is achieved by injecting a DNA construct (containing the transgene) into the male pronucleus of a fertilized oocyte. The transgene may integrate as a tandem repeat within the recipient genome. Blastocysts are allowed to develop in vitro and are then transferred to pseudopregnant female mice. If the transgene has integrated into the genome of the germline, the transgenic offspring (founders) will transmit the transgene to their offspring.

C57BL/6

Pseudopregnant female

Chimeric pups

FIG. 17.13 A gene can be effectively deleted from (knocked out of) an animal’s specific tissue or at a specific developmental stage by regulating the location and timing of cre expression in the animal.

CRISPR-CAS9 AND GENOME EDITING One of the most promising recent developments in molecular biology (and perhaps all of medicine) has been the emergence and rapid improvement of approaches to alter or edit the genetic material of living organisms.32 In general terms, gene editing seeks to create one or more specific modifications within the genetic sequence of living cells. By introducing double-stranded DNA breaks (DSBs) in precise genomic locations and then providing synthetic DNA fragments that share homology with the regions flanking the DSB but that also contain the desired sequence alteration, one can use the cell’s intrinsic homologous recombination mechanism33 to introduce targeted modifications to host genomes (Fig. 17.14). Two recently developed technologies have harnessed the sequence-specific binding capacity of bacterially derived systems to introduce these targeted DSBs, allowing the widespread adoption of gene editing techniques and revolutionizing the field of genetic engineering. Transcription activator–like effector nucleases (TALENs), which are derived from Xanthomonas bacteria, are engineered restriction nucleases that can be designed to bind specific DNA sequences and introduce DSBs at targeted sites.34 Similarly, approaches based on the clustered regularly interspersed short palindromic repeats (CRISPR) system of Streptococcus pyogenes and its CRISPR-associated protein 9 (Cas9) endonuclease employ a single RNA molecule (the guide RNA) that binds to specific DNA sequences, targeting them for cleavage by the Cas9 enzyme (Fig. 17.14).35,36 Because the Cas9 cleavage site is defined by the sequence of the guide RNA molecule, editing with CRISPR/Cas9 can be readily targeted to many sites of the genome. Because of this adaptability, CRISPR/ Cas9-based techniques have been widely adopted for gene editing in eukaryotic cells. CRISPR-based approaches have been used to generate countless genetically modified cell lines and engineered animal models. Clinical trials of the therapeutic administration of CRISPR edited cells are ongoing and showing great promise in a range of diseases, including the hemoglobinopathies (ClinicalTrials.gov numbers NCT03432364 and NCT03655678) and

genome by disrupting it or deleting an essential domain in embryonic stem cells that can then be transferred to blastocysts, in which they may be incorporated into the germline tissue of the developing embryo. A gene-targeting construct is transfected into embryonic stem (ES) cells, and a disruption cassette replaces a part of the cell’s gene by the process of homologous recombination. Because this process is inefficient, a positive selection gene (Neo) is incorporated within the disruption cassette and a negative selection gene (TK) is incorporated outside the cassette to eliminate untransfected cells and transfectants with integration of the targeting construct elsewhere in the genome. Rare cells that have undergone homologous recombination are expanded in culture and injected into blastocysts. Chimeric offspring, into which the targeted embryonic stem cells have been incorporated, can be recognized by the contribution of agouti (brown) targeted (L129) stem cells to the nonagouti (black) coat of the recipient (B6) blastocyst. If the stem cells have contributed to the offspring germline, the offspring will transmit the disrupted gene to its offspring.

hemophilia B (NCT02695160). Despite these early successes of CRISPR editing, technical limitations of this system, such as incorrectly editing the gene sequence or altering gene sequences at unintended sites, have been the primary obstacles to its more widespread adoption. Intensive research of CRISPR-based editing systems has led to enormous technical improvements in both the specificity and fidelity of editing with traditional Cas9 nucleases.37 These investigations have also produced new CRISPR-based editing tools, including base editors capable of precisely creating point mutations without generating double-stranded breaks; Cas recombinases and transposons that mediate rearrangements of large genomic segments; and “prime editors” that specifically overwrite existing DNA sequences at targeted DNA sites with high fidelity.38 These tools expand the landscape of CRISPR-based applications and are facilitating novel investigations of gene expression, regulation, and epigenetics.37 Furthermore with the development of prime editing39,40 and its potential to correct disease-causing mutations in terminally differentiated cells, the field may be on the verge of a revolution in therapeutic genome editing. Although CRISPR editing holds enormous promise for research, therapeutic, and potentially curative purposes,40 these approaches continue to be limited by the imperfect binding specificity of CRISPR RNAs.41 Based on the

CHAPTER 17  Principles and techniques in molecular biology

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EDITING DNA VIA CRISPR-CAS9-DIRECTED CLEAVAGE AND HOMOLOGY-DIRECTED REPAIR 1 Genomic DNA target

Guide RNA

2 Recognition of target DNA sequence Cas9 enzyme

FIG. 17.14  CRISPR–Cas9 editing is a gene editing approach to introduce targeted genetic changes at specific genomic locations. A genetic region of interest is targeted by CRISPR-Cas9 components, creating double-strand breaks (DSBs) that flank the desired gene editing target. By introducing an exogenous single-stranded DNA repair template that contains the edited DNA sequence, the DSB repair by homologous recombination incorporates the edited DNA sequence into the endogenous DNA.

3 Cas9 generates double strand DNA breaks

4 Homology-directed repair with donor template DNA

Single-strand DNA donor template

5 Edited genomic DNA target

presence of sequence homology across genomes, these binding molecules almost always recognize DNA sequences distant from the targeted region, creating undesired DSBs and “off-target” mutations that may produce deleterious effects in otherwise properly edited cells.41,42 As a result, methods to sensitively identify edited cells without off-target mutations, as well as approaches to improve the specificity of the DNA binding to prevent the introduction of off-target mutations, remain important areas of investigation.43,44

ANALYSIS OF PROTEINS The regulation of expression of proteins in cells pertinent to rheumatologic disease is often analyzed. Flow cytometry allows detection of cell surface and intracellular proteins recognized by specific antibodies on a single-cell basis and, with multicolor staining, permits the simultaneous analysis of the expression of several molecules in specific cell populations. Because of the ease of this technique, it is commonly used. To identify the location of a protein of interest within tissues, immunohistochemistry is often used; again, the detection of the protein is dependent on its recognition by specific antibodies. For localization within a cell, electron microscopy or confocal microscopy and immunofluorescence are often used. Transfection of cells with proteins fused to GFP to be detected under video imaging is a modern technology used to track localization and movement of the molecule in a living cell (see Fig. 17.3). Immunoblotting or western blotting is still the most widely used technique to identify protein expression, modification, and interactions with other proteins. In brief, proteins are separated by sodium dodecyl sulfate– polyacrylamide gel electrophoresis, transferred to a membrane, and detected by specific antibodies bound to enzymes such as horseradish peroxidase. These antibody–protein complexes are detected by chemiluminescence, autoradiography, or similar methods (Fig. 17.15). Protein function is regulated by various post-translational modifications and through dynamic protein–protein interactions; indeed, a paradigm shift in cell signaling has been the understanding of the importance of these

interactions. For instance, tyrosine phosphorylation and serine/threonine phosphorylation are major modifications that regulate protein function and assembly of protein complexes. Increasingly, antibodies against phosphorylated forms of various proteins are being made available for the dissection of signal transduction pathways. These antibodies can be used in immunoblotting (see Fig. 17.15) and even in flow cytometry. Protein–protein interactions can be analyzed by various techniques. Coimmunoprecipitation of one protein with another is a standard technique, but the interactions can be influenced by the detergents used to lyse the cells. Immunoprecipitation reactions require a specific antibody to the protein of interest. Alternatively, using a GST–fusion protein pull-down assay provides good evidence for protein–protein interactions without the need to produce a specific immunoprecipitating antibody. The GST-tagged protein binds with high affinity to glutathione attached to agarose beads. Noninteracting proteins are removed by washing. Proteins that remain bound to the GST-tagged protein can then be assayed by two-dimensional gel electrophoresis or other analytic techniques. A third method for assessing protein–protein interactions is far-western blotting, in which a labeled recombinant protein is used to “blot” a membrane in which cell lysates have been separated. If the recombinant protein interacts with a cellular protein, the interaction is visualized as a “band.” Fluorescence resonance energy transfer (FRET) can be used to study protein–protein interactions in living cells as an important complement to strictly biochemical methods. Energy emitted by a fluorophore can be transferred to an acceptor fluorophore, causing sensitized emission at a longer wavelength only if the two molecules are in extremely close proximity (T and 1298A>C.12–14 The 677 C>T polymorphism causes impaired enzyme activity as well as hyperhomocysteinemia and has been shown to increase methotrexate related toxicity, although these data are inconclusive. The 6TT polymorphism, found in patients with RA, can lead to discontinuation of methotrexate as it causes elevated transaminases, nausea, rashes, alopecia, as well as hyperhomocysteinemia.13–17 The MTHFR 1298CC allele had a reduced likelihood of MTX-related side effects, and no association was found between the 677 genotype and toxicity.18 However, another study observed an association of the 1298AA genotype with increased risk for toxicity in Whites1,5,18 and also observed an increased risk for toxicity in East Asian and Korean patients with RA.19,20 Additionally, among patients with RA, the 1298AA SNP is associated with higher rates of cardiac morbidity.21 A study by Kumagai et al.22 found no association between either the 1298 or the 677 genotype in the likelihood of toxicity. In their studies, among those patients who received folate supplementation, the majority of toxicities reported were nonhepatic related, in contrast to the patient cohorts for which these associations were reported, in which few if any patients received folate supplementation and the majority of toxicities were hepatic. Van Ede et al. had similar findings14 and reported

179

that folate supplementation reduces the incidence of hepatic but not nonhepatic MTX-related adverse events. The study could indicate that the pharmacogenetics of MTX-induced hepatic toxicity differs from that of other forms of toxicity. More recent reviews of SNP associations with toxicity show even more inconsistent results with very poor reproducibility of studies across populations and for individual SNPs.23 Further studies are required to identify and establish the roles of confounding factors influencing the pharmacogenetic factors influencing MTX toxicity. Associations with MTX efficacy have also been reported. Urano et al.16 found that in patients with RA treated with MTX, those with the MTHFR 1298 C allele and those with the 766C-1298C haplotype received lower doses than did those without them. However, in a metaanalysis, Fan et al. reported no significant effect of this gene on methotrexate outcome.24 Kumagai et al.22 reported associations of homozygosity for two alleles of thymidylate synthase with higher MTX dosage and 50% or greater improvement in serum C-reactive protein levels, respectively. Neither Berkun et al.18 nor Kumagai et al.22 found associations between either the MTHFR 677 or 1298 genotype and efficacy. Wessels et al.25 reported that the 1298AA genotype was associated with improved efficacy of MTX. Furthermore, a multigene pharmacogenetic model was developed by Wessels et al.25 that included genes for MTX metabolism and purine and pyrimidine synthesis. In the case of both MTX efficacy and toxicity, there has been a lack of consistency in the identification of associations across studies, particularly with regard to MTHFR genotype (Tables 21.1 and 21.2). To address these inconsistencies, which may relate to cohort size and statistical power, Fisher and Cronstein26 conducted a metaanalysis of published studies on MTHFR SNPs and risk for toxicity. In the metaanalysis, the C677T SNP was associated with increased risk for toxicity (odds ratio [OR] = 1.71; 95% confidence interval [CI], 1.32–2.21). As discussed earlier, a number of factors may contribute to variability, and in this instance, relatively small patient populations and inconsistent phenotyping criteria may be at least partially responsible. More recently, other SNPs have been identified that may interfere with MTX metabolism and potentially affect the effectiveness of MTX therapy or cause toxicity. The 80G>A SNP of the SLC19A1 protein results may affect MTX transport into the cell and thus interfere with intracellular MTX-PG

Table 21.1

Selected Sampling of Studies Investigating the Association of the Methylenetetrahydrofolate Reductase Single-Nucleotide Polymorphism C677T Allele to the Response of Patients With Rheumatoid Arthritis to Methotrexate Study

Year

Association

Findings

Van Ede et al.14

2001

Efficacy

Urano et al.16 Kumagai et al.22 Berkun et al.18 Wessels et al.25 Raganathan et al.27 Choe et al.19 Song et al.20

2002 2003 2004 2006 2008 2012 2014

Toxicity None None Toxicity Toxicity Toxicity Toxicity

Increased toxicity and risk for discontinuing MTX therapy because of adverse events Increased toxicity None significant None significant Increased toxicity Increased toxicity Increased toxicity Increased toxicity

MTX, Methotrexate.

Table 21.2

Selected Sampling of Studies Investigating the Association of the Methylenetetrahydrofolate Reductase Single-Nucleotide Polymorphism A1298C Allele to the Response of Patients With Rheumatoid Arthritis to Methotrexate Study

Year

Association

Findings

Urano et al.16 Kumagai et al.22 Berkun et al.18 Dervieux et al.28 Wessels et al.25

2002 2003 2004 2006 2006

Choe et al.16 Song et al.20

2012 2014

Efficacy None Toxicity Toxicity Efficacy and toxicity Toxicity Toxicity

Increased efficacy None significant Decreased toxicity Increased toxicity Increased efficacy and increased toxicity Increased toxicity Increased toxicity

180

SECTION 1  Scientific Basis of Rheumatic Disease

levels.29 Specifically, the rs1051266 variant associates with intracellular MTX-polyglutamate levels. A recent metaanalysis of 12 studies (n = 2049) reported an association with MTX treatment response (OR = 1.49 of AA genotype, P = .001).30 Another polymorphism affecting transport of methotrexate into a cell is the 1420C>T variant of serine hydroxymethyltransferase. Located on the SHMT1 gene, this polymorphism is associated with increased influx and methotrexate toxicity.12 Another important enzyme, involved in nucleotide synthesis and specifically de novo thymidylate biosynthesis, is thymidylate synthetase (TYMS), which converts dUMP to dTMP. Methotrexate polyglutamate, the active derivative of methotrexate, interferes with TYMS, leading to dTMP depletion and increased uracyl DNA incorporation. This process leads to DNA injury and ultimately cell death.31 Patients with RA who have triple repeat of 5′-untranslated end of the TYMS gene in homozygous form (TSER*3/*3) exert high TYMS mRNA expression requiring higher methotrexate dosing to achieve a response. A six–base pair deletion in the 3′ untranslated region impairs TYMS mRNA stability and lower gene expression, conferring a great response to conventional methotrexate doses.12,22,27,32 Another polymorphism in a key enzyme in methotrexate metabolism is ATIC 347C>G SNP, which decreases ATIC’s enzymatic activity and affects AICAR accumulation and adenosine release. Methotrexate inhibits AICAR, which leads to increased adenosine and AICAR levels. This SNP is associated with increased methotrexate efficacy but also increased toxicity in some studies.28 These findings are summarized in Table 21.3. ADORA2A and ADORA3 are adenosine receptors that are part of the adenosine-mediated antiinflammatory pathway. These receptors are known to be overexpressed in patients with rheumatoid arthritis, and the increased release of adenosine into extracellular space mediates the antiinflammatory effects of methotrexate. Polymorphisms in ADORA2A and ADORA3 genes may have an impact on the efficacy and toxicity of MTX in patients with RA. One study by Grk et al.35 showed carriers of ADORA2A rs17004921 T allele had a higher DAS28 decrease after 6 months of treatment than patients with CC genotype. Carriers of ADORA3 gene and TAA haplotype were associated with bone erosions and hepatotoxicity. Epigenetically, another biomarker of methotrexate response is DNA methylation, which is the process in which a methyl group is added to a cytosine-guanine (C-G) dinucleotide (CpG). About 70% of CpGs are methylated in the genome36 and cluster in gene promoter regions, called CpG islands. These islands are usually hypomethylated in transcriptionally active genes.37 There is increasing evidence for a role of DNA methylation in susceptibility to RA. One study found and replicated associations of four differentially methylated positions that were both identified by 4 weeks of MTX initiation and correlated with clinical response at 6 months.38

AZATHIOPRINE The role of SNPs in the gene for thiopurine methyltransferase (TPMT) has been the focus of many studies in determining susceptibility to toxicity from azathioprine (AZA).39,40 Black et al.39 reported that five of six individuals who incurred toxicity out of a cohort of 67 patients receiving azathioprine for rheumatologic disease were heterozygous for mutant TPMT alleles. Another study of a group of patients with RA treated with azathioprine who were experiencing adverse effects showed a significantly decreased level of TPMT activity relative to those who did not, and toxicity developed in seven of eight patients with “intermediate” TPMT activity.41 Liu et al., in a large metaanalysis,

Table 21.3

Selected Sampling of Studies Investigating the Association of the SLC19A1 80G>A and ATIC 347C>G Single-Nucleotide Polymorphisms to the Response of Patients With Rheumatoid Arthritis to Methotrexate Study

Year

SNP

Efficacy

Toxicity

Findings

Drozdzik et al.33

2007

S

NS

Dervieux et al.28

2006

NS

S

Wessels et al.25

2006

SLC19A1 80G>A ATIC 347C>G ATIC 347C>G

S

S

Grabar et al.34

2010

ATIC 347C>G

NS

S

Increased efficacy Increased toxicity Increased efficacy and toxicity Increased toxicity

NA, Not applicable, outcome (efficacy or toxicity) was not examined in the study; NS, not significant association; S, significant association; SNP, single-nucleotide polymorphism.

demonstrated a strong association between TPMT polymorphisms and adverse effects of azathioprine, such as bone marrow toxicity and gastric intolerance but not with hepatotoxicity.42 The data strongly support that the TPMT genotype is a useful predictor of azathioprine-associated toxicity. Outside of the TPMT genotype, NUDT15 SNPs have been identified that strongly influence thiopurine tolerance in patients with acute lymphoblastic leukemia (ALL) and inflammatory bowel disease.43 There has been a case report of a Chinese patient with Sjögren syndrome with wild-type TPMT ∗3C who was diagnosed with AZA-induced severe toxicity due to NUDT15 mutation, a gene that mediates the hydrolysis of some nucleoside diphosphate derivatives. It is a poor metabolizer genotype of this enzyme. In this case, the TPMT enzyme was normal.44 The NUDT15 poor metabolizer phenotype is observed among East Asian patients and NUDT15 deficiency is also more prevalent in individuals of Hispanic ethnicity, particularly those with high levels of Native American genetic ancestry.45

SULFASALAZINE It has been well known that sulfasalazine pharmacokinetic properties, efficacy, and toxicity are influenced by acetylator phenotype,46 and the relationships of alleles of the N-acetyltransferase 2 (NAT2) gene with these phenotypes have become increasingly understood.47 Kumagai et al.48 reported that the NAT2 genotype is associated with both the pharmacokinetics (sulfapyridine/N-acetylsulfapyridine) and efficacy of sulfasalazine treatment in a cohort of patients with RA. In a group of patients with RA, Tanaka et al.49 found that slow acetylators who lacked the NAT2*4 allele experienced adverse effects from therapy more often than did fast acetylators who had at least one NAT2*4 haplotype. Kita et al.50 showed that the differences between NAT2 genotype groups in the pharmacokinetic profiles of sulfasalazine are enhanced after multiple dosing relative to single dosing. These are among the studies demonstrating the importance of variants of the NAT2 gene on sulfasalazine outcomes. Recently, a genome-wide association study of 36 sulfasalazine-induced agranulocytosis that included 9,380,034 polymorphisms and 180 HLA alleles with 5,170 population controls was conducted. It revealed that the HLA region on chromosome 6 was highly associated with sulfasalazine-induced agranulocytosis. The authors particularly noted HLA‐B*08:01 haplotype HLA‐DQB1*02:01‐DRB1*03:01‐B*08:01‐C*07:01 (OR = 3.79; 95% CI, 1.63, 8.80; P = 0.0019) and with HLA‐A*31:01 (OR = 4.81; 95% CI, 1.52, 15.26; P = 0.0077) to have the most significant associations.51

BIOLOGIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS Many of the pharmacogenetic studies of biologic agents have been on tumor necrosis factor (TNF) antagonists for the treatment of RA. Data reported from early studies were of associations in small cohorts. Martinez et al.52 reported associations within the major histocompatibility complex with response to infliximab after 3 months of therapy in a cohort of 78 patients with RA. Mugnier et al.53 found that among a group of 59 patients with RA treated with infliximab, those with TNF-α–308 G/G genotype had better response than did those with the A/A or A/G genotypes. This finding was substantiated by a large metaanalysis conducted by Zeng et al., which showed that individuals with the A allele had weaker anti-TNF-alpha treatment response than those with the G allele. This polymorphism is thought to be a valuable predictor of anti-TNF-alpha treatment response.54 Another study based on 123 patients with RA showed that the combination of –308 TNF1/TNF1 and –1087 G/G was associated with response to etanercept, but a combination of SNPs within the interleukin-1 receptor antagonist and transforming growth factor-β1 gene was associated with nonresponse.55 Criswell et al.,56 in a larger population study, reported that the combination of two human leukocyte antigen class II, antigen D–related beta chain 1 (HLA-DRB1) shared-epitope alleles as well as two extended haplotypes, which included the HLA-DRB1 shared-epitope alleles and six SNPs in the lymphotoxin-α (LTA)/TNF region, were associated with a better response to etanercept. The significance of any of these findings remains unclear given the clinical observation that individuals who do not respond to one anti-TNF-alpha biologic agent may respond to a different one. One of the largest cohort studies was reported by Maxwell et al.57 They examined eight SNPs in the region containing the TNF gene in 1050 patients with RA, including 455 prescribed etanercept and 450 prescribed infliximab. An association between the TNF-308 genotype and change in the 28-Item Disease Activity Score (DAS28) was observed, thus replicating the TNF-308 findings of other investigators. However, a subsequent systematic review and metaanalysis, the largest metaanalysis published to date and involving more than 2800 patients, concluded that the TNF-308 variant is not a predictor

CHAPTER 21  Precision medicine and pharmacogenomics in rheumatology of response.58 Studies examining RA risk alleles have identified the PTPRC gene, which encodes protein tyrosine phosphatase, receptor type C (also known as CD45), as a predictor of response, which has been replicated.59,60 However, a subsequent metaanalysis failed to confirm PTPRC as a predictor of response to anti-TNF biologics.61 Another study looked at polymorphisms of natural killer group 2 member D (NKG2D), which serves to activate and function as a costimulatory receptor on immune effector cells including NK and T cells. Iwaszko et al. examined 280 patients with RA receiving anti-TNF therapy and found that both the NKG2D rs225336 and rs1049174 polymorphisms were significantly associated with efficacy of TNF inhibitors while rs2255336 GG or rs1049174 CC genotype showed inefficient therapy.62 Fcγ receptors found on mononuclear cells play a role in cellular immunity through cell-mediated and complement-dependent cytotoxicity and immune complex clearance. A polymorphism in the FCGR3A gene has been shown to alter response to biologics. The F/F phenotype allows for favorable responses to infliximab, adalimumab, and etanercept.63–65 FCGR gene SNPs have also been linked to responses to rituximab, which was confirmed in a study of Hungarian patients.66 Additionally, SNPS in IL6 gene and B-lymphocyte stimulator have also been associated with rituximab response.67,68 MicroRNAs (MiRNAs) have also been studied with regards to response to therapy to anti-TNF agents. MiRNAs are a class of noncoding single-stranded RNAs that modulate gene expression posttranscriptionally by base-pairing to target messenger RNAs.69 Interestingly, many dysregulated miRNAs have been identified in patients with RA.70 Krintel et al., in a double-blinded placebo-controlled study, found that a combination of low expression of miR-22 and high expression of miR-886.3p was associated with EULAR good response.71 Finally, recent studies have approached the question by using the unbiased GWAS design to identify genetic predictors of response. A pilot GWAS published by Liu and colleagues72 on a small cohort of patients identified a number of promising candidate SNPs. However, these SNPs failed to be replicated as predictors of response in an independent Spanish RA cohort.73 A GWAS study in Japanese patients found three genomic regions associated with anti-TNF response, one of which overlapped with a genomic region previously identified in a different population.74 More recently, a larger GWAS was performed to identify additional candidate SNPs, and replication studies will also be required.75 While GWAS studies of responses to TNF inhibitors have shown that SNPs can explain up to 40% to 50% of variance seen in swollen joint count and erythrocyte sedimentation rate, no strong association has been detected.76

CONCLUSION The work discussed in this chapter provides some evidence for the notion that pharmacogenetic properties of antirheumatic drugs are likely to play an important role in the future of rheumatology. Because the majority of this work consists of studies focusing on single-allele associations, these data may, in fact, represent only the beginning of what such studies will ultimately yield. As is the case in complex disease genetics, it is likely that the genetic components of drug response will be found to be conferred by multiple genes. Among the challenges for researchers is the difficulty in obtaining patient cohorts of sufficient size so that the number of patients in each genotypic category can provide adequate statistical power for analysis. Resolving these issues will require the implementation of large-scale, prospective association studies. Ultimately, the promise of pharmacogenetics will be fully realized when genetic biomarkers can predict who will be more likely to respond to an individual drug and who may incur a drug-related toxicity77 (Fig. 21.1). The value of pharmacogenetics research to the field of rheumatology, although promising thus far, is likely to continue to grow as the tools and knowledge available to investigators continue to evolve. As genotyping and analysis tools and patient cohort data required for large-scale genome-wide studies capable of teasing out alleles with increasingly small effect sizes continue to improve, so will investigators’ understanding of the target diseases, as well as the mechanisms of action of drug therapies and their toxicities. The convergence of these data is certain to enhance the power of pharmacogenetics research and thus the promise of rationally individualizing therapy with the use of genetics in the future of clinical medicine.

ACKNOWLEDGMENTS This work was supported by grants from the National Institutes of Health to Dr. Greenberg (K23 AR054412) and to Dr. Cronstein (AR56672, AR56672S1, AR54897, AR046121) and by a grant from the NYU-HHC Clinical and Translational Science Institute (UL1TR000038). The authors acknowledge the contributions of Dr. Fors-Nieves, who was the author of this chapter in the previous edition.

181

DRUG-RELATED TOXICITY VS. BENEFIT IN A COHORT

+ Benefit + Toxicity

No benefit + Toxicity

All patients with the same diagnosis No benefit No toxicity

+ Benefit No toxicity

FIG. 21.1  Pharmacogenetics has the potential to identify which patients will benefit from a drug with a robust clinical response and which patients will incur drug-related toxicity. (Adapted with permission from Marsh S, McLeod HL. Pharmacogenetics: from bedside to clinical practice. Hum Mol Genet 2006;15:R89–93.)

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N-Acetyltransferase 2 genotype correlates with sulfasalazine pharmacokinetics after multiple dosing in healthy Japanese subjects. Biol Pharm Bull. 2001;24(10):1176–1180. Wadelius M, Eriksson N, Kreutz R, et al. Sulfasalazine-induced agranulocytosis is associated with the human leukocyte antigen locus. Clin Pharmacol Ther. 2018;103(5):843–853.

52. Martinez A, Salido M, Bonilla G, et al. Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum. 2004;50(4):1077–1082. 53. Mugnier B, Balandraud N, Darque A, Roudier C, Roudier J, Reviron D. Polymorphism at position -308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum. 2003;48(7):1849–1852. 54. Zeng Z, Duan Z, Zhang T, et al. Association between tumor necrosis factor-alpha (TNFalpha) promoter -308 G/A and response to TNF-alpha blockers in rheumatoid arthritis: a meta-analysis. Mod Rheumatol. 2013;23(3):489–495. 55. Padyukov L, Lampa J, Heimburger M, et al. Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis. 2003;62(6):526–529. 56. Criswell LA, Lum RF, Turner KN, et al. The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum. 2004;50(9):2750–2756. 57. Maxwell JR, Potter C, Hyrich KL, et al. Association of the tumour necrosis factor-308 variant with differential response to anti-TNF agents in the treatment of rheumatoid arthritis. Hum Mol Genet. 2008;17(22):3532–3538. 58. Pavy S, Toonen EJ, Miceli-Richard C, et al. Tumour necrosis factor alpha -308G->A polymorphism is not associated with response to TNFalpha blockers in Caucasian patients with rheumatoid arthritis: systematic review and meta-analysis. Ann Rheum Dis. 2010;69(6):1022–1028. 59. Cui J, Saevarsdottir S, Thomson B, et al. Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy. Arthritis Rheum. 2010;62(7):1849–1861. 60. Plant D, Prajapati R, Hyrich KL, et al. Replication of association of the PTPRC gene with response to anti-tumor necrosis factor therapy in a large UK cohort. Arthritis Rheum. 2012;64(3):665–670. 61. Pappas DA, Oh C, Plenge RM, Kremer JM, Greenberg JD. Association of rheumatoid arthritis risk alleles with response to anti-TNF biologics: results from the CORRONA registry and meta-analysis. Inflammation. 2013;36(2):279–284. 62. Iwaszko M, Swierkot J, Kolossa K, Jeka S, Wiland P, Bogunia-Kubik K. Influence of NKG2D genetic variants on response to anti-TNF agents in patients with rheumatoid arthritis. Genes (Basel). 2018;9(2). 63. Radstake TR, Petit E, Pierlot C, van de Putte LB, Cornelis F, Barrera P. Role of Fcgamma receptors IIA, IIIA, and IIIB in susceptibility to rheumatoid arthritis. J Rheumatol. 2003;30(5):926–933. 64. Sfar I, Dhaouadi T, Habibi I, et al. Functional polymorphisms of PTPN22 and FcgR genes in Tunisian patients with rheumatoid arthritis. Arch Inst Pasteur Tunis. 2009;86(1-4):51–62. 65. Tutuncu Z, Kavanaugh A, Zvaifler N, Corr M, Deutsch R, Boyle D. Fcgamma recep tor type IIIA polymorphisms influence treatment outcomes in patients with inflammatory arthritis treated with tumor necrosis factor alpha-blocking agents. Arthritis Rheum. 2005;52(9):2693–2696. 66. Pal I, Szamosi S, Hodosi K, Szekanecz Z, Varoczy L. Effect of Fcgamma-receptor 3a (FCGR3A) gene polymorphisms on rituximab therapy in Hungarian patients with rheumatoid arthritis. RMD Open. 2017;3(2):e000485. 67. Fabris M, Quartuccio L, Lombardi S, et al. The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis. Autoimmun Rev. 2012;11(5):315–320. 68. Gragnani L, Piluso A, Giannini C, et al. Genetic determinants in hepatitis C virus–associated mixed cryoglobulinemia: role of polymorphic variants of BAFF promoter and Fcgamma receptors. Arthritis Rheum. 2011;63(5):1446–1451. 69. Iorio MV, Croce CM. MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol. 2009;27(34):5848–5856. 70. Stanczyk J, Pedrioli DM, Brentano F, et al. Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 2008; 58(4):1001–1009. 71. Krintel SB, Dehlendorff C, Hetland ML, et al. Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis. Pharmacogenomics J. 2016;16(2):141–146. 72. Liu C, Batliwalla F, Li W, et al. Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. Mol Med. 2008;14(9-10):575–581. 73. Suarez-Gestal M, Perez-Pampin E, Calaza M, Gomez-Reino JJ, Gonzalez A. Lack of replication of genetic predictors for the rheumatoid arthritis response to anti-TNF treatments: a prospective case-only study. Arthritis Res Ther. 2010;12(2):R72. 74. Honne K, Hallgrimsdottir I, Wu C, et al. A longitudinal genome-wide association study of anti-tumor necrosis factor response among Japanese patients with rheumatoid arthritis. Arthritis Res Ther. 2016;18:12. 75. Plant D, Bowes J, Potter C, et al. Genome-wide association study of genetic predictors of anti-tumor necrosis factor treatment efficacy in rheumatoid arthritis identifies associations with polymorphisms at seven loci. Arthritis Rheum. 2011;63(3):645–653. 76. Massey J, Plant D, Hyrich K, et al. Genome-wide association study of response to tumour necrosis factor inhibitor therapy in rheumatoid arthritis. Pharmacogenomics J. 2018;18(5):657–664. 77. Marsh S, McLeod HL. Pharmacogenomics: from bedside to clinical practice. Hum Mol Genet. 2006;15(Spec No 1):R89–93.

The microbiome in rheumatic diseases Julia Manasson • Steven B. Abramson • Jose U. Scher

Key Points ■ Many rheumatic and autoimmune diseases are categorized as complex and polygenic disorders. Genes have a clear role in their pathogenesis, but environmental factors appear to be required for the development of disease. ■ Multiple lines of epidemiologic and clinical investigation have implicated several microorganisms in inflammatory rheumatic disorders; however, causation is not established. ■ The microbiome is defined as the totality of microbial communities and their genes within a biologic niche; the human microbiome is vast and complex and outnumbers the host genome by several orders of magnitude. ■ Culture-independent, high-throughput DNA- and RNA-sequencing technologies— coupled with deeper insight into host mucosal immunology—have significantly advanced our understanding of the role of microorganisms in modulating health and disease. ■ Germ-free and gnotobiotic experiments have provided a deeper understanding of host– microbial interactions and have shown the ability of gut bacteria to induce both local and systemic autoimmunity in genetically predisposed animal models. ■ The role of the oral, gut, and skin microbiomes in human autoimmunity continues to be recognized as a potential contributor to disease mechanism. ■ Bacterial byproducts and associated metabolites, independent of microbial antigenic properties, can also modulate immune responses in the host. ■ Pharmacomicrobiomics, an emerging field that describes the complex interaction of drugs with the microbiome, is increasingly considered an important factor for precision medicine therapeutic approaches in autoimmune disease.

INTRODUCTION All mammals, including humans, are home to trillions of bacteria from the instant they are born. Immediately afterward, a massive, complex, and dynamic community of microorganisms rapidly begins to populate most cavities and surfaces of our bodies (including the skin, airways, genitourinary, and gastrointestinal [GI] tracts), coexisting with us rather harmoniously for the rest of our lives. This microbiome represents the totality of the ecologic communities of symbiotic, commensal, and pathogenic microorganisms (and their genomes) that we necessarily procure from the environment.1 The interdependent, synergistic biologic bond is based on a mutually beneficial exchange. Humans provide an appropriate nutritional environment for bacteria, fungi, and viruses, which in return help shape the mucosal immune system, degrade complex polysaccharides, and produce vitamins and other factors essential for our survival.2 Until very recently, however, most of these microorganisms have been largely ignored as determinants of health and disease. Many rheumatic and connective tissue disorders are currently categorized as complex polygenic autoimmune diseases. Despite recent advances in molecular pathogenesis and treatment, most arthritides can be ameliorated but not cured, and their etiology remains elusive. Genes have a clear contribution to susceptibility, but genetic effects require environmental factors to explain differences in disease incidence. Characterizing the human microbiome is now possible because of exponential advances in bacterial DNA–sequencing technologies. Largely as a result of the National Institutes of Health (NIH) Human Microbiome Project (HMP) and the European Metagenomics of the Human Intestinal Tract (MetaHit) consortium, an almost complete catalogue of intestinal, periodontal, urogenital, airway, and skin microbial communities is now in existence.3,4 This knowledge, coupled with renewed interest in mucosal immunology, provides important insights, suggesting that the human microbiome represents an environmental factor capable of influencing autoimmune disease manifestations.

THE MICROBIOME Humans undergo embryonic maturation within a naturally protected, sterile habitat. Immediately after birth, vaginal- or skin-derived bacteria (depending on the delivery technique) colonize the neonate’s GI tract and other

22

body surfaces.5 For several months, there is a period of relative taxonomic instability. Over time, however, phylogenetic richness and species diversity increase, and by the end of the first year of life, particularly with the introduction of solid foods, the gut microbiota expands, stabilizes, and adopts the characteristics of adult communities.6 At this stage, the human microbiome is quantitatively vast and complex. In total, 100 trillion microorganisms live in our body spaces and outnumber human cells by a factor of 107 (though recent reports estimate this ratio to be closer to 1-to-1).8 The adult human gut alone contains on average 2 kg of bacteria, whose collective genome encodes approximately 3.3 million different genes—100 times more than that of its human host (“metagenome”). Although more than 1000 different species from a dozen divisions colonize the GI tract, the microbiome of healthy humans is dominated by four major bacterial phyla: Firmicutes, Bacteroidetes (which combined represent about three quarters of the total gut community), and to a lesser degree, Proteobacteria and Actinobacteria.9 Although the intestinal microbiome is robust and resilient, over time, many factors can alter its overall composition, including acute dietary changes, infections, and the use of several medications, leading to a dysbiotic process capable of modulating the local and systemic immune response.10 Novel insights into the biologic properties of microbial end products and the effects of immunosuppressive therapies on the microbiome continue to expand our understanding of the complex and potentially transformative relationship between the microbiome and its host.

MUCOSAL BARRIERS AND HOST-IMMUNE INTERACTIONS Physiologic intestinal inflammation and homeostasis in health Dietary patterns and antibiotic use can certainly alter the composition of the microbial community in the intestine.11 However, the mechanism by which the microbiome is selected, established, and maintained within a given individual remains uncertain. Nevertheless, the symbiotic processes and bidirectional crosstalk between the microbiome and host immune system are becoming better understood. Indeed, the idea that commensal bacteria are merely a group of passive organisms that obtain nutritional benefit at the host’s expense has become untenable. Cells from both the innate and adaptive immune systems in the lamina propria actively cooperate to maintain a state of homeostasis (Fig. 22.1, left panel). In this healthy state, a massive amount of antigenic material derived from diet and commensal flora is actively tolerated by mucosal-associated lymphoid tissue to mutually benefit the microbiota and its host.12 Through evolution, several biologic checkpoints have been established to keep these two “biologic universes” separate and prevent microorganisms from accessing the lamina propria and, eventually, the peripheral organs and tissues. A physicochemical and immune barrier represents the first line of defense. A thick mucus layer,13 enteric antimicrobial proteins,14 and high levels of secretory immunoglobulin A (sIgA)15 are all designed to prevent a flood of undesired flora (or any of their components) into the host. Tightly adherent epithelial cell columns that further contain bacterial invasion provide a second protective strategy. Enterocytes not only function as a strict anatomic boundary but also have functional antimicrobial properties.16 These cells produce a variety of bactericidal proteins such as defensins, cathelicidins, and C-type lectins. Furthermore epithelial cells express Toll-like receptors (TLRs) in their cellular membrane that allow recognition of pathogen-associated molecular patterns (PAMPs) in microorganisms, activation of the signaling adaptor molecule MyD88 (myeloid differentiation primary-response protein 88), and induction of downstream inflammatory responses. Intraepithelial lymphocytes (IELs), a heterogeneous population of CD4+ and CD8+ T cells that reside between epithelial enterocytes, serve as a third type of protective mechanism. They have cytolytic capabilities, which allow for the elimination of infected and damaged cells, as well as regulatory functionality, promoting epithelial cell healing and repair.17,18 If still insufficient, the intestinal lamina propria harbors the largest and most varied immune armamentarium in mammals. Bacterial proteins and surface molecules such as lipopolysaccharides and other microbe-associated molecular pattern factors interact with TLRs and 183

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SECTION 1  Scientific Basis of Rheumatic Disease HOST AND MICROBIOME CROSSTALK IN HEALTHY STATE AND AUTOIMMUNE ARTHRITIS

Host genetics

Homeostasis

Diet

Antibiotics

Dysbiosis

Gut lumen Mucus layer Epithelial cells

Th17

PSA

Dendritic cell

Lamina propria

Th1 Treg

Plasma cell

Macrophage Blood vessel

Circulation

Peripheral immune system

SAA ATP CCL5?

Spleen

Lymph node

B cell

Bone Ligament

Autoreactive Th1 and Th17 → proinflammatory cytokines (IL-17, IFN-γ, TNF, etc.) Immune-complex deposition Macrophage, fibroblast, and osteoclast activation → cartilage and bone degradation

Pannus formation

Cartilage Synovial fluid Synovial membrane Bone Healthy Joint

Inflammatory Arthritis

FIG. 22.1  Left panel, In the healthy state, balanced host–microbial interaction is essential for maintenance of homeostasis. A thick mucus layer, epithelial cells, and secretory IgA form a physicochemical barrier that prevents direct contact with gut-associated lymphoid cells, which constantly survey the contents of the intestinal lumen and eliminate undesired antigens. Commensal bacteria such as Bacteroides fragilis can activate pro-tolerogenic machinery. A specific cell wall component, polysaccharide A (PSA), is sufficient to induce activation of regulatory T cells (Tregs), production of interleukin-10 (IL-10), and repression of type 17 helper T cells (Th17) to avoid uncontrolled inflammation. Right panel, When genetic, dietary, or environmental factors alter the balance in composition of the microbiota, a state of dysbiosis ensues. Potentially harmful bacteria (e.g., segmented filamentous bacteria or Lactobacillus spp.) predominate and promote local activation and expansion of proinflammatory cells (Th17 cells, Th1 cells, and others) through several molecules (such as adenosine-5′-triphosphate [ATP], serum amyloid A [SAA], or CCL5 signaling). These autoreactive T cells migrate to peripheral immune compartments and activate B cells to differentiate into autoantibody-producing plasma cells. These cells and antibodies then migrate to synovial tissue, where the inflammatory cascade is amplified through the activation of effector components, including macrophages, fibroblasts, osteoclasts, cytokines, and proteinases. If self-perpetuating, this process can lead to arthritis and joint destruction. IFN-γ, Interferon-γ; TNF, tumor necrosis factor. (Adapted with permission from Scher JU, Abramson SB. The microbiome and rheumatoid arthritis. Nat Rev Rheumatol 2011;7:569–578.)

related pattern recognition receptors in the host innate immune cells.19 Dendritic cells, macrophages, and natural killer cells continuously survey the lumen to process and phagocytose antigens in order to trigger an appropriate immune response. What ultimately defines this homeostatic state between the host and microbiome is a delicate balance in the type and predominance of CD4+ T cells in the lamina propria.20 A necessary state of “physiologic” gut mucosal inflammation is driven by a permanent but low-level activity of effector cells, including the helper T cells Th1, Th2, and Th17 and their respective

signature cytokines interferon-γ, interleukin-4/13 (IL-4/13), and IL-17/22. Regulatory T cells (Tregs), a tolerogenic subset of T cells, produce IL-10 and transforming growth factor-β (TGF-β) to proactively counterbalance the potentially exaggerated proinflammatory effects. A fundamental aspect in the maintenance of this equilibrium directly relates to the way that the adaptive immune system reacts. Paradigm-changing work in mucosal immunology has recently altered the way in which we understand the dichotomy between innate and adaptive immunity.21 Surprisingly, even a single intestinal commensal taxon is sufficient to activate CD4+ T cells and shift the

CHAPTER 22  The microbiome in rheumatic diseases balance toward proinflammatory or antiinflammatory responses. Segmented filamentous bacteria (SFBs), commensal gram-negative anaerobes, are able to activate Th17 cells on their own,22 but a specific polysaccharide of Bacteroides fragilis, polysaccharide A (PSA), can stimulate Tregs and promote broad tolerogenic effects through the TLR2 signaling pathway.23 These Treg-inducing properties have also been demonstrated for indigenous gut Clostridium species.24 Natural killer T cells (NKT cells) have also been implicated as important modulators of intestinal immune homeostasis between the host and commensal microbiota.25 These are a subset of T cells that recognize lipid antigens presented by CD1d, an atypical MHC class I molecule. There are two main subtypes—type I or invariant NKT cells (iNKT cells), which express a semi-invariant T cell receptor, and type II or noninvariant NKT cells, which lack the receptor.26 Several murine studies suggest that the absence of bacteria early in life (i.e., germ-free [GF] mice) contributes to the proliferation of mucosal NKT cells and results in severe intestinal inflammation and colitis. This effect is reversed with exposure to conventional microbiota early in life.25,27 Intriguingly, NKT cells can also prevent commensal microbial colonization by stimulating the production of IFN-γ and the subsequent release of antimicrobial peptides by Paneth cells, which ultimately influences gut microbial composition.25,28

Dysbiosis as a trigger for autoimmunity An imbalance in the composition of microbiota (a state called dysbiosis) may ensue if potentially pathogenic bacteria expand or beneficial bacteria become less abundant (Fig. 22.1, right panel).21 This leads to an alteration in the local immune response, typically dominated by proinflammatory cells and their products. When the reaction is self-regulated, the result is beneficial for both the host and the microbiome because detrimental microorganisms are typically eliminated. When a state of dysbiosis perpetuates, however, uncontrolled local inflammation is expected. However, the notion that an altered microbiome could influence systemic immune activation (or even lead to distal extraintestinal autoimmunity) is rather novel. Several studies have now shown that unique commensal species can initially affect the local adaptive immune response and subsequently trigger (or prevent) tissue-specific systemic autoimmunity. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, manipulation of the gut microbiome exacerbates the incidence and severity of EAE.29,30 In the nonobese diabetic mouse model of type 1 diabetes, colonization by commensal microbes reduces pancreatic inflammation and autoantibody production and abrogates disease.31

RESEARCH METHODS FOR STUDY OF THE HUMAN MICROBIOME The vast majority of existing microorganisms cannot be isolated in culture, either because they are fastidious growers or because their nutritional or oxygen requirements are unknown. This leaves about 80% of all bacteria unidentified.9 Next-generation culture-independent DNA-sequencing technologies now permit these microbiologic challenges to be circumvented. A component of prokaryotes’ small ribosomal subunit, 16 S ribosomal RNA (16 S rRNA), is now used to establish phylogenetic analyses in microbiome studies.32 This gene is uniquely found in bacterial cells, has highly conserved primer binding sites, and is therefore very useful for determining which members of a given community are present without prior knowledge. The gene is also advantageous because it does not amplify human DNA but it does possess several hypervariable regions with sequences unique to each bacterial species, thereby allowing extensive taxonomic identification without the need for culture.33,34 Bacterial DNA is typically extracted from human samples of choice and further amplified by using universal 16 S primers. High-throughput DNA sequencing is then performed, and the obtained sequences are aligned, trimmed, and subsequently classified. This approach provides an overall understanding of which bacterial species are represented in a given community and their relative abundance. Such studies have established associations among patients with autoimmune disorders (many examples provided below). This methodology, though useful for establishing correlative associations, does not consider the functional enzymatic capabilities of the microbiome. The physiologic activities of these “second genomes” can provide insight into mechanisms of disease as well.35 For example, a seminal study comparing the gut microbiota of monozygotic twins discordant for obesity revealed similar taxonomic content among groups. However, there was a significant (and constant) variation in enzymatic pathways that differentiated obese from lean individuals.36 This approach, known as metagenomics, which is performed with whole-genome shotgun sequencing, complements

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the 16 S studies and requires the complete DNA sequencing of genes found in a given community. Beyond functionality, alignment of full genomes can also provide knowledge about potential islands of pathogenicity or even antigenic structures embedded in the microbiome, which may in turn help in the discovery of factors triggering local and systemic autoimmunity. Aside from DNA sequencing, the study of metatranscriptomics, proteomics, and metabolomics is of high relevance for understanding the behavior of the microbiome and its impact on the host. Because different combinations of microbial taxa can produce similar byproducts, a number of techniques have been developed to better define how microbial communities function. Metatranscriptomics defines the collection of genes expressed by a particular microbial community. Similarly, proteomics and metabolomics define the proteins and metabolites collectively produced by the community.37,38 Unique molecular components of bacteria (and/or their byproducts) rather than entire genetic or enzymatic structures may be sufficient to alter the mammalian immune response. This has been illustrated in the case of the periodontopathic bacterium Porphyromonas gingivalis and its relationship with the pathogenesis of rheumatoid arthritis (RA). P. gingivalis– derived enzymes such as α-enolase appear to be sufficient for triggering inflammatory joint disease in predisposed murine models39 (see RA microbiome section). Similarly, polysaccharide A–containing B. fragilis (but not the polysaccharide A knockout variant) is able to protect against EAE.40 Notably, certain dietary components are metabolized by specific intestinal microbiota into proactive modulators of T cells and inflammatory mediators. For example, short-chain fatty acids (SCFAs) activate Tregs in the lamina propria even in the absence of bacteria.41 Trimethylamine-N-oxide (TMAO), a derivative of L-carnitine produced in the presence of Prevotella spp., has been linked to atherosclerosis and cardiovascular events.42 This is of importance because it promotes the notion that (at least hypothetically) specific parts of unique microorganisms and/or their metabolites could serve as biomarkers for autoimmune disease and as a basis for new therapeutic approaches.

THE MICROBIOME IN ANIMAL MODELS OF INFLAMMATORY ARTHRITIS The physiologic and metabolic importance of the gut microbiome and its role in the maturation of the host immune system has been studied with the use of gnotobiotic experiments. In a gnotobiotic animal, only certain known strains of bacteria and other microorganisms are present. Because these gnotobiots are normally reared in a germ-free (GF) or microbially controlled environment, they are a unique tool to investigate symbiotic relationships between a host and one or more microorganisms of interest.43 In a similar experimental fashion, several studies have assessed the influence of intestinal bacteria as triggers for inflammatory arthritis (Fig. 22.2). Since the 1970s, multiple animal models have been described as being susceptible to arthritis only when exposed to microorganisms, particularly those from the intestinal flora. The original report showed a protective effect of germs in an adjuvant-induced arthritis rat model in which severe inflammatory arthritis developed in the totality of animals raised in a GF state, as opposed to a significantly lower incidence in conventionally reared rats.44 Research involving the streptococcal cell wall–induced rat arthritis model illustrates another classic example of these interactions. In this model, conventionally raised animals are typically resistant to joint inflammation, but GF rats become susceptible to arthritis.45 Many more studies from the 1980s revealed that specific gram-negative enterobacteria either protected46 or induced47 inflammatory arthritis in GF rats, thus raising the possibility of intestinal microbiota as a triggering factor. In an elegant set of experiments in the field of spondyloarthritis (SpA), Taurog and colleagues48 described the need for commensal (and not necessarily pathogenic) intestinal bacteria in the development of both local intestinal inflammation and peripheral arthritis in HLA-B27 transgenic rats (a spontaneous model of SpA in which multiple copies of the HLA-B27 and human β2-microglobulin transgenes are microinjected). In GF rats, signs of mucosal or joint damage do not develop. Taken together, these results provided the initial support for the hypothesis of an interrelationship between alterations in the gut microbiome (dysbiosis) and the development of systemic inflammatory arthritis. The original literature was indeed ambiguous about whether the intestinal flora was protective of or detrimental to joint physiology, but mechanistic insight had been scarce. Clearly, the host’s genetic background and even gender could modulate susceptibility to arthritis after exposure to a given microbiome. This was elegantly illustrated in a study of murine collageninduced arthritis in which HLA genes were differentially expressed.49 Using 16S rRNA gene pyrosequencing, arthritis-susceptible HLA-DRB1*0401 mice were found to have an intestinal microbiota dominated by a Clostridium-like

186

SECTION 1  Scientific Basis of Rheumatic Disease COMMENSAL MICROBIOTA AS TRIGGER OF INFLAMMATORY ARTHRITIS IN ANIMAL MODELS II1rn–/–

II1rn–/– Lactobacillus activates TLR2 and TLR4 Decrease in Treg function and increase in Th1/Th17 activity IL-17 and endogenous TLR4 agonist mediate joint inflammation

Lactobacillus sp. K/BxN

K/BxN

SFB CLA/AA (rats)

SFB promotes Th17 differentiation in lamina propria Th17 cells migrate to periphery IL-17 activates autoreactive B cells and production of autoantibodies Immune-complex deposition in joints

CLA/AA (rats) Flora-dependent anti-HSP65 in GF animals Unclear mechanism

Germs from conventional cages Germ-free cages Conventional cage

FIG. 22.2  Gnotobiots are animals that are kept germ-free (GF) until known specific microorganisms are introduced in a controlled setting. Use of this experimental approach has advanced our understanding of how local changes in the intestinal microbial community (dysbiosis) are capable of producing an imbalance in the proinflammatory and antiinflammatory immune response and ultimately trigger autoimmunity at distal sites. Segmented filamentous bacteria (SFB) are sufficient to activate lamina propria type 17 helper T (Th17) cells in the K/BxN model of inflammatory arthritis. These cells migrate to the periphery, produce interleukin-17 (IL-17) (their signature cytokine), and stimulate plasma cells to produce arthritogenic autoantibodies. However, when kept in GF conditions, arthritis does not develop in these animals. Lactobacillus is also a proarthritogenic microorganism in the IL1rn−/− model. An increase in Th17 cell activity and a decrease in regulatory T cell (Treg) function are key to the development of joint inflammation. Colitis or arthritis does not develop in the HLA-B27 transgenic rat in the GF state. Inflammation is activated by gut commensals such as Bacteroides. AA, Adjuvant arthritis; CIA, collagen-induced arthritis; TLR2, Toll-like receptor 2. (Adapted with permission from Scher JU, Abramson SB. The microbiome and rheumatoid arthritis. Nat Rev Rheumatol 2011;7:569–578.)

bacterium, but the guts of *0402 mice were enriched with members of the Porphyromonadaceae family and Bifidobacterium genus. Even though DRB1*0402 mice contained a dynamic sex- and age-influenced gut microbiome, only DRB1*0401 mice had altered mucosal immune function and increased gut permeability. The same phenomenon is seen in human studies, where HLA-B27, HLA-DRB1, and HLA-A24 influence gut microbial composition and diversity, irrespective of disease.50,51 Since the late 2000s, the use of gnotobiotic mice has expanded our knowledge about the role of the gut microbiome in inflammatory arthritis (see Fig. 22.2). For example, autoimmune T cell–mediated arthritis develops spontaneously in IL-1 receptor antagonist knockout (IL1rn−/−) mice unless the animals are kept under GF conditions. When these mice are monocolonized with a strain of the commensal Lactobacillus bifidus, rapid and severe arthritis develops, comparable to that of conventionally raised mice.52 An imbalance in the Treg/Th17 cell response and subsequent TLR activation seems to explain the mechanism behind Lactobacillus-triggered arthritis in this model. The K/BxN T-cell receptor transgenic mouse is another well-studied model of inflammatory arthritis that is caused by autoreactive T cell– driven production of autoantibodies against glucose-6-phosphate isomerase.53 Here again, the incidence and severity of arthritis are decreased in GF animals, largely because of the lower activation of peripheral Th17 cells. However, the introduction of a single gut-residing commensal SFB restores the disease phenotype,54 and arthritis is abrogated when the mice are treated with SFB-targeting antibiotics from birth. Gut and joint inflammation in the SKG mouse, another Th17-driven model characterized by a single point mutation in ZAP-70, is also flora dependent, although it is mostly fungal in origin. SKG mice do not develop disease under germ-free conditions, but introduction of fungal beta-glucans (zymosan, curdlan, or laminarin) under the same conditions triggers a severe chronic arthritis.55 Interestingly, a recent report showed that Th17 cells in this model can promote joint inflammation by stimulating fibroblast-like synoviocytes to secrete GM-CSF and by inducing the expansion of synovial-resident innate lymphoid cells.56 Taken together, these data suggest that a particular intestinal microbiota is required to trigger (if not drive) systemic autoimmunity and subsequent inflammatory arthritis in animal models. It also ascribes to the notion that a state of dysbiosis may require genetic host susceptibility, as illustrated by

the inability of wild-type animals to mount an inflammatory response even in the presence of “proarthritogenic” gut flora.

THE MICROBIOME IN HUMAN INFLAMMATORY ARTHRITIS The relevance of enteropathic arthritis to human rheumatic disease can be found in the pathogenesis of several arthritides. Spondyloarthritis, particularly enteric reactive arthritis (ReA) and inflammatory bowel disease (IBD)related arthropathy, are the most prevalent examples. Other notable entities include jejunoileal bypass–arthritis syndrome, celiac disease, the microscopic colitis spectrum, and Whipple disease. The skin, gut, and periodontal microbiomes have also been implicated in the etiopathogenesis of psoriasis (PsO)/psoriatic arthritis (PsA) and RA.

SPONDYLOARTHRITIS Spondyloarthritis comprises a spectrum of multiple related but phenotypically distinct disorders, including IBD-related arthropathy, ReA, PsA, ankylosing spondylitis (AS), pediatric enthesitis-related arthritis (ERA), and undifferentiated SpA.57 There is a constellation of several potential clinical manifestations ranging from axial and peripheral arthritis to psoriasis, uveitis, and bowel inflammation. The link between joint and gut inflammation in the SpA spectrum is well established in both murine models58,59 and humans. The strongest association is between IBD and AS—AS develops in as many as 16% of patients with IBD, almost 50% of whom exhibit some compromise of their sacroiliac joints.60 Conversely, up to two-thirds of patients with SpA show signs of subclinical microscopic gut inflammation, most notably in 60% of those with AS and 90% of those with enteric ReA.61 Mucosal inflammation affects both the terminal ileum and colon and could either be acute (bacterial enterocolitis–like) or chronic (Crohn’s-like). Whereas the acute form is associated with transient arthritis, the chronic type is seen in patients with persistent joint inflammation, who are at higher risk for full-blown IBD. Gut inflammatory changes fluctuate with arthritis activity and vice versa.62 Interestingly, circulating antibodies against enteric microbes present in patients with IBD, such as anti-I2, are also found in the plasma of patients with AS.63 Moreover, the efficacy of sulfasalazine for both IBD and peripheral SpA (a drug that is poorly absorbed by the gut) represents another

CHAPTER 22  The microbiome in rheumatic diseases manifestation of the gut–joint linkage. Using low-throughput denaturing gradient electrophoresis and polymerase chain reaction (PCR) methods, one study showed a significant decrease in intestinal sulfate-reducing bacteria (i.e., Desulfovibrio spp.) in patients with AS versus control participants,64 an alteration that is also found in patients with IBD. This led to the use of a cocktail of commensal bacteria for the treatment of SpA. Even though the randomized clinical trial did not demonstrate significant benefit over placebo,65 there is a clear need for further diagnostic and therapeutic exploration. A subsequent study comparing terminal ileal biopsies of patients with AS to healthy participants demonstrated distinct microbial signatures in AS that were driven by seven core families of bacteria, providing further support for the gut-joint axis in disease development.66 Stoll and colleagues67 looked at pediatric ERA, a type of juvenile SpA, and demonstrated decreased abundance of Faecalibacterium prausnitzii in ERA compared with healthy control participants, a finding that is analogous to patients with IBD.68 F. prausnitzii has been linked with increased production of SCFAs, particularly butyrate,69 which, as discussed, is associated with the promotion of Tregs. Pediatric patients with ERA also clustered into two distinct groups, one dominated by Bacteroides spp. and the other by Akkermansia muciniphila.67 To further explore the significance of this altered microbiome, the investigators performed whole-genome sequencing and metabolomic analyses, which showed that pediatric ERA was associated with decreased taxonomic diversity and diminished content of fecal water metabolites.70 Using the HLA-B27 transgenic rat model of SpA, Lin, Asquith, and colleagues showed that HLA-B27 expression is associated with alterations in gut microbiome expression.71,72 Intriguingly, they also found evidence of progressive dysbiosis with age, marked by a significant decrease in the relative abundance of Firmicutes spp. and an increase in Proteobacteria spp. as well as Akkermansia muciniphila.72 These dynamic perturbations were associated with changes in the intestinal immune environment, including enhanced expression of Th1 and Th17 cytokines (IL-17A, IL-23, and IFN-γ), expansion of Th17 cells in the colonic mucosa, dysregulation of antimicrobial peptide expression, and increased production of bacterial-specific IgA. All of these changes predated the development of significant clinical colitis. Most intriguingly, the group further demonstrated that colonization with A. muciniphila was associated with both gut and joint inflammation as animals that progressed to arthritis exhibited significantly higher levels of this taxon.72 However, a subsequent study of this animal model in three different genetic backgrounds showed that HLA-B27-related effects on the gut microbiota and clinical phenotype were highly dependent on host-genetic background.73

Inflammatory bowel disease–related arthropathy Inflammatory bowel disease is a spectrum of autoimmune disorders affecting the GI tract, more commonly the colon and small intestine. The major types of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). Concomitant nonaxial joint inflammation develops in about one-third of all patients. Two forms of peripheral arthropathy have been described. Type I, which is typically found in UC, is oligoarticular in nature and usually follows IBD activity. Type II tends to be chronic and polyarticular, with a course that is independent of gut mucosal inflammation.74 In addition, as discussed, axial arthropathy is significantly higher in those with IBD. Whereas AS is reported in 1% to 16% of patients, asymptomatic sacroiliitis occurs in up to 45% of patients with IBD.75 Although no single taxon has ultimately been implicated, most reports confirm a state of dysbiosis with an overall decrease in phylogenetic diversity. Both patients with CD and patients with UC have decreased biodiversity, a lower proportion of Firmicutes, and an increase in Gammaproteobacteria.76 Microbial clades differentially abundant in IBD include Roseburia and Phascolarctobacterium (decreased in CD and UC) and Ruminococcaceae (decreased in CD only), along with a significant increase in Enterobacteriaceae (specifically Escherichia and Shigella genera).77 A dramatic reduction in the relative abundance of Firmicutes, one of the two major phyla along with Bacteroidetes, has consistently been reported. Several members of this group are known producers of potent antiinflammatory SCFA metabolites, such as acetate (Ruminococcaceae) and butyrate (Roseburia). In patients with CD, a specific decrease in F. prausnitzii has also been described and validated.78 Permanent reductions in all of these clades, coupled with an increase in pathobionts from the Escherichia and Shigella group, may ultimately have functional consequences on the ability of the host to repair the gut epithelium and regulate local inflammatory responses. Whether these IBD-associated alterations in the gut microbiome differ in patients with articular manifestations is unknown. Intriguingly, mice deficient in any step of the inflammasome pathway involving NLRP6 (nucleotide-binding oligomerization domain [NOD]-like receptor family pyrin domain–containing 6), ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain [CARD]), caspase-1, or IL-18 show

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an alteration in gut microbial ecology. This shift in microbiota is dominated by members of the Prevotellaceae family and is associated with an IBD-like phenotype that is transmissible to cohoused wild-type mice.79

Psoriatic arthritis and psoriasis Psoriatic arthritis is a chronic inflammatory arthritis that affects individuals with psoriasis of the skin (PsO). Whereas the prevalence of PsO is approximately 2% to 3% in the general population, the incidence of PsA in patients with PsO is about 30%.80 For reasons that are unclear, PsA typically occurs after the onset of skin disease. The pathogenesis of PsA remains poorly understood, and the current paradigm posits that in the presence of strong genetic risk factors (e.g., HLA class I molecules such as HLA-B*27 and B*39),81 PsA develops in individuals with PsO after exposure to currently unidentified environmental factors, and arthritogenic antigens may trigger innate immune responses that secondarily drive adaptive immunity and lead to systemic and joint inflammation. Although genes are important in the pathogenesis of PsA, there are apparent limitations to their contribution, as demonstrated by a modest concordance rate in first-degree relatives and monozygotic twins.82,83 Proposed environmental triggers include viruses, vaccinations, bacterial infections, trauma, and stress. Moreover, PsA has specifically been associated with changes in the gut microbiota. As described, PsA develops in HLA-B27-overexpressing rats only in the presence of intestinal microbes, but subclinical gut mucosal inflammation has also been found in patients with active PsA,84 mostly in those with predominantly axial disease. Furthermore a history of infections requiring antibiotics is associated with the occurrence of arthritis in patients with PsO.85 It has also been shown that dendritic cells from patients with PsA (but not from those with PsO) have an impaired immune response to bacteria.86 These data reinforce the notion of an altered bacterial clearance mechanism in PsA that eventually leads to chronic systemic inflammation in joints, entheses, skin, and even the gut. The human skin microbiome has been studied with high-throughput DNA-sequencing techniques. Surprisingly, its diversity is much greater than anticipated from the original culture-based reports.87 Four different phyla predominate: Actinobacteria, Firmicutes, Bacteroidetes, and Proteobacteria. However, the relative abundance of the skin microbiome is directly dependent on the physiologic condition of a given topographic region and is associated with factors such as moisture (high abundance of Staphylococcus and Corynebacterium spp.) and sebaceous content (predominance of Propionibacterium spp.). Poststreptococcal PsO, which could evolve into chronic PsO in 40% of cases, is a well-established bacterial-associated mechanism.88 Moreover, the composition of the cutaneous microbiota in patients with PsO reveals striking differences at both the phylum and species levels compared to healthy skin. For instance, in one study, Firmicutes were overrepresented but Actinobacteria and Propionibacterium acnes both underrepresented in untreated psoriatic plaques compared with unaffected skin from the same patients with psoriasis and normal control participants.89 In a different study, Firmicutes was the most abundant phylum in patients with PsO and healthy control participants, but levels were higher in the healthy control population. Furthermore, Proteobacteria was overrepresented, but Propionibacterium spp. and Staphylococcus spp. were underrepresented in patients with PsO.90 These alterations may be the result of an inhospitable microenvironment for the organisms or, equally possible, they may play a protective role against PsO. The role of the gut and cutaneous microbiome in the transition from PsO to PsA, in which inflammation is not just limited to the skin but also spreads to include the joints and entheses, is an attractive hypothesis and a matter of intense research. A study by our group showed that the gut microbiome of PsO and patients with PsA is less diverse than in healthy control participants. Both groups demonstrated lower abundance of Coprococcus spp., but the PsA group was further characterized by significant reductions in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. This correlated with higher levels of sIgA and lower levels of receptor activator of nuclear factor kappa-B ligand (RANK-L) in the intestinal lumen of patients with PsA compared with patients with PsO and healthy control participants. All three groups had similar quantities of SCFAs, but both patients with PsO and PsA had reduced levels of medium-chain fatty acids (MCFAs) hexanoate and heptanoate.91 Taken together, these alterations may represent a breach in the intestinal barrier or may possibly help facilitate the inflammatory response.

RHEUMATOID ARTHRITIS Since the discovery of the microscope and microorganisms by Antony van Leeuwenhoek in the 18th century, successive hypotheses attempted to link the oral and intestinal microbiome with the etiology of RA. Notably, Sir William Osler described arthritis deformans as being caused

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by tuberculosis,92 the focal sepsis hypothesis attributed periodontal flora as the cause of RA,93 and the toxemic factor theory proposed that substances produced by intestinal microorganisms are ultimately responsible for the joint inflammation in rheumatoid patients.94 Paleopathologic and epidemiologic evidence, although debatable, suggests that RA is a transmissible New World disease that spread to the rest of the planet after conquest.95 This is based on the lack of skeletal remnants with RA-like erosions outside the Americas and a higher prevalence of the disease in Native Americans than in other populations. Moreover, until very recently, the incidence of RA appeared to be declining.96 Because genetic changes occur over several generations, this decrease has been attributed to a possible “birth cohort” effect or “hygiene hypothesis.” Such theories propose a role for an infectious agent that was presumably highly prevalent a century ago but has been slowly eradicated by introduction of the modern lifestyle and dietary modifications. Exposure to this agent by subsequent generations may have therefore decreased along with the incidence of the disease. Several clinical reports have implicated specific pathogenic microorganisms as triggers for RA, mostly through indirect evidence (serologic and PCR methods) and circumstantial observations. These microorganisms include viruses, retroviruses, bacteria, and mycoplasmas. However, a precise causal effect could not be established.

The intestinal microbiome in rheumatoid arthritis The idea that intestinal microorganisms are associated with the development of RA is not novel. Classic examples at the beginning of the 20th century include the albuminous putrefaction therapies of Andrews and Hoke and the toxemic factor hypothesis of Carl Warden. Beyond convincing animal model data on the role of intestinal bacteria in RA-like disease, there is evidence that therapeutic regimens seemingly targeting the enteroarthropathy connection are successful in the clinic. Many of these drugs have been classified as disease-modifying antirheumatic drugs (DMARDs) and are still in use today. This notion was originally developed in the 1940s when sulfasalazine became the first rationally designed compound for the treatment of rheumatic disease. Because RA was thought to be caused by streptococci found in milk,97 sulfasalazine was created in a deliberate effort to combine a sulfonamide antibiotic (against enteric bacteria) with a salicylate (antiinflammatory agent) through an azo bond.98 Sulfasalazine as well as the antimalarial agent hydroxychloroquine are currently used for mild cases of RA. Moreover, triple DMARD therapy (a combination of sulfasalazine, hydroxychloroquine, and methotrexate) remains a top choice for patients with RA who have poor prognostic features and moderate or high levels of disease activity, regardless of disease duration,99 and appears to be equivalent in efficacy to the combination of methotrexate and a biologic agent for early RA.100 Tetracycline antibiotics also proved to be efficacious in the treatment of early seropositive RA,101 which led to the approval of minocycline as a DMARD. Despite these encouraging clinical outcomes, the underlying mechanisms of action for these drugs—particularly their specific antibiotic properties—have never been completely elucidated. The community composition of intestinal bacteria in patients with RA has been studied with low-throughput technologies. Via gas–liquid chromatography or limited oligonucleotide probing, patients with RA were found to have fewer Bacteroides groups compared with control participants.102 These approaches, however, remain inadequate and nonspecific for the characterization of the entire gut microbiota. Efforts using high-throughput DNA sequencing have been much more revealing.103 Using 16 S rRNA and shotgun sequencing, our group identified a strong association of Prevotella spp. (specifically Prevotella copri) in patients with new-onset untreated RA (NORA) compared to those with chronic RA (CRA) and healthy control participants. The latter two groups were dominated by Bacteroides spp. Furthermore enzymatic analysis revealed lower abundance of purine metabolic pathways, including tetrahydrofolate biosynthesis (THF), in NORA. This has important implications for the metabolism of methotrexate, which in itself inhibits the production of THF from dihydrofolate and serves as a mainstay of RA therapy.104 Notably, Maeda and colleagues looked at the mechanisms by which altered gut microbial composition may contribute to the development of inflammatory arthritis. They inoculated fecal samples of healthy control participants and participants with RA who had a high prevalence of Prevotellaceae into GF SKG mice. Although these mice spontaneously developed arthritis when reared in a conventional facility, the phenotype was abrogated under GF conditions. However, mice harboring the human RA microbiome had a much more robust intestinal Th17 response and developed a severe arthritis upon treatment with zymosan (a fungal β-glucan), providing a mechanism of how gut dysbiosis can contribute to downstream immune events leading to distal joint inflammation.105 A novel approach for antigen detection in

chronic inflammatory arthritides was recently developed and used to identify peptides from a protein of P. copri that is presented by HLA-DR and capable of stimulating T- and B-cell responses in 40% of patients with RA but not in other rheumatic diseases or healthy control participants.106 Two autoantigens specific for RA were also identified in inflamed synovial tissue, which share homologous T-cell epitopes with Prevotella and stimulate T- and B-cell responses.107 These two key studies provide evidence for immune recognition of P. copri in RA and a potential mechanism of pathogenesis. Prevotella spp., however, is not uniquely associated with RA and appears to play a role in other chronic inflammatory disorders. Using the Pstpip2cmo murine model that spontaneously develops osteomyelitis, Lukens and colleagues showed that the intestinal microbiome of these mice has a much higher proportion of Prevotella spp. Most intriguing was the fact that a diet rich in fat and cholesterol reduced the abundance of Prevotella spp. and appeared to protect the mice from disease onset.108

The oral microbiome in rheumatoid arthritis At the turn of the 20th century, the widely prevalent oral sepsis hypothesis led to the use of tooth extraction as a widespread treatment of RA. It lasted for several decades and was eventually deemed ineffective. In the past decade, a vast body of published literature has shown epidemiologic associations between the presence of periodontal disease (PD) and RA. PD was more common and severe in patients with RA than in those with osteoarthritis.109 In another study, participants with RA had an eightfold increase in likelihood of periodontitis compared with control participants.110 Others have found a less robust correlation, thus suggesting that study methodologies and the definition of PD have been variable. Multiple lines of investigation have also implicated P. gingivalis, a common periodontopathic bacterium, as a possible trigger for joint inflammation.111 P. gingivalis is a gram-negative anaerobe that contains a unique enzyme—peptidyl arginine deiminase (PADI)—that is capable of citrullinating arginine peptide residues in a calcium-dependent post-translational modification process. According to this model, citrullinated residues turn into neopeptides that are recognized by antigen-presenting cells in the appropriate genetic context (i.e., HLA); this leads to the activation of T and B cells, which ultimately stimulates the production of anticitrullinated peptide antibodies (ACPAs) by plasma cells and unfolding inflammatory responses within the joint. Evidence to support this model is derived from in vitro and in vivo studies. PADI-sufficient P. gingivalis—but not other periodontal bacteria or a PADI knockout strain—is able to citrullinate human fibrinogen and α-enolase.112 In susceptible DR4-IE transgenic mice, both autoimmunity and inflammatory arthritis develop when animals are immunized with P. gingivalis enolase (both citrullinated or uncitrullinated), suggesting a pathogenic role in the initiation of disease.39 Citrullination of proteins occurs as a part of physiologic cellular processes, particularly in apoptosis. The joints of patients with RA, however, have abnormally high levels of both citrullinated proteins and ACPAs.113 There is evidence that ACPAs are responsible for the initiation of RA because these antibodies (along with rheumatoid factor [RF]) can be found several years before any clinical manifestations become evident.114 Furthermore there appears to be a positive serologic correlation between P. gingivalis exposure, ACPA titers, and RA,115,116 with first-degree relatives demonstrating an intermediate antibody profile compared to healthy control participants.115 The first study that directly looked at the presence of oral microorganisms used multiplexed pyrosequencing to compare the bacterial composition of subgingival microbiota in NORA and control participants.117 Notably, patients with RA exhibited a high prevalence of PD at disease onset, and their subgingival microbiota was similar to that of patients with chronic RA and healthy participants with comparable PD severity. Overall, P. gingivalis was found in 55% of patients with RA versus 27% of control participants, thus suggesting a potential common pathway for RA and PD and a potential role for P. gingivalis in a subset of patients with RA. A more recent study by Zhang and colleagues showed that dysbiosis is present not only in the guts of patients with RA (as described in an earlier section) but in the oral microbiome as well.118 The authors performed metagenomic shotgun sequencing and then carried out a metagenome-wide association study from salivary, dental, and fecal samples of patients with treatment-naïve patients with RA and healthy control participants. They demonstrated an underrepresentation of Haemophilus spp. at all three sites, which negatively correlated with RA-specific antibodies, RF, and ACPA. Conversely, there was an overrepresentation of Lactobacillus salivarius in patients with at all three sites, which positively correlated with RA-specific antibodies and disease activity. Most important, however, was the finding that DMARD (especially methotrexate) treatment altered the microbiome toward resembling that of healthy control participants. These changes, in turn, were more apparent in participants who had a better clinical response to DMARDs.

CHAPTER 22  The microbiome in rheumatic diseases

THE MICROBIOME IN SYSTEMIC LUPUS ERYTHEMATOSUS Systemic lupus erythematosus (SLE) is a chronic inflammatory multiorgan disease with a wide spectrum of manifestations. SLE is driven by the production of autoantibodies that lead to antigen-antibody immune complexes. One of the earliest antinuclear autoantibodies, which appears even before the onset of clinical symptoms, is directed against the RNA-binding autoantigen Ro60.119 Notably, a recent study showed that skin, oral, and gut microbiota contain many commensal bacterial species with Ro60 orthologs. Furthermore serum taken from patients with lupus with antibodies against commensal Ro60 and CD4 memory T-cell clones specific for Ro60 autoantigens were activated by these bacteria,120 suggesting a role for commensal organisms in SLE pathogenesis. There is likewise evidence of gut microbial dysbiosis in lupus. A study of a lupus cohort of Spanish patients who were in disease remission demonstrated reduction of the Firmicutes and expansion of the Bacteroidetes phyla,121 findings that were corroborated in a Chinese cohort of patients with SLE with active disease.122 Another study performed in the United States on patients with active SLE found no differences in the Firmicutesto-Bacteroidetes ratio compared to healthy controls but did demonstrate lower diversity levels.123 In a larger cross-sectional study, there was an inverse association of SLE disease activity with gut microbial diversity and a direct positive correlation between active lupus nephritis and abundance of Ruminococcus gnavus.124 A recent report also demonstrated that translocation of a gram-positive bacterium, Enterococcus gallinarum, to the liver and other tissues of a SLE mouse model triggers an autoimmune response that is suppressed with administration of antibiotics.125 They also found evidence of DNA from E. gallinarum in the livers of patients with lupus and autoimmune hepatitis,125 further suggesting that specific microorganisms could actually be triggers for disease.

PHARMACOMICROBIOMICS Pharmacomicrobiomics is an emerging field of research that characterizes how variations in the microbiome affect the action and potential toxicity of drugs.126 There are a number of mechanisms by which microorganisms can influence the way drugs are processed, including direct microbial interference, alteration of host gene expression affecting drug metabolism, production of intermediate metabolites that compete for binding sites with drugs, and modulation of drug immune effects, just to name a few.127 Several studies have looked specifically at immunosuppressive drugs applied to autoimmune diseases. One example is the above-mentioned sulfasalazine, a DMARD used in the treatment of RA, which was designed as a prodrug. Composed of 5-aminosalicylic acid and sulfapyridine, sulfasalazine is activated in the distal gut by cleavage of the azo bond between these two components. A study as early as 1972 showed that sulfasalazine metabolism is dependent on gut microorganisms. When the drug is given to conventional rats, it is fully metabolized, and none of it is recovered in the feces or urine. However, more than 50% of the drug is recovered in the feces of GF rats. When bacteria from conventional rats are introduced into GF rats, sulfasalazine is again fully metabolized.128 The microbiome also plays a key role in drug efficacy. For example, patients with CD who respond to anti-integrin and anti-IL-12/23 therapies tend to have a more diverse gut microbiome pretreatment.129,130 In RA, methotrexate-induced shifts in intestinal bacterial relative abundance of the Bacteroidetes phylum are associated with improved drug response.131 In axial SpA, patients who respond to tumor necrosis factor alpha inhibitors (TNFis) exhibit a more resilient pretreatment gut microbiome and higher relative abundance of Dialister posttreatment, whereas nonresponders are characterized by higher abundance of Salmonella.132 Just as the microbiome modulates response to therapy, drugs can alter gut microbial composition.133 In fact, an in vitro screen of over 1000 different drugs, many without antibiotic or antimicrobial properties, found that 24% directly affect the growth of at least one bacterial isolate.133 Common agents include nonsteroidal antiinflammatories (NSAIDs)134 and proton pump inhibitors (PPIs).135,136 Another relevant example is cyclophosphamide, an alkylating agent used in the treatment of cancer as well as SLE. Viaud and colleagues demonstrated that cyclophosphamide alters the microbial composition of the small intestine in the murine model, resulting in the translocation of certain gram-positive bacteria into secondary lymphoid organs and stimulating an immune response driven by Th1 and Th17 cells.137 In psoriasis, IL-17A blockade results in the expansion of Proteobacteria and reduction of the Bacteroidetes and Firmicutes phyla.138 Furthermore, clinical trials of IL-17A blockade in PsA have demonstrated increased risk for the development of candidiasis,139,140 and in rare cases it has resulted in overt gut inflammation.141–143 In fact, trials of IL-17A inhibitors (IL-17i) in CD were

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stopped due to the unexpectedly high rate of disease exacerbation.144 These manifestations have been corroborated by our group, where a recent study showed that use of IL-17i is associated with a significant expansion of intestinal Candida albicans in a subgroup of patients with SpA/PsA.145 Despite the accumulated evidence, further research is needed to elaborate how changes in the microbiome can alter the efficacy of immunomodulatory drugs and the type of microbiome that is needed for an adequate drug response without adverse effects. This will ultimately provide answers as to why certain patients respond to the same drugs better than others.

MANIPULATING THE MICROBIOME TO MODULATE AUTOIMMUNE DISEASE Given that microbial dysbiosis has a strong correlation with autoimmune disease, it may be possible to alter the microbiota in order to improve disease outcomes. One approach is through diet. Several studies have shown that a protein-rich diet is associated with enrichment of Bacteroides, whereas a carbohydrate-based diet is associated with enrichment of Prevotella.146–148 Other trials have demonstrated beneficial outcomes of a Mediterranean diet on inflammation and physical function in RA.149,150 Although unclear, the dietary effects could be linked to an increased production of SCFAs,151 which are known to upregulate Tregs that can abrogate systemic inflammation.41,152 In psoriatic disease, a metaanalysis performed by Millsop and colleagues found that fish oil resulted in the greatest clinical benefits compared to other supplements.153 Another approach to modifying the microbiome is the use of prebiotics and probiotics. Prebiotics are supplements that promote the growth and/or activity of beneficial microorganisms, while probiotics contain living beneficial microorganisms.148 One successful example is an animal model of chemically induced colitis that has features similar to CD, where a diet rich in MCFAs prevents the development of gut inflammation.154 Another example is the HLA-B27 transgenic rat, where supplementation with propionate attenuates the development of SpA-like inflammation.155 In RA, supplementation with certain strains of Lactobacillus results in the reduction of disease activity scores.156–158 Finally, given its success in Clostridium difficile159 infections and IBD,160 fecal microbiota transplantation (FMT), or the transfer of gut microbial communities from healthy donors to patients, appears to be a potentially beneficial strategy. This approach is currently being examined in peripheral PsA by the Danish Efficacy and Safety of Fecal Microbiota Transplantation in Peripheral Psoriatic Arthritis (FLORA) clinical trial.161 Yet many considerations must be answered before FMT becomes a viable therapy for autoimmune disease, including which microorganisms would be beneficial for improving disease outcomes, the optimal dose and route of delivery (i.e., oral vs rectal), as well as the frequency of procedures needed for a durable response.

CONCLUSION New DNA- and RNA-sequencing technologies paired with multiomic strategies and gnotobiotic experimental approaches have brought novel insights into the potential mechanisms of disease behind autoimmune processes. It is now possible to characterize thousands of bacteria, their function, and their interactions in exquisite detail. Animal models have shown the capacity of specific oral and intestinal commensal bacteria to activate proinflammatory cells, which then initiate and perpetuate deleterious effects in the joints and other extraintestinal tissues. The clinical implications of these discoveries, along with novel areas of research such as pharmacomicrobiomics and methods for modifying microbial composition, open a new perspective in rheumatic and autoimmune research, as well as personalized medicine approaches.

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157. Zamani B, Golkar HR, Farshbaf S, et al. Clinical and metabolic response to probiotic supplementation in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial. Int J Rheum Dis. 2016;19:869–879. 158. Hatakka K, Martio J, Korpela M, et al. Effects of probiotic therapy on the activity and activation of mild rheumatoid arthritis—a pilot study. Scand J Rheumatol. 2003;32:211–215. 159. Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. New Engl J Med. 2013;368:407–415. 160. Paramsothy S, Paramsothy R, Rubin DT, et al. Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis. 2017;11:1180–1199. 161. Kragsnaes MS, Kjeldsen J, Horn HC, et al. Efficacy and safety of faecal microbiota transplantation in patients with psoriatic arthritis: protocol for a 6-month, double-blind, randomised, placebo-controlled trial. BMJ Open. 2018;8:e019231.

Section

2

CLINICAL BASIS OF RHEUMATIC DISEASE

Principles of epidemiology Julia F. Simard • Elizabeth V. Arkema

Key Points ■ The practice of epidemiology spans from study design and data collection to statistical analysis and interpretation and considers not only the likelihood of bias but also the implications and generalizability of the results. ■ Distinctions between prevalence and incidence, for example, may seem to be subtleties of little practical significance; however, even these simple principles can completely alter the interpretation of a study. ■ Understanding where data come from and what they represent is fundamental in both the critical evaluation of published studies and the design and implementation of one’s own research.

INTRODUCTION WHAT IS EPIDEMIOLOGY? Epidemiology is the study of the determinants and distribution of disease in a population. Its methods support clinical research, randomized trials, and observational studies. It can be used to describe who is impacted by a particular illness, at what rate or likelihood a person may develop complications, and what happens to them in the long run. Descriptive studies might characterize patient populations with regards to prevalence or risk. On the other hand, studies of association explore relationships between exposures and outcomes.

WHAT CAN EPIDEMIOLOGIC METHODS ACCOMPLISH? The field of epidemiology, often conflated with statistics, is not restricted to the analysis of data. Instead, epidemiology spans from the initial design of a study to determining what data will be collected, who will be included, how exposures and outcomes will be defined, which statistical analysis to perform, and how to interpret results in the appropriate context. Epidemiology considers not only the likelihood of bias and its potential impact on the findings but also the generalizability of the results. One might answer relatively simple questions such as, “What is the incidence and prevalence of giant cell arteritis in 2016?” to more complex inquiries such as, “Do psychosocial factors explain the residual risk of cardiovascular disease among patients with rheumatoid arthritis (RA) in whom traditional cardiovascular risk factors alone do not explain the excess risk?”

WHAT WILL BE COVERED IN THIS CHAPTER? This chapter introduces readers to key pieces of epidemiologic study design, beginning with how to define a study population, exposures, and outcomes. The chapter discusses key features and considerations in descriptive epidemiologic studies such as prevalence, reverse causation, and the ecological fallacy. The chapter then introduces analytic epidemiology, its study designs, measures of association, and common biases.

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HOW TO STUDY AND DEFINE POPULATIONS A population is composed of individuals who are defined by at least one common trait, which can be in terms of personal characteristics, a defined place, or a time period. An epidemiologic study’s eligibility criteria outline the inclusions or exclusions used to identify the study population. This first important step affects how one analyzes and interprets the study results.1 A representative sample of a population within a defined geographic area or time period may be generalizable to larger populations. Alternatively, one may want to include individuals who are less representative but are more likely to participate and successfully complete the study, such as in the Nurses’ Health Study, which included nurses who were motivated and had adequate medical knowledge to fill out questionnaires about their health.2 Populations are dynamic. Individuals can move in and out of a geographic area, or personal characteristics can change over time, making some people no longer eligible for inclusion in the defined population. To deal with this, person-time is used to represent the amount of time someone spends in a population.

DEFINING THE PIECES OF AN EPIDEMIOLOGIC STUDY DEFINING EXPOSURE What constitutes an exposure is broad, from genetic polymorphisms, to coffee consumption, to biologic disease-modifying antirheumatic drugs, to another disease. The common feature is that an exposure precedes whatever the specific outcome of interest is. It might be called a predictor, risk factor, or protective factor. And although we tend to avoid causal language in epidemiology, the exposure is often thought of as a potential “cause” of the outcome. However, it is important to underscore that in epidemiology, we typically speak in terms of association and not causation.3 How an exposure is defined has implications on the interpretation of findings. For example, one might ask whether there is an association between alcohol consumption and Sjögren syndrome, but how is alcohol consumption defined? A binary (or indicator) variable can represent whether an individual is a consumer or not. However, if recent consumption is important or previous consumption among current abstainers is of relevance, this simplified definition might not appropriately answer the question. Alcohol consumption could be defined based on type, average grams per week, recent consumption, or ever binge drinking. Most exposures can be defined many ways; see Table 23.1 for examples. When defining exposure, it is also important to carefully consider time in relation to onset of the outcome. In the case of some rheumatologic diseases with protracted diagnostic periods, exposure before clinical diagnosis does not necessarily capture the “etiologically relevant time window.” More simply, if it takes up to 2 years for a patient to go from symptom onset to clinical diagnosis, then exposures or risk factors for developing the disease should precede

193

SECTION 2  Clinical Basis of Rheumatic Disease

194 Table 23.1

Coding and Representing Different Types of Data Type of Variable (in Terms of Alcohol)

What It Represents

How It Can Be Coded

Example

Indicator, dichotomous, binary

Presence or absence of a feature

Ever vs never drinker

Categorical

Multiple options (usually >2) that are not numerical or ordered This is an ordered categorical variable represented by numbers

Yes vs no 1 vs 0 A vs B A vs B vs C vs D

Current, past, or never

0, 1, 2, 3, …

0: No drinks weekly

Ordinal

Continuous

Quantity (countable or not countable)

EXPOSURE TIME AND SYMPTOM ONSET VS. DELAYED DISEASE DIAGNOSIS

m pto

et

ons

is

nos

g Dia

Sym

Exposure? Relevant exposure

Prevalent disease

FIG 23.1  Illustration of etiologically relevant exposure time with respect to symptom onset versus disease diagnosis in setting of delayed diagnosis.

symptom onset. When symptoms are present, one could argue that the exposure has had its impact and that exposures captured between symptom onset and diagnosis are less relevant to the etiology of disease (Fig. 23.1).

DEFINING OUTCOME Outcomes are often defined as a disease diagnosis and can be identified through interviews, questionnaires, laboratory tests, and medical records. An outcome could be defined several different ways. For example, in a study of the relationship between an exposure and the development of RA as the outcome, one could use administrative databases and require a certain number of visits listing an International Classification of Diseases (ICD) code specific for RA. One could instead go through medical records and identify individuals fulfilling specific classification criteria. The decision on how to define the outcome requires a balance between the resources available and the validity of the outcome definition (validity is discussed in more depth later in the chapter). For some diseases, a diagnosis is not always so clear-cut, which makes defining the outcome more difficult. ICD codes are usually used for administrative and billing purposes, not originally for research, and not every physician is marking carefully in patient charts each disease criterion fulfilled. Furthermore, the time of disease onset can be uncertain, but it is extremely important for capturing the etiologically relevant time window. Thus, an outcome could be a marker for disease or preclinical manifestations, such as a positive anti-CCP (cyclic citrullinated peptide) test result.

DESCRIPTIVE EPIDEMIOLOGY Descriptive epidemiology is used to estimate population parameters, such as the proportion of individuals with juvenile idiopathic arthritis (JIA) who are anti-CCP positive, the mean age of patients with JIA, or how many new cases of JIA are diagnosed every year. Typical epidemiologic terms used in descriptive studies are prevalence, incidence, and risk.

0, 1, …, 14, …, 22, …

1: 1–3 drinks weekly 2: 4–6 drinks weekly 3: 7–10 drinks weekly 4: 11+ drinks weekly Average grams of alcohol consumed daily

Prevalence is the proportion of individuals with the disease of interest out of the total population at a point in time. Prevalence measures are useful when studying the burden of disease in a population. Incidence, which can be called incidence proportion, cumulative incidence, or risk, is a measure of occurrence. Incidence is the number of new cases of disease out of the total population at risk of becoming a case (i.e., disease free at the start of follow-up) over a specific time period. The inverse of incidence is survival, the percentage of individuals alive and disease free after a certain number of years (e.g., 5-year survival rate). One can also measure the incidence rate, which is the number of new cases of the total person-time contributed by the study population at risk of becoming a case. Incidence and prevalence are closely related. Prevalence is affected by the number of new cases (incidence) and the duration of disease. Many chronic diseases, such as systemic lupus, have a relatively low incidence but a long duration (i.e., long survival with the disease) and therefore the prevalence is higher than the incidence. In rheumatic disease epidemiology, we often want to study the experience of a population of individuals with a disease. It is important to note that whether these individuals have incident (newly diagnosed) or prevalent disease (diagnosed recently or many years ago) may markedly change our findings. For example, patients with newly diagnosed RA may be younger, have less joint damage, and have fewer comorbidities. However, those still living with a disease (prevalent cases) may actually be a healthier subset because they have survived with the disease long enough to be able to be included in the study. This is an example of depletion of susceptibles, also called survivor bias.

ANALYTIC EPIDEMIOLOGY TRADITIONAL STUDY DESIGNS During the design phase of a project, decisions are made about how the study population will be sampled or obtained, what sources of data will be used, and what information will be collected to answer the study question of interest. One’s question or hypothesis dictates the most appropriate design and, at the same time, what one can infer is limited by the design. Therefore, the design phase of a project is important. Surveys, questionnaires, and censuses collect data that are often cross-sectional. Cross-sectional studies collect information on exposure, outcome, and additional covariates of interest at the same time. This allows for estimation or reporting of prevalence and can also be used to consider the relationship between the prevalence of multiple features. For example, a survey that asks about cigarette smoking and hypertension yields information about whether individuals are current, former, or never smokers and whether they have a history of hypertension. This is insufficient information to establish an appropriate timeline—when did they start or stop smoking? And how does it relate to the onset of hypertension? The inferences one can draw using these data are a function of the data collection methods. For this reason, survey development, chart review forms, and other data collection methods should be carefully curated to ensure that the data collected will allow the question of interest to be answered without concerns of reverse causation (when the outcome actually causes the exposure) or misclassification. In cohort study designs, individuals in the study population are selected based on their exposure status and then their outcome is ascertained. Eligible individuals are identified by some membership-defining event, which might

CHAPTER 23  Principles of epidemiology be defined by geography or diagnosis, for example, and must be at risk for the outcome of interest. In a well-designed cohort study, exposure temporally precedes outcome. Although this overcomes the potential limitation of reverse causation from some cross-sectional studies, it hinges upon the appropriate design and collection of these data. In cohorts, the underlying time component may lend itself to a longitudinal study with extensive follow-up and, at times, repeated measurements. The longer the follow-up time, the higher the probability that some participants may withdraw, die, or be lost to follow-up. Censoring is a term used to describe this—the investigator no longer knows what happens to an individual, so that the individual stops contributing follow-up time and information and is thus censored. Using person-time data and estimating rates, as opposed to odds or risks, allows the investigator to account for this. Case–control studies sample individuals based on the outcome of interest and define those with the outcome as cases and those without the outcome as controls. Then investigators determine what the distribution of exposure is in these cases and controls. These designs are often criticized because their commonly retrospective nature may increase the chance of recall bias or other misclassification. These concerns may have more to do with the way that the data are collected than the design in general. For example, asking cases and controls to recall their exposure before diagnosis date for cases and an index date for control participants may lead to bias, particularly if the exposure of interest is perceived by cases to be related to the disease. To avoid this, investigators could instead collect data on the exposure from a medical chart that was recorded before the outcome of interest occurred. Identifying appropriate controls for a case–control study is also difficult, and inappropriate controls can lead to selection bias (more on this below).4 Despite these challenges, if done correctly, case–control studies can be an efficient way to answer a research question. Instead of collecting exposure and outcome information on the whole population of interest, a sample of cases and control participants can be obtained and results, if done correctly, are equivalent to those from a cohort study.

OTHER STUDY DESIGNS The above traditional study designs typically examine groups of people defined on the basis of either an exposure or an outcome. In some alternative study designs, individuals act as both the exposed and unexposed or only those with the outcome are included. There are also study designs that investigate not at the level of the individual but at the level of a group or population. In ecological studies, group-level comparisons are made as opposed to individual-level comparisons. This design typically leverages data from regions to look at correlations between factors describing groups. For example, one could compare the sales of a specific medication in counties and the mortality rates. If the investigator found that the counties with more medication sales had a higher mortality rate, it might help generate some interesting hypotheses about what drives this association. However, in this setting, one cannot conclude that the use of the medication causes death. In fact, the individuals dying may not be those who are using that medication. This is referred to as ecological fallacy. Case-only designs have been used in a number of settings but largely in gene–environment interaction studies. Restricting a study to include only cases allows for the identification of the interaction between a gene and an exposure (when the gene and exposure together have a stronger effect than each alone). This design estimates the association between exposure and genotype among cases and assumes that the two factors are independent in the underlying source population. One limitation of this design is that main effects of the exposure or genotype cannot be estimated. However, it avoids the challenge of identifying appropriate controls. A case-crossover study is another case-only design in which only individuals who have experienced the outcome are included and each subject serves as his or her own control. This design is used when the exposure of interest is transient and is believed to trigger a sudden or acute outcome.5 The exposure is measured in at least two time windows, the case window (the time period preceding the event) and the control or reference window (a time period that provides an estimate of the usual exposure). If more cases are exposed in the case window compared with the control window, it suggests that the exposure is associated with the outcome. Case-crossover studies eliminate the need to adjust for between-person confounders and some within-person confounders that are stable over time (e.g., sex). However, this study design can be limited if there is a change in exposure over time, such as a natural increase in medication use over time. To remove the effect of time trends, a case-time–control study design can be used, in which a parallel case-crossover analysis is conducted in a group of control participants.6 A systematic review and meta-analysis compiles results from several studies to summarize the evidence on the association between exposure and

195

outcome. This method can be especially useful when several similar studies have examined the same association but were underpowered. Some investigators believe that this method yields the highest level of evidence, but metaanalyses are not immune to biases of their own. If biased studies are included or if the studies are selected for inclusion in a biased way (publication bias), the summary estimate is also biased. Studies can be very different from each other—with different populations, exposure measurements, and outcome definitions—yielding heterogeneous estimates and consequently making pooled results unreliable. For more information on how to conduct a metaanalysis, see the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.7

MEASURES A measure of disease frequency quantifies how often the disease outcome has occurred in a group of interest. Some measures include proportion, risk, and rate as described earlier. One measure of frequency is odds, which is used in case–control studies. A measure of effect or association compares measures of disease frequency for two or more groups. The comparison between the risk of disease in the exposed and risk of disease in the unexposed, for example, can be done by calculating either a risk difference or a risk ratio. The risk difference is the risk in the exposed minus the risk in the unexposed. The risk ratio is calculated by dividing the risk in the exposed by the risk in the unexposed. Similarly, one could calculate a prevalence ratio, an incidence rate ratio, or an odds ratio. The choice of measure of disease frequency and measure of effect depends on the type of study design used and the goal of the research study (Table 23.2 and Fig. 23.2). There are two additional ratio measures that readers may come across. The hazard ratio, which is estimated by Cox proportional hazards models in survival analysis, is similar to an incidence rate ratio. The standardized mortality ratio (SMR) is a ratio comparing the observed deaths with what was expected. More generally, standardization is a method that allows for the comparison of rates across populations that are different in terms of age and sex, for example, when comparing the crude rates may be inappropriate.8 Interval estimates, such as confidence intervals, are typically presented alongside frequencies and measures of association. These estimates provide information about the precision of the point estimate accounting for the standard deviation and sample size. The risk difference can also be referred to as attributable risk. Additional measures such as the population attributable risk and population attributable fraction have been described in detail elsewhere and capture how the incidence would change if the exposure were eliminated. Effect modification, sometimes referred to as interaction, is present when the relationship between exposure and outcome differs by values of some third variable. For example, if an increased risk of infection in psoriasis is observed only in men and there is no association among women with psoriasis, then investigators should consider effect modification by sex.

SOME NOTES ABOUT MEASURES AND MODELING Anyone who reads the scientific literature and even the news cannot help but hear about P values, statistical significance, and hypothesis testing. These procedures and probabilities, along with the model one chooses to

Table 23.2

Measures of Disease Frequency and Effect Equation Frequency measures

Prevalence (P) Risk (R) Incidence rate (IR) Odds

n with disease/n total n new cases of disease/n total disease-free at start of follow-up over X years n new cases of disease/n total person-time observed over follow-up R/(1 − R) or P/(1 − P)

Effect measures

Risk ratio (RR) Incidence rate ratio Odds ratio (OR) Risk difference Rate difference

Rexposed/Runexposed IRexposed/IRunexposed Oddsexposed/Oddsunexposed Rexposed − Runexposed IRexposed − IRunexposed

SECTION 2  Clinical Basis of Rheumatic Disease

196

EXAMPLE INCIDENCE RATE CALCULATION

DIRECTED ACYCLIC GRAPH ILLUSTRATING A CONFOUNDER

Start with a group of people with and without the exposure and follow them over time looking for the outcome.

Confounder

Exposure

Outcome

FIG 23.3 Schematic, also called a directed acyclic graph (DAG), illustrating a Start follow-up

confounder.

15 5 10 Time since start of follow-up (yr)

0

Exposed Unexposed

20

Case Lost to follow-up

In this depiction, 10 people are enrolled in a cohort study at time 0 and followed for 20 years, At the start of the study, 5 people are unexposed, and 5 people are exposed. During follow-up, 2 people are lost to follow-up, and 4 people are diagnosed with the disease (3 exposed and 1 unexposed.) Cases

Person-time

Exposed

3

72.5

Unexposed

1

82.5

Rate ratio = (3/72.5) / (1/82.5) = 3.4 The exposure is associated with a 3.4-fold increased rate of the outcome.

FIG 23.2 Worked example of 10 individuals and incidence rate ratio calculation. Each line represents one person.

use, all have assumptions that dictate their appropriateness and their interpretation. Traditionally a predefined cutoff value of significance (alpha level, α) is decided to be 0.05, and the P value is computed from the data. The P value, even if all model assumptions are correctly specified, does not tell the investigator whether the hypothesis is right or what the association is. More words of caution about P value and confidence interval interpretation can be found in Greenland.9 Generally, the interpretation of a study’s results should not necessarily focus on statistical significance but should take all of the evidence into account, including the direction and magnitude of the association, and consider whether the findings are due to truth, chance, or bias.

TYPES OF BIAS Bias occurs when there is a flaw in (1) the study design, (2) the methods of data collection, or (3) the methods of data analysis. Bias causes a distortion of the conclusions about a relationship between an exposure and outcome. Some results can be affected by random error, which tends to lead to lower precision in the estimate. The next section focuses on sources of systematic error, which can decrease the validity of a study and lead to incorrect conclusions.

CONFOUNDING A confounder is defined as a factor that is (1) associated with the exposure, (2) associated with the outcome independent of exposure, and (3) not on the pathway between exposure and outcome. More simply, many think of a confounder as a “common cause” of both exposure and outcome that introduces an imbalance in the data (Fig. 23.3). Bias due to confounding arises when this factor is not accounted for in the analysis or design of a study, and it induces an association between exposure and disease even if

they are unrelated. Confounding is one of the major concerns for bias in observational research and one of the reasons why randomization in trials is beneficial. In the design phase of a nonrandomized study, restriction or matching can be used to minimize confounding. Via restriction, the associations between the confounding factor with exposure and outcome are removed because everyone in the restricted study population is required to have the same value of the confounder. For example, sex is a common confounder, and by restricting a study to include only women, there is no longer a way for exposure and disease to be influenced by sex. In matching, the study population is chosen to have a similar distribution of the confounding variable. Matching can be quite powerful but needs to be carefully considered, particularly in case–control studies, in which it may inadvertently introduce confounding or bias the association toward the null.10 Confounding by indication is a type of confounding most common in pharmacoepidemiology in which an association is influenced by the underlying indication for treatment (the exposure). For example, patients with psoriatic arthritis are more likely to start a new aggressive therapy if they have failed on other treatments and have uncontrolled severe disease. In studies examining whether the therapies are associated with increased risk of outcomes such as loss of function, disability, or death, the investigator may not be able to determine whether the increased risk of disability observed in the treated patients is due to the treatment or the fact that these patients had uncontrolled severe disease. In the analysis phase of a study, confounding factors can be adjusted for by including them in statistical models or stratifying results by the confounding factor. If the confounder was not measured correctly, there can still be residual confounding. The use of propensity scores in observational research is helpful to adjust for multiple confounders and may lead to balance of the measured factors across exposure categories. However, this does not guarantee the same balance for unmeasured factors that randomization typically provides.11 In a randomized control trial (RCT), the determination of treatment arms (exposure) is generally not related to any measured or unmeasured factors because it has been randomly assigned and therefore cannot introduce confounding. This assumption of no confounding in the RCT setting may be compromised if participants withdraw from the study or are censored for other reasons and censoring is related to the treatment and outcome (even in the absence of observing the outcome).

SELECTION BIAS Selection bias arises when participants are selected into the study in a biased way, causing the observed association to be different than the true association. This can be caused by factors that influence either how participants end up in the study in the first place (recruitment) or how participants end up staying in the study (retention).12 We present some simple examples of selection bias in different types of studies and suggest additional reading on this topic for those interested.13 In a case–control study, selection bias occurs when the exposure of interest is associated with the selection of cases, control participants, or both. In a study of the effect of postmenopausal estrogen on the risk of coronary heart disease (CHD), women hospitalized with CHD were identified as cases. Control participants were selected from women who were hospitalized with a hip fracture. If estrogen has a protective effect on hip fracture, the control participants are less likely to have been exposed to estrogen, and therefore estrogen is associated with being selected as a control. Another type of control should be selected to avoid bias. In cohort studies, selection bias can be caused when an inappropriate comparison group is used, such as including an exposed group from one data source and an unexposed group from another. An example of this is “healthy worker bias” in occupational epidemiology. An exposed group is chosen from a register of workers and an unexposed group is chosen from the community. Because people who can work are, in general, healthier than those who do not work, the comparison with the community is not

CHAPTER 23  Principles of epidemiology

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appropriate. This is why population-based studies are often thought of as being less affected by selection bias, although they are still not immune to this problem. More commonly, selection bias can affect a cohort study through differential loss to follow-up or informative censoring. In this situation, people who remain in the study to be analyzed no longer represent the original study population. For example, in a trial comparing two treatments, participants on treatment A are more likely to experience side effects and drop out of the study. The individuals left to analyze in the treatment A group are only those who have not experienced the side effect and may appear healthier than those on treatment B. Comparing the two groups may falsely lead to the conclusion that treatment A is associated with better outcomes. The term depletion of susceptibles is sometimes used to describe the latter two situations—one group (in this case, those treated with A) has lost those individuals who may be more susceptible to the effects of exposure.

an outcome definition is accurate, which is defined as the proportion of people who truly have the disease identified by the outcome definition.

IMMORTAL TIME

Big data and data availability are on the rise, but the principles of epidemiology remain the same. Having data is not enough. One needs to understand where the data come from and what they represent. This chapter has introduced key study designs, principles of defining exposures and outcomes, numerous caveats to the interpretation of findings, and an overview of measures. This chapter is a simplified introduction to aid in the interpretation of studies and consideration of future work. Epidemiology and clinical research can be complicated, and consulting with experts in this field may help identify important considerations in study design, analysis, and interpretation of results if the reader wishes to pursue this type of research.

As its name suggests, immortal time occurs when individuals contribute follow-up time but cannot have the outcome in question. Of course, no one is immortal, but this bias occurs via the design of a study. When, for example, exposure is determined after recruitment but the entire time under observation is classified as exposed, the investigator has introduced immortal time. In this simple form, using a person-time analysis where an individual can contribute time to the unexposed and exposed may correct the bias. Historical context, more examples, and additional complexities of immortal time bias, with an emphasis on pharmacoepidemiology, can be found elsewhere.14

MISCLASSIFICATION Any factor in a study may be subject to some misclassification, which crudely arises when the data that the researcher has collected do not reflect the true value of that factor. This can be either random (sometimes referred to as nondifferential) or systematic (also called differential misclassification) and can lead to bias. The type and degree of misclassification dictate the direction and magnitude of the potential bias. Exposures, outcomes, or other important variables can all be susceptible to bias due to misclassification. Nondifferential misclassification of exposure typically means that the way in which individuals have inaccurate or misclassified values for the exposure is random or not related to the outcome of interest. As a result, nondifferential misclassification adds noise, which tends to bias associations toward the null (i.e., underestimating the association), although this is not always true. On the other hand, the direction of differential misclassification may not tend toward a conservative bias. Recall bias, as described earlier, is an example of differential misclassification of the exposure because cases recall their exposure differently than control participants. In some instances, the direction of bias caused by differential misclassification cannot be predicted. Validity is important when considering the extent of misclassification in a study. There are numerous measures of validity; the most commonly known are sensitivity and specificity. Sensitivity is the proportion of cases who truly have the disease, and specificity is the proportion of noncases who truly do not have the disease. The positive predictive value is also useful for determining if

GENERALIZABILITY If the results of a study are expected to be similar in another population, the study is said to be generalizable to that other population, or to have external validity. The eligibility criteria and the composition of the study population should be taken into account. To determine whether a study is generalizable, one can ask the question: “Would we expect the results seen in study population X to be the same in population Y?” If there is a plausible biologic difference between populations X and Y that would cause the association to be different, generalizability may be limited; for example, if population X was all female and population Y was all male.

SUMMARY

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 1. 1 12. 13. 14.

Keyes KM. Epidemiology Matters: A New Introduction to Methodological Foundations. Oxford, UK: Oxford University Press; 2014. Colditz GA, Hankinson SE. The Nurses’ Health Study: lifestyle and health among women. Nat Rev Cancer. 2005;5(5):388–396. Rothman KJ, Greenland S, Lash TL. Modern Epidemiology. 3rd ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008. Wacholder S, et al. Selection of controls in case–control studies. I. Principles. Am J Epidemiol. 1992;135(9):1019–1028. Maclure M, Mittleman MA. Should we use a case-crossover design? Annu Rev Public Health. 2000;21:193–221. Suissa S. The case-time–control design. Epidemiology. 1995;6(3):248–253. Moher D, et al. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–269. W64. Naing NN. Easy way to learn standardization: direct and indirect methods. Malays J Med Sci. 2000;7(1):10–15. Greenland S, et al. Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations. Eur J Epidemiol. 2016;31(4):337–350. Szklo M, Nieto FJ. Epidemiology: Beyond the Basics. 3rd ed. Burlington, MA: Jones & Bartlett Learning; 2014. Sainani KL. Propensity scores: uses and limitations. PM R. 2012;4(9):693–697. Kleinbaum DG, Sullivan KM, Barker ND. A Pocket Guide to Epidemiology. New York: Springer; 2007. Choi HK, et al. Selection bias in rheumatic disease research. Nat Rev Rheumatol. 2014;10(7):403–412. Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol. 2008;167(4): 492–499.

24

Principles of clinical outcome assessment Sindhu R. Johnson • Zahi Touma

Key Points ■ Define the measurement need before choosing an instrument. What do you want to measure? Who constitutes your population? Why do you want to measure? ■ Outcome measures should be sensible, valid, reliable, responsive, and feasible, particularly for use in routine clinical care. ■ Variations in outcome may occur due to biologic differences within individuals (intraindividual variation), biologic differences across individuals (interindividual variation), and/or variations occurring through the act of measurement (error around the change). ■ Minimal important difference and achievable, acceptable, or desirable health states can help interpret if a change in outcome is meaningful. ■ Core sets of outcome measures have been recommended for use in clinical trials for an increasing number of rheumatic diseases.

INTRODUCTION Clinical outcome assessment is a critical facet of being a rheumatologist, needed in both patient care and research studies (observational studies and clinical trials). Rheumatologists measure and assess a wide array of important outcomes including disease activity, damage, response to therapy, health-related quality of life (HRQoL), adverse events, economic impact, disability, and others. Rheumatologists also use measurement science to classify or categorize clinical phenomena according to a given attribute (e.g., European League Against Rheumatism [EULAR]/American College of Rheumatology [ACR] classification criteria for systemic lupus erythematosus [SLE] or mild/moderate/severe disease activity).1,2 However, these clinical outcomes are often complex, requiring instruments that have the ability to measure them. Furthermore, these clinical outcomes do not have a gold standard. Measurement science (also known as clinimetrics) is the field of science dedicated to clinical outcome instrument development and evaluation.3 Whereas the term “variable” may describe an element (e.g., swollen joint count), an index may comprise a number of variables (e.g., DAS28).3,4 An index may be used to make a diagnosis, grade disease severity, estimate prognosis, choose a treatment, or evaluate an outcome.3 Other terms utilized to designate an instrument may include a scale, score, staging system, rating system, or criteria.3 Some health status instruments have been developed specifically to assess certain conditions or particular aspects of those conditions (condition-specific measures; e.g., lupus QoL), whereas others have been developed to permit measurement across several or many diseases (generic measures; e.g., Short-Form Health Survey [SF-36]).5,6 It is valuable to understand the principles of clinical outcome assessment. The first and most important step in measurement is to clearly define your measurement need before choosing an instrument. First, define your concept (What do you want to measure? e.g., disease activity). Second, specify the population (Who constitutes your population? e.g., patients with rheumatoid arthritis) and, third, define the purpose (Why do you want to measure? e.g., to evaluate response to therapy). With this knowledge, one can choose the right instrument for the right population and purpose. The use of a good instrument with appropriate measurement properties (sensibility, validity, reliability, and responsiveness) will increase confidence of findings within a study and facilitate comparisons across studies.

change over time7 (Table 24.1). Classification criteria are an example of a system designed to discriminate those with a disease from those with a mimicking condition.8 The Systemic Lupus International Collaborating Clinics (SLICC) damage index is an example of a predictive index as the score at 5 years has high predictive value for survival.9 The SF-36 and Health Assessment Questionnaire Disability Index (HAQ-DI) are examples of evaluative indices for HRQoL and disability, respectively.5,10,11 It is also important to ask what one wants to measure. It is helpful if the construct or conceptual framework of what one wants to measure is clearly defined.12 A conceptual framework is a model representing the relationships between the items and the construct to be measured.13 A construct is a well-defined and precisely demarcated subject of measurement; that is, the phenomenon that the instrument attempts to capture.3,13 Many constructs in rheumatology such as disease, HRQoL, or disability lack a single gold standard or diagnostic test. These constructs comprise a variety of symptoms or signs, may be confounded by individual characteristics, and have an impact on the patient. Taking the time to define the conceptual framework of the phenomenon being measured is worthwhile as the concept, population, and purpose shape the content and format of an instrument.13 Furthermore, by using conceptual frameworks in research, one may better identify and measure constructs that are important and meaningful to the lives of people with rheumatic diseases.14

SENSIBILITY Sensibility is an indication of the usefulness of a measure.15,16 Principles used to appraise sensibility include a statement of the purpose for which the measure will be used, including population, setting, content validity, face validity, and feasibility.17,18 Face validity evaluates if the information being sought reflects the personal attributes of the patient or if there is biologic coherence of the items. Content validity evaluates if the components of an instrument reflect the conceptual framework14 and relative importance of each item for the purpose of the instrument. Content validity ensures that an instrument includes all pertinent items without important omissions. The depth of a measure is evaluated by the prevalence of floor and ceiling effects referring to the percentage of the sample achieving the best and worst scores possible. McHorney and Tarlov suggested that ceiling and floor effect should occur in less than 15% of respondents.19 Feasibility refers to the ease of use and administration of the instrument (associated time- and cost-burden of a specific instrument). It is important to note reading level (ideally targeted at grade 7). It is recommended that self-administered outcome measures (e.g., questionnaires of HRQoL; e.g., SF-36) be simple, short, and as self-explanatory as possible.20,21 Instructions should be brief and clear. Questions should not be too long (less than 25 words) and avoid vague words, overlapping alternatives, double negatives, or double-barreled questions.20,21 The recommended standard for feasibility is that self-reported instruments should be completed in less than 15 minutes15 (Fig. 24.1).

Table 24.1

Types of Health Status Measures Type of Measure

Example

Discriminative instrument

An instrument to discriminate between mild/moderate/ severe disease activity of patients with rheumatoid arthritis in a cross-sectional design A predictive test to foretell who will develop a disease or outcome (e.g., Framingham risk score to predict cardiovascular events) A measure of disease activity to determine responders on follow-up visit at 12 months in a drug trial

PURPOSE OF MEASURING A CLINICAL OUTCOME

Predictive instrument

The first principle of clinical outcome assessment is determining why one would want to measure an outcome. Using Kirshner and Guyatt’s framework, health care outcome measures have three purposes: to discriminate between subjects, predict prognosis or results of another test, and evaluate

Evaluative instrument

198

Adapted from Kirshner and Guyatt.7

CHAPTER 24  Principles of clinical outcome assessment

199

MEASUREMENT PROPERTIES OF INSTRUMENTS

Construct validity

Sensibility Matches the concept being measured and feasible

Content validity

Reliability

Internal consistency

Test-retest reliability

Convergent

Face validity

Criterion validity

Cross-cultural validity

Inter-rater reliability

Divergent

Responsiveness

Known-group validity

Interpretability (thresholds of meaning [MCID])

FIG. 24.1  Measurement properties of instruments.

VALIDITY

RELIABILITY

Validity is a measure of the extent to which an instrument specifically measures the phenomenon of interest.14 There are different facets of validity (Fig. 24.1). Criterion validity evaluates if the index produces consistent results with directly observable phenomena.14 Criterion validity is assessed by statistically testing a new measurement technique against an independent criterion or standard (concurrent validity) or against a future standard (predictive validity).22 Criterion validity is an estimate of the extent to which a measure agrees with a gold standard (i.e., an external criterion of the phenomenon being measured such as synovial biopsy in patients with rheumatoid arthritis or kidney biopsy in patients with SLE). The major challenge in criterion validity testing, for questionnaire-based measures, is the general lack of gold standards. Indeed, some purported gold standards themselves may not provide completely accurate estimates of the true value of a phenomenon. Construct validity evaluates the extent to which the measurement is related in a coherent way to other measures, also not physically verifiable, but is part of the same phenomenon.14 Construct validity encompasses concurrent (convergent and divergent validity), known-groups, and longitudinal construct validity (responsiveness). Convergent and divergent construct validity are tested by studying relationships between a measure to another measure of the same or similar attribute (convergent) or a measure where no relationship is expected (divergent). Convergent construct validity is assessed by the statistical correlation between scores on a single health component, as measured by two different instruments. If the correlation coefficient is in the same direction (positive) and appreciably above zero, the new measure is said to have evidence on convergent construct validity with another measure. McHorney et al. defined the strength of correlation as weak if 0.7.23 In contrast, divergent construct validity testing compares correlation coefficients between scores of two different instruments of an unrelated construct (e.g., measures of physical and emotional function). Known-group construct validity involves the comparison of at least two “known” groups different in the target construct and comparing their scores on the new instrument. Ideally, these groups should be different, and then we demonstrate that the difference exists on the new instrument using appropriate parametric and nonparametric statistics (t test, analysis of variance, regression analyses, etc.). To test construct validity, a priori hypotheses, always based on the literature evidence and the knowledge about a specific concept, should be developed. Once a priori hypotheses are developed, the relationships between the scores of different measures can be evaluated to test the hypotheses. It is very important to remember that construct validation is an ongoing process—you can never say an instrument is valid, but you can say that an instrument is valid within a defined population with similar clinical context. For instance, SF-36 has validity evidence for the assessment of HRQoL in SLE.

Reliability defines the extent to which the measurement procedure yields the same result on repeated determinations. Consistency, reproducibility, repeatability, and agreement are synonyms for reliability (see Fig. 24.1). Interrater reliability evaluates the reproducibility of the results when the instrument is administered at the same time by two raters. Intrarater reliability evaluates the reproducibility of the index when administered by the same rater over a period of time (ideally 7–14 days), when the phenomenon has not changed. It does not follow that because a measure is reliable it is also valid or vice versa (Fig. 24.2).

RESPONSIVENESS Responsiveness refers to the ability to accurately detect change when it has occurred.24 The ability to detect change is the quintessential requirement of a successful outcome measure for evaluating change over time and the patient’s response to treatment. The primary goal of clinical outcome assessment in evaluative research (e.g., clinical trials) is to detect clinically important changes in some aspect of a condition. To detect change, a measurement technique needs to be targeted to aspects of the disease amenable to change, using content and scaling methods that allow detection of change, and be applied at a point in time when change might have occurred.25 An assessment technique may fail to record any clinical improvement for a number of reasons (e.g., patient lacked response potential, had poor adherence with the treatment program, or received inefficacious treatment; the outcome measure was not sensitive to change over time; or a type II error occurred because of inadequate sample size) (Fig. 24.1). Checklists have been proposed for selecting a measure for clinical outcome assessment.26,27 The checklist outlined in Table 24.2 is relevant for the selection of an instrument for use in clinical practice as well as use in clinical research (observational studies and clinical trials).

Quality assessment of methods in studies of measurement properties and its statistics The quality of methods in studies of measurement properties (validity, responsiveness, etc.) is central and ensures a high level of evidence with low risk of bias. Several critical appraisal tools have been developed to guide in the assessment of quality of methods of studies of measurement properties (e.g., COSMIN checklist [Consensus-based Standards for the Selection of health status Measurement INstruments], EMPRO (Evaluating the Measurement of Patient-Reported Outcomes], and others).28,29 It is necessary to have a good understanding of the statistics and the accuracy of the results used in studies on measurement properties. Several critical appraisal tools provide explicit guidance on the standards of accuracy on each measurement properties (e.g., Terwee et al.30). For instance, correlation coefficients are frequently used as a measure of the strength of association (not a measure of agreement).22 Thus when assessing reliability, intraclass correlation coefficients should be used for continuous measures

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INTERPRETABILITY In addition to identifying instruments with good measurement properties, one needs to interpret if the observed change is meaningful (Fig. 24.1). Minimal important difference (MID) is a term that denotes the smallest observed change that is material. A number of synonyms have also been proposed in the literature33 (Table 24.5). Perspective influences the choice of terms, as the perspective may be that of the patient or the clinician. The value of an MID can be determined for different settings or applications. Most commonly, the interpretation of an MID relates to longitudinal evaluation at the group level. For patient care, an MID value for use at the individual level is more applicable.33 The MID is a metric of clinical significance, which is different than statistical significance. Two main approaches have been used to determine the MID: anchorbased approaches and distribution-based approaches. Anchor-based approaches use an external marker of change termed the “anchor” to identify the occurrence of change in the target concept of interest.33 What constitutes an appropriate anchor is debatable. Distribution-based approaches use internal quantifications of statistical variability in the sample and the magnitude of effect as a proxy to MID quantification in the target measure of interest.33 The distribution-based approach is a less favored approach to MID termination because of the lack of valuation of the importance of the change.33 Rather, this approach provides a starting point to determine the interpretation of change through defining the noise that must be surpassed in order to interpret the change that is important.33 Although improvement with treatment is a very important goal, it is also important to determine the value of the final health state attained. Several proposals have emerged that identify achievable, acceptable, or desirable health states.34

EXAMPLES OF CLINICAL OUTCOME ASSESSEMENT FIG. 24.2  Differentiation of systemic error (bias) and random error (noise).

Table 24.2

Checklist for Selecting an Instrument Attribute

Description

Conceptual framework Purpose Population Sensibility Validity

Model representing the relationships between the items and the construct to be measured What does the instrument aim to measure? Individuals in whom the instrument should be used Usefulness of an instrument The extent to which an instrument specifically measures the phenomenon of interest The extent to which the measurement procedure yields the same result on repeated determinations Ability to measure change over time Ease of administration, time to completion, affordability, patient and assessor burden

Reliability Responsiveness Feasibility

and kappa statistic for categorical measures.22,31 In evaluating construct validity using correlation coefficients, both strength and direction should be clearly stated in the methods of the study a priori; otherwise, data interpretation can become complex and potentially biased. Commonly used statistical tests for evaluating reliability, validity, and responsiveness are summarized in Table 24.3.

Variations in outcome measurement Variations in the assessment of outcomes can occur for a number of reasons. Rheumatologists should be aware of the sources of variation to can ascertain if the change in outcome is clinically relevant. A change in outcome may occur due to biologic differences within individuals (intraindividual variation), biologic differences across individuals (interindividual variation), and/or variations occurring through the act of measurement (error around the change). It is important to differentiate between the error around the change (statistical error) and true change (signal) (Table 24.4). Together, the sources of variation impact validity and reliability. The implementation of strategies to reduce the sources of variability will lead to improved quality of the outcome measurement.32

Global assessments Global assessments by patient and physician of the patient’s overall condition are commonly used in clinical trials and in clinical practice. It is important to specify in the wording of the global question which aspects of the patient’s condition are being considered (e.g., overall health status, symptom severity, disease activity, or an anatomic area). The patient global assessment is particularly important because it can be phrased to assess current status or change in symptom status and can be focused on a particular anatomic area, the condition in general, or the patient as a whole. Alternatively, it can be used to assess drug tolerability or efficacy or other aspects of the treatment program (e.g., palatability, compliance, affordability, convenience). The time frame over which the patient should consider his or her status should be defined (e.g., 48 hours, 1 week). The physician global assessment may consider, in addition, aspects of the condition that are not assessable by the patient (e.g., radiographic change and biochemical, hematologic, and immunologic abnormalities) and may provide insight into whether the patient tends to amplify or minimize reported symptoms. Again, the physician requires clear specification as to which aspects of the condition should be considered when making his or her assessment. The time frame for the physician global assessment usually should be specified as “today” because the assessor generally has no knowledge of the patient’s interval status other than that described by the patient and captured by the patient global assessment. Patients and physicians may differ in their perceptions of the patient’s global assessment of disease activity or symptom severity. The determinants and consequences of this discrepancy need careful consideration, particularly by practitioners and researchers using interviewer-administered outcome questionnaires, in which there is potential for interaction between the interviewer and patient.

MULTIDIMENSIONAL HEALTH STATUS INSTRUMENTS Numerous disease-specific and generic multidimensional health status measures have been developed. They are either self-administered or occasionally interviewer administered. Many outcome measures are protected by copyright or trademark. The main reason for an originator to register copyright and trademark is to secure necessary protection for the measure, and this forms the basis for maintaining its integrity, authenticity, and appropriate usage. HRQoL can be assessed using a multi-item questionnaire such as the SF-36 (and its derivatives), Nottingham Health Profile (NHP), or EuroQol.35,36

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Table 24.3

Summary of Statistical Tests or Methods for Evaluating Validity, Reliability, and Responsiveness Statistical Test or Method

Description

Reliability

Bland-Altman scatter plots Cohen kappa (κ) statistic Intraclass correlation coefficient Cronbach alpha (α) statistic

Permit the distribution of pairwise data to be appreciated. Provides a visual approach and illustrates the agreement for test– retest reliability. A metric reflecting agreement beyond chance; can be weighted or unweighted and adjustments made for bias and prevalence. It is used to assess reliability for categorical measures. Used in intrarater and interrater agreement analyses; to assess reliability in continuous measures. A measure of average interitem correlation in scales; used to evaluate internal consistency.

Validity

Factor analysis

Rasch analysis

Procedure for evaluating the interrelationships between items, in a scale, to higher latent and unmeasured constructs. It facilitates grouping of similar items in one domain. Two types of factor analysis exist, exploratory and confirmatory, and two major techniques (principal component analysis and common factor analysis). Factor analysis is often used to assess structural validity of scales and helps in reducing the number of items. Repeated factor analyses on the same instrument using different data sets may yield conflicting results. Based on item response theory (IRT) and is increasingly being used to test outcome scales against mathematical models using a probabilistic form of hierarchical or Guttman scaling. The Rasch model attempts to scale variables along a continuum, but not all Rasch analyses of the same instrument necessarily agree with one another. Although, in general, individuals who can perform tasks of a particular degree of difficulty should be able to perform all tasks purported to be less difficult, this is not always the case.

Responsiveness

ANOVA (analysis of variance) Student’s t-test Effect size Standardized response mean Relative efficiency

Used to evaluate known-group construct validity and responsiveness. Used to evaluate responsiveness and known-group construct validity. Change score between Time 1 and Time 2/baseline standard deviation of time 1. Change score between Time 1 and Time 2/change score standard deviation. Square of the ratio of two t or z statistics.

ASSESSMENT OF ADVERSE REACTIONS

Table 24.4

Sources of Variation in Outcome Assessment Variation Biologic variation

Variations within individuals Variations across individuals

Changes of a particular construct (e.g., disease activity) in a person Biologic differences between people

Measurement variation

Outcome assessment tool Rater

The instrument used to make the assessment The individual conducting the assessment

Table 24.5

Summary of Concepts to Indicate Meaningful Change Term

Concept

Minimal important difference (MID)

Meaningful change based; not dependent on clinical judgment but could be dependent on objective measures, harm, or benefit Meaningful change, often anchored to patient perspective

Minimal clinically important difference (MCID) Minimal important change (MIC) Minimal detectable change (MDC) Subjectively significant difference (SSD) Clinically important difference (CID) Clinically important responder (CIR) Adapted from Engl et al. 2018.33

Used to denote meaningful change within a group over time from the patient perspective Degree of change required to differentiate from measurement error Used to emphasize anchors based on the patient perspective Clinically relevant difference between groups, not specifically minimal Meaningful improvement at the individual level

Adverse reactions caused by treatment can result in symptoms, clinical signs, laboratory abnormalities, or death. Problems often arise in detecting, categorizing, attributing, and grading adverse events. Adverse event rates differ significantly depending on whether the assessment is based on open-ended questioning or structured questionnaires or is determined by a standard protocol. Various systems have been developed for categorizing adverse reactions to treatment. Attribution is the process of ascribing adverse reactions to interventions or other causes. The etiologic relationship is often graded as “none,” “possible,” “probable,” or “definite.” Often severity is rated as being “mild,” “moderate,” or “severe.” A mild adverse reaction is one that is easily tolerated by the patient, causes minimal discomfort, and does not interfere with everyday activities. A moderate adverse effect is an adverse experience that causes sufficient discomfort to interfere with normal everyday activities, and a severe reaction is an adverse experience that is incapacitating and prevents normal everyday activities. Finally, it is important to categorize the outcome of an adverse reaction; for example, as “resolved,” “improved,” “unchanged,” “worsened,” “hospitalization required,” “hospitalization prolonged,” or “death.”

MEASUREMENT IN CLINICAL TRIALS There are more than 100 different rheumatic disorders, each presenting a different challenge in outcome measurement. Regulatory authorities such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as well the American College of Rheumatology have pioneered the development of several evidence-based, consensus-driven guidance documents. The FDA document on patient-reported outcome measures is particularly important in understanding the challenges of measuring patient-centered outcomes in regulatory environments.37 The 14 characteristics detailed in the FDA document are (1) concepts being measured, (2) number of items, (3) conceptual framework of the instrument, (4) medical condition for intended use, (5) population for intended use, (6) data collection method, (7) administration mode, (8) response options, (9) recall period, (10) scoring, (11) weighting of items or domains, (12) format, (13) respondent burden, and (14) translation or cultural adaptation availability. Established in 1992, the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT, now revised to represent Outcome Measures in Rheumatology) group provides guidance on improving outcome

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measurement through data-driven and consensus processes. When trying to decide what should be measured, OMERACT recommends identifying domains through the literature, obtaining consensus from relevant stakeholders, and then voting on the core set domains. The OMERACT onion model considers domains in concentric circles that differentiate outcome measures that are mandatory in all trials, measures that are important but optional, and measures for reach research purposes.38 OMERACT provides freely available tools including workbooks and instructional videos to teach these methodologies. In summary, the ability to measure and evaluate clinical outcomes is critical to clinical practice and the conduct of clinical research. In this chapter, we introduced the importance of specifying the conceptual framework of the phenomenon under study. We reviewed the measurement science attributes of a good instrument: sensibility, validity, reliability, and responsiveness. We reviewed commonly used statistical tests, sources of measurement variation, and measures of interpretability. Together these comprise fundamental principles of clinical outcome assessment.

REFERENCES 1. Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019;2019(78):1151–1159. 2. Petri M, Kim MY, Kalunian KC, Grossman J, Hahn BH, Sammaritano LR, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med. 2005;353:2550–2558. 3. Feinstein AR. Clinimetrics. New Haven: Yale University Press; 1987. 4. van der Heijde DM, van ‘t Hof MA, van Riel PL, Theunisse LA, Lubberts EW, van Leeuwen MA, et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis. 1990;49:916–920. 5. Ware Jr. JE, Sherbourne CD. The MOS 36-item Short-Form health survey (SF-36). I. Conceptual framework and item selection. MedCare. 1992;30:473–483. 6. McElhone K, Abbott J, Shelmerdine J, Bruce IN, Ahmad Y, Gordon C, et al. Development and validation of a disease-specific health-related quality of life measure, the lupusqol, for adults with systemic lupus erythematosus. Arthritis Rheum. 2007;57:972–979. 7. Kirshner B, Guyatt G. A methodological framework for assessing health indices. J Chronic Dis. 1985;38:27–36. 8. Johnson SR, Goek ON, Singh-Grewal D, Vlad SC, Feldman BM, Felson DT, et al. Classification criteria in rheumatic diseases: a review of methodologic properties. Arthritis Rheum. 2007;57:1119–1133. 9. Nived O, Jonsen A, Bengtsson AA, Bengtsson C, Sturfelt G. High predictive value of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for survival in systemic lupus erythematosus. J Rheumatol. 2002;29: 1398–1400. 10. Johnson SR, Hawker GA, Davis AM. The health assessment questionnaire disability index and scleroderma health assessment questionnaire in scleroderma trials: an evaluation of their measurement properties. Arthritis Rheum. 2005;53:256–262. 11. Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the Health Assessment Questionnaire, Disability and Pain Scales. J Rheumatol. 1982;9:789–793. 12. Wilson IB, Cleary PD. Linking clinical variables with health-related quality of life. A conceptual model of patient outcomes. JAMA. 1995;273:59–65. 13. de Vet HCW, Terwee CB, Mokkink LB, D.L. K. Measurement in Medicine. New York: Cambridge University Press; 2011. 14. Hawker GA, Gignac MA. How meaningful is our evaluation of meaningful change in osteoarthritis? J Rheumatol. 2006;33:639–641. 15. Wright JG, McLeod RS, Lossing A, Walters BC, Hu X. Measurement in surgical clinical research. Surgery. 1996;119:241–244.

16. Feinstein A. The theory and evaluation of sensibility. In: Feinsetin A, ed. Clinimetrics, Yale University Press; New Haven; 1987:141–165. 17. Rowe BH, Oxman AD. An assessment of the sensibility of a quality-of-life instrument. Am J Emerg Med. 1993;11:374–380. 18. Bombardier C, Tugwell P. A methodological framework to develop and select indices for clinical trials: statistical and judgmental approaches. J Rheumatol. 1982;9:753–757. 19. McHorney CA, Tarlov AR. Individual-patient monitoring in clinical practice: are available health status surveys adequate? QualLife Res. 1995;4:293–307. 20. Sheatsley PB. Questionnaire contruction and item writing. In: Rossi PH, Wright JD, Anderson AB, eds. Handbook of Survey Research. Elsevier; 1983:195–230. 21. Dillman DS, Smyth JD, Christian LM. Internet, mail, and mixed-mode surveys. The Tailored Design Method. Hoboken, NJ: John Wiley & Sons; 2009. 22. Streiner DL, Norman GR. Health Measurement Scales. A Practical Guide to Their Development and Use. 4th ed., Oxford: Oxford University Press; 2008. 23. McHorney CA, Ware Jr. JE, Raczek AE. The MOS 36-item Short-Form health survey (SF36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993;31:247–263. 24. de Bruin AF, Diederiks JP, de Witte LP, Stevens FC, Philipsen H. Assessing the responsiveness of a functional status measure: the Sickness Impact Profile versus the SIP68. J Clin Epidemiol. 1997;50:529–540. 25. Beaton DE, Bombardier C, Katz JN, Wright JG. A taxonomy for responsiveness. J Clin Epidemiol. 2001;54:1204–1217. 26. Greenhalgh J, Long AF, Brettle AJ, Grant MJ. Reviewing and selecting outcome measures for use in routine practice. J Eval Clin Pract. 1998;4:339–350. 27. DeVellis RF. A consumer’s guide to finding, evaluating, and reporting on measurement instruments. Arthritis Care Res. 1996;9:239–245. 28. Mokkink LB, Terwee CB, Patrick DL, Alonso J, Stratford PW, Knol DL, et al. The cosmin checklist for assessing the methodological quality of studies on measurement properties of health status measurement instruments: an international Delphi study. Qual Life Res. 2010;19:539–549. 29. Valderas JM, Ferrer M, Mendivil J, Garin O, Rajmil L, Herdman M, et al. Development of EMPRO: a tool for the standardized assessment of patient-reported outcome measures. Value Health. 2008;11:700–708. 30. Terwee CB, Mokkink LB, Knol DL, Ostelo RW, Bouter LM, de Vet HC. Rating the methodological quality in systematic reviews of studies on measurement properties: a scoring system for the COSMIN checklist. Qual Life Res. 2012;21:651–657. 31. Weir JP. Quantifying test–retest reliability using the intraclass correlation coefficient and the SEM. J Strength Cond Res. 2005;19:231–240. 32. Feinstein AR. Clinical Epidemiology: The Architecture of Clinical Research. Philadelphia: W. B. Saunders Company; 1985. 33. Engel L, Beaton DE, Touma Z. Minimal clinically important difference: a review of outcome measure score interpretation. Rheum Dis Clin North Am. 2018;44:177–188. 34. Tubach F, Ravaud P, Beaton D, Boers M, Bombardier C, Felson DT, et al. Minimal clinically important improvement and patient acceptable symptom state for subjective outcome measures in rheumatic disorders. J Rheumatol. 2007;34:1188–1193. 35. Hunt SM, McKenna SP, McEwen J, Backett EM, Williams J, Papp E. A quantitative approach to perceived health status: a validation study. J Epidemiol Community Health. 1980;34:281–286. 36. EuroQol Group EuroQol—a new facility for the measurement of health-related quality of life. Health Policy. 1990;16:199–208. 37. US Department of Health and Human Services Food and Drug Administration. Guidance for Industry. Patient-reported outcome measures: Use in medical product development to support labeling claims. Silver Springs, MD; 2009 Contract No: Document Number FDA-2006-D-0362. 38. Maxwell LJ, Beaton DE, Shea BJ, Wells GA, Boers M, Grosskleg S, et al. Core domain set selection according to omeract filter 2.1: The OMERACT methodology. J Rheumatol. 2019;46:1014–1020.

Principles of health economics John B. Wong

Key Points n Economic analyses in medicine include cost, cost–benefit, cost-effectiveness, and cost–utility analysis. n The most commonly used method in health care is cost–utility analysis, often for health technology assessment to determine the most efficient use of resources. n Beyond cost-effective use of resources, however, equity issues and budget impact analyses affect policymaker decisions. n Economic analyses can inform comparative effectiveness and cost-effective care and can promote evidence-based effective and efficient care, such as in the management of patients with rheumatoid arthritis.

INTRODUCTION What does economic evaluation have to offer rheumatology? With the growth in biologic drugs, medical devices, tests, and imaging modalities, diagnostic and treatment options have greatly expanded, so health care costs have risen substantially worldwide. Increasingly, payers and policymakers seek to examine the appropriateness of care; some patients must grapple with out-of-pocket costs and taxes for health care, and clinicians may confront access restrictions and performance measures. Thus, besides efficacy as determined by randomized controlled trials (RCTs) and effectiveness as assessed in real-world experiences, clinicians increasingly should become cognizant about efficient use of health care resources. The Global Burden of Disease Study found that musculoskeletal disorders affect 1.3 billion individuals worldwide, incurring 138 million years lived with disability and substantial and increasing health expenditures in many high- and middle-income countries.1 Simply considering disease costs, however, does not provide a measure of the value of an intervention; that is, whether the intervention’s benefit justifies its cost. Driven in part by advances in health care technology, such as biologic treatments for rheumatoid arthritis (RA),2 medical care costs account for a growing proportion of every country’s gross domestic product (GDP). Besides the budget impact, economists consider the opportunity costs of these expenditures; that is, would society have accrued greater benefit from spending some of those health care dollars instead on education, social welfare, environment, defense, or an alternative societal investment?3 Similarly, what is the societal return on investment for health care budget spent on specific diseases (e.g., rheumatic disorders) vs other conditions? Health economic analyses seek to determine the optimal use of societal resources by assessing the value obtained from alternative uses for those resources and prioritizing the uses for those resources.4 This chapter discusses the basic concepts of economic analysis including cost-effectiveness analysis for health technology assessment, followed by applications of these principles in rheumatology.

CONCEPTS OF HEALTH ECONOMIC ANALYSIS TYPES OF COSTS Costs are usefully divided into three main types, which are described in Box 25.1.

PERSPECTIVES Economic analyses may be done from a variety of perspectives (listed in Table 25.1), which then affects the types of costs considered.5,7,8

TYPES OF ECONOMIC ANALYSES Cost analysis Cost analysis (e.g., cost minimization, cost identification, cost consequence, or cost burden) measures the economics of a disease or treatment.7 Typical costs include direct medical and health care costs, costs associated

25

with adverse effects, savings from prevention or alleviation of disease, and possibly costs of additional disease from prolonged life expectancy. These costs may vary depending on the analytic perspective and time horizon.4 In comparative cost analysis (cost minimization), alternative strategies are demonstrated or assumed to yield equivalent health outcomes, so this kind of analysis identifies the optimal strategy by determining the “cheapest.” Because alternative health interventions rarely have the same effectiveness, cost minimization analysis is an uncommon and rarely appropriate comparative health economic analysis.7 To demonstrate significance, cost burden analyses assess the future economic and health burden of diseases such as osteoporosis and RA.9,10

Cost–benefit analysis In cost–benefit analysis, all costs and health benefit outcomes are expressed in terms of a single monetary attribute; for example, dollars.7 Costs are determined as with cost minimization, but health benefits are translated into a monetary amount. Thus, cost–benefit analysis provides a measure of absolute economic cost and absolute economic benefit. The net present value is economic benefit minus the economic cost. If the net present value is positive, then savings from benefits exceed the cost of expenditures, so policymakers could simply pick the strategies with the highest net present value when choosing which programs to fund. Although many applied economists view cost–benefit analysis as the gold standard,11 it is not as well accepted in health care because of difficulties associated with placing a monetary value on health benefits (e.g., a human life).7,8

Cost-effectiveness analysis Instead of placing a monetary value on human life, cost-effectiveness analysis (especially a subset called cost–utility analysis) has become the most prevalent form of economic analysis in health care. Costs continue to be expressed in the same unit, but benefits are expressed as a meaningful clinical outcome (e.g., satisfaction of the American College of Rheumatology 20% improvement criteria [ACR20]).7 In cost-effectiveness analysis, an intervention is compared with standard care by dividing the intervention cost by its effectiveness to yield the average cost-effectiveness ratio.7,8 However, for technology assessment, the average cost-effectiveness ratio can be misleading, so the preferred outcome measure is the incremental cost-effectiveness ratio (ICER) comparing two (or more) alternative strategies (Fig. 25.1).5,7,8 It divides the additional cost of the new intervention by its additional clinically meaningful benefit, which results in one of four possible outcomes (see Fig. 25.1): (1) higher costs and lower effectiveness when the new strategy is inferior or dominated, (2) lower costs and higher effectiveness when the new strategy is dominant or cost saving, (3) lower costs and lower effectiveness (rare), or (4) higher costs and higher effectiveness. For the last two situations, an ICER can be calculated; for example, the incremental cost to obtain one more ACR20 response. Policymakers should not adopt new strategies that are dominated but should adopt those that are cost saving. Typically, however, a more effective option usually costs more, so to choose more effective but also costly strategies, policymakers could choose to fund interventions that fall below an acceptable threshold called the societal willingness to pay; that is, interventions that supply sufficient value for which the benefit is judged to be worth the additional cost; for example, an ICER of $1 to achieve an additional ACR20 response may be acceptable, but $1 million for that additional ACR20 may not be.

Cost–utility analysis To avoid the difficulties associated with comparing alternative effectiveness measures—for example, cost to achieve an ACR20 response vs cost to avoid a myocardial infarction (MI)—cost–utility analysis uses a standardized effectiveness measure, namely, length and quality of life, expressed as quality-adjusted life-years (QALYs). In such a case, the incremental cost-effectiveness of coronary stenting for MI could be compared with that of biologic therapy for RA because both would be expressed as cost per 203

SECTION 2  Clinical Basis of Rheumatic Disease

204

BOX 25.1  TYPES OF HEALTH COSTS

INCREMENTAL COST-EFFECTIVENESS RATIOS FOR INTERVENTIONS

Formal health care sector costs include the following: resources paid for by third-party payers or by patients out of pocket required for an intervention or consequences of this intervention to provide care such as hospitalizations, procedures, surgeries, outpatient office visits, rehabilitative and nursing home care, care by physicians and allied health professionals, medications, devices, equipment, supplies, tests, and home care.5 n Informal health care sector costs5 include the following: n Patient time for the time spent seeking or participating in care; for example, travel and waiting time and receiving treatment n Unpaid caregiver time for informal caregiver time during treatment and in the future n Transportation costs including nonmedical services for travel and lodging. n Non-health care sector cost include productivity costs (formerly called indirect costs) refer to loss of employment due to morbidity (disability, absenteeism, reduced productivity while working) or mortality (reduction in life expectancy) that conversely could be improved through a health intervention.5 For example, the families of children with juvenile rheumatoid arthritis spent 5% of their income on out-of-pocket medical and nonmedical costs and lost salary.6 Table 25.1 lists other cost sectors. These costs should only be considered from the societal perspective and are particularly relevant for health interventions that promote public health when benefits can fall outside of the health care sector; for example, alcohol and substance use treatments and the criminal justice system.5 Table 25.1

Perspectives of Health Costs Perspective

Includes

Health care

All formal health care sector costs including medical services paid for by third-party payers and those paid for by patients out of pocket All formal health care sector, informal health care sector (patient time, unpaid caregiver time, transportation costs), and nonhealthcare sectors (productivity, consumption, social services, legal or criminal justice, education, housing, environment, other [e.g., friction costs])

Societal

INCREMENTAL COST-EFFECTIVENESS RATIO Cost with new - Cost with usual Life expectancy with new - Life expectancy with usual

Dominated

Incremental costs

↑ Costs ↓ Effectiveness

Cost-effectiveness ratio

↑ Costs ↑ Effectiveness Incremental effectiveness

↓ Costs ↓ Effectiveness

↓ Costs ↑ Effectiveness Cost saving

FIG. 25.1  The incremental cost-effectiveness ratio (ICER) describes the additional cost and the additional benefit obtained from a new intervention compared with standard of care. When the net cost and net benefit are considered, the new intervention may cost more or less and may yield more benefit or less, thereby yielding differences that fall into one of four quadrants. Dividing the net cost by the net benefit yields the cost to achieve one additional benefit (the ICER).

QALY gained (the cost to increase life expectancy by 1 QALY). Approving or funding interventions that are cost saving or those that have the lowest ICER would provide society with the greatest benefit for a fixed health care budget. A league table of ICERs illustrates how a policymaker might use such information to determine value and funding priorities (Fig. 25.2).12–16 If payers had $1 million to spend, allocating that amount to colon cancer screening would yield 66 QALYs ($1 million ÷ $15,100 per QALY gained) for the population as opposed to fewer than 3 QALYs ($1 million ÷ $331,000 per QALY gained) with digital mammography for all women (see Fig. 25.2).12,15

Cost per life-year gained

n

$350,000 $300,000 $250,000 $200,000 $150,000 $100,000 $50,000 $0

Colon CA screen

Generic ART

Intense Rx Hemodialysis Digital diabetes mammography

FIG. 25.2 Published incremental cost-effectiveness ratios (ICERs). The graph displays published incremental cost-effectiveness ratios for five interventions: colon cancer (CA) screening with colonoscopy, generic antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection, intense treatment (Rx) for diabetes mellitus, hemodialysis for end-stage renal disease, and digital mammography screening for breast cancer. Lower ICERs indicate more efficient use of resources (i.e., more “bang for the buck”).

BOX 25.2  KEY MESSAGE The incremental cost per quality-adjusted life-year gained can be considered to be equivalent to the present cost (in current year or year in which the analysis was performed) to increase life expectancy by 1 year of perfect health in that same analysis year.

QUALITY OF LIFE Of particular relevance in rheumatology, patients, clinicians, and policymakers increasingly recognize the importance of quality of life to account for disease morbidity, beyond simply length of life. Quality of life is typically scaled from 1 for perfect health to 0 for death, so individuals with morbidity receive only partial credit for each year that they are alive.5,7,8 For instance, if the quality-of-life adjustment factor is 0.4 for severe disability, patients with severe disability who live for 10 years receive credit for living 4 quality-adjusted years. A treatment that entirely prevents this severe disability potentially increases QALYs by 6 years. In contrast to interventions that reduce mortality and add “years to life,” interventions that prevent disability or restore quality of life provide economic value by adding “life to years.” Thus, in cost–utility analysis, the outcome measure represents the incremental cost to increase life expectancy by 1 “QALY gained,” which is equivalent to increasing life expectancy by 1 year of perfect health.

TIME HORIZON AND DISCOUNTING The time horizon for the economic analysis refers to the time period under consideration, which may range from short (e.g., during hospitalization) to lifelong or lifetime (or in between) depending on the perspective. When longer time horizons are examined, present costs are typically more valuable than future ones, not simply because of inflation but also because present expenditures could alternatively be invested productively to yield a larger future amount.5,7,8 For example, given a choice between being given $100 now or $100 a year from now, most individuals would prefer to receive that money now. Hence, the $100 a year from now is worth less today (i.e., has a lower present value). How much less depends on the annual discount rate, which varies by country. In the United Kingdom, the rate is 3.5%, and in the United States, it is 3%,5,8 so US$100 a year from now has a present-day worth of US$96.62 in the United Kingdom and US$97.09 in the United States. Reflecting the higher present value of money, discounting is consistent with health care policies seeking to minimize current fiscal year health budgets and is particularly relevant for preventive treatments because treatment occurs now and disease complications occur in the future. For example, the cost of biologic therapies for patients with RA occurs now, but disability or expensive joint replacement costs occur in the future. With a 3% annual discount rate, spending $20,000 this year would be comparable to spending only $14,882 in 10 years, or spending $30,000 in 10 years equals $40,317 now. Because costs are discounted, health benefits are also discounted, so future health benefits are valued less than current benefits accruing now (Box 25.2).

CHAPTER 25  Principles of health economics

REFERENCE CASE To reduce methodologic variability in economic evaluations, in 1996 the U.S. Panel on Cost-Effectiveness Analysis in Health and Medicine (updated in 2017) established a reference case set of minimum standards that included the societal perspective, reasonably long time horizons, ICERs, QALYs, discounting, and sensitivity analyses to assess the robustness of the results.5 Within rheumatology, the Outcome Measures in Rheumatology Clinical Trials (OMERACT) group has additional methodologic guidance.17–20

HEALTH TECHNOLOGY ASSESSMENT Over the past 30 years, health technology assessment (Fig. 25.3) to inform health policy and clinical decision making has grown worldwide as a multidisciplinary systematic approach to assess and to inform health policy and clinical decision making concerning the introduction of, access to, and diffusion of innovative health technologies, including medications, devices, diagnostics, and treatments. As one example, the United Kingdom’s National Institute for Health and Care Excellence (NICE) technology appraisal guidance evaluates new and existing medicines and treatments based on a review of clinical and economic evidence. The evaluation of clinical evidence assesses how well the drug works, and the evaluation of the economic evidence determines how well the drug works relative to its costs; that is, whether the drug provides sufficient value. NICE recognizes an evidence hierarchy with a preference for direct headto-head RCT efficacy studies and indirect comparisons as a second choice. However, because NICE also appreciates the limitations of such efficacy studies—namely, selected populations, short time spans, and limited comparators—it supplements efficacy studies with good-quality observational or effectiveness studies. The economic evidence considers a societal perspective and usually a lifetime time horizon to account for future benefits and economic savings or expense. Because randomized trials have limited follow-up, achieving the lifetime time horizon involves computer simulation modeling of the relevant disease and treatments, including mortality (as life expectancy) and morbidity (as quality of life adjustments) as might occur from the disease or treatment plus that occurring in a matched general population.

DECISION ANALYSIS MODELING Despite rigorous systematic reviews of efficacy and effectiveness of health care interventions, patients, clinicians, and policymakers may remain in doubt about what they should do because of uncertainty, trade-offs, and values. First, residual uncertainty may remain regarding meaningful patient-relevant outcomes because of (1) reliance on surrogate outcome measures, (2) limited follow-up time, (3) subgroup analyses with an inadequate sample, or (4) restrictive inclusion and exclusion criteria in the RCTs. Second, treatment decisions often involve trade-offs. Treatment benefits may

occur, but harms may also ensue. Thus, optimal decision making for individuals may depend not only on their risk factors but also on their values (or preferences) regarding the outcomes, and those values and preferences may vary widely in a population. Decision and cost-effectiveness analyses typically invoke a prescriptive, normative approach to decision making in the face of uncertainty by explicitly structuring decisions into (1) choices (alternative treatment strategies), (2) chances (the likelihood of outcomes resulting from the choices), and (3) consequences (valuation of the outcomes in terms of mortality, morbidity, and costs). The decision models then calculate the costs and utility of each treatment and the difference between the alternatives as an extension (or decline) in life expectancy or quality (morbidity)-adjusted life expectancy and an increase or decrease in costs. The most commonly used computer models are health state transition (Markov or Monte Carlo) simulations, in which a predefined and mutually exclusive set of health states represents the natural history of disease.10,21 The patient cohort starts the simulation in a health state such as well or a set of health states (e.g., some well and others sick). Time is divided into ticks of the clock represented by Markov cycles of a specified duration (e.g., 1 year). Over time, patients move among these health states; some may die, some may become sick, and some may maintain their same state of health. The simulation continues until all patients in the cohort die or until a fixed time has elapsed. By tracking survival, quality of life, and costs for each cohort member, the Markov model estimates life expectancy, quality-adjusted life expectancy (QALE), and lifetime costs. By accounting for the time elapsed, these disease models can discount both costs and QALE. In such models, innovative treatments may provide value by prolonging life (e.g., decreasing the risk of dying from illness), by decreasing the likelihood of becoming sick (e.g., preventing morbidity) or increasing function as preserved or improved quality of life, and by lowering disease costs through avoidance or delay of expensive disease complications (e.g., surgery). As an alternative approach, discrete event simulation models capture the occurrence of a health event (e.g., death, worsening or improving health) in entities such as patients.22 These events may occur at any time point (i.e., “discrete”) but not at predetermined jumps in time. Arising from industrial engineering, these types of models are useful for examining complex systems involving interactions among individuals, populations, and their environments; for example, with limited resources such as donor organs that result in waiting queues. Health care applications have included modeling biologic processes, redesigning health care delivery, allocating donor organs based on geography, designing clinical trials, and evaluating health policy.

COST-EFFECTIVENESS THRESHOLDS How much one is willing to pay for something depends in part on one’s financial situation. Similarly, for health care policymakers, what is considered to provide value and be “cost-effective” depends in part on each country’s economy and its willingness to pay for that benefit; that is, its HEALTH TECHNOLOGY ASSESSMENT

Perspectives: Health care Societal

FIG. 25.3 The boxes on the left represent sources of data and information regarding health interventions and the natural history of a disease to assess the chances of disease incidence and progression and testing or treatment benefit and harm coupled with health outcomes, length of life, costs, and quality of life. For each strategy, the likelihoods of the resulting outcomes (probabilities) are then coupled with the value of the outcomes to determine the costs and effectiveness, which leads to a decision and action that form health policy and patient care choices. The boxes at the top represent potential perspectives for the analysis and the four main types of economic analyses that can also inform the decision and action.

Randomized controlled trials Observational studies Predictive models Clinical outcomes Life expectancy Quality-of-life preferences Costs

205

Cost analysis Cost benefit Cost effectiveness Cost utility

Structure of the problem Decision tree Likelihood of outcomes Probabilities Values of the outcomes Utilities Costs Process Evaluating the decision tree

Decision and action

Policy guidelines Patient care choices

206

SECTION 2  Clinical Basis of Rheumatic Disease

Table 25.2

Table 25.3

World Health Organization Cost-Effectiveness Thresholds Based on Per Capita Gross Domestic Producta

Incremental Cost-Effectiveness of Eight Alternative Treatment Strategies for Severe Rheumatoid Arthritis After Failing Conventional DiseaseModifying Antirheumatic Drugs

Region AFRO (Africa) AMRO (Americas) EMRO (Eastern Mediterranean) EURO (Europe) SEARO (Southeast Asia) WPRO (Western Pacific)

Subregions—Patterns of Child and Adult Example Country Mortalityb Within Region

2005 CostEffectiveness Threshold (US$)

D, E A, B, D B, D

South Africa (E) United States (A) Saudi Arabia (B)

6500 120,000 31,000

A, B, C B, D

United Kingdom (A) Thailand (B)

91,000 15,000

A, B

China (B)

21,000

Strategy

The threshold for high cost-effectiveness equals the cost-effectiveness threshold divided by 3; for example, $40,000 for the United States and $30,000 for the United Kingdom. b Each region is divided into subregions based on patterns of child and adult mortality in groups ranging from A (lowest) to E (highest). Data from World Health Organization. Table: threshold values for intervention cost-effectiveness by region, 2005. http://www.who.int/choice/costs/CER_levels/en/index.html. a

cost-effectiveness threshold. In 2005, authors writing on behalf of the World Health Organization (WHO) suggested that this threshold could be based on the “average per capita income for a given country or region,”23 wherein an intervention is “cost-effective” if the incremental cost-effectiveness ratio (expressed as disability-adjusted life years gained) falls below three times a country’s per capita income or GDP per capita. An intervention is “highly cost-effective” if the ratio falls below that country’s per capita income. The World Bank has published GDP per capita in current U.S. dollars for countries, for regions, and by income (Table 25.2).24 For comparison, although some recommend a $300,000 threshold in the United States,25 the most frequently cited cost-effectiveness threshold is $100,000 per QALY gained, which is similar to the per capita GDP threshold of $62,800 for “high cost-effectiveness.” In the United Kingdom, NICE methods guidance suggests a threshold of £20,000 to £30,00026 (about €25,000 to €38,000 or US$28,000 to US$42,000) per QALY, similar to US$42,900 GDP per capita. As in the United States, some recommend raising the threshold to £70,000 ($110,000),27 yet others suggest lowering it.28 Raising the willingness-to-pay threshold not only expands the number of treatments that become “cost-effective” but also has implications for the benefit per expenditure. For instance, spending $100,000 on strategies with an ICER of $100,000 per QALY gained would buy 1 year, but spending it on those with an ICER of $50,000 per QALY gained would yield 2 years. In particular, policymakers should consider whether these last few dollars spent “at the margin” on health care treatments with higher ICERs would yield greater societal benefit if spent elsewhere.

BUDGETS Allocating resources strictly based on cost-effectiveness does not account for yearly budgets because these cost-effectiveness analyses usually consider a lifetime time horizon, including future cost savings from disease prevention or reduction in morbidity or mortality. For maximally efficient resource allocation, policymakers would establish their health care budget for the fiscal year and then treatments would be funded going in order from cost-saving ones to those with the lowest ICER up to those with the highest ICER while accounting for their budget impact of intervention costs, disease prevalence, treatment eligibility, and available health delivery infrastructure in the upcoming year until the next year’s budget is entirely expended. In this case, the societal willingness-to-pay threshold would be the funded intervention that had the highest ICER. However, policymakers may also consider other attributes such as equity or fairness and the distribution of benefits to some and not others; for example, to incentivize treatments for rare conditions.8

ECONOMIC APPLICATIONS IN RHEUMATIC DISEASES RHEUMATOID ARTHRITIS As an example of applications of these economic principles, NICE used the health technology assessment approach outlined to perform a systematic review and economic evaluation of biologic treatments (adalimumab,

Methotrexate (MTX) Tocilizumab + MTX Abatacept + MTX Infliximab + MTX Certolizumab pegol + MTX Adalimumab + MTX Golimumab + MTX Etanercept + MTX

Incremental CostEffectiveness Ratio Comparing Each Strategy vs Methotrexate (US$ Per Quality-Adjusted Life Expectancy Gained)

Incremental CostEffectiveness Ratio With the Cost-Effectiveness Frontier (US$ Per QualityAdjusted Life Expectancy Gained)

57,827 54,466 55,126 56,707 58,394 58,264 58,367

Extendedly dominateda 54,500 Dominateda Extendedly dominateda Dominateda Extendedly dominateda 102,400

See text for explanation.

a

etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab, and abatacept) for RA.29 For patients eligible for methotrexate (MTX) who failed conventional disease-modifying antirheumatic drugs (cDMARDs), the strategies considered consisted of sequences of treatment: (1) initial MTX followed by cDMARD; (2) initial biologic DMARD (bDMARD) with abatacept, adalimumab, etanercept, infliximab, certolizumab pegol, or golimumab + MTX followed by rituximab + MTX followed by tocilizumab + MTX followed by cDMARD; and (3) tocilizumab + MTX followed by rituximab + MTX followed by cDMARD. The underlying efficacy evidence consisted of 15 RCTs combined in a network metaanalysis to estimate the relative European League Against Rheumatism (good or moderate Disease Activity Score [DAS28]) and American College of Rheumatology (ACR20, ACR50, and ACR70) responses of these treatments. The RCTs also informed treatment-related serious adverse event rates. The British Society for Rheumatology Biologics Register (BSRBR) data informed Health Assessment Questionnaire (HAQ) disability score improvement (0.317 for moderate and 0.672 for good DAS28 responses) and subsequent HAQ trajectory. After treatment stoppage for adverse events or loss of efficacy, the initial HAQ improvement would be lost. Drug, monitoring, and disease costs were taken from national unit costs. The discrete event computer model simulated the prognosis and costs for MTX-experienced patients with DAS between 3.2 and 5.1 who were individually sampled from the BSRBR. An exact hypothetical clone of that patient was treated using each treatment strategy. Over the initial 6-month period, that patient could have a good or moderate European League Against Rheumatism (EULAR) response or no response. Initial favorable responses led to improved HAQ scores. The HAQ was then used to estimate a pain score, hospitalization costs, and disease-related excess mortality. The HAQ and the pain score together were used to estimate quality of life with the EuroQol five dimensions of health instrument (EQ-5D). HAQ trajectory after response for bDMARDs was assumed to be linear between time points and was based on BSRBR data and that for cDMARDs from the Early Rheumatoid Arthritis Study (ERAS) inception cohort. The duration of response for both treatments was estimated from BSRBR data. If response was lost or if a serious adverse event occurred, the patient would move on to the next treatment in that strategy’s treatment sequence. The analytic time horizon was lifetime. The model used the national health care and social services payer perspective with a 3.5% annual discount rate for both costs and benefits. The simulation continued for each patient until death. When the simulation for one patient was completed, a second hypothetical patient was then analyzed and so on. By tracking cost, quality of life, and length of life for each patient over time, the computer simulation calculated QALE and cumulative lifetime costs for each strategy for that patient and then summed results for all patients considered. Table 25.3 displays the ICER results for simulations of 20,000 patients with severe RA with cost converted into U.S. dollars (assuming $1.40 = £1). The ICER can be calculated for alternative comparators. To address the value of these interventions relative to the current standard of care, ICERs for all bDMARDs vs MTX ranged from $54,500 to $58,400 per QALY gained. Alternatively, the cost-effectiveness frontier method asks how all of the strategies might compare against one another. In this method, ICERs

CHAPTER 25  Principles of health economics

207

are calculated relative to the next cheapest nondominated strategy. A strategy is “dominated” or inferior to the cheaper one if it costs more and has a lower effectiveness. The dominated strategy is then eliminated, and the ICER for the next most expensive strategy is compared with the cheaper nondominated strategy. For nondominated strategies, the ICER may be higher for a less expensive strategy than for a more expensive one. In that case, the less expensive strategy is a less efficient use of resources, so it also should be eliminated because of “extended or weak dominance.” When analyzed with this cost-effectiveness frontier method, intravenous abatacept + MTX vs MTX has an ICER of $54,500 per QALY gained and etanercept + MTX has an ICER of $102,400 vs intravenous abatacept + MTX. All other strategies are eliminated. The independent Technology Appraisal Guidance reviewed these results and noted “small differences between the bDMARDs,” so instead of calculating the cost-effectiveness frontier, it focused on the median $58,200 ICER results that included rituximab in the sequence of bDMARDs and a sensitivity analysis that examined patients with the fastest HAQ progression (median, $35,400 ICER). Although the upper range of the ICER fell above the usually acceptable $42,000 willingness to pay range for NICE, the Technology Appraisal Guidance recognized the benefit of these innovative medications and concluded by recommending any of these medications in combination with MTX but only if the DAS28 exceeds 5.1 and if patients have tried a combination of cDMARDs, including MTX.30

to cost-effectiveness, the committee noted that the $29,700 median ICER for bDMARDs for severe active RA fell above the usual NICE thresholds of $14,300 to $21,400, but the committee felt that the most plausible ICER fell between $29,700 and the $18,100 ICER for patients with severe active RA and the fastest HAQ progression. The committee ultimately recommended bDMARDs + MTX for patients with severe RA (DAS28 > 5.1) and unresponsive to combination cDMARDs or bDMARD alone if MTX intolerant or if MTX is contraindicated.

MULTIPLE TECHNOLOGY ANALYSIS

1. Global Burden of Disease Study Collaborators, Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries in 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1211–1259. 2. Wong JB. Cost-effectiveness of anti-tumor necrosis factor agents. Clin Exp Rheumatol. 2004;22:S65–S70. 3. Fuchs VR. Health care expenditures reexamined. Ann Intern Med. 2005;143:76–78. 4. Weinstein MC, Stason WB. Foundations of cost-effectiveness analysis for health and medical practices. NEJM. 1977;296:716–721. 5. Neumann PJ, Saunders GD, Russell LB, et al. Cost-Effectiveness in Health and Medicine. 2nd ed New York: Oxford University Press; 2017. 6. Allaire SH, DeNardo BS, Szer IS, et al. The economic impacts of juvenile rheumatoid arthritis. J Rheumatol. 1992;19:952–955. 7. Drummond MF, Sculpher MJ, Torrance GW, et al. Methods for the Economic Evaluation of Health Care Programmes. 3rd ed. Oxford: Oxford University Press; 2005. 8. Hunink MGM, Weinstein MC, Wittenberg E, et al. Decision Making in Health and Medicine: Integrating Evidence and Values. Cambridge: Cambridge University Press; 2014. 9. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22:465–475. 10. Wong JB, Ramey DR, Singh G. Long-term morbidity, mortality, and economics of rheumatoid arthritis. Arthritis Rheum. 2001;44:2746–2749. 11. Meltzer MI. Introduction to health economics for physicians. Lancet. 2001;358:993–998. 12. Pignone M, Saha S, Hoerger T, et al. Cost-effectiveness analyses of colorectal cancer screening: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137:96–104. 13. Winkelmayer WC, Weinstein MC, Mittleman MA, et al. Health economic evaluations: the special case of end-stage renal disease treatment. Med Decis Making. 2002;22:417–430. 14. Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in the United States. N Engl J Med. 2008;359:821–832. 15. Tosteson AN, Stout NK, Fryback DG, et al. Cost-effectiveness of digital mammography breast cancer screening. Ann Intern Med. 2008;148:1–10. 16. Walensky RP, Sax PE, Nakamura YM, et al. Economic savings versus health losses: the cost-effectiveness of generic antiretroviral therapy in the United States. Ann Intern Med. 2013;158:84–92. 17. Gabriel S, Drummond M, Maetzel A, et al. OMERACT 6 Economics Working Group report: a proposal for a reference case for economic evaluation in rheumatoid arthritis. J Rheumatol. 2003;30:886–890. 18. Gabriel S, Drummond M, Suarez-Almazor ME, et al. OMERACT 5 Economics Working Group: summary, recommendations, and research agenda. J Rheumatol. 2001;28:670–673. 19. Gabriel S, Tugwell P, O’Brien B, et al. Report of the OMERACT task force on economic evaluation. Outcome Measures in Rheumatology. J Rheumatol. 1999;26:203–206. 20. Gabriel SE, Tugwell P, Drummond M. Progress towards an OMERACT-ILAR guideline for economic evaluations in rheumatology. Ann Rheum Dis. 2002;61:370–373. 21. Siebert U, Alagoz O, Bayoumi AM, et al. State-transition modeling: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force—3. Med Decis Making. 2012;32:690–700. 22. Karnon J, Stahl J, Brennan A, et al. Modeling using discrete event simulation: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force—4. Med Decis Making. 2012;32:701–711. 23. Bertram MY, Lauer JA, Joncheere KD, et al. Cost-effectiveness thresholds: pros and cons. Bull World Health Organ. 2016;94:925–930. 24. Table: GDP per capita (current US$). All Countries and Economies (Accessed 26 February 2020) at https://data.worldbank.org/indicator/NY.GDP.PCAP.CD. 25. Neumann PJ, Cohen JT, Weinstein MC. Updating cost-effectiveness—the curious resilience of the $50,000-per-QALY threshold. N Engl J Med. 2014;371:796–797. 26. Devlin N, Parkin D. Does NICE have a cost-effectiveness threshold and what other factors influence its decisions? A binary choice analysis. Health Econ. 2004;13:437–452. 27. Towse A. Should NICE’s threshold range for cost per QALY be raised? Yes. BMJ. 2009;338:b181.

In a 2021 multitechnology assessment for people with RA previously treated with MTX, the median ICERs for bDMARD + MTX were $29,700 for severe active disease and $36,500 for moderate active disease.31 Sensitivity analyses examining a wider evidence base, linear HAQ progression, alternative utility values, median probabilistic results ranged from $24,800 to $29,300 for severe disease and from $25,900 to $37,200. In additional analyses, for people with RA previously treated with MTX, the median ICERs for bDMARD rose to $34,500 for severe active disease and $42,000 for moderate active disease. For people with severe active RA not previously treated with MTX, the median ICERs for bDMARD + MTX rose to $48,800 and to $55,400 for bDMARD alone. If patients with the fastest HAQ progression could be identified, median ICERs would fall to $18,100 for bDMARD + MTX, $20,400 for severe active disease, and $20,700 for moderate active disease.

BIOSIMILAR DRUGS In a key therapeutic topic (not formal NICE guidance) retired in 2019, NICE defined a biosimilar medicine as “a biological medicine which is highly similar to another biological medicine already licensed for use … which has been shown not to have any clinically meaningful differences from the originator biological medicine in terms of quality, safety and efficacy.”32 The NICE position has been that biosimilars will be considered as part of a multiple technology appraisal, so the 2021 multitechnology assessment update included two biosimilar products designed to be similar to infliximab for patients with moderate RA failing cDMARDs only. These biosimilars have identical indications, contraindications, adverse reactions, and administration schedules but require additional monitoring currently. UK list prices for a year of therapy for a 70-kg person are $7193 and then $6294 per year for the originator version vs $6474 and then $5665 per year for biosimilar versions (a 12.5% savings), but negotiated discounted prices occur routinely, typically in confidence. The ICER for infliximab was reduced to $21,700 per QALY gained for the severe active subgroup and to $26,900 per QALY gained in the moderate active subgroup. The ICERs for patients with the fastest HAQ progression were $13,000 for severe active disease and $14,600 for moderate active disease.

RESOURCE IMPACT NICE also performed a budget impact analysis for moderate active RA following cDMARD failure.33 It estimated the number of people in England receiving a bDMARD (adalimumab, etanercept, or infliximab) or targeted disease-modifying antirheumatic drug (tsDMARD; e.g., filgotinib) based on the prevalence of RA, the proportion with moderate RA, the proportion not responding to two or more cDMARDs, and the proportion of those receiving a bDMARD or tsDMARD.

RECOMMENDATION The NICE Appraisal Committee considered the clinical and cost-effectiveness data including the consequences of RA and the value of the benefits of these treatments by people with RA and clinical experts.31 With regard

CONCLUSION Economic analyses in medicine include cost, cost–benefit, cost-effectiveness, and cost–utility analyses. The most commonly applied method in health care is cost–utility analysis, which is often used for health technology assessment to determine the most efficient use of resources. Beyond cost-effective use of resources, however, equity issues and budget impact analyses affect policymaker decisions. For clinical practice, these economic analyses not only inform cost-effective care, such as in assessing treatment strategies in RA, but also summarize evidence of harms and benefits of the options and thereby promote evidence-based effective and efficient care.

REFERENCES

208

SECTION 2  Clinical Basis of Rheumatic Disease

28. Claxton K, Martin S, Soares M, et al. Methods for the estimation of the National Institute for Health and Care Excellence cost-effectiveness threshold. Health Technol Assess. 2015;19(14):1–503. v–vi. 29. Stevenson M, Archer R, Tosh J, et al. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation. Health Technol Assess. 2016;20(35):1–610. 30. National Institute for Health and Care Excellence, Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed (Accessed 11 July 2016, 2016, at www.nice.org.uk/guidance/ta375.)

31.

National Institute for Health and Care Excellence, Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for moderate rheumatoid arthritis after conventional DMARDs only have failed (Accessed 19 Sept 2021 at www.nice.org.uk/ guidance/ta715.) 32. National Institute for Health and Care Excellence, Biosimilar medicines. Key ther apeutic topic (Accessed 19 Sept 2021 at www.nice.org.uk/advice/ktt15/resources/ biosimilar-medicines-pdf-58757954414533.) 3. National Institute for Health and Care Excellence, Resource impact report: adalimumab, 3 etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for moderate rheumatoid arthritis after conventional DMARDs only have failed (partial review of TA375) (TA715). (Accessed 19 Sept 2021 at www.nice.org.uk/guidance/ta715/resources/ research-impact-report-pdf-9194461597.)

Principles of genetic epidemiology Gisela Orozco • Stephen Eyre

Key Points n The majority of rheumatic conditions have a complex etiology in which multiple genetic and environmental effects interact to cause disease. n For most rheumatic diseases, the major susceptibility locus resides in the human leukocyte antigen region with class II or class I alleles, suggesting an immunemediated component to these conditions. n Genome-wide association studies using hundreds of thousands of single-nucleotide polymorphisms genotyped in large samples of cases and controls have successfully identified large numbers of susceptibility loci for the rheumatic diseases. n Identification of genetic factors for rheumatic disease etiopathogenesis is likely to assist in risk prediction, early diagnosis and intervention, differential diagnosis and resolution of clinical heterogeneity, variation in treatment response, and discovery of novel drug targets.

INTRODUCTION A genetic basis for the majority of rheumatic conditions is now established, and for a small number of these diseases the genetic contribution is clear and can be attributed to a disease-causing mutation in a single gene. Examples of such monogenic disorders include some cases of multiple epiphyseal dysplasia and periodic fevers. For single-gene disorders the penetrance of the disease-causing allele may not always be complete (i.e., the presence of a mutation may not result in the full disease phenotype), although the conditions are inherited in a strict Mendelian fashion in either a dominant or a recessive way. In contrast, the more common rheumatic diseases are not inherited as a simple Mendelian trait but are the cumulative result of multiple genetic and environmental effects. The challenge of identifying risk factors for these complex diseases is significantly greater; however, in the past decade, significant advances in the characterization of variation across the genome and the development of high-throughput, accurate, and affordable technologies for single-nucleotide polymorphism (SNP) genotyping have resulted in major advances in the identification of genetic loci for complex diseases. The focus of this chapter is to describe the current approaches used to identify susceptibility loci for complex diseases and, in particular, to illustrate how, since the introduction of SNP-based whole-genome association studies in 2007, using rheumatoid arthritis (RA) as an example, knowledge of complex disease risk loci has increased exponentially. The genetics of a number of monogenic musculoskeletal disorders and of the complex diseases of RA, ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and osteoarthritis (OA) are described in separate chapters.

COMPLEX RHEUMATIC DISEASES A large number of rheumatic conditions, including RA, juvenile idiopathic arthritis (JIA), SLE, OA, osteoporosis, and AS, are now considered to represent complex disease phenotypes. Twin studies have proved to be useful in confirming the existence of a genetic component to susceptibility and in estimating the relative contributions of both genetic and environmental effects. Monozygotic twins are genetically identical, sharing 100% of their DNA. If a disease is caused solely by genetic factors, it would be expected that when one twin develops the condition, the co-twin should also be affected. The proportion of monozygotic twins in which both are affected is referred to as the level of disease concordance. Crude monozygotic twin disease concordance figures reflect approximately the relative contribution of genetic factors and environmental or stochastic events. These estimates can be further refined by comparing concordance rates in monozygotic twins with those observed in dizygotic (nonidentical) twins, who only have, on average, 50% of their genes in common. Because both monozygotic and dizygotic twins usually share early environmental exposures, monozygotic and dizygotic disease concordance figures can be modeled to more accurately measure disease heritability. Monozygotic and dizygotic twin concordance figures for a number of rheumatic conditions are summarized in Table 26.1.1–10

26

Many twin studies have been based on relatively small data sets or have suffered from sampling bias and should be interpreted with caution. For RA, estimates of monozygotic twin disease concordance range from 12% to 34%. Analysis of heritability of RA suggests that up to 60% of disease etiology is likely to be explained by genetic factors.11 An alternative strategy for assessing increased familial risk is to compare the levels of disease risk for close blood relatives of probands (affected cases) with that seen in the open population. One measure used is that of the familial disease recurrence risk; for RA, this has been calculated as being between 2 and 10.12 Thus, first-degree relatives of patients with RA are 2 to 10 times more likely to develop the disease than individuals without an RA-affected relative. This approach has been further modified to take into account how rare or common a disease is in the population. The coefficient of familial clustering (λ) was defined by Risch13 as a measure of how much genetic or shared environment component is involved in the etiology of a disease. This is calculated by dividing the sibling recurrence risk by the population prevalence. Depending on which published figures for RA sibling risk and prevalence are used, the λ for RA has been estimated to be between 2 and 10.14 The λs values for a range of rheumatologic and autoimmune conditions are summarized in Table 26.2.14–20

RATIONALE FOR INVESTIGATING THE GENETIC BASIS OF RHEUMATIC DISEASES An understanding of the risk factors for disease has the potential to impact on medicine and patient care at a number of points. Knowledge of genetic susceptibility factors could be used to identify individuals in whom modification of lifestyle might be advised to minimize exposure to environmental triggers of disease. Although in diseases with a low population prevalence, such as RA, it is difficult to identify a cohort of patients who would go on to develop disease, it has been shown that informing genetically high-risk groups of healthy individuals of their risk can help to modify lifestyle, reducing their risk of disease.21 Identifying potential cases before the onset of symptoms or at the very earliest stages of the disease process may identify a window of opportunity in which therapeutic interventions might be used to prevent development of the full-blown disease. These possibilities may be futuristic; more immediately achievable targets include the identification of novel targets for therapies. This has already been illustrated in RA, in which a large genetic analysis in European and Asian cohorts demonstrated how disease risk genes are targets for existing therapies; for example, for blood cancers, including leukemia and Hodgkin lymphoma.22 In addition, a number of biologic therapies that are successfully used in the treatment of rheumatic disease target pathways implicated through genetic studies, such as tofacitinib (Jak/Stat), tocilizumab (interleukin-6R [IL-6R]), and abatacept (cytotoxic T lymphocyte–associated protein 4 [CTLA4]), providing a proof of principle as to the utility of genetics in drug discovery. Indeed, a study indicated that pharmaceutical targets with supporting genetic evidence are twice as likely to provide a successful therapeutic.23 Rheumatoid arthritis is an example of a disease showing considerable heterogeneity in terms of clinical presentation and disease course, making it challenging for clinicians to identify patients who should be targeted for most aggressive therapies and those in whom the condition may relapse with little or no intervention. Evidence suggests that this heterogeneity is at least partly genetically determined24,25 and thus the identification of genetic markers to predict outcome would have significant clinical utility. Response to therapies also is likely to be genetically determined, and the identification of markers to predict likely treatment response or identify those at risk of adverse events would have major advantages in improving targeting of expensive therapies. Being able to achieve any or all of the above will have significant impact on the diagnosis and treatment of patients and will lead to a more personalized approach to disease.

209

210

SECTION 2  Clinical Basis of Rheumatic Disease

Table 26.1

Twin Concordance Rates Condition

Monozygotic Concordance (%)

Dizygotic Concordance (%)

Rheumatoid arthritis

34

4.9

32 12.3 21

6.0 3.5 0

Systemic lupus erythematosus

15.4 57 24 25

3.6 0 3 0

Ankylosing spondylitis

50 75

15 13

Reference Harvarld and Hauge1 Lawrence2 Aho et al.3 Bellamy et al.4 Silman et al.5 Block et al.6 Deapen et al.7 Grennan et al.8 Jarvinen9 Brown et al.10

Table 26.2

Sibling Recurrence Risks Condition Rheumatoid arthritis Systemic lupus erythematosus Ankylosing spondylitis Behçet disease Juvenile idiopathic arthritis Systemic sclerosis Paget disease

λs

5–10 20 46 11.4–52.5 15 11–158 14

Reference Ollier and Worthington14 Vyse et al.15 Brown et al.16 Gul et al.17 Glass and Giannini18 Englert et al.19 Ralston20

λ, Coefficient of familial clustering.

APPROACHES FOR IDENTIFYING DISEASE GENES Historically, two different scientific strategies have been used to search for genetic variants that determine susceptibility to disease: linkage and association studies. Traditional parametric linkage analysis, used with great success to identify loci determining monogenic diseases, relies on the use of multicase extended pedigrees, of the type rarely available for complex rheumatic diseases. In contrast, nonparametric linkage analysis carried out on smaller “affected sibling pair” pedigrees has been widely used to search for complex disease genes. These studies depend on the analysis of hundreds of highly informative genetic markers (usually microsatellites) mapping at regular intervals of the whole genome in large numbers of families. The markers are used to identify regions of the genome shared “identical by descent” by the affected sibling pairs more frequently than expected by chance that are therefore likely to contain disease genes. Before the advent of genome-wide association studies (GWASs), linkage studies offered the only method for screening the whole genome in a hypothesis-free approach.26 The success of linkage studies in identifying risk loci for complex diseases was limited, and based on current understanding of typical effect sizes, this is because the majority were underpowered. In contrast, association studies are based on the comparison of polymorphic markers in cohorts of cases and control participants, with a difference in allele or genotype frequency providing evidence that the polymorphism, or one in linkage disequilibrium with it, is associated with disease. The vast majority of association studies before GWASs were candidate gene investigations based on a limited number of polymorphisms. Sequencing of the human genome and the subsequent exponential increase in the identification and characterization of millions of polymorphic markers were vital to the development of association studies that screened the whole genome. Also critical was the development of technologies for rapid and accurate genotyping of SNP markers in large numbers of samples. In the past few years, GWASs and targeted association studies have superseded whole-genome linkage in the study of complex disease genetics, so discussion here is limited to those approaches.

ASSOCIATION STUDIES The principle of association studies is simple and is based on the assumption that the marker under investigation is either causally related to disease or

strongly correlated with the causal variant (i.e., in linkage disequilibrium). A difference in the allele or genotype frequency between groups of cases and control participants provides evidence of disease association of the variant under investigation. Before 2007, disease association studies targeted candidate genes or were the approach used to fine-map linkage peaks. The advent of technologies facilitating accurate, high-throughput genotyping of hundreds of thousands of SNPs has heralded the era of GWASs in which association studies screening the genome in a hypothesis-free manner are carried out using 0.5 to 1 million SNPs and large numbers of cases and control participants. Providing basic epidemiologic principles (discussed later) are followed, both candidate gene and GWASs are robust approaches and the key methods by which new susceptibility loci will be identified and characterized.

Selection of cases and control participants Perhaps the most common reason given for false-positive associations is population stratification. This arises when the population studied contains subpopulations that differ both in allele frequency and in the prevalence of the disease under study. Allele frequency differences among ethnic groups are well documented, and most studies endeavor to take cases and control participants from the same ethnic group. Methods to test for and correct for population stratification have been available for some time,27 and the availability of large amounts of sequence data from increasing numbers of ethnically diverse populations means robust reference panels can be used, making the identification of even subtle population substructure now readily achievable. GWASs have a built-in opportunity to adjust for population-based differences of cases and control participants, and the utility of three different approaches for these large data sets—(1) structured association tests, (2) principal component analyses, and (3) linear mixed modeling—has been demonstrated. The availability of such methods brings an additional advantage to GWASs in that it becomes possible to use large common population controls for studies in different diseases and different populations, resulting in significant cost savings.28 Additionally, due to the differences in genetic substructure observed between different ethnicities, GWAS in affected individuals from different ethnic backgrounds has the potential to better pinpoint the causal variants and fine-map the associated signals.22 A further consideration when sampling subjects for association studies is whether the cases are truly representative of the disease group as a whole. This issue is well illustrated by studies of human leukocyte antigen (HLA) associations in patients with RA. Numerous studies over many years have characterized the HLA-DRB1 associations with RA and have shown quite variable effect sizes.29 What now emerges is that most of the earlier studies and those showing the highest effect sizes tended to be based on hospital-derived cohorts of patients, which typically included patients with more severe disease. It was only by the establishment of prospective primary care–based cohorts with longitudinal follow-up, such as the U.K. Norfolk Arthritis Registry, that it was demonstrated that the HLA shared-epitope alleles much less strongly associated with inflammatory arthritis (odds ratio [OR] = 1.8; 95% confidence interval [CI], 1.4–2.4). The risk increases for cases satisfying American College of Rheumatology criteria (OR = 2.3; 95% CI, 1.7–3.1) but is strongest for hospital-based studies (average fivefold increased risk), suggesting that shared-epitope alleles may be more important in influencing disease severity than susceptibility.30 Indeed, a study using the more recent SNP-based classification of HLA risk in RA determined that HLA haplotypes associated with differences in outcome, morbidity, and treatment response.31 More recently, large population-based cohorts with extensive phenotype data attached, such as the UK Biobank and the Estonia Biobank, have become available to enhance genetic studies. A study in OA doubled the number of known osteoarthritis risk loci by leveraging the UK Biobank and Arthritis Research UK Osteoarthritis Genetics (arcOGEN) resources.32 There are now novel statistical analysis techniques, such as linkage disequilibrium (LD) regression, that can estimate the amount of homogeneity within genetic cohort studies. One such analysis demonstrated how anticitrullinated protein antibody (ACPA)-positive and ANCA-negative RA can be misclassified in studies, affecting resultant analysis.33

Power and effect sizes The power of a study to detect a genetic effect size depends on the sample size of the study and the frequency of the alleles that predispose to disease. Most association studies use similar numbers of cases and control participants, although more power is gained by increasing the ratio of control participants to cases (a ratio of four times more controls than cases is considered the most efficient). It is now clear that the effect size for the majority of complex disease loci is very small, with the majority identified so far having

CHAPTER 26  Principles of genetic epidemiology

211

ORs below 1.5, emphasizing the importance of using adequately powered studies, which for GWASs of most diseases means sample sizes of many thousands.

demonstrate the importance of considering the cell specificity for functional biology experiments.60,61

Selection of genetic markers

WHOLE-GENOME ASSOCIATION STUDIES OF RHEUMATOLOGIC CONDITIONS

Candidate genes for association studies have tended to be selected on the basis of either pathology or biologic processes. SNPs have been the markers most commonly used, largely because they are most easily genotyped. Three major initiatives have focused on the identification and characterization of SNPs; as a result, it is now possible to select markers in a systematic and efficient manner to ensure coverage of common variation (minor allele frequency >1%) for a given locus or gene. First, the sequencing of the human genome provided a template against which genetic variation could be studied and mapped; second, the availability of markers was dramatically increased by characterization of millions of polymorphic markers (http://www.ncbi. nih.gov/SNP); and third, patterns of linkage disequilibrium between markers (http://www.hapmap.org) originally defined with data generated from four populations (Yoruba, Nigeria, n = 90; North American Whites living in Utah, n = 90; Han Chinese, n = 45; and Japanese, n = 44), extending to 1300 samples across 11 populations. More recently, the 1000 Genomes Initiative (http://www.1000genomes.org), which involves the complete resequencing of the genome, has determined more than 84 million variants using 2500 individuals across 24 populations and, as such, has become the reference database for population genetics. The presence and knowledge of linkage disequilibrium between markers mean that it is usually unnecessary to type every known variant at a locus of interest. Data for untyped polymorphisms can be imputed using programs such as IMPUTE.34,35

Analysis and interpretation of results

Applying a significance threshold of P = 0.05 means that 1 in 20 observed associations will have occurred by chance. Performing multiple tests, such as after a GWAS, without adjustment of the threshold is certain to generate false-positive findings.36 Applying a Bonferroni correction is thought to be overly conservative, particularly if SNPs are in linkage disequilibrium with each other. An alternative is to perform permutation testing to empirically test the probability of having observed an association by chance.37 The issue of multiple testing is key in the interpretation of GWASs based on the comparison of many hundreds of thousands of markers. A generally accepted threshold for the current generation of GWASs (500,000 to 1 million SNPs) is P < 5 × 10−8. Replication of findings in an independent cohort provides compelling evidence that the original result was real and not a false-positive finding, although recently, moves toward large-scale, international metaanalyses, often involving tens of thousands of subjects, generate sufficient power and robust findings for the confident assignment of disease risk variants.

SUCCESSFUL EXAMPLES OF CANDIDATE ASSOCIATION STUDIES The first genetic associations in rheumatic diseases were identified some 30 years ago and were with alleles of genes located in the HLA region.38–40 Since then, many other associations between HLA antigens and a wide range of rheumatic diseases have been reported, a considerable number of which have been replicated. A detailed discussion of how HLA may contribute to the etiology of RA, including advances made by SNP based HLA typing, has been given elsewhere (see Chapter 94).

PROTEIN TYROSINE PHOSPHATASE N22 Protein tyrosine phosphatase N22 (PTPN22) is one of a number of protein tyrosine phosphatases involved in regulating the immune response. A functional polymorphism of the PTPN22 gene, 1858C>T, was initially found to be associated with type 1 diabetes.41 Subsequently, researchers performed a large-scale case–control association study of candidate genes for RA (16,000 SNPs) and found that the most significant association was with the same nonsynonymous SNP identified in the type 1 diabetes study.42 The initial association to RA has since been replicated in all of the studies that have followed.43–50 Association to the same SNP has been found in JIA,43 SLE,45,51–53 autoimmune thyroid disease,54–58 and a number of other autoimmune diseases.59 Interestingly, the 1858C>T variant is found only extremely rarely in Asian populations, and there is no evidence that PTPN22 has a role in RA susceptibility in Asians. Even though the disease-associated variant in PTPN22 resulted in an amino acid change, the elucidation of the functional impact of this variant has proved surprisingly difficult and has served to

The proof of principle investigation that demonstrated the practicality and utility of GWASs came in 2007 from The Wellcome Trust Case Control Consortium (WTCCC), which undertook a genome-wide analysis of seven common diseases, including RA. A total of 500,000 SNPs were genotyped using the Affymetrix Gene Chip 500k Mapping Array Set in 2000 cases from each of seven diseases and a set of 3000 common controls, all samples from White U.K. residents.62 For RA, markers in the HLA-DRB1 and PTPN22 gene regions were highly significantly associated with disease (P < 5 × 10−7). Strong but not incontrovertible evidence of association was detected in more than 50 additional loci (P < 10−4-5 × 10−7) (Fig. 26.1) Analysis of markers from these loci in large independent sample sets has since confirmed RA loci at 6q23,63 10p15, 12q13, and 22q13,64 implicating the genes TNFAIP3, PRKCQ, KIF5A, IL2RB, and AFF3, respectively. Further GWASs in different populations and metaanalyses of GWASs providing ever greater power have led to identification of more than 100 RA loci in all populations (Fig. 26.2).22,65,66 Successful GWASs have now been carried out for all of the major rheumatologic conditions, including SLE,67 AS,68 OA,69 psoriatic arthritis (PsA),70 JIA,71 and systemic sclerosis.72 In all cases, the studies have both confirmed some of the established associations and identified new susceptibility loci. Genome-wide association studies can now be carried out as a matter of routine. One challenge that remains is to distinguish all true-positive associations from among a considerable number of highly significant results arising as false positives. Increasing sample sizes and metaanalyses offer one solution, but statistical and bioinformatic advances offer great potential to assist with this challenge. For example, integrating the wealth of existing data73 generated on how a genome functions, where it is most active, and the genes it is expressing in certain cell types into the analysis can help prioritize putatively functional variants,74 or incorporating genetic evidence from similar traits, using Bayesian conditioning, can leverage power from existing data to inform putative disease trait loci.75 GWASs have already provided a wealth of information about the genetic basis of rheumatic disease. By overlaying disease-associated regions with specific DNA regions active in certain cell types, GWASs have indicated the cells most likely to be involved in disease (generally T cells).76 GWASs have also highlighted the diseases that share a genetic background (e.g., surprisingly, JIA shows most genetic overlap to type 1 diabetes,75 and PsA to IBD70) and ones in which the associated genetic regions play opposing roles of risk and protection (e.g., IL-6R in RA and asthma)65 (Fig. 26.3).77 Although rapid progress has been achieved in the identification of disease susceptibility markers implicating genetic loci, for the most part, our understanding of these loci and how associated alleles cause disease is very limited. One of the reasons for this is that disease associations are generally to be found in DNA regions that regulate genes and not in the genes themselves. Because these regions can be large distances from the nearest gene, it is often not obvious which gene is implicated, the mechanism that increases the risk of disease, and which cell types are most affected.78 Therefore, the key questions to interpret the genetic findings are to assign a causal variant, gene, cell type, and mechanism to the genetically associated regions in order to fully translate GWAS findings into clinical benefit.

NEW HORIZONS Progress in complex disease genetics has been driven largely by remarkable advances in technology and computer-based informatics. The first sequencing of the human genome completed just 20 years ago required the efforts of a major international consortium for 10 years, with teams of scientists and many DNA-sequencing machines. In contrast, we are now entering an era when resequencing the genome of an individual is possible in hours at affordable prices. The impact that such information could have on medicine and rheumatology specifically is yet to be fully appreciated. Furthermore, the postgenome era has led to a greater realization that disease etiology and processes should not just be viewed one-dimensionally from the level of gene sequence but rather in the context of cell-specific transcription and translation into proteins under different conditions and over time on the background of complex combinations of genetic background. One of the major findings from GWASs is that the impact of genetic changes that increase the risk of developing a rheumatic disease is likely to be on the exquisite regulation of genes in certain cell types under certain conditions

212

SECTION 2  Clinical Basis of Rheumatic Disease A MANHATTAN PLOT ILLUSTRATES THE ASSOCIATION OF MARKERS IN A GWAS HLA

PTPN22 25

–Log10 (P value)

20

15

10 TNFAIP3 5

0

1

2

3

4

5

6

7

8

9

10

11

12

13 14 15 16 17 18 19 20 2122

Chromosome

FIG. 26.1  A Manhattan plot illustrates the association of markers in a genome-wide association study. Each dot represents the P value for comparison of genotype frequencies for each marker when comparing cases (n = 2000) and control participants (n = 3000). Shades of blue are used to represent alternate chromosomes. Levels of significance of association are indicated. Red spots: P < 5 × 10−7; green spots: P < 10−5-5 × 10−7; yellow spots: P < 10−4.64

DISCOVERY OF RA SUSCEPTIBILITY LOCI

HLA-DRB1

PTPN22

TNFAIP3 STAT4 TRAF1 IL2/IL21

1978

2004

2007

CD40 CCL21 TNFRSF14 IL2RB CTLA4 PRKCQ KIF5A IL2RA AFF3

REL BLK TAGAP CD28 TRAF6 PTPRC FCGR2A PRDM1 CD2-CD58

ANKRD55 SPRED2 C5orf30 RBPJ CCR6 IRF5 PXK

TYK2 IRAK1 TL3 RASGRP1 PADI4 IL6R IRF8 ARID5B RUNX1 IKZF3 POU3F1 RCAN1 CD5 GATA3 PTPN2 BACH2 RAD51L1

2008

2009

2010

2012

TNFRSF9 MTF1-INPP5B LOC100506023 LBH ACOXL CFLAR-CASP8 PLCL2 EOMES IL20RB CLNK TEC IRF4 ETV7 PPIL4 JAZF1 CDK6 TPD52 GRHL2 PVT1 10p14 ZNF438

WDFY4 SFTPD FADS1-FADS2-FADS3 CEP57 ATM ETS1 CDK2 SH2B3-PTPN11 COG6 PRKCH RAD51B TXNDC11 C1QBP MED1 CD226 ILF3 IFNGR2 UBASH3A UBE2L3-YDJC SYNGR1 P2RY10

2014

FIG. 26.2  A timeline of the discovery of rheumatoid arthritis (RA) susceptibility loci illustrating the impact of a genome-wide association study.

of stimulation. This level of complexity has meant the focus on interpretation of GWAS results has shifted to gene regulation and the changes to the DNA structure (epigenetic changes) that the disease risk DNA variants confer to alter protein expression.78 Major new advances in genome editing technology, in the form of CRISPR/Cas9, mean that a molecular toolkit is now readily available to rheumatology researchers that allows the alteration of the genetic framework (e.g., from nonrisk to risk) in a laboratory environment to empirically test for the first time the consequences of the implicated genetic backbone. This will inform the discovery of how genetic variation influences biologic pathways, cell types, and immune environments in the disease process. Knowledge will in turn inform approaches to stratified medicine, adaptation of the use of existing therapies, identification of novel therapies, and potentially cures. Adding to the challenge of designing the

best therapeutic for every patient is the increasing realization that response to drug treatment, in terms of both efficacy and adverse reactions, is largely encoded within our genes; this is poised to have great impact in the field of rheumatology, with pharmacogenetic studies beginning to explain poor response or adverse reactions in some patients. The full translation of the information that resides in our genome and how it relates to complex diseases will only come through understanding the effect of environmental risk factors for disease. These could be gene– nutrient, gene–microbiome, gene–lifestyle (e.g., alcohol, smoking), or gene–drug interactions (pharmacogenetics). Such studies are difficult, and many can only be appropriately addressed through large longitudinal population-based cohorts that enable premorbid environmental exposure data and biologic samples to be collected.

CHAPTER 26  Principles of genetic epidemiology OVERLAP OF SUSCEPTIBILITY OF AUTOIMMUNE DISEASE LOCI

23. 24.

CD

RA RUNX3 FASLG UBE2E3 LTF IL12A LPP

MMEL1 REL STAT4 DDX6 IRAK1

IRF4 PTPRK UBE2L3 ICOSLG

RGS1 IL18RAP UBASH3A SH2B3 CCR5 CCR3

CTLA4 / CD28 IL2_IL21 BACH2 TNFAIP3

IFIH1 INS ERBB3 IL7R CTSH CLEC16A

TRAF1 PADI4 CCL21 CD40

TAGAP PRKCQ MHC PTPN2

26.

27. 28. 29.

PTPN22 IL2RA ORMDL3 KIF5A CD226 C1QTNF6 IL10 COBL GLIS3 CD69

25.

IL27 PGM1

30.

31. 32.

33.

T1D 34.

FIG. 26.3 Considerable overlap of susceptibility of autoimmune disease loci is becoming apparent. Illustrated here are some of the loci identified for type 1 diabetes (T1D), celiac disease (CD), and rheumatoid arthritis (RA). The specific markers associated with each disease may differ.

35. 36. 37.

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38.

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Nelson MR, Tipney H, Painter JL, et al. The support of human genetic evidence for approved drug indications. Nat Genet. 2015;47(8):856–860. Plant D, Wilson AG, Barton A. Genetic and epigenetic predictors of responsiveness to treatment in RA. Nat Rev Rheumatol. 2014;10(6):329–337. https://doi.org/10.1038/ nrrheum.2014.16. [Epub 2014 Feb 18]. Lee JC, Espéli M, Anderson CA, et al. Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway. Cell. 2013;155(1):57–69. https:// doi.org/10.1016/j.cell.2013.08.034. [Epub 2013 Sep 12]. Ollier W, Worthington J. Investigation of the genetic basis of rheumatic diseases. In: Hochberg M, Silman AJ, Smolen J, eds. Rheumatology. 4th ed. Philadelphia: Elsevier; 2008:123–131. Pritchard JK, Rosenberg NA. Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet. 1999;65:220–228. Tian C, Gregersen PK, Seldin MF. Accounting for ancestry: population substructure and genome-wide association studies. Hum Mol Genet. 2008;17:R143–R150. Ollier W, Thomson W. Population genetics of rheumatoid arthritis. Rheum Dis Clin North Am. 1992;18:741–759. Thomson W, Harrison B, Ollier B, et al. Quantifying the exact role of HLA-DRB1 alleles in susceptibility to inflammatory polyarthritis: results from a large, population-based study. Arthritis Rheum. 1999;42:757–762. Viatte S, Plant D, Han B, et al. Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response. JAMA. 2015;313(16):1645–1656. Tachmazidou I, Hatzikotoulas K, Southam L, et al. Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019;51(2):230–236. Han B, Pouget JG, Slowikowski K, et al. Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases. Nat Genet. 2016;48(7):803–810. Marchini J, Howie B, Myers S, et al. A new multipoint method for genome-wide association studies via imputation of genotypes. Nat Genet. 2007;39:906–913. Howie B, Fuchsberger C, Stephens M, et al. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet. 2012;44(8):955–959. Colhoun HM, McKeigue PM, Davey SG. Problems of reporting genetic associations with complex outcomes. Lancet. 2003;361:865–872. Hirschhorn JN. Genetic approaches to studying common diseases and complex traits. Pediatr Res. 2005;57:74R–77R. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med. 1978;298:869–871. Winchester R. B lymphocyte alloantigens, cellular expression and disease significance with special reference to rheumatoid arthritis. Arch Intern Med. 2005;20:159–163. Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HL-A 27. Lancet. 1973;1:904–907. Bottini N, Musumeci L, Alonso A, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004;36:337–338. Begovich AB, Carlton VE, Honigberg LA, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004;75:330–337. Hinks A, Barton A, John S, et al. Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene. Arthritis Rheum. 2005;52:1694–1699. Steer S, Lad B, Grumley JA, et al. Association of R602W in a protein tyrosine phosphatase gene with a high risk of rheumatoid arthritis in a British population: evidence for an early onset/disease severity effect. Arthritis Rheum. 2005;52:358–360. Orozco G, Sanchez E, Gonzalez-Gay MA, et al. Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum. 2005;52:219–224. Viken MK, Amundsen SS, Kvien TK, et al. Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases. Genes Immun. 2005;6:271–273. van Oene M, Wintle RF, Liu X, et al. Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn’s disease, in Canadian populations. Arthritis Rheum. 2005;52:1993–1998. Simkins HM, Merriman ME, Highton J, et al. Association of the PTPN22 locus with rheumatoid arthritis in a New Zealand Caucasian cohort. Arthritis Rheum. 2005;52:2222–2225. Zhernakova A, Eerligh P, Wijmenga C, et al. Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population. Genes Immun. 2005;6:459–461. Seldin MF, Shigeta R, Laiho K, et al. Finnish case-control and family studies support PTPN22 R620W polymorphism as a risk factor in rheumatoid arthritis, but suggest only minimal or no effect in juvenile idiopathic arthritis. Genes Immun. 2005;6:720–722. Kyogoku C, Langefeld CD, Ortmann WA, et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet. 2004;75:504–507. Reddy MV, Johansson M, Sturfelt G, et al. The R620W C/T polymorphism of the gene PTPN22 is associated with SLE independently of the association of PDCD1. Genes Immun. 2005;6:658–662. Chung SA, Criswell LA. PTPN22: its role in SLE and autoimmunity. Autoimmunity. 2007;40:582–590. Smyth D, Cooper JD, Collins JE, et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes. 2004;53:3020–3023. Qu H, Tessier MC, Hudson TJ, et al. Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study. J Med Genet. 2005;42:266–270.

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56. Velaga MR, Wilson V, Jennings CE, et al. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocrinol Metab. 2004;89:5862–5865. 57. Skorka A, Bednarczuk T, Bar-Andziak E, et al. Lymphoid tyrosine phosphatase (PTPN22/ LYP) variant and Graves’ disease in a Polish population: association and gene dose-dependent correlation with age of onset. Clin Endocrinol (Oxf). 2005;62:679–682. 58. Criswell LA, Pfeiffer KA, Lum RF, et al. Analysis of families in the Multiple Autoimmune Disease Genetics Consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet. 2005;76:561–571. 59. Vang T, Miletic AV, Bottini N, et al. Protein tyrosine phosphatase PTPN22 in human autoimmunity. Autoimmunity. 2007;40:453–461. 60. Vang T, Congia M, Macis MD, et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet. 2005;37(12):1317–1319. 61. Zhang J, Zahir N, Jiang Q, et al. The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nat Genet. 2011;43(9):902–907. 62. Wellcome Trust Case Control Consortium, Genome-wide association study of 14,000 cases of seven common diseases and 3000 shared controls. Nature. 2007;447:661–678. 63. Thomson W, Barton A, Ke X, et al. Rheumatoid arthritis association at 6q23. Nat Genet. 2007;39:1431–1433. 64. Barton A, Thomson W, Ke X, et al. Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. Nat Genet. 2008;40:1156–1159. 65. Stahl EA, Raychaudhuri S, Remmers EF, et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010;42(6):508–514. 66. Eyre S, Bowes J, Diogo D, et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012;44(12):1336–1340. 67. Bentham J, Morris DL, Cunninghame Graham DS, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015;47(12):1457–1464.

68. Cortes A, Hadler J, Pointon JP, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet. 2013;45(7):730–738. 69. arcOGEN Consortium arcOGEN Collaborators. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study. Lancet. 2012;380(9844):815–823. 70. Bowes J, Budu-Aggrey A, Huffmeier U, et al. Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis. Nat Commun. 2015;6:6046. 71. Hinks A, Cobb J, Marion MC, et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet. 2013;45(6):664–669. 72. Mayes MD, Bossini-Castillo L, Gorlova O, et al. Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. Am J Hum Genet. 2014;94(1):47–61. 73. Pickrell JK. Joint analysis of functional genomic data and genome-wide association studies of 18 human traits. Am J Hum Genet. 2014;94:559–573. 74. Kichaev G, Yang W-Y, Lindstrom S, et al. Integrating functional data to prioritize causal variants in statistical fine-mapping studies. PLoS Genet. 2014;10:e1004722. 75. Onengut-Gumuscu S, Chen W-M, Burren O, et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet. 2015;47(4):381–386. 76. Farh KK, Marson A, Zhu J, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518(7539):337–343. 77. Gregersen PK, Olsson LM. Recent advances in the genetics of autoimmune disease. Annu Rev Immunol. 2009;27:363–391. 78. Martin P, McGovern A, Orozco G, et al. Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci. Nat Commun. 2015;6:10069.

Interpreting the medical literature for the rheumatologist Robert B.M. Landewé

Key Points ■ Randomized controlled trials are not necessarily the best solution for every clinical question; many relevant clinical questions are better addressed in well-designed and appropriately analyzed observational studies. ■ Statistical significance is not a goal per se. Statistical testing ideally is only a minor part of the analysis of clinical research, and the merits of a “significant P value” are all too often overrated. ■ It is very important that trial designers make a clear distinction between trials with a superiority design and trials with a noninferiority design. It is even more important that readers of the trial reports are aware of the differences between the two and interpret them accordingly. ■ Only appropriate communication about the internal and external validity of trials will ultimately result in appropriate implementation of trial data and improvement in patient care.

INTRODUCTION In medicine, there is a strong belief that randomized controlled trials (RCTs) are superior to observational studies. Randomization does provide indisputable strengths, but data show that RCTs and observational studies often arrive at the same conclusion. Furthermore there are theoretical and practical problems that preclude the acceptance of RCTs as the only source of useful information: (1) RCTs often address research questions that do not serve the main interest of clinicians, (2) many research questions cannot be solved by RCTs, and (3) an RCT has methodologic requirements that should be met to optimally favor its benefits. Large observational studies are frequently considered second rate; however, observational cohort studies are sometimes the only source of data available and can often supply useful information to complement RCTs. Although the fundamental theory underlying an RCT—and the primary analysis of an RCT—is relatively simple, practical trial conduct faces many potential pitfalls that may eventually result in violation of prognostic similarity and introduce bias. Examples are inadvertent unblinding of a study drug (e.g., if the study treatment is very effective but the placebo is not), unbalanced nonrandom discontinuation (e.g., if the study drug is responsible for adverse drug reactions that cause selective dropout), or simply poor trial conduct or overt misconduct (e.g., if patients do not show up for visits; assessors do not measure outcomes with scrutiny; or, at worst, nonexisting or virtual patients with faked response patterns are reported). It is the investigators’ responsibility to optimize trial conduct and data collection, to perform a correct analysis of the data, and to transparently describe the process and results of the trial in the medical literature; this is “good clinical practice.” The consumers of these reports, peer reviewers, scientists, rheumatologists, workers in the pharmaceutical industry, regulatory authorities, and others, have their own responsibility. They have the obligation to interpret the data carefully by weighing their integrity and importance; to be unprejudiced with respect to the investigators’ interpretations; and to translate trial data into useful, clinically applicable information. This process has gained attention as “critical appraisal,” and the literature provides superb guidance on how to critically appraise the report of an RCT.1, 2 Medical journals have agreed on guidelines with respect to trial report (e.g., Consolidated Standards of Reporting Trials [CONSORT] guidelines3), thus tremendously improving appropriate reporting. Good clinical practice and critical appraisal are applicable to observational research without prejudice, although the focus may be slightly different. The checklist for STrengthening in Reporting of OBservational studies in Epidemiology (STROBE), for example, has been published in an attempt to improve the quality of reports in this field.4, 5 In this chapter, the focus is primarily on methodologic elements that in the author’s opinion are the most important in critically appraising the results of clinical trials and observational studies with respect to application to clinical practice. Because some of these elements specifically pertain to RCTs, others primarily refer to observational studies, and there is also

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a generic category pertaining to both types of research, three categories of critical appraisal will be discussed: one primarily referring to RCTs, one referring to observational studies, and one referring to both.

LEVELS OF EVIDENCE During the past decade, the accessibility of medical literature has tremendously improved. To date, the majority of practicing rheumatologists have almost immediate access to (abstracts of) all medical studies that have been reported in the literature. In addition, metaanalysis and systematic literature review, in which the available literature is weighed and judged in a systematic manner and the data are sometimes pooled, have become an art of science. In an attempt to bring some order to the quality of epidemiologic research and consequently to prioritize types of research with respect to methodologic rigor, several scales have been developed. One of the more comprehensive scales (with most differentiation) is the Oxford Centre for Evidence-Based Medicine scale, which applies levels of evidence to five different study scenarios (therapy, prognosis, diagnosis, differential diagnosis, and economic analysis).6 In general, such scales rate systematic reviews and appropriately conducted metaanalyses higher than individual RCTs, followed by observational studies and then case series, with expert opinion at the lowest level. Although level-of-evidence scales can be very helpful in prioritizing (the quality of) studies, a note of caution is needed. Frequently, a study is inappropriately rated. An unplanned subgroup observation in the context of an RCT, for example, should not be rated level 1 because the result is not obtained in an unbiased manner (see later), but a methodologically weak RCT also does not deserve a rating of 1. Sometimes “low-grade evidence” is the only kind of evidence that can be obtained; for instance, if the disease under study is very rare or if an RCT is considered unethical. Those who have been involved in the development of recommendations realize that a lot of what physicians do on an everyday basis is based on “expert opinion” and not substantiated by any study at all. Rather than relying entirely on levels of evidence, readers of the medical literature should rate the studies themselves and try to obtain some insight on what the aim of the study is, how the study has been performed, and what the impact of the results should be with regard to their own patients.

RANDOMIZED CONTROLLED TRIALS OR OBSERVATIONAL STUDIES? A typical RCT investigates whether a new drug, strategy, or intervention is efficacious and safe compared with an equivalent treatment or placebo. The trial involves patient selection and randomization before the treatment begins and thereafter a predetermined follow-up time to establish whether the primary endpoint (measure of the treatment effect) has been met. The most characteristic feature—and the major advantage of an RCT—is randomization. Technically, this process divides all known and unknown prognostically important factors similarly across treatment groups at baseline and thereby creates a similar prognosis. In other words, treatment groups are similar in everything except allocated treatment. Prognostic similarity at baseline is important for attributing an observed effect to a particular treatment rather than to an imbalance in some unrelated but prognostically important factor. Randomized controlled trials also have important drawbacks. They might lack external validity (generalizability). Inclusion criteria and exclusion criteria ensure that the trial population is a particular selection of the entire population with a certain disease. An RCT includes patients who are “prone to change,” who might have a high level of adherence to the protocol to ensure retention, or who have a low probability of adverse reactions from comorbidities, comedications, or both. Consequently, such a trial population comprises highly motivated, often educated individuals who have a high level of disease activity but are otherwise healthy. This scenario usually does not appropriately reflect the common clinical situation. 215

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Another disadvantage of RCTs is their often relatively short follow-up time. There are several trivial explanations for this, but the most important one is that true prognostic similarity exists only at baseline and gets increasingly lost over time. Take, for example, comedications or other coincident interventions. A short follow-up period is methodologically advantageous (see the later section Internal Validity and External Validity) but may in rheumatology reflect only a small part of the entire duration that a patient is under observation for a chronic disease in real practice. As a consequence, RCTs often use surrogate endpoints rather than endpoints that truly reflect the clinical outcome of the disease. An appropriate example in this respect is the use of bone mineral density as a surrogate outcome measure for fractures in osteoporosis trials. It depends largely on the study question whether an RCT will provide the most appropriate answer. RCTs do provide a reliable impression of the short-term efficacy and safety of drugs in the selection of patients. They do not, however, provide information about an individual patient’s prognosis, long-term results, or relevant outcomes, and they do not provide information about rare events. It is here that observational studies, with many patients and long follow-up, have proven their value.

CRITICAL APPRAISAL I: ISSUES PERTAINING TO RANDOMIZED CONTROLLED TRIALS INTERNAL VALIDITY AND EXTERNAL VALIDITY A trial is a rather artificial construct that usually serves one main purpose: to investigate whether a particular treatment is efficacious. In general, elements of trial design, such as selection of patients, sample size, choice of the comparative intervention, and duration of the trial, are chosen in such a manner that the trial can optimally demonstrate a treatment effect; that is, a difference in efficacy between the new treatment and the control intervention. The methodologic rigor of a trial, which is dependent on these elements of trial design, is referred to as internal validity. Understandably, trials often do not resemble clinical practice. Rheumatoid arthritis (RA) trials, for example, frequently include patients with a high level of disease activity, which may form only a minority in clinical practice. The extent to which clinical trial results can be extrapolated to common clinical practice is referred to as external validity. External validity is much more diffuse than internal validity. It depends on how the consumer of the data interprets the results, how these results are presented, how convincingly the investigators have argued their message, and how credible they are in the eyes of the beholder (see also the later section Conflict of interest). It depends on whether the reader thinks that the data from the trial are applicable to an individual patient in the reader’s own practice. Undoubtedly, external validity will be judged as being unsatisfactory if internal validity falls short. The opposite is not necessarily true, however. A trial with high internal validity can easily have insufficient external validity. An increasingly common example in RA is an RCT with 1000 patients who have high disease activity that tests a new treatment against the “currently best available disease-modifying therapy for RA” and finds a small, statistically significant difference in favor of the new treatment that is not clinically relevant. Such a new treatment will probably be approved by drug registration authorities if it is considered safe because it has proven superiority in a well-conducted trial with high internal validity. Needless to say, this effective treatment with doubtful advantage over existing treatments should not be broadly applied in common clinical practice without further consideration (external validation). Readers of trial reports should weigh the balance between internal and external validity: which prevails when one falls short of the other and which elements are important in translating the trial result into clinical practice.

EFFICACY vs EFFECTIVENESS It is of utmost importance to be informed about the underlying aim of the trial, which is not necessarily the same as the primary study objective. Drug registration trials under the auspices of the pharmaceutical industry serve a different purpose than do investigator-initiated trials with treatment strategies. Whereas the former are often referred to as explanatory or efficacy trials and are characterized by a high level of internal validity, the latter—pragmatic trials or effectiveness trials—more closely resemble clinical practice and often find their basis in questions emerging from clinical practice and as a consequence have a higher level of external validity.7 The results of explanatory trials are frequently very robust and confirm the efficacy of the drug tested beyond statistical doubt but may fall short in terms of clinical significance. Examples are numerous and include any trial that presents the results of a “new drug” tested against placebo or an active comparator.

Effectiveness trials often have a more understandable trial result that is more easily applicable to individual patients, but the results may be biased; for example, by imperfections in blinding and changes in the type and intensity of treatment during the trial. An interesting type of trial that belongs to this group is the benchmark trial in RA. The essential characteristic of a benchmark trial is that treatment (type, intensity, or both) is not kept constant during the course of the trial but is dependent on the clinical response of the individual patient (whether the benchmark is met). Such a trial mimics everyday clinical practice very well but is in conflict with the fundamental theory underlying RCTs, namely, that patient groups in a trial are prognostically similar during the trial. The methodologic robustness of the trial is to some extent jeopardized by increased clinical face validity. Readers should have knowledge of these elements because they are relevant for interpreting the results and deciding about their usefulness for application to individual patients.

SUPERIORITY TRIALS AND NONINFERIORITY TRIALS Textbooks in clinical trial design teach that the underlying null hypothesis should be carefully formulated during the design phase of the trial. The formulation of the null hypothesis, which in theory is the hypothesis that is challenged by experimentation (the trial), tells immediately whether the basic design of the RCT is aimed at proving superior efficacy of a new treatment (the superiority design) or at proving that a new drug treatment is as effective as a comparator drug for ethical reasons frequently the current standard of therapy (the noninferiority design). Most RCTs still have a superiority design, with the null hypothesis being that the new treatment is as efficacious as placebo or a comparator treatment. The design of the trial and the sample size are dependent on a minimally important difference, which is determined in advance by the investigators and serves as the basis for calculations of sample size. In rheumatology, many consecutive RCTs have resulted in a number of treatments that have proven efficacy against placebo or against the standard-of-care therapy. An affluence of effective treatments such as in RA has its other side of the coin. First, there is increasing sympathy for the ethical argument that progress in the treatment of rheumatic diseases should have its consequences for the standard of care in this disease. The immediate implication with regard to trial design is that conventional RCTs with placebo as therapy in the control group will be considered unethical. The more effective the therapy in the control group, the more difficult it is to surpass the effect in the control group with a new treatment—the classic superiority trial will be increasingly unfeasible. Second, even though we have an affluence of effective drugs for conditions such as RA, there is a knowledge gap with respect to drug efficacy in mutual comparisons. Using previous argumentation, these pregnant clinical questions cannot be solved with classic trial designs. This is why we currently see an increasing number of noninferiority trials in rheumatology.8, 9 Such trials have the null hypothesis that the new drug is inferior to the effective treatment in the control arm and embark on determination of an appropriate noninferiority margin. More than the choice of a minimally important difference in superiority trials, the choice of a noninferiority margin in a noninferiority trial is a highly subjective decision that includes elements of efficacy, safety, and cost and can make or break the interpretability of such a trial. It is crucial that readers know about elements of the null hypothesis, such as choices and considerations related to the design type of the trial (superiority vs noninferiority) and to levels of minimally important difference and noninferiority margin.

STATISTICAL POWER Every RCT should technically be able to reject the null hypothesis if the alternative hypothesis reflects the truth—it should have sufficient statistical power. One could justifiably argue that trials with insufficient power should not have been executed. It is unethical to expose patients to potentially harmful drugs if the trial is not able to demonstrate superiority or noninferiority of that drug; if it fills the medical literature with data that are inconclusive and, consequently, poses a risk for misinterpretation and inappropriate application to patient care; and if it is extremely cost-ineffective to conduct trials that do not meet their goals. So, it seems obvious that the reader of a trial report should judge if the statistical power was appropriate. Many do not realize that statistical power is more than sample size alone. Although the latter is important, statistical power is, among other factors, dependent on the outcome measure (the responsiveness and discriminatory capacity) and the expected effect size (the anticipated difference between the new treatment and the control treatment). The wording justifying the sample size of the trial provides, to some extent, resolution of the power

CHAPTER 27  Interpreting the medical literature for the rheumatologist considerations. In sample size calculations, patient numbers are calculated for a given primary outcome measure with an assumption for its variability, for given values of beta (1 − statistical power), and for a predefined effect size. Sometimes the anticipated effect size is based on realistic assumptions stemming from previous studies, but all too often an effect is chosen that has no scientific precedent (“20% between-group difference”). Some investigators want 80% statistical power, others choose 90% power as preference, and all too often the reader is left with the impression that convenience outweighs theoretic arguments about power: “the calculation should fit.” Rather than only describing the sample size calculation per se (which is often done inappropriately), the trial report should include argumentation for the chosen assumptions, such as the level of the minimal clinically important difference, the noninferiority margin, the level of beta, the historic precedents, and so on, and the reader should try to interpret this cautiously.

INTENTION-TO-TREAT ANALYSIS Every investigator, every trial designer, and every clinician know about the dogmatic character of the intention-to-treat (ITT) principle underlying the main analysis of a clinical trial. Although occasionally a paper mentions a surrogate of ITT (e.g., “modified ITT analysis”), the definition of ITT is crystal clear. It means that all patients in the trial are considered to belong to the group that they were originally allocated to by randomization, regardless of what has happened to them after randomization, during the trial. The justification for this somewhat dogmatic principle is that the ITT analysis is the most conservative analysis because it reflects the prognostic similarity that was created at baseline by randomization. All other types of analyses, including “modified ITT,” are second rate because they allow retrograde patient selection at baseline to some extent. The typical completers analysis, for example, includes only patients who have done well with the allocated study treatment and ignores those who have discontinued treatment and may differ from the completing patients in terms of prognosis (prognostic dissimilarity). In fact, completers of an RCT form a selected group of patients and should be considered an observational cohort rather than a trial group (see later). Intention to treat is not a certificate for an appropriate trial analysis. The trial report should spell out how patients who do not provide actually measured trial data are handled (see the later section Missing Data). It should mention how data generated by patients who discontinued the trial medication but showed up at visits are handled. Last but not least, there is no generic means of data manipulation in this regard. For example, considering every dropout to not have changed (improved) in a clinical trial involving patients with RA and ACR20 (American College of Rheumatology 20% improvement criteria) as the primary outcome measure is probably conservative because a proportion of these patients will have had a clinical response. However, considering these dropouts as not having changed in a clinical trial with radiographic progression as the outcome measure is all but conservative because it looks as if the dropouts did not have progression, and a trial arm with a high proportion of premature discontinuations may show spurious benefit. In summary, ITT together with appropriate handling of data, including appropriate imputation, works conservatively in that it tends to reduce a treatment contrast. Conservatism, however, is not necessarily a guarantee for a more truthful trial result. In a noninferiority trial, ITT may spuriously lead to a conclusion of noninferiority, whereas in truth, unbalanced withdrawal, poor trial conduct, or unintended cointerventions may be responsible for the absence of a difference between treatment groups. An example may clarify this statement (Table 27.1). Suppose that two analgesic drugs (A and B) are compared with respect to their ability to relieve pain in an RCT and that drug A is in truth more effective than drug B (which, of course, you do not know in reality). The primary outcome measure is the number of patients with a 40% decrease in pain on a visual analog scale. Suppose also that patients take additional acetaminophen if they experience too much pain (“rescue analgesia”). Expectedly, the proportion of patients taking additional medication is lower in group A (the better treatment) than in group B (10 patients vs 30 patients). Also expectedly, only 2 of these 10 patients in group A needing additional drug experienced a response (the severe cases), but 20 of the 30 patients needing additional drug (the milder cases) in group B experienced a response (attributable to comedication). Table 27.1 shows how different types of analysis (ITT vs per-protocol design) work with regard to response percentages and treatment effect. Keep in mind that in reality, drug A is more efficacious than drug B. The unbalanced use of comedication resulted in (only) 5% more responses in group A than in group B if analyzed by ITT. This is a small difference, probably not compatible with a conclusion of superiority of drug A in a trial with a superiority design but easily compatible with a

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conclusion of noninferiority of drug B in a trial with a noninferiority design. The picture changes, however, if the analysis is repeated on a per-protocol basis. Now, the treatment effect consists of almost 20% more responders in group A than in group B, probably compatible with the superiority of drug A in a trial with a superiority design and incompatible with the noninferiority of drug B in a trial with a noninferiority design: ITT analysis is conservative with respect to concluding superiority of a drug in a superiority design (even if in reality superiority exists). Per-protocol analysis is conservative with respect to concluding noninferiority in a noninferiority design. Analysis of noninferiority trials is not yet a closed book, but experts are in favor of simultaneously presenting ITT and per-protocol analyses so that readers can judge for themselves. It is always wise to be careful with interpretation if both analyses differ importantly (such as in this example).

SUBGROUP ANALYSES The issue of subgroup analysis in clinical trials is controversial. Proponents of subgroup analysis point to its hypothesis-generating potential. Opponents argue that subgroup analysis is irresponsible data mining that involves fishing for statistically significant differences by splitting up the trial population into smaller subgroups. Both parties are right to some extent. Subgroup analysis can sometimes help disentangle incomprehensible trial results and can raise attention about new, previously unacknowledged phenomena. However, inappropriate subgroup analysis can also provide spurious results, either by coincidence (multiple testing effects) or by unintended patient selection mechanisms. An example of the latter is as follows: The investigators of an RCT compare radiographic progression in a subgroup of patients with an early clinical response and a subgroup of patients without an early response and find that progression is significantly lower in the first subgroup. This result, however, may easily be confounded by less severe disease at baseline in the favorable subgroup. It is relevant to some extent to divide subgroup analysis into preplanned and post-hoc subgroup analysis. The former refers to the design phase of the trial and includes analyses in subgroups that are of potential relevance, such as the treatment effect in men and women separately or in patients who are rheumatoid factor positive and negative. Importantly, and in contrast to post-hoc subgroup analysis, the decision to perform and report such an analysis cannot be driven by knowing the data. In practice, however, it is often difficult to discern whether a preplanned subgroup analysis was truly preplanned. Methodologically, preplanned subgroup analysis is superior to post-hoc analysis only if the subgroups of interest were created by stratified randomization, which means randomization within the subgroups. It is hoped that stratified randomization creates prognostic similarity within the strata (a trial within a trial) and that, if performed appropriately, provides sufficient statistical power to detect a meaningful difference within the subgroup. Usually, subgroup analysis is not performed in subgroups created by stratified randomization. If subgroup analysis is performed and the question of interest is whether a particular treatment performs differently in subgroup X than in subgroup Y, it is important to realize that the analytic translation of this question refers to testing statistical interaction. Fig. 27.1 shows an example of such an interaction. In the first panel, treatment A is less effective than treatment B, both in the subgroup of patients with high disease activity and in the subgroup of patients with low disease activity. The treatment effect is similar in both subgroups: no interaction.

Table 27.1

Example of Intention-to-Treat Analysis

Number of patients who discontinued the trial Number of patients who completed the trial With clinical response Number of patients taking rescue medication With clinical response Response percentages based on: Intention-to-treat analysis Completers analysis Per-protocol analysis

Treatment A (n = 100)

Treatment B (n = 100)

85

85

25 10

20 30

2

20

25% (25/100) 29% (25/85) 31% (23/75)

20% (20/100) 24% (20/85) 9% (5/55)

15

15

218

SECTION 2  Clinical Basis of Rheumatic Disease AN EXAMPLE OF INTERACTION 7

7

6

6

5

A

5

4

B

4

A

B

3

3 A

2

B

1

A

2

B

1 0

0 Baseline

Endpoint

Baseline

Endpoint

FIG. 27.1  Results of subgroup analysis of an imaginary clinical trial comparing two treatments (dashed line with squares, treatment A; solid line with triangles, treatment B) in a subgroup with high baseline disease activity and a subgroup with low baseline disease activity. See text for clarification.

In the second panel, however, the treatment effect is dependent on the subgroup of disease activity. Although treatment A seems to be effective in patients with low disease activity, though less effective than treatment B, it seems to be completely ineffective in patients with high disease activity even though treatment B is still effective in this subgroup: interaction. Very often, absence of efficacy in the subgroup of patients with high disease activity is found and reported while the other subgroup is ignored, so it is not clear whether a presumed effect is truly attributable to a specific subgroup. This type of subgroup analysis makes sense only if the interaction is demonstrated and confirmed statistically. The issue of how to statistically test interaction is beyond the scope of this chapter. In summary, subgroup analysis can be informative, but there are certain rules of play, among which the most important is probably interpretation of subgroup analyses cautiously and with reservation.

CRITICAL APPRAISAL II: ISSUES PERTAINING TO OBSERVATIONAL STUDIES TYPES OF COHORTS Usually, observational research involves the prospective follow-up of a group of individuals (cohort) with regard to a particular outcome. That outcome can be an event (e.g., death, clinical remission) but can also be a disease activity state over time (e.g., time-averaged disease activity state, mean swollen joint count). The types of cohorts that may be encountered in the literature can grossly be divided into two: healthy cohorts and clinical cohorts. It is relevant for the reader of an article to realize what type of cohort is being studied.

Healthy cohorts Healthy cohorts are large cohorts of individuals who are healthy with respect to the outcome of interest (although possibly not in other aspects). Frequently, study subjects belong to some group of easily traceable individuals (e.g., nurses or physicians). The outcome of interest is usually simple and unequivocal (e.g., mortality), cohorts are large, and follow-up is typically long. The research question of interest might refer to an intervention but also to a potential risk factor or an exposure. Famous examples of healthy cohort studies are the Baltimore Longitudinal Study of Aging, the Framingham study, the Johns Hopkins Precursors Study, and the Nurses Health Cohort. Very often and understandably, these large cohorts are used to address multiple different study questions and are sometimes therefore referred to as “multipurpose cohorts.”

Clinical cohorts Clinical cohorts include patients with one or more features in common who are observed for a definite or indefinite time with respect to one or more primary outcomes. There are several types of clinical cohorts. Inception cohorts include and follow all patients in whom a particular disease is diagnosed (disease duration at baseline = 0). Prevalence cohorts include and follow patients with a particular disease at a certain point in time (disease duration at baseline >0). Patient registries include and follow patients with a particular disease and a particular feature (e.g., patients with RA who start

a particular treatment). The distinction between cohorts and registries is subtle and frequently, but not always, relates to the time of follow-up. (see also Use of registries) A cohort generally has a previously defined (limited) follow-up (although this follow-up duration is often adjusted over time); a registry has, in principle, an undefined (unlimited) follow-up duration. A particular type of an observational cohort that is frequently seen in rheumatology is the follow-up cohort of an RCT, the purpose of which is often to investigate whether a particular effect seen in an RCT can be sustained over a longer period. Occasionally, trial arms of the original RCT are preserved during the follow-up period, but often they are not. Importantly, results from follow-up studies of RCTs should not be interpreted as though they have the same scientific rigor as the RCT itself. The prognostic similarity created by randomization exists only at baseline and is increasingly lost over time, particularly when trial blinding is unveiled and patients are asked to continue in a follow-up study. The type of longitudinal bias that might arise is discussed in the next section. One specific limitation of such cohorts with regard to generalizability is that patients in the cohort stem from a clinical trial and reflect a population with relatively severe disease, high disease activity at baseline, and so on. One should keep in mind that relatively mild cases are by definition not included in the cohort, which has implications for the interpretability of prognostic variables derived from such cohorts. Rules for analyzing and interpreting long-term observational studies following RCTs have recently been released.10

Use of registries Registries have proven extremely useful in rheumatology to evaluate the long-term safety of new drugs. Rare adverse drug effects that are considered clinically relevant for public health, such as malignancies, fatal infections, or fatal thrombosis, often occur at a frequency of less than 1:500, far too few to raise suspicion in RCTs. Such events cannot be studied reliably in RCTs for several reasons. First, many of these rare events also occur at a certain rate in the unaffected population (background signal), and it requires large groups to create sufficient contrast between treated and untreated patients. Second, it may take far longer than the duration of an RCT before they occur. Third, RCTs often include relatively healthy patients (see also the section Internal validity and external validity) who inherently have lower likelihoods of rare events. Registries are a far better reflection of common clinical practice and provide better risk estimates for rare events. The field of rheumatology has fostered several useful nationwide registries over time, with funding by pharmaceutical industries. Good registries include patients with a particular disease treated with and without the treatment of interest. Proper control groups in registries have been of key importance for the interpretability of safety. Since treatment and control groups in registries are not formed by randomization but by physicians’ treatment decisions, confounding by indication always looms (see the later section Confounding by indication). Sophisticated analytical techniques (e.g., propensity matching) can partly overcome the disturbing influences of this type of bias but are not easily understood by clinical readers. It is only by relying on analytical results of registries that TNFi drugs can nowadays be considered safe with respect to inducing malignancies (an exception of relatively minor importance is nonmelanoma skin cancer) and a broad scope of far rarer events. It is because of registries that we, for example, know

CHAPTER 27  Interpreting the medical literature for the rheumatologist that the use of the IL-6 inhibitor tocilizumab is associated with an increased rate of lower gastrointestinal tract perforations. And it will be the registries that will give final resolution about whether or not the new class of JAK inhibitors will increase the risk of venous thromboembolism. The European League Against Rheumatism (EULAR) recommendations task forces for the management of RA, PsA, and axSpA rely for their assessment of long-term safety particularly on controlled data from nationwide registries and consider data from short-term RCTs or LTE thereof as insufficiently informative.

SELECTION BIAS Looking at the characteristics of observational studies as outlined earlier, it is obvious that they are a better reflection of common clinical practice than RCTs are, perhaps with the exception of follow-up studies of RCTs. This is also their major advantage. However, cohorts and registries are not unselected populations. A number of selection mechanisms might influence the interpretation of results; three well-known examples will be discussed.

Left-censorship bias Left-censorship bias can occur if patients with particular characteristics are inadvertently excluded from the observational cohort because they are simply not available. Suppose that you want to investigate the relationship between cyclooxygenase-2 (COX-2) inhibitors and cardiovascular morbidity in a database of 10,000 patients, including all prevalent patients with osteoarthritis. The study does not include patients who were at such high risk for cardiovascular death that the outcome (death) has already occurred before entry into the study. As a consequence, the observed mortality rate in this cohort might be an underestimate of the truth, especially if COX-2 inhibitors are particularly dangerous in high-risk patients. In general, left-censorship bias occurs at formation of the cohort or before the cohort is formed, it refers to selection based on differences in disease severity, and it is important only if severity is related to the outcome of interest. By definition, its influence is difficult to quantify, and it is impossible to adjust for left-censorship bias in the analysis.

Right-censorship bias Right-censorship bias is also known as “selective dropout” or “attrition.” Suppose, in an RCT using a COX-2 inhibitor, that patients at higher risk for adverse gastrointestinal (GI) events had a higher dropout rate than did those at low risk. This would lead to a spuriously low rate of adverse GI events in the patients who remain in any open follow-up. A type of right-censorship bias that most readers will be familiar with is bias by trial completion, or “completers” bias, which is often seen in follow-up studies of RCTs. Only patients who perceive that their treatment is effective or who tolerate it best (or both) remain in the study, which provides favorable study results for that drug. Right-censorship bias occurs when the composition of the cohort is determined during follow-up, refers to selection based on differences in disease severity or disease activity, and is important if severity or activity is associated with outcome. Right-censorship bias can be quantified and adjusted for in the analysis to some extent.

Confounding by indication Confounding by indication refers to the question of which patients begin treatment with which drug. Suppose, in a clinical practice setting, that patients at high risk for GI events are initially given COX-2 inhibitors and those at lower risk are given conventional nonsteroidal antiinflammatory drugs (NSAIDs). A higher event rate is found in patients treated with COX-2 inhibitors than in those treated with NSAIDs; however, the rate in these high-risk patients might still be lower than it would have been if they had been treated with conventional NSAIDs. Confounding by indication can occur before as well as after composition of the cohort; it refers to situations in which the severity of the disease determines the choice of treatment, and it is important if treatment and disease severity are both related to outcome. There are techniques such as propensity matching that quantify the severity of disease, so it is possible to some extent to adjust for confounding by indication.

CRITICAL APPRAISAL III: ISSUES PERTAINING TO RANDOMIZED CONTROLLED TRIALS AND OBSERVATIONAL STUDIES GENERALIZABILITY As argued earlier, the type of patients included in a study is of pivotal importance with respect to interpretation of the trial results. In efficacy trials,

219

statistical power—the probability that the trial confirms the superiority of a new treatment if such superiority truly exists—is of eminent importance. Discriminatory ability and sensitivity to change of the outcome measures are factors that contribute to statistical power. The outcome measures propagated for clinical trials in RA, such as the ACR11 and EULAR12 response criteria, perform best—and have been validated—in patient groups with high levels of disease activity, which is why most efficacy trials include such patients. In the spectrum of patients with RA, however, these patients do not constitute a majority, which may have implications for interpretation of the trial results. It is possible, if not likely, that many patients with RA with less active disease do not necessarily need the “new treatment” that tested most effectively in the efficacy trial but can do very well with the comparator drug. Another discrepancy between observational studies (clinical practice) and RCTs is the paucity of clinically relevant comorbid conditions in RCTs compared with clinical practice because patients with relevant comorbidities are usually excluded. Similar reasoning can be followed regarding compliance or, in general, any reason that increases the probability of premature discontinuation, nonresponse, or both. It is very important when appraising a report of a clinical trial to realize that the patients in the trial do not necessarily resemble individual patients in clinical practice and that such discrepancies may have consequences for translation of the trial results. Study reports should include all necessary information about disease activity, severity, and prognosis (which they often do), as well as information about relevant comorbidity and comedication (which they often exclude), to allow the reader an appropriate interpretation of generalizability.

MISSING DATA Ideally, RCTs and observational studies should provide complete data. In practice, however, studies without missing data do not exist: patients miss planned visits for whatever reason and do that more frequently than any investigator would consider acceptable; patients withdraw consent, lose motivation, and drop out; patients report adverse events to the investigator, who decides to discontinue the patient from the study; the investigator and patient are disappointed with regard to a drug effect and decide to stop; or a patient moves and gets lost to follow-up. All of these examples create missing data. Although the examples given here are very familiar to every reader (and will be considered inherent to clinical practice), the methodology, statistical analysis, and interpretation of the study results do not very well comply with the problem of missing data. It is crucial to realize the issue of missing data before the study starts and to consider scenarios on how to handle missing data. There is not one acceptable generic solution, but by far the worst solution is to entirely withdraw the patient from the analysis. Usually, discontinuation is a nonrandom process, which means that the reason why patients withdraw is somehow associated with disease severity and therefore with the probability of achieving an outcome or a treatment response (confounding). Ignoring these patients means that in a trial, treatment groups cannot be considered prognostically similar anymore, which is probably the most important violation of trial methodology that can be committed, and that in observational studies the results may be biased by selection. Data imputation is the only alternative. Imputation means that an imaginary, nonmeasured value is attributed to missing assessments so that the patient with missing data remains in the analysis, but the question obviously is what to impute. Nonresponder imputation is a popular and conservative means of data imputation in clinical trials with a response measure (e.g., ACR20) as the primary outcome variable. It simply attributes nonresponse to every patient who discontinues participation in the trial, irrespective of the reason for discontinuation. Last observation carried forward (LOCF) and baseline observation carried forward (BOCF) are popular means of imputing continuous data in which the last value or the baseline value that was actually measured, respectively, is imputed as a substitute for subsequent missing assessments. Worst-case scenarios impute the worst group value or the value representing the 95th percentile. Imputation of group means or group medians is also used. Linear interpolation can be useful if in-between data points are missed, and linear extrapolation is used if the expected time course follows an approximately linear trend. Finally, sophisticated computer algorithms (e.g., Bayesian, Markov chain, Monte Carlo multiple imputation procedure) are increasingly applied that use multiple imputation techniques, but this often goes at the cost of comprehensibility. Discussion of such techniques is beyond the scope of this chapter. As argued, there is not a single acceptable means of imputation. Nonresponder imputation usually works well if a predefined response is the outcome of interest, and LOCF seems to be a reasonably conservative approach for imputation of missing continuous data in a setting in which

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SECTION 2  Clinical Basis of Rheumatic Disease

treatment should improve a preexistent state (e.g., disease activity, physical function). In theory, trial results (i.e., the treatment contrast) should not be dependent on what means of data imputation is used for missing data. The only transparent way of confirming the robustness of the study result is to perform and show sensitivity analyses for the missing data. This means that different means of imputation are performed and the consequences checked with regard to the outcome of interest.

DATA INTERPRETATION Probably the most important means of communicating study results is by graphs. A well-designed graph provides far more information than does a table with comprehensive descriptive data, such as means, standard deviations, and so on. An appropriate graphic representation of the treatment results can provide a good idea about the relative efficacy of a new treatment in comparison to a control drug at first glance. Every reader of articles of RA clinical trials will be familiar with the informative bar graph representation of ACR20/50/70 responses per group. More cumbersome is the graphic representation of radiographic progression. The most frequently used Sharp– van der Heijde progression score usually has a skewed distribution, which means that the data are not normally distributed. Very often, a data set of radiographic progression scores includes a high number of zero-scores and a relatively low number of positive scores, with a minority of extreme progression scores at the right side of the spectrum. This feature means that the usual parametric descriptive statistics such as means and standard deviations do not appropriately reflect what has actually happened in the group. Medians and percentiles (25%, 75%) do a better job in that respect, but median progression in modern clinical trials of RA is often zero in the intervention and control groups, and progression is statistically significantly different. Probability plots have been proposed to fill in this gap in communication.13 A probability plot shows every individual change-score per trial arm; it is ordered from the lowest through the highest observed value and is plotted against its cumulative probability. By superposing the plots of the trial arms in one graph, it is clear at first glance how the groups have performed with respect to radiographic progression. Tabulation of data is important for several reasons: (1) to underscore the authors’ conclusions and make them transparent to critical appraisal, (2) to make additional inferences for data interpretation (examples are calculations for the number needed to treat and effect sizes for researchers interested in the performance of outcome measures), and (3) as a source for the metaanalyst. It is critical that the authors of a trial report realize that their data may be used for several scientific purposes, and they should provide sufficient information. It is difficult to give exact guidelines because the prerequisites are different for different outcome measures, but a few examples may help. When the ACR response is used as an outcome measure, it is crucial to report not only proportions but also crude numbers (nominator as well as denominator). When continuous outcome measures (e.g., swollen joint count, disease activity state) are reported, data about status, as well as change, should be provided as means and appropriate standard deviations (rather than meaningless standard errors of the mean), in addition to the actual number of patients used in the analysis. When distributions of continuous outcome measures are overtly skewed (e.g., radiographic progression scores), the investigators should present not only means and standard deviations but also medians and key percentiles (e.g., 25th, 75th).

THE STATISTICAL TEST The main goal of statistical analysis in the report of a trial or an observational study is to challenge the null hypothesis or, in other words, to find probabilistic support for a difference observed between treatments (trial) or for an (predictive) association (observational study). A second aim of statistical testing is to determine the robustness of a demonstrated effect. In contrast to what is often done, in reality, statistical analysis should take only a modest place in the report of a study because improper use of P values may jeopardize the scientific interpretation of a study.14 However, many authors cannot resist the attractiveness of “P < 0.0001” and build their articles around the statistical test result rather than the opposite. Unfortunately, many of these authors are unable to reproduce the correct interpretation of P < 0.0001 and counter critical questions about the relevance of the effect with, “It is highly statistically significant, though, isn’t it?” thus implying that the effect is clinically important. The P value is a probability, namely, the probability that even if it is assumed that the null hypothesis is correct, it is nevertheless rejected. This sentence is comprehensible only if one realizes that the clinical trial one is looking at is just one (random) example of many, let us say 1000, imaginary similar trials. Whoever accepts this will also accept that all 1000 imaginary

trials will have 1000 different results. The majority differ only slightly, a few will have more deviant results simply by coincidence, and a very few will even have extremely deviant results in either direction, but in truth, the difference should be zero! In theory, such differences could be of such a magnitude that they lead to rejecting the null hypothesis. We talk about erroneous rejection of the null hypothesis, or a type I error. The P value is the probability of a type I error. P < 0.0001 means that there is very, very small chance of a type I error. It could be said that the result is very robust and that such a P value adds to the credibility of the trial (internal validity). It does not say that the difference that was found is a relevant difference or that an effect is meaningful. Current efficacy trials are often so powerful in statistically underscoring small differences that very good P values can be obtained with treatment effects that are negligible when considered in the context of patient care. So, statistically significant does not imply clinically relevant. The opposite is also true: Not statistically significant does not mean not relevant or, in other words, “the absence of evidence is not the same as evidence of absence (of a meaningful effect),” a statement referring to type II error (see later). The second aim of statistical analysis is to determine how robust the trial results are. Actually, one is interested in the implications with respect to the size of the treatment effect. Usually, a 95% confidence interval (CI) is used to describe the bandwidth for estimates of the treatment effect. Elaborating on the discussion about P value, the 95% CI is best understandable by imagining that a particular trial is done 1000 times. Ninety-five percent of the time, the trial result (the estimate of the treatment effect) will lie between the limits of the 95% CI, but 5% of the time, the treatment effect will take a more extreme value. The relationship between P value and 95% CI is further clarified in Fig. 27.2. Suppose a clinical trial in patients with RA with two treatment arms (A vs B) and (improvement in) disease activity state as the outcome measure. Three possible treatment effects are plotted in a diagram that a reader of metaanalyses may be familiar with. The zero treatment effect reflects the level of equivalence. All three scenarios represent a trial result in which treatment B is better than treatment A (more improvement in disease activity state with B than with A). The P values are presented per scenario. The arrows represent the 95% CIs around the mean improvements in disease activity state. Note that the 95% CIs of scenarios A and C lie entirely to the right of zero. Both treatment effects are statistically significant (P < 0.05); the null hypothesis of “no difference” is rejected. Note that the 95% CI in scenario B crosses zero. The treatment effect is not statistically significant (P = 0.05); the null hypothesis is not rejected. Note also that notwithstanding a smaller treatment effect in scenario C than in scenario B, the treatment effect in C is statistically significant, as represented by a narrower 95% CI. We say that the trial result is more precise. It is the combination of statistical information and information about the preciseness of the treatment effect that makes 95% CIs such attractive tools in clinical trials. To improve information exchange and interpretation of trial results, it is almost mandatory to present 95% CIs around the mean treatment effects and not only P values. As with many generic rules, the balance occasionally dips to the other side: It is not particularly useful and often confusing to present 95% CIs of variables not related to treatment effects (or related to hypothesis testing). An example is the presentation of 95% CIs around the mean 28-Item Disease Activity Score (DAS28) at baseline.

Conflict of interests A conflict of interest (COI) is a situation in which a person (e.g., a researcher-physician) or a particular organization (e.g., a hospital department or a guideline committee) is involved in multiple interests, often financial but also otherwise (e.g., scientific credits, publications). Serving one interest

TREATMENT EFFECTS

A

P = 0.01

B

P = 0.1

C

P = 0.04 Treatment A better

0

Treatment B better

FIG. 27.2  Treatment effects and 95% confidence intervals of three potential scenarios (A, B, and C) for an imaginary clinical trial comparing treatment A and treatment B. See text for clarification.

CHAPTER 27  Interpreting the medical literature for the rheumatologist may work against another interest, and a situation of conflicting loyalties may arise that determines the content of the relationship and may influence the public opinion. Potential COI is the situation in which a real COI has not (yet) been proven but the appearance of such is enough to put the relationship under public scrutiny. The classic example of potential COI in medicine is the clinical researcher lead authoring an article for a journal about a drug developed by a pharmaceutical company. The motives of the researcher may be truly altruistic and scientific, aiming at alleviating patients’ suffering (e.g., effective medicines). But at the same time, a precious lead authorship of a scientific article may also foster the career of a clinical researcher and make this researcher less “suspicious” of conflicting loyalties. Occasionally, a purely financial arrangement is the main motive. The interests of profit-aiming pharmaceutical industry are financial by default; this is not meant here as a disqualification. The means by which pharmaceutical companies in the Western world operate is legal and in general societally accepted, but many consider the principle of profit-making as being at odds with the supposedly altruistic principles that drive physicians. In general, it is extremely difficult to track down the real reasons for a researcher to liaise with a pharmaceutical company, which means that potential COI always looms. While no measure will protect us from those with immoral intentions, there is consensus that the best way to deal with potential COI is to make all financial and nonfinancial bonds that exist between parties public. This is nowadays considered good clinical practice and increasingly required by conference boards and editors of scientific journals. A commonly made mistake by individual researchers is that they waive this moral obligation using the argument that a potential COI in their case is not a real one: they claim that they did not receive financial compensation. This argument fails since potential and real should be judged from the perspective of the public instead of the individual researcher. Declaring COI is an investment in trust. Leave it to the readers of your articles, or the attendants of your talks, to decide if your work deserves their trust in light of what you have transparently declared as potential COI. Guideline committees in some countries may take a more principal stand: They sometimes refuse committee members who have declared potential COIs. This is a highly debated stand in a world in which most physicians, especially those with relevant knowledge and expertise of the matter, maintain contacts with profit-making industries. Forbidding them to take part in guideline committees implies that their potential COIs, declared by them in good faith, are considered real COIs, and consequently their knowledge and expertise are wasted.

CONCLUSION In this chapter, a wide array of points to consider in the critical appraisal of RCTs and observational studies have been addressed. Emphasis is placed on

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issues referring to external validity or generalizability because that is what most rheumatologists need to know. As mentioned in the Introduction, the choice of issues addressed is subjective, and the chapter is by no means intended to cover everything that is important in appraising study data. It is hoped that the points raised will increase awareness of the importance of the interplay between the clinical investigator responsible for the study report and the consumer of the data, often the clinician, who has to decide about application of the study results to the area of clinical medicine, which affects individual patients. Only appropriate communication in this area will ultimately improve patient care.

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Guyatt GH, Sackett DL, Cook DJ. Users’ guides to the medical literature: II. How to use an article about therapy or prevention: A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA. 1993;270:2598–2601. Guyatt GH, Sackett DL, Cook DJ. Users’ guides to the medical literature: II. How to use an article about therapy or prevention: B. What were the results and will they help me in caring for my patients? Evidence-Based Medicine Working Group. JAMA. 1994;271:59–63. Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomized controlled trials—the CONSORT statement. JAMA. 1996;276:637–639. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147:573–577. Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Ann Intern Med. 2007;147:W163–W194. Oxford Centre for Evidence-Based Medicine. Levels of evidence. Available at: www.cebm. net/index.aspx?o=1025, 2012. McMahon AD. Study control, violators, inclusion criteria and defining explanatory and pragmatic trials. Stat Med. 2002;21:1365–1376. Landewé RBM, van der Heijde D. New concepts of clinical trials in rheumatoid arthritis: a boom of noninferiority trials. Curr Opin Rheumatol. 2016;28(3):316–322. Landewé RB, Smolen JS, Weinblatt ME, et al. Can we improve the performance and reporting of investigator-initiated clinical trials? Rheumatoid arthritis as an example. Ann Rheum Dis. 2014;73(10):1755–1760. Buch MH, Silva-Fernandez L, Carmona L, et al. Development of EULAR recommendations for the reporting of clinical trial extension studies in rheumatology. Ann Rheum Dis. 2015;74:963–969. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727–735. van Riel PL, van Gestel AM, van de Putte LB. Development and validation of response criteria in rheumatoid arthritis: steps towards an international consensus on prognostic markers. Br J Rheumatol. 1996;35(suppl 2):4–7. Landewe R, van der Heijde D. Radiographic progression depicted by probability plots: presenting data with optimal use of individual values. Arthritis Rheum. 2004;50:699–706. Goodman SN. Aligning statistical and scientific reasoning: misunderstanding and misuse of statistical significance impedesceince. Science. 2016;352:1180–1181.

28

Ethics in clinical trials Paul L. Romain • Robert H. Shmerling

Key Points ■ Ethical challenges are common in the design and implementation of clinical research. ■ Notable abuses of clinical research subjects during the 20th century have been an impetus for the development of widely accepted ethical guidelines for research on human subjects. ■ While ethical guidelines exist to protect the rights and welfare of clinical trial participants, vigilance is warranted to reassess their relevance, revise them as needed, and ensure adherence.

INTRODUCTION Clinical research trials seek to generate useful and generalizable medical knowledge; to do so, they must recruit the participation of human subjects. However, these individuals may or may not personally benefit by enrolling in the trial and through their participation may experience harm. Indeed, through the design of a clinical trial, an investigator or sponsor has the potential to influence trial outcomes and could focus on how to maximize the likelihood of a powerful or positive result at the expense of individual study participants. For example, a placebo arm or the use of a suboptimal comparator may make it easier to demonstrate the activity or apparent superiority, respectively, of a new drug, but study subjects randomized to receive placebo or the inadequate therapy may be undertreated; this is particularly important when effective treatments are already available for the condition being studied. Therefore, “ethical guardrails” with policies and procedures to encourage their application have been developed to facilitate just and humane clinical research. This chapter describes key elements of ethical clinical research and some of the ethical challenges facing clinical researchers and study subjects, and it explores some of the ways these challenges may be addressed. Conflicts of interest, important considerations in any clinical research, are covered elsewhere (see Chapter 27); a comprehensive review of the conduct and regulation of clinical research involving human subjects, including the design and performance of clinical trials and the regulatory process for drug approvals, is also beyond the scope of this chapter.

“ETHICAL GUARDRAILS” IN CLINICAL RESEARCH By its very nature, clinical research involving human subjects presents a number of ethical challenges,1–6 and these have led to the development of a number of the guidelines, regulations, and codes that are operational today. Many of these were created in the wake of horrifying abuse of human subjects, including the Nazi experimentation with prisoners during the Holocaust7,8; the Tuskegee Syphilis Study of untreated syphilis9; human radiation experiments, which were carried out by the US government10; and the Willowbrook hepatitis experiments, in which children with intellectual disabilities were intentionally infected with viral hepatitis.11 Cloaked under the guise of scientific research, these “trials” are now understood as clear violations of the most basic tenets of ethical medical care and principles of respect for human subjects, including autonomy, beneficence, nonmaleficence, and justice.1,12 Less dramatic yet pervasive lapses in the conduct of research involving human subjects have also been highlighted in more recent decades as the recognition has drawn attention to the clinical research enterprise.2,13 As a result, panels of experts, researchers, and ethicists created recommendations in an effort to ensure clinical research is scientifically and ethically sound. These included provisions we may now take for granted, including requirements that trials have a scientifically justifiable design, provide informed consent, minimize risks to study subjects, and protect vulnerable groups. When viewed in the context of what came before they existed, these documents have substantially changed the clinical research landscape. Some of the most groundbreaking and impactful of these include: 222

The Nuremberg Code14 n The Declaration of Helsinki15 n The Belmont Report12 n The International Ethical Guidelines for Health-related Research Involving Human Subjects16 n The World Health Organization’s Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products17 In addition, the Food and Drug Administration (FDA) has issued multiple iterations of recommendations and regulations for clinical trials researchers,18 including the Federal Policy for the Protection of Human Subjects (termed the “Common Rule”), which was updated in 2017 and enacted over several years.19 The regulations that form the revised Common Rule describe the standards for any US government–funded biomedical and behavioral health human research and is also widely applied regardless of funding source by academic institutions in the United States. The main elements of the regulations include requirements for the following: assuring compliance by institutions that conduct research; securing and documenting informed consent; and institutional review board (IRB) composition and function, including the review of research. It also specifies protections for several classes of vulnerable research subjects, including pregnant women, fetuses and children, and prisoners, as well as in vitro fertilization. The development of ethical guidelines in recent decades represents enormous progress in the promotion and implementation of ethical clinical trials, although ethical challenges in all disciplines of medicine, including rheumatology,20,21 continue to arise. This makes it especially important to maintain vigilance regarding adherence to ethical standards and to reassess, recalibrate, and revise these policies and guidelines over time. n

KEY PRINCIPLES FOR ETHICAL CLINICAL TRIALS Despite their importance, most of the regulatory guidelines had their genesis in response to problems raised by specific research-related scandals, such as deception, lack of consent, and lack of disclosure, and/or were designed to provide specific regulatory guidance. Not surprising, the specific dicta in these guidelines can be inconsistent, and exceptions to their applicability may arise.22 A further advance for the protection of research subjects from exploitation and the critical evaluation and testing of research guidelines has been the development by Emanuel and colleagues from the US National Institutes of Health of a more comprehensive and systematic framework to describe the key principles that underlie ethical clinical research.5,22–24 This framework includes seven key components, briefly summarized here in the order they would need to be considered in developing and performing a clinical trial: n Social and clinical value—Ethical research should lead to advancement in generalizable knowledge or improvements in health; it should consider the consequences for the research subjects and other present or future patients, as well as others in the community and elsewhere in the world. This promotes nonexploitation and good use of scarce resources. Examples of low-value or valueless research may include research that is not disseminated, “me-too” studies that are not needed for confirmation of prior results, and nongeneralizable research. n Scientific validity—The research should use rigorous scientific methods and be practically feasible and should produce reliable, valid, and interpretable results. As with social value, scientifically valid research promotes nonexploitation and good use of scarce resources. Research that is designed in a way that introduces bias in the allocation of subjects, the comparisons chosen, or its number of subjects or outcome measures may fail to meet this requirement. n Fair subject selection—Individuals and groups should be recruited and enrolled for studies based on the scientific goals of the research, and those most likely to benefit should share the benefits and burdens. This approach to study participation promotes the principle of justice, unlike the use of vulnerable classes of subjects for risky research and

CHAPTER 28  Ethics in clinical trials

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the enrollment of rich or privileged persons for potentially beneficial research. Similarly, certain groups (e.g., women or ethnic minorities) should not be excluded from participation unless they are particularly susceptible to risk or there is another scientifically valid reason for their exclusion. n Favorable risk–benefit ratio—Physical, psychological, economic, and social risks, as well as inconvenience, should be minimized for research subjects, while maximizing potential benefits, and the benefits to individuals and society should outweigh or be proportional to the risks. Ethical principles promoted by a favorable risk–benefit ratio include nonmaleficence, nonexploitation, and beneficence. Although research subjects may receive some health services due to their participation, the provision of such benefits is not the purpose of clinical research. Uncertainty regarding risks and benefits tends to be even greater in early (phases 1 and 2) than in later (phases 3 and 4) research trials. n Independent review—Independent review of research design, subject selection, and risk–benefit estimates can help to reduce the potentially negative effects of the multiple conflicts of interest that investigators may have25 and helps to support public accountability and ensure that society does not benefit from the abuse of subjects. Such review requires relevant expertise and is typically performed, depending on the locale, by granting agencies and local institutional review boards (human research committees) before and during studies and by data and safety monitoring boards during clinical trials. Independent review should be performed by groups without a vested interest in the study itself. n Informed consent—This process, which is required out of respect for patient autonomy, ensures that potential research subjects are accurately informed regarding the purpose, methods, risks, benefits, and alternatives to the research. The subject should have the capacity to understand the information and how it relates to them and make a voluntary decision to participate in the research. Exceptions to the need for individual informed consent may include children or adults lacking decision-making capacity, for whom a surrogate decision maker may provide consent on behalf of the prospective subject; the surrogate’s view should be based on what decision the research participant would have made if they were able to do so and be directed by an understanding of the prospective subject’s values and interests. Newer clinical research methods, such as the use of the Internet and of mobile devices, pose novel challenges and require critical examination to ensure ethical informed consent processes.26 n Respect for potential and enrolled subjects—Throughout the research process there is an obligation to protect confidentiality, permit subjects to withdraw from the research, provide new information regarding risks and benefits that becomes available (particularly when it may affect their decision to participate), and monitor the subject’s welfare. These requirements, together with informing the subjects of what was learned from the research, promote the values of respect for the subject’s autonomy and welfare. All of the elements described above are required for ethical clinical research, although exceptions may exist (e.g., lack of informed consent for research of certain medical emergencies), and sometimes maximizing a given value may conflict with optimizing another. In such cases research design may need to be adjusted to balance the requirements for a specific ­situation. Although all of the requirements are considered both necessary and (collectively) sufficient, they need to be appropriately adapted to the health, cultural, technologic, and economic conditions in which the research is undertaken. An eighth requirement—collaborative partnership—is sometimes included explicitly in this ethical framework but may be implicit in some of the other requirements, such as social and clinical value and fair subject selection. Collaborative partnership requires community participation in the planning, conduct, and oversight of research, and research results should be integrated into the health system where it takes place. This issue is especially relevant to international research performed in the developing world by outside sponsors. Examples of mechanisms to enhance collaborative partnership include community advocates on local advisory boards and patient advocates on scientific advisory committees.

to investigators and ethicists,13,27–29 because their use allows for the greatest “methodologic rigor,” as well as often serving to meet some regulatory requirements for drug approval. However, placebo comparisons may expose the patient to substantial risk of temporary or permanent discomfort, injury, or death. Accordingly, the Declaration of Helsinki advocates that the “benefits, risk, burdens, and effectiveness of a new method should be tested against those of the best current … methods.”15 This approach is particularly relevant in rheumatology, where use of a placebo, for example, in a patient with inflammatory arthritis has the potential to result in permanent joint damage and in systemic lupus erythematosus may result in critical and potentially irreversible critical organ involvement. The potential for such risk needs to be minimized and depends on an estimate of the duration of placebo use that may be judged as safe and on the condition and type of patients under study. However, use of active comparators requires that optimal clinically effective and safe doses of the active comparator be used for the study to be clinically useful, have societal value, show a justifiable risk– benefit ratio, and avoid misleading conclusions.21 Thus, in circumstances in which effective treatments are available and some potential for harm may arise as a result of using a placebo, there should be a compelling methodologic advantage to justify the use of a placebo design. It has been suggested that situations in which placebos may be justified include conditions with a high frequency of placebo responses, those with a waxing and waning clinical course or frequent spontaneous remissions, those for which existing therapies are only partly effective or have led to serious side effects, and those conditions that are sufficiently uncommon that methodologic considerations make a trial of sufficient size to demonstrate a clinically meaningful difference not feasible.29 “Therapeutic misconception” impacts several elements important to ethical trials. This term refers to the fact that study subjects may not appreciate the difference between clinical care and clinical research: the former is intended to improve the well-being of the patient, whereas the latter is intended to contribute to generalizable knowledge of the condition under investigation.30–32 Precise definitions of therapeutic misconception are a matter of debate.33,34 One proposed definition is that “therapeutic misconception exists when individuals do not understand that the defining purpose of clinical research is to produce generalizable knowledge, regardless of whether the subjects enrolled in the trial may potentially benefit from the intervention under study or from other aspects of the clinical trial.”35 Patients may carry the expectation into the research setting that their personal interests will be attended to and that their participation will not result in a loss of individualized care and treatment optimization that characterize the clinical encounter. Therapeutic misconception may be difficult to dispel and poses challenges for informed consent, although how to approach these issues is a matter of debate as well.33–36 Henderson and colleagues have suggested that the following dimensions of research should be understood by research participants: the scientific purpose of the trial; the study procedures, the uncertainty inherent in the trial (including clinical equipoise) regarding the efficacy and the safety of the intervention that is being tested, the general adherence of trials to defined protocols, and that in the setting of the trial (and unlike in the health care setting) any clinicians involved as trial investigators have the role of the researcher; that is, to evaluate the efficacy and safety of the intervention under study.33,35

SELECTED CHALLENGES IN CLINICAL TRIAL ETHICS

ACKNOWLEDGMENT

Several complex ethical issues merit particular mention. These include the selection of comparators and use of placebo and recognition and management of the therapeutic misconception, which impact subject selection, recruitment, and informed consent. The selection of comparators for randomized clinical trials poses particular challenges, and the use of placebos has been a matter of great interest

REFERENCES

CONCLUSION Clinical trials are a central tool of medical research that enhances our ability to improve the care of patients with rheumatologic and other disorders. Advancing the care of patients through research involving clinical trials carries great potential for both benefit and harm. Thus it is of utmost importance in the conduct of clinical trials that investigators, institutions, and governments adopt systems and practices that are ethically sound. Practices that effectively incorporate and balance the respective ethical dimensions of clinical research will not only help to avoid the exploitation of research subjects and maintain public trust and support of clinical research but also advance clinical science and the medical care and health of the individual, the community, and society as a whole.

The authors acknowledge the contributions of C. Ronald MacKenzie, MD, who was the author of this chapter in the previous edition.

1. 2.

Rothman D. Ethics and human experimentation. N Engl J Med. 1987;317:1195–1199. Beecher HK. Ethics and clinical research. N Engl J Med. 1966;274:1354–1360.

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3. Beauchamp TL, Childress JF. Principles of Biomedical Ethics, 5th ed., Oxford: Oxford University Press; 2001. 4. Emanuel EJ, Grady C, Crouch RA, et al. The Oxford Textbook of Clinical Research Ethics. Oxford: Oxford University Press; 2008. 5. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA. 2000;283:2701–2711. 6. Lefor AT. Scientific misconduct and unethical human experimentation: historic parallels and moral implications. Nutrition. 2005;21:878–882. 7. Bagatur E. Nazi medicine—part 1: musculoskeletal experimentation on concentration camp prisoners during World War II. Clin Orthop Relat Res. 2018;476:1899–1905. 8. Bagatur E. Nazi medicine—part 2: the downfall of a profession and Pernkopf’s anatomy atlas. Clin Orthop Relat Res. 2018;476:2123–2127. 9. Brandt AM. Racism and research: the case of the Tuskegee Syphilis Study. Hastings Cent Rep. 1978;6:21–29. 10. McCally M, Cassel C, Kimball DG. U.S. government–sponsored radiation research on humans 1945–1975. Med Glob Surviv. 1994;1:4–17. 11. Krugman S. The Willowbrook hepatitis studies revisited: ethical aspects. Reviews of infectious diseases. 1986;8:157–162. 12. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont report: ethical principles and guidelines for the protection of human subjects of research. Available at: https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html. Accessed July 16, 2020. 13. Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. 1994;331:394–398. 14. The Nuremberg Code, 1949. Available at: https://history.nih.gov/display/history/ Niremberg+Code. Accessed July 16, 2020. 15. World Medical Assembly. Declaration of Helsinki. Available at https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. 16. Council for International Organizations of Medical Sciences. International ethical guidelines for biomedical research involving human subjects. Geneva 2016. Available at: https:// cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf Accessed July 16, 2020. 17. Proposed WHO guidelines for good clinical practice (GCP) for trials on pharmaceutical products. WHO drug information 1992. Available at: https://apps.who.int/iris/handle/10665/47572. Accessed July 16, 2020. 18. FDA Regulations: Good Clinical Practice and Clinical Trials. Available at: https://www.fda. gov/science-research/clinical-trials-and-human-subject-protection/regulations-good-clinical-practice-and-clinical-trials. Accessed July 16, 2020.

19. Federal Policy for the Protection of Human Subjects (‘Common Rule’), 2018. Available at: https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=83cd09e1c0f5c6937cd9d7513160fc3f&pitd=20180719&n=pt45.1.46&r=PART&ty=HTML. Accessed July 16, 2020. 20. MacKenzie CR, Meltzer M, Kitsis EA, Mancuso CA. Ethical challenges in rheumatol ogy: a survey of the American College of Rheumatology membership. Arthritis Rheum. 2013;65:2524–2532. 21. Shmerling RH. Editorial: the ethics of recent gout trials. Arthritis Rheumatol. 2016;68:2057–2060. 22. Emanuel EJ, Wendler D, Grady C. An ethical framework for biomedical research. In: Emanuel EJ, Grady C, Crouch RA, et al. The Oxford Textbook of Clinical Research Ethics. Oxford: Oxford University Press,; 2008:123–135. 23. Emanuel EJ, Wendler D, Killen J, Grady C. What makes clinical research in developing countries ethical? The benchmarks of ethical research. J Infect Dis. 2004;189:930–937. 24. NIH Clinical Center: Ethics in Clinical Research. May 11, 2020 update. Available at: https:// clinicalcenter.nih.gov/recruit/ethics.html#:~:text=But%20by%20placing%20some%20people,the%20integrity%20of%20the%20science. Accessed July 16, 2020. 25. Romain PL. Conflicts of interest in research: looking out for number one means keeping the primary interest front and center. Curr Rev Musculoskelet Med. 2015;8:122–127. 26. Grady C, Cummings SR, Rowbotham MC, et al. Informed consent. N Engl J Med. 2017;376:856–867. 27. Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments, part I: ethical and scientific issues. Ann Intern Med. 2000;133:455–463. 28. Freedman B. Placebo-controlled trials and the logic of clinical purpose. IRB. 1990;12:1–6. 29. Emanuel EJ, Miller FG. The ethics of placebo-controlled trials: a middle ground. N Engl J Med. 2001;345:915–919. 30. Appelbaum PS, Roth LH, Lidz CW, et al. False hopes and best data: consent to research and the therapeutic misconception. Hastings Cent Rep. 1987;17:20–24. 31. Hochhauser M. Therapeutic misconception and recruiting doublespeak in the informed consent process. IRB. 2002;24:11–12. 32. Levine RJ. The distinction between research and treatment. In: RJ Levine, Ethics and Regulation of Clinical Research. 2nd ed. Vienna: Urban and Schwarzenberg; 1986. 33. Churchill LR, King NMP, Henderson GE. Why we should continue to worry about the therapeutic misconception. J Clin Ethics. 2013;24:381–386. 34. Wendler DS. Time to stop worrying about the therapeutic misconception. J Clin Ethics. 2012;23:272–289. 35. Henderson GE, Churchill LR, Davis AM, et al. Clinical trials and medical care: defining the therapeutic misconception. PLoS Med. 2007;4:e324. 36. Romain PL. Access to clinical care via clinical trials: is it ethically possible? Nat Clin Pract Rheumatol. 2008;4:166–167.

Section

3

APPROACH TO THE PATIENT

History and physical examination Anthony D. Woolf

Key Points ■ The management of any musculoskeletal problem requires assessing its cause and effect and understanding the needs and expectations of the person. ■ History taking is the most important skill in rheumatology. ■ The physical examination is pivotal in confirming the cause of musculoskeletal problems. ■ Assessment of the musculoskeletal system should form part of any general medical examination. ■ History and examination characterize the problem and identify the syndrome, which, combined with knowledge and investigations, leads to the diagnosis. ■ The consultation involves a patient-centered phase for the patient’s story; a physician-centered phase to clarify the story by interrogation and examination; and an interactive phase during which the patient and physician discuss their concerns, findings, and conclusions and come to a shared decision on management plans. ■ The consultation and its outcome must meet the expectations of the patient.

INTRODUCTION Musculoskeletal complaints are among the most common symptoms and are the greatest cause of disability globally. Their management is not just of any underlying condition or disease process but must meet the needs and expectations of the person, which is usually to be able to do what they want without pain. This requires the cause and effect of any musculoskeletal problem to be established. Any clinician evaluating such patients needs to characterize the problem and its impact; establish the cause; and develop and communicate a management plan. If unable to identify the cause, the clinician must at least be able to describe the abnormality and recognize whether it is important and requires a more skilled assessment. When the person is reviewed, the clinician must be able to assess response to treatment and be able to recognize the lack of expected response. Musculoskeletal problems may be part of other diseases. Musculoskeletal conditions are also a frequent part of multimorbidity, particularly with aging. A holistic and integrated approach therefore needs to be taken with assessment and management. Many common musculoskeletal problems can be managed effectively in the community by the primary care team, but other less common or more serious problems require specialist management, often within the context of a multidisciplinary team. Different competencies are needed for these different levels and models of care and different members of the team.1 All clinicians who may encounter someone with a musculoskeletal problem should be able to recognize an abnormality of the musculoskeletal system and whether it is important by being able to perform a screening assessment in combination with basic knowledge of musculoskeletal conditions.2 A clinician providing more expert management will require greater competency in clinical assessment, more detailed knowledge of the possible causes, and knowledge of the use of investigations to make a diagnosis. In this chapter, a basic screening assessment of the musculoskeletal system is described that is appropriate as part of a general examination to

29

identify whether any abnormality is present. A more detailed evaluation of a person with a musculoskeletal problem is also presented. From such assessment, the syndrome that the person is complaining of should be identified, and with appropriate knowledge and investigation, a differential diagnosis should be possible. The needs and expectations of the person with the musculoskeletal complaint must be considered to ensure a patient-centered care plan with clear goals that focus not just on managing the condition but also on knowing what is important to the person and enabling them to fully participate in what he or she wants and needs to do.

SCREENING ASSESSMENT Musculoskeletal conditions should always be sought by routine screening as part of any general history and examination. If an abnormality is identified, a more detailed assessment is necessary. This screen takes only a few minutes and is easy to annotate, so it can be part of the routine examination of all patients. It has been validated in a general medical setting and within undergraduate training.3 All clinicians should be able to perform this.

SCREENING HISTORY The common symptoms of any musculoskeletal condition are pain, stiffness, and limitation of function. Joint disease is often associated with swelling. Sensitive functional tests are (1) the ability to dress without difficulty, including socks and shoes, which is a complex activity that uses both the upper and lower limbs; and (2) the ability to ascend and descend stairs without difficulty, which is sensitive in detecting abnormality in the lower limbs. The following screening questions will quickly establish the presence or absence of major musculoskeletal problems. ■ Do you have any pain or stiffness in your arms, legs, neck, or back? ■ Do you have any swelling of your joints? ■ Do you have any difficulty washing and dressing? ■ Do you have any difficulty going up or down stairs or steps? Musculoskeletal conditions are often associated with fatigue, anxiety, and depression and other systemic features. General inquiry should be made about the person’s health.

SCREENING EXAMINATION Any significant abnormalities of the spine, arms, or legs should be identified by inspection at rest and during certain movements and with brief palpation and stress tests of selected joints. Normality is looked for in the appearance, posture, and resting position of the joints and in smooth movement through the expected normal range. Whenever any joint is affected by a musculoskeletal condition, one movement is usually nearly always affected, which is assessed in this screening. The gait, arms, legs, and spine (GALS) should be assessed. ■ Gait. Observe the patient walking forward for a few feet, turning, and walking back again. Abnormalities in the different phases should be 225

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SECTION 3  Approach to the Patient

recognized: heel strike, stance phase, toe-off, and swing phase. Look for abnormalities in movement of the arms, pelvis, hips, knees, ankles, and feet during these phases. ■ Inspection of the standing patient. View the patient from the back, side, and front to look for any abnormalities, in particular, abnormalities in posture and symmetry. Examine for tenderness by applying pressure at the midpoint of each supraspinatus muscle and rolling an overlying skinfold. ■ Spine. Ask the patient to flex and extend the neck and rotate it laterally to each side. Place several fingers on the lumbar spinous processes, ask the patient to bend forward and attempt to touch the toes while standing with the legs fully extended, and observe and feel for normal movement of the spine. ■ Arms. Ask the patient to place both hands behind the head with the elbows fully back. This is a sensitive test for many components of the shoulder apparatus. Straighten the arms down to the side of the body and then inspect with the patient’s elbows bent to 90 degrees, palms down, and fingers straight. Turn the hands over and make a tight fist with each hand. Place, in turn, the tip of each finger on the tip of the thumb. Squeeze the metacarpals from the second to the fifth. ■ Legs. With the patient reclining on an examination table, flex each hip and knee in turn while holding and feeling the knee. Then passively rotate the hip internally. With the patient’s leg extended and resting on the table, examine for tenderness or swelling of the knee by pressing down on the patella while cupping it proximally. Squeeze all the metatarsals and finally inspect the soles of the feet for callosities. Any abnormalities identified should be documented so that they can be assessed more completely.

ASSESSING A MUSCULOSKELETAL PROBLEM AIMS AND KEY PRINCIPLES The management of someone who presents with or is identified at screening as having a musculoskeletal problem requires the characterization of the problem that he or she is complaining of to identify the syndrome and offer a differential diagnosis. Then, with knowledge of musculoskeletal conditions and appropriate investigations, a clinical diagnosis can be made. The impact the problem has on the person and her or his needs and expectations must also be understood for an appropriate management plan to be developed and mutually agreed on. Musculoskeletal problems are the most pervasive of conditions that affect all aspects of life. This understanding is central to providing person-centered care that meets the whole needs of the person and not just providing a disease management approach. Assessment of a person’s musculoskeletal problem requires good clinical skills and knowledge of functional anatomy, the features of common musculoskeletal conditions, their complications and risk factors, and the role of investigations. Pattern recognition is important and gained from knowledge and experience (vide infra). However, musculoskeletal conditions are common and can coexist. It should not be assumed that each symptom relates to a single diagnosis. The consultation must fulfill the expectations of the patient, and his or her concerns must be identified and met (Table 29.1). A common complaint is that they were not listened to but talked to. The patient must share in decision making about their management and have a full understanding of the management plan and what treatment response and prognosis to expect. This is of particular importance because often the patient’s expectations cannot be met, and some treatments do not have an immediate benefit. It is important therefore that the physician shows empathy and gains the confidence of the person and establishes a relationship of trust and understanding. The person must have the ability to actively participate in her or his management, for which she or he requires knowledge and support. This is most important if the condition is chronic. The physician has a key role but can be supported by other approaches such as the use of educational materials (printed and online); self-help groups; and other health workers, such as rheumatology nurses, physician assistants, occupational and physical therapists, podiatrists, and social workers, as appropriate. If a person is being reassessed, response to treatment needs to be determined both in terms of the disease process and the impact of the problem. It must be compared with the expected response to mutually decide whether any modification of the management plan is needed. Many standardized assessments for musculoskeletal conditions can be used to measure impact and monitor response to treatment. Patient-relevant outcome measures should be used when possible.

Table 29.1a

What Is the Patient’s Expectation of the Consultation? Nature of the problem Management of the problem

n

what is wrong, what is the cause of my problem?

n

what can be done to help my problem? what treatment is most appropriate? how do I manage pain and use pain medications? what management options are there beyond medications? what can I do to help myself? where can I get self-help resources and support?

n n n n

Information and support Activities

n n n

Future

n n n

what activities can I do? whether and when can I do the things I need and want to do? how am I progressing? have I improved? what might the future bring? what else can be done?

Table 29.1b

What Are the Patient’s Expectations of the Clinician? Good communication skills

n

Appreciation of impact

n

Being supportive Willingness to discuss alternative and complementary therapies Shared decision making

n

Awareness of own limitations and when to refer

n

n

n

able to listen, to put people at ease, and to make them feel comfortable to ask questions being empathic and able to appreciate the impact of the MSK condition on their lives re-enforcing their feelings of self-efficacy open to recognizing and discussing the patient’s use of different approaches open to working with patients to make decisions and to provide sufficient and accessible information to support this process clinicians should know their own limitations, be open and honest about it, and know when to refer

THE CONSULTATION TO ASSESS A MUSCULOSKELETAL PROBLEM: KEY COMPONENTS The consultation consists of several phases: listening and observing, inquiring, performing an examination, investigating, interpreting the findings, and communicating the conclusion and management plan. During the consultation, observe the patient’s overall appearance, movements, and manner. Use your knowledge and experience to recognize typical features and patterns of different musculoskeletal conditions to make a diagnosis and management plan. This will also direct the inquiry, examination, and any future investigations. In the majority of cases, it is necessary to make a complete assessment of the entire person, particularly because an apparently simple local problem may be the manifestation of a more generalized condition or the symptoms may be referred from a distant site. Multimorbidity is also common. When dealing with a musculoskeletal problem, investigations are usually necessary only to confirm clinical suspicion regarding the diagnosis and to help gauge disease activity, prognosis, and choice of treatment. They should follow logically from the findings of the consultation and be performed only if the results will influence management.

HISTORY History taking is by far the most important part of the evaluative process. First clarify what has brought the person to the consultation. What are the symptoms, when did they start and was there any apparent cause, how have they evolved, and what impact they have (Box 29.1)? Explore other potentially relevant factors such as the medical history and risk factors related to lifestyle or occupation. Establish what the patient’s concerns, expectations, and needs are. Ask what matters to them as well as what is the matter with them. Is the person prevented from doing activities of daily living, work, sleep, or leisure activities? Are there factors that may influence its impact, such as the person’s domestic and socioeconomic environment?

What are the symptoms? Symptoms specifically related to musculoskeletal conditions are most often pain and stiffness, frequently accompanied by loss of function, which can

CHAPTER 29  History and physical examination BOX 29.1  CHARACTERIZATION OF A MUSCULOSKELETAL PROBLEM

Table 29.2

n

Common Patterns of Referred Pain

n n n n n

What are the symptoms? Mode of onset and chronology Site and distribution of the symptoms Associated symptoms, preceding illnesses or injuries, red flags, and other relevant clues Response to health interventions The impact on activities, participation, and quality of life

BOX 29.2  SYMPTOMS OF A MUSCULOSKELETAL PROBLEM

Source of Pain

Pattern of Referral

Cervical spine Shoulder Lateral epicondyle Carpal tunnel Lumbar spine

Occiput, shoulders Lateral aspect of the arm Midforearm region Radial fingers, occasionally the forearm or arm Sacroiliac joints, buttocks, posterior aspect of the thigh, lower part of the leg, foot Groin, medial aspect of the thigh, medial aspect of the knee, greater trochanter, buttock above the gluteal fold Lateral aspect of the thigh, buttock

Hip joint

Specific symptoms n Pain

Trochanteric bursa

227

n Stiffness n Swelling n Deformity n Weakness n Instability n

Loss of function

General symptoms n

Fatigue and malaise Emotional lability—fear, anxiety, depression n Sleep disturbance n Symptoms of systemic diseases n

Table 29.3

Types of Pain and Their Causes Type

Pain Pattern

Cause

Bone pain

Pain at rest and at night

Mechanical joint pain Osteoarthritic joint pain

Pain related to joint use only Pain on joint use, stiffness after inactivity, pain at the end of the day after use Pain and stiffness in the joints in the morning, at rest, and with use; acuteness and severity can indicate the probable cause Pain on selective movements, localized periarticular or soft tissue tenderness Diffuse pain and paresthesia in the dermatome worsened by specific activity Pain unaffected by local movement

Tumor, Paget disease, fracture Unstable joint

Red flags n

Weight loss

n Fever n

Temple headache, pain with scalp tenderness, visual disturbance Loss of sensation n Loss of motor function n Difficulties with urination or defecation

Inflammatory joint pain

n

Other possible symptoms n n

Color changes or coldness of digits or limbs Altered sensation

Periarticular and soft tissue pain

Neuropathic

limit activities and restrict participation. Mobility and dexterity are most often limited. Stress, anxiety, and depression are common. Nonspecific symptoms, especially fatigue, may be present as well. Red flags for potentially serious conditions must be recognized (Box 29.2). Characterization of these symptoms helps the physician differentiate a musculoskeletal complaint into one of several “syndromes” and make a differential diagnosis within the syndrome: ■ Joint problem, including inflammatory and noninflammatory (mechanical or osteoarthritis [OA]) ■ Regional pain problem (including periarticular and soft tissue problems) ■ Generalized pain problem (with or without stiffness) ■ Neck or back pain problem ■ Muscle problem (pain, stiffness, or weakness) ■ Bone disorder ■ Systemic problem with musculoskeletal symptoms

Pain Pain is the most common symptom of musculoskeletal conditions and has the greatest impact on people, affecting their function and quality of life, in particular sleep. The characteristics of the pain can help identify its cause. What are the site and distribution of the pain? Ask the patient to demonstrate where the pain is felt and where it is most severe. They are often inaccurate in saying what structure is affected—“my hip” usually means a problem affecting any part of the hind quarter. Is the pain generalized or localized? How easily can it be localized? Articular and periarticular pain often radiates widely and presents far from its origin. Such referred pain is felt in the dermatome related to the myotomal or sclerotomal origin of the affected structure (Table 29.2). Pain from bone and periosteum radiates little and is localized more reliably. Generalized pain can be caused by fibromyalgia or polymyalgia rheumatica. Whereas pain in several joints suggests arthritis, bone disorders such as multiple myeloma or metastatic malignancy must be considered in those with multiple sites of pain that are related not just to joints. Examine the patient to clarify the anatomic site of origin of the pain.

Referred

Osteoarthritis

Inflammatory, infective, crystal induced (acute, exquisite tenderness) Bursitis, tenosynovitis, tendinitis, enthesitis

Root or peripheral nerve compression

What are its characteristics? The features of the pain, the time and mode of onset, and its diurnal pattern provide diagnostic clues. Severity is subjective, although it indicates the probable impact that pain is having. The pattern of evolution of the pain should be established in conjunction with the development of any other symptoms—how the patient has arrived at the present situation. There are two types of pain. Whereas nociceptive pain results from a stimulus or lesion in peripheral tissues that causes a painful impulse to be transmitted by an intact nervous system, neuropathic pain arises as a direct consequence of a lesion or disease affecting the nervous system. Different causes of nociceptive pain have their own characteristics (Table 29.3). For example, whereas gout usually begins in the middle of the night and quickly escalates into an intolerable persistent pain, OA is characterized by use-related pain and stiffness of the affected joints with inactivity. Mechanical pain is generally related to use. Inflammatory joint pain is present at rest and with use and is usually worse at either end of the day. Neuropathic pain is diffuse and described as superficial burning, stinging, or prickling pain; as deep aching pain; or as paroxysmal, electric shock–like pain. It is often evoked by a specific activity such as skin stimulation, pressure over affected nerves, and changes in temperature or emotion and is associated with paresthesia in the dermatome. It may include allodynia (pain caused by a stimulus that does not normally provoke pain), hyperalgesia (when there is an increased sensitivity to pain), and hyperesthesia (when a nonnoxious stimulus causes the sensation of pain). Bone pain is typically present at rest and at night. These types of pain give clues but are not diagnostic. What precipitates, worsens, or improves the pain? Periarticular problems are often induced by a specific type of repetitive activity. Spinal stenosis can be suspected from a history of activity-related buttock and

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SECTION 3  Approach to the Patient

leg pain that improves rapidly with rest only to recur after further activity, and walking downhill (which extends the spine) causes more pain than walking uphill. The response to exercise in contrast to rest is a typical feature of sacroiliitis or spondylitis. Rest usually improves the pain from OA but has little effect on inflammatory pain. The response to antiinflammatory analgesics vs simple analgesics can help distinguish an inflammatory cause of the symptoms, such as ankylosing spondylitis, from mechanical back pain; the response of polymyalgia rheumatica to low-dose glucocorticoid therapy is diagnostic.

Stiffness “Stiffness” is used to describe different scenarios, and a careful examination is necessary to be certain about correct attribution of this symptom. People often describe a generalized “stiffness” after prolonged rest or the day after an unusual level of exercise, which is more common as people age. More specifically, people frequently describe stiffness related to symptomatic joints. Whereas an inflammatory joint disorder is generally associated with prolonged morning and evening joint stiffness, OA is associated with shortlived stiffness after inactivity. Morning stiffness of the shoulder and pelvic girdle muscles is characteristic of polymyalgia rheumatica. The duration of morning stiffness can indicate the activity of rheumatoid arthritis (RA) or polymyalgia rheumatica. Stiffness of movement of the fingers can relate to tenosynovitis (sometimes with triggering), joint disease, or tightening of the soft tissues, such as with systemic sclerosis or Dupuytren contracture. “Stiffness” can also be used to describe a reduced or limited range of movement or by the patient to describe the difficulty in movement associated with muscle diseases such as inflammatory myositis, Parkinson’s disease, or motor neuron disease. “Locking” describes the sudden inability to perform a particular movement and suggests a specific mechanical event in which some internal derangement actually causes the joint to lock in one position until a trick movement or help is used to free it. This is a classic symptom of a loose body or torn meniscus of the knee joint, but it also occurs in the finger with triggering secondary to stenosing tenosynovitis.

diagnosis, expectations for prognosis, future aspirations, and fear of losing independence. Depression can also directly modulate pain and loss of function. In addition, sleep disturbance secondary to pain can affect mood.

What are the mode of onset, pattern, and chronology of the various symptoms? The pattern is important in identifying the cause (vide infra). The distribution and chronologic pattern of symptoms therefore need to be established. How did the patient arrive at the present situation? When and how did it start—is the onset recent, or is it something that has been happening for several months or longer? Disorders lasting for more than 6 weeks are considered chronic. Was the onset sudden or gradual? Was it spontaneous or after some specific event such as trauma or an infection? What was the subsequent course with respect to time and the pattern of distribution of the symptoms? If articular, does it involve one joint (monoarthritis), a few joints (oligoarthritis describes up to four joints), or many joints (polyarthritis describes five or more joints)? Does it involve peripheral small joints or large joints or have an axial distribution? Has it followed an additive, intermittent or episodic, or migratory course? Is it symmetric or asymmetric? What associated symptoms or signs have developed and when? Do the symptoms fit some recognized pattern? It is important, however, to avoid forcing the symptoms into a pattern—musculoskeletal conditions are common, and different conditions can coexist.

Associated symptoms, preceding factors, red flags, and other clues

Weakness can indicate a muscle disorder such as inflammatory myositis or a neuropathy. The pattern of muscle weakness, whether generalized or in a proximal or distal distribution, should be established. Regional weakness is more likely to have a specific cause. However, “weakness” may be used by a patient to describe different things, such as general fatigue or difficulty with movement because of joint disease or pain. A sensation of “giving way” and general instability of the lower limbs can result from knee pain or weak quadriceps muscles. A joint may be unstable and suddenly give way because of muscle weakness, or it may be related to the ligaments being ruptured or lax in hypermobility.

Musculoskeletal conditions often have systemic features, and systemic disorders often have musculoskeletal symptoms. Ask about the patient’s general health and inquire about the presence of systemic symptoms, such as fever, night sweats, or weight loss and other “red flags” (see Box 29.2), which may indicate the presence of a serious systemic disorder such as a malignancy, infection, or active inflammatory disease. Did any preceding trauma or repetitive or unusual use take place? Review the patient’s general health—current, recent, and any possible relevant past history. Questions should be directed by knowledge of associated symptoms of the conditions under consideration (Table 29.4). For example, with spondyloarthritis one should inquire about a recent diarrheal illness, urethritis, uveitis, psoriasis, and mucocutaneous problems. The previous medical history may include past events that give clues to the present problem, such as a previous attack of unexplained epilepsy in someone with SLE, fetal loss or thrombosis with antiphospholipid syndrome, or hypermobility in childhood or past joint trauma as a risk factor for OA. The family history can help in the differential diagnosis in some situations, although almost everyone has a relative with arthritis, and familial associations are seldom predictive. Useful clues include a recent flulike illness in the family or other close contacts for viral arthritis; nodal arthritis affecting the mother when deciding whether small-joint polyarthralgia of the hands is early RA or nodal OA; or a family history of ankylosing spondylitis, iritis, or psoriasis in a young man with back pain. Recognized risk factors for the development and outcome of musculoskeletal conditions include obesity, lack of physical activity, poor diet, depression, smoking, excess alcohol intake, previous injuries, and activities that expose people to sprains and strains, such as sports or occupation. Recognized “yellow flags” for chronicity of back pain include job dissatisfaction, unavailability of light work, depression, and low educational level.

Loss of movement or function

Previous health interventions and symptom response

Musculoskeletal conditions often cause difficulty performing various activities, which may be the main complaint. Establish whether any particular movements and functions are restricted and whether such restriction relates to pain and stiffness or is a primary problem. Painless loss of movement suggests tendon rupture or a neurologic cause.

What interventions have been tried—prescription, and over-the-counter pharmacologic treatments, physiotherapy, dietary supplements, or complementary therapies? Are they taking opioids, and is this appropriate? What was the response to different interventions? Did the patient benefit or sustain any adverse effects? What are the patient’s attitude to and probable compliance with any treatment? The response to treatment can contribute to diagnosis, such as the response of inflammatory disorders such as ankylosing spondylitis to antiinflammatory therapy or the rapid and almost miraculous response to glucocorticoids that is typical of polymyalgia rheumatica. Drugs themselves may also be the cause of the problem, as in drug-induced lupus and thiazide diuretics and gout.

Swelling and deformity Swelling may involve soft tissues, the joint, or bone. Did it follow an injury? Did it appear rapidly or slowly? Is it painful? Does it come and go, or is it gradually enlarging? Careful examination is needed to establish its nature and cause. Joint swelling is a sign of disease, and examination is necessary to confirm whether it is related to the joint or a periarticular structure and to establish whether it is caused by an effusion, inflammatory synovial proliferation, or bony growth. Imaging such as ultrasonography may be required. Recognition of any deformity requires familiarity with the musculoskeletal system to distinguish normal variation from abnormal findings.

Weakness and instability

Fatigue and malaise Fatigue is a manifestation of most generalized rheumatic disorders, including RA, systemic lupus erythematosus (SLE), and, most notably, fibromyalgia. Fatigue can relate to depression. It may also result from poor sleep related to pain. Fatigue may be severely disabling and is very distressing to the person. The fatigue associated with RA or SLE is a good indicator of systemic disease activity. The fatigue of fibromyalgia is usually associated with lack of concentration and poor-quality sleep.

Anxiety and depression Anxiety and depression are common accompaniments of a musculoskeletal problem and are influenced by factors such as knowledge of the possible

What is its impact? The impact of pain and disability associated with the musculoskeletal condition must be assessed in relation to the patient’s needs and aspirations. The framework of the World Health Organization’s International Classification of Functioning, Disability, and Health4 provides a useful way to look at the

CHAPTER 29  History and physical examination Table 29.4

Associated Symptoms, Signs, and Conditions Neurologic

Mouth

Eyes

Skin

Symptom

Possible Diagnosis

Headaches Numbness or paresthesia Weakness Stroke Epilepsy Dry mouth Mouth ulcers

SLE, temporal arteritis Neuropathy—compression

Dry eyes Red eyes Visual loss Rash Psoriasis Livedo reticularis Erythema nodosum Telangiectasia Other Photosensitivity Ulcers Raynaud phenomenon Nodules

Respiratory

Gastrointestinal

Genitourinary

Alopecia Pleuritis Breathlessness

Indigestion, history of peptic ulcer Diarrheal illness Renal stones Dysuria

Genital ulcers

Vaginal discharge

Trauma

Nonspecific symptoms

Fracture Ligament rupture Sprains and strains Malaise Fever Weight loss Fatigue Anorexia

Hematologic

Obstetric history

Aging Thrombosis or thromboembolism Anemia Fetal loss—early and late Intrauterine growth retardation Preeclampsia

Myositis, neuropathy Antiphospholipid syndrome SLE Sjögren syndrome Reactive arthritis, Behçet disease, IBD Sjögren syndrome Spondyloarthritis Temporal arteritis Psoriatic arthritis SLE Acute sarcoid or erythema nodosum arthropathy Systemic sclerosis Viral—rubella, human parvovirus Connective tissue disease Behçet disease, vasculitis Connective tissue disease OA, RA, gout, hyperlipidemia, SLE, rheumatic fever, polyarteritis nodosa, multicentric histiocytosis SLE Connective tissue disease Pulmonary involvement with inflammatory disease, e.g., systemic sclerosis, RA Nonsteroidal-associated gastritis or ulceration Reactive arthritis, IBD Gout Reactive arthritis, Behçet disease, acute gonococcal arthritis Reactive arthritis, Behçet disease, acute gonococcal arthritis Reactive arthritis, Behçet disease, acute gonococcal arthritis Osteoporosis Osteoarthritis in the future Hypermobility syndrome Inflammatory disease, malignancy SLE, septic arthritis Inflammatory disease, malignancy Inflammatory disease Inflammatory disease, malignancy Polymyalgia rheumatica Antiphospholipid syndrome Inflammatory disease Antiphospholipid syndrome Antiphospholipid syndrome Antiphospholipid syndrome

IBD, Inflammatory bowel disease; OA, osteoarthritis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

229

effect of any health condition on the functioning of an individual in terms of loss of function and presence of symptoms, limitation of activities, and restriction of participation within the personal and environmental context of the person’s life. Maintaining or restoring function should be the goal of management. Explore what the patient needs to do and would like to do in everyday activities and the impact the musculoskeletal condition has on these. These include personal care; tasks of daily living; tasks for others, whether paid or unpaid; and personal, social, and leisure activities. Musculoskeletal problems commonly affect mobility and dexterity. They are a major cause of work loss. Find out the patient’s frustrations and concerns. Establish how their problem interacts with activities including work, and learn how they cope with these limitations and the amount of support she or he has at home and at work. The effect on health-related quality of life can be formally assessed by using various validated generic and disease-specific questionnaires, preferably using patient-relevant outcome measures.5

Social history and occupation Knowing the patient’s socioeconomic background is important in assessing the condition and its impact and in planning management. Occupation and work-related tasks may have a causal role or an effect on the symptoms, or alternatively, the symptoms may have an effect on work. Understanding the person’s occupation and work tasks also gives a clearer idea of the person’s needs and how to help him or her return to work.

EXAMINATION There should be a strong clinical suspicion of the nature of the problem from the history that needs confirmation by a careful examination. The aim of examination is to identify and characterize any abnormality and look for any other relevant clues to diagnosis. The combination of the examination with the history should establish the key characteristics of the problem, clarify the syndrome, and enable a differential diagnosis.

General examination A full general examination forms an important part of the assessment of a person with a musculoskeletal problem. More frequent associated findings of rheumatic and musculoskeletal diseases relate to the skin and nails, neurologic system, and eyes (see Tables 29.4 and 29.7).

Regional examination of the musculoskeletal system A systematic approach to examination should be taken, but be sure to address any questions raised by the history or screening examination. The sequence can vary, but in general, it is easiest to look at the patient as a whole and during walking and standing to observe gait and posture. Then work from the head downward, first with the patient standing to examine the upper limbs, spine, and pelvis and then supine to complete the examination of the pelvis and spine and to examine the lower limbs (Boxes 29.3 to 29.5). Posture The normal symmetry of the body helps identify abnormalities in posture. Observe the whole person while he or she is standing and dressed only in underwear and look for equality of height of landmarks—the tips of the shoulders, the scapulae, the pelvic brim, and the crease of the buttocks. Inspect the spine carefully for its normal curves, and identify any scoliosis. Look at the feet during normal posture. Gait Gait demonstrates the integrated function of the lower limbs and will reveal abnormalities in the musculoskeletal system. Further assessment of the lower limbs will be necessary to identify the specific cause of any abnormality in gait, if present. Certain abnormal patterns of gait are well recognized. Pain in one limb causes avoidance of weight bearing by that limb and shortening of that phase of the gait cycle. The cycle is asymmetric, with shorter steps on the painful limb, and is described as an antalgic gait. Weakness of the hip adductors results in dipping of the pelvis to the other side when bearing weight on the affected limb. During the gait cycle, the person leans the upper part of the body over the weak hip to compensate for this and maintain balance. This Trendelenburg gait is apparent as side-to-side movement of the shoulders when walking. Such movement of the shoulders is also seen with an inequality in leg length, which leads to tilting of the pelvis during the gait cycle. An alternative gait with leg length inequality is to flex the knee of the longer leg to clear the ground during the swing phase, with consequent dipping of the person up and down. A foot drop results in a high-stepping gait to avoid tripping on the toes during the swing phase.

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SECTION 3  Approach to the Patient

Identifying and characterizing any abnormalities The expected appearance and ranges of movement of the musculoskeletal system need to be known so that abnormalities can be recognized and described such as an abnormal resting position, swelling, deformity, muscle wasting, or abnormal movement. Warmth, crepitus, tenderness on palpation, instability, or weakness may be present. Abnormalities for different reasons may be present as musculoskeletal conditions may coexist. Inflammation Inflammation of joints is characterized by pain on motion, tenderness on pressure, warmth, redness, and swelling. Pain is often apparent on movement, and tenderness is elicited by gentle palpation. Warmth is detectable mainly in medium-sized joints (e.g., the knee, ankle, and wrist joints) (Fig. 29.1). Redness is uncommon but is seen with acute gout, especially around the big toe, and with infection. Swelling of an inflamed joint is characterized by its articular origin, is fluctuant because of synovial proliferation or effusion, and is tender, but in OA, bony swelling along the joint line may be apparent. A number of specific techniques can be used for detection of synovitis and effusion at different joints (Fig. 29.2). In early inflammatory arthritis or in well-controlled disease, it may be difficult to detect swelling. Joint pain without abnormal findings on examination is called arthralgia and is not always a specific sign of joint disease. Inflammation of periarticular structures such as bursae or entheses must be carefully distinguished from inflammation of the joint. Inflammation of muscle is characterized by tenderness. Damage Joint damage is recognized by the presence of deformity, crepitus, movement in an abnormal plane, and loss of joint range of movement not secondary to pain or inflammation. Crepitus is a palpable sensation resulting from the movement of one roughened surface over another. In OA of the knee, patellofemoral crepitus has a fine quality. This should be distinguished from the coarser, clicking sensation encountered in normal joints. Deformity Joint deformity usually refers to malalignment or subluxation of two articulating bones in relation to one another and is identified by abnormal posture, often more apparent on weight bearing or with certain movements, such as occurs with developmental scoliosis of the spine. A severely damaged joint from RA or OA may limit movement in the normal plane. For example, the elbow is a simple hinge joint; hence, its normal range is flexion/extension and rotation only; loss of full extension is a common deformity. Biomechanical abnormalities Every joint has a normal spectrum of range of joint motion, which varies with age, gender, genetics, and ethnic origin. Motion outside this range may be considered hypermobility, increased range of motion, or hypomobility, limitation of motion. Biomechanical abnormalities in scoliosis can result in symptoms such as back pain; benign joint hypermobility syndrome is associated with polyarticular joint pain; and foot pain is often caused by abnormal biomechanics. Joint range of motion is reduced by inflammation (the bulk of the inflamed synovium and the effusion) or by irreversible damage to the joint structures (articular cartilage and subchondral bone). Movement is first lost from the extremes of the range. Complete loss of movement is described as ankylosis. What other features are of diagnostic importance? Some systemic features (see Table 29.4) may be of diagnostic importance or of value in assessing severity. Many of these features are easily visible skin signs such as psoriasis, nail fold capillary abnormalities, or telangiectasia, but others, such as pulmonary fibrosis or neuropathy, need to be identified by careful general examination.

Method of examination Look at the entire person, including posture and movement, and then examine each region by comparing one side with the other. It is usually necessary to examine the full musculoskeletal system to correctly assess the problem, but most emphasis is placed on the probable origins of the symptoms while remembering that pain is frequently referred and that any examination must consider all possible causes. Explain to the patient what you are about to do, and ask whether he or she thinks that any part of the examination is likely to be painful. The key elements of the examination to identify the clinical signs of musculoskeletal conditions (Box 29.6) are to look, feel, move, and stress (Table 29.5). These steps are usually performed in an integrated manner. Special tests may be necessary to identify specific problems.

Look

Attitude and spontaneous movement An inflamed joint is most comfortable when the periarticular structures are at greatest laxity and intracapsular pressure is least. Pain is most severe when intracapsular pressure is greatest. An indication of the severity of the pain is given by the protection with which the person treats the affected region. Swelling and deformities Look for swelling but palpate to characterize whether it is caused by synovial thickening, joint effusion, bony enlargement, or a combination of these features. Look for any deformities of the joints, bones, or spine (Table 29.6); determine if they are reducible. Skin Look at the skin, both that overlies the affected region and elsewhere, for changes (Table 29.7); pay particular attention to the hands and nails because of the many abnormalities that can occur. Wasting Look for loss of muscle bulk. Arthropathy can cause widespread wasting around the joint. More localized wasting suggests a tendon, muscle, or peripheral nerve lesion. Swelling of a joint can give a false impression of adjacent loss of muscle.

Feel

Warmth First feel gently for warmth, which is best evaluated by using the backs of the fingers and comparing the finding with that of a normal structure (see Fig. 29.1). Warmth is a cardinal sign of inflammation but may be detected only over large joints. Tenderness The presence and localization of tenderness are important in identifying the cause of the problem (Table 29.8). Examine carefully to establish whether it is the joint line or periarticular region. If the tenderness is muscular, is it generalized, such as in myositis, or localized, such as the characteristic tender points of fibromyalgia? Feel for tenderness by gradually increasing pressure while watching the person for any reaction and releasing as soon as the presence of tenderness is established. Apply pressure only until blanching of the nail of the examining fingers occurs. Percuss the vertebrae to detect localized tenderness. Swelling Determine the precise location and anatomic associations of the swelling; whether it is tender; and whether it involves fluid, soft tissue, or bone. Swelling of a joint is confined by the capsule and is most apparent with any weaknesses in the capsule; for example, an effusion in the knee may be associated with a popliteal cyst. Fluid and soft tissue are ballotable; this is the principle of the patellar tap and the interlocking-C examination of the interphalangeal joints (see Fig. 29.2).

Move Palpating the joint and periarticular structures while moving gives further information about the pain and tenderness, as well as crepitus from the joint or tendon sheaths. Three methods can be used to assess joint movement—active, passive, and against resistance. ■ To examine joints, a combination of active and passive movement is recommended. ■ To detect lesions in tendons or at tendon–osseous junctions, the against-resistance method is principally of use. ■ To measure muscle power, the against-resistance method is the principal technique. First establish the active range and, if reduced, see whether it is greater with passive movement, but be cautious because this may be painful. If the problem is unilateral, compare the affected with the unaffected side. Formal measurement of range of motion is of limited value. Involvement of the joint, in particular, synovitis, usually restricts all movement. Restriction of movement in one plane is characteristic of periarticular lesions, tenosynovitis, or internal derangement of the joint. Pain in all directions of movement is associated with synovitis. Pain in just one plane of movement indicates a localized articular or periarticular problem. Pain throughout the range of movement is more characteristic of mechanical problems such as OA. Resisted active movement is valuable in identifying problems related to the muscle tendon or enthesis. This should be performed with the joint in neutral position. Reproduction of pain indicates that it is originating from

CHAPTER 29  History and physical examination BOX 29.3  REGIONAL EXAMINATION OF THE MUSCULOSKELETAL SYSTEM—HEAD, SPINE, AND PELVIS

Cervical spine Look Feel

Look for hyperextension caused by thoracic kyphosis or loss of normal lordosis. Percuss the vertebrae for tenderness. Palpate the paraspinal muscles for spasm or tenderness. Actively turn the head to the right, left, flexion, extension, rotation to the left and right, and lateral flexion to the left and right with the examiner gently guiding the head to ensure that maximum range is reached. Problems related to the cervical spine are often associated with neurologic symptoms and signs, which should be elicited.

Move Tests

Posture and alignment of the head and neck Extension.

Right rotation.

Flexion.

Left rotation.

Right lateral flexion.

Left lateral flexion.

Temporomandibular joints Feel

Palpate over the joint line for tenderness, crepitus, or clicking. The joint can be palpated anterior to the tragus or from within the external auditory meatus. Feel for crepitus or clicking on movement. Open the mouth wide. Deviate the lower jaw side to side.

Move

Mouth opening.

Mouth opening.

Side-to-side movement of the jaw.

Side-to-side movement of the jaw.

Dorsal spine Look Feel Move

Look for any kyphosis or scoliosis. Look for any asymmetry of the scapulae. Percuss the vertebrae for tenderness. Palpate the paraspinal muscles for spasm or tenderness. Fix the pelvis by sitting and rotate the upper part of the body to the right and left with the examiner gently guiding the shoulders to ensure that maximum range is reached.

Right rotation.

Left rotation.

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SECTION 3  Approach to the Patient

232

BOX 29.3  REGIONAL EXAMINATION OF THE MUSCULOSKELETAL SYSTEM—HEAD, SPINE, AND PELVIS—cont’d

Lumbar spine Look Feel Move

Stress

Tests

Look for a normal lordosis or any scoliosis. Look for any asymmetry of the pelvic brim or the crease of the buttocks. Percuss the vertebrae for tenderness. Palpate the paraspinal muscles for spasm or tenderness. While standing in an erect posture, bend forward as though trying to touch the toes, bend backward to arch the back, and bend from side to side. The person may be able to place the hands flat on the ground if hypermobile. Flexion can be more formally assessed with the Schober test by measuring extension of a line drawn when upright from 10 cm above and 5 cm below the level of the posterior iliac spines as identified by the dimples of Venus. Tests for tension of the lumbar roots should be performed when patient is lying down. Femoral nerve stretch test: With the person lying prone, hold the ankle and passively flex the knee as far as it will go. The test is positive if pain is felt in the isolateral anterior aspect of the thigh. Sciatic nerve stretch test: With the person lying supine, gently raise the straight leg to the maximum angle achievable without significant pain and then dorsiflex the ankle. An increase in pain indicates sciatic nerve root tension. The lumbar spine houses the lumbar spinal nerve roots, and neurologic symptoms and signs should be elicited. Lumbar flexion.

Lumbar extension.

Left lateral flexion.

Right lateral flexion.

Pelvis and sacroiliac joints Look Feel Stress

Look for asymmetry of the pelvic brim and the lower part of buttocks. Palpate for tenderness in the buttocks. Palpate the sacroiliac joints for tenderness. Stress the sacroiliac joints for tenderness. Various methods can be used to compress or distract the joint to elicit tenderness, such as pushing on both iliac wings when the person is lying supine.

Test for cruralgia.

Test for sciatica.

Test for sciatica.

CHAPTER 29  History and physical examination BOX 29.4  REGIONAL EXAMINATION OF THE MUSCULOSKELETAL SYSTEM—UPPER EXTREMITY

Shoulder Look Feel Move

Tests

Look for any asymmetry in the scapulae and posture or muscle wasting. Palpate over the midpoint of each trapezius and the supraspinatus to identify tender spots. Palpate over the acromioclavicular joint line, glenohumeral joint line, and bicipital groove. Actively elevate the arms into the air. Actively place the hands behind the head. Actively place the hands behind the back. Steady the scapula and, with the elbow at 90 degrees, rotate internally and externally; then passively abduct, flex, and internally and externally rotate the shoulder. Several methods can be used to establish whether impingement is present. Abduction and external rotation.

Flexion.

Adduction, extension, and internal rotation.

Elevation.

Extension.

External rotation.

Internal rotation.

Abduction.

Adduction.

Elbow Look Feel Move

Look for any swelling or deformity. Joint swelling is first apparent in the para-olecranon groove. The olecranon is a common site for bursitis and rheumatoid nodules. Palpate over the para-olecranon groove for synovial swelling or tenderness. Palpate over the medial and lateral epicondyles for tenderness. Assess the laxity of the skin if considering hypermobility. Passively extend and flex the elbow and look for hyperextension.

Palpate over the medial and lateral epicondyles for tenderness.

Elbow flexion.

Elbow extension.

Assess for elbow hyperextensibility.

Wrist Look

Feel Move

Stress

Look for any swelling or deformity. Swelling over the dorsum involves the joint or extensor tendon sheath. With active extension of the fingers, swelling of the extensor tendon sheath moves—the tuck sign. Look for squaring of the base of the palm because of swelling of the carpometacarpal joint seen in osteoarthritis. Typical deformities in established rheumatoid arthritis are volar subluxation and radial deviation at the wrist with dorsal subluxation of the ulnar styloid. Palpate over the joint line for tenderness or synovial swelling. Passively flex and extend the wrist. Assess for hypermobility by passively moving the thumb toward the volar aspect of the forearm with the wrist in full flexion. Use resisted flexion, extension, or pronation if assessing epicondylitis at the elbow. Assess stability of the inferior radioulnar joint by demonstrating movement when pressing down on the radial head—the piano key sign.

233

SECTION 3  Approach to the Patient

234

BOX 29.4  REGIONAL EXAMINATION OF THE MUSCULOSKELETAL SYSTEM—UPPER EXTREMITY—cont’d Wrist flexion.

Wrist extension.

Resisted active wrist extension to test for lateral epicondylitis.

Resisted active wrist flexion to test for medial epicondylitis.

Wrist ulnar movement.

Wrist radial movement.

Assess supination.

Assess pronation.

Hand Look

Feel

Move

Look for any swelling or deformity. Is the swelling specific to joints or tendons or is it diffuse? Look for any associated clues. Much can be learned from the hand. Look for wasting of the small muscles; inspect the skin, nails, and nail beds. Typical deformities in established rheumatoid arthritis are ulnar deviation of the fingers at the metacarpophalangeal joints, hyperextension at the proximal interphalangeal joint with flexion at the distal interphalangeal joint (swan-neck deformity), or flexion at the proximal interphalangeal joint with hyperextension at the distal interphalangeal joint (boutonnière deformity). A Z-deformity of the thumb can be seen in systemic lupus erythematosus. Palpate over each joint line for tenderness or bony or synovial swelling. Squeezing across all the knuckles together can be used as a composite assessment for tenderness of the metacarpophalangeal joints. Palpate the tendon sheaths during movement to detect crepitus or tendon nodules. Feel the quality of the skin for induration, thickening, or laxity. Actively make a tight fist with palmar aspect uppermost to see whether all fingers fully flex and estimate strength of grip by observing blanching of the palmar surface of the hand on release of the fist. Actively make a firm pinch grip between the thumb and fingers individually. Passively extend the fifth finger to assess for hypermobility.

Actively make a fist.

Release the grip and observe the palm for blanching.

Squeeze across the metacarpophalangeal joints.

Palpate the tendon sheaths

Assess grip strength.

Assess for hypermobility of the thumb and wrist.

Assess hyperextensibility of the fifth finger.

Palpate the proximal Palpate the metacarpophalangeal joints. interphalangeal joints.

Assess pinch grip.

CHAPTER 29  History and physical examination

235

BOX 29.5  REGIONAL EXAMINATION OF THE MUSCULOSKELETAL SYSTEM—LOWER EXTREMITY Observing gait is an important part of assessing the lower limbs. Examination should be done with the person lying on a bench. Measure leg length if a pelvic tilt when standing suggests shortening or with a discrepancy in the position of the medial malleoli with a straightened pelvis. Pain in the hindquarter is often called “hip pain” but can have many origins that need elucidation by examination.

Hip Look Feel Move

Observation of the person walking will have given some information about the hips. Wasting of the buttock or thigh muscles from disuse may be apparent. Palpation should be used to clarify the origin of any symptoms. The word hip is used to describe symptoms anywhere in the hindquarter. Tenderness is usually related to tendinitis or bursitis. With the person supine, actively and then passively flex the hip as far as possible with the knee in flexion to look for contralateral movement. With the hip passively flexed to 90 degrees, rotate it internally and externally by holding the foot, supporting the thigh, and moving the lower part of the leg inward and outward while being careful to not inflict pain. Internal rotation is often affected first in disorders of the hip joint. With the person lying supine and the leg fully extended, hold the contralateral anterior superior iliac spine to prevent movement of the pelvis and passively abduct and adduct the leg. With the person lying prone or on the side, passively extend the straightened leg. Assess leg length by the relative position of the medial malleoli with the pelvis straightened.

Internal rotation.

External rotation.

Hip flexion—passive—to look for contralateral movement.

Hip flexion—active.

Abduction.

Adduction.

Knee Look

Feel Move

Stress

Knee flexion.

Observation of the person walking will have given some information about the knees. Wasting of the thigh muscles from disuse may be apparent. Instability may be present. Look for any swelling and its exact site because it may relate to the joint or periarticular structures. Look for any deformity. Typical deformities are fixed flexion, valgus, or varus. Palpate for tenderness or swelling and establish the affected structures. Palpate the joint line for tenderness. Assess for articular swelling and effusion by the bulge sign or patella tap (see Fig. 29.2). Palpate for a popliteal cyst. With the person supine, passively flex the knee as far as possible with the hip in flexion. If the hip is also abnormal, hang the leg over the side of the bench to examine flexion of the knee without hip flexion. With the person lying supine, fully extend the leg in an attempt to touch the back of the knee onto the bench. Assess passively if the knee will hyperextend. Anterior and posterior stability should be tested to assess the cruciate ligaments. Medial and lateral stability should be tested to assess the collateral ligaments and for loss of joint space.

Knee extension.

Stress the cruciate ligaments.

Stress the collateral ligaments.

SECTION 3  Approach to the Patient

236

BOX 29.5  REGIONAL EXAMINATION OF THE MUSCULOSKELETAL SYSTEM—LOWER EXTREMITY—cont’d

Foot and ankle Look

Feel Move

Observe the feet when standing and during walking. Look for a normal longitudinal arch and, during the gait cycle, look for normal heel strike and take-off from the forefoot. Look for any callosities beneath the metatarsal heads and for any swelling and redness of the toes. Swelling of the metatarsophalangeal joints can separate the toes so that daylight becomes visible between them. Look for any deformities. Deformities include pes planus (flattening of the longitudinal arch); pronation of the foot; valgus deformity of the hindfoot (eversion of the subtalar joint); pes cavus (high longitudinal arch); talipes equinovarus; hallux valgus; subluxation of the metatarsophalangeal joints; and “claw,” “hammer,” and “mallet” deformities of the toes. Symptoms may relate to the joint, periarticular bone, tendons, and their sheaths and insertions, or bursae. Palpate for tenderness or swelling, and establish the affected structures. Squeeze across the metatarsus, and if tenderness is noted, examine the metatarsophalangeal joints individually. Actively flex and extend the ankle. Actively invert and supinate and then evert and pronate the foot. Passively deviate the heel medially (inversion) and laterally (eversion) by grasping the heel between the thumb and index finger of one hand and moving it while anchoring the lower part of the leg with the other hand. Passively rotate the forefoot on the hindfoot by grasping the forefoot between the thumb and fingers while anchoring the heel with the other hand to assess the midtarsal joint. See whether the patient is able to stand on the toes, which requires an intact posterior tibialis tendon.

Metatarsal squeeze.

Ankle flexion.

Ankle extension.

Inversion and supination.

Eversion and pronation.

Subtalar inversion.

Subtalar eversion.

Midtarsal rotation.

Assessing the first metatarsophalangeal joint.

the muscle, tendon, or tendon insertion related to that movement. Passively stretching the tendon or ligament may also reproduce the pain. Listening during joint movement may detect fine crepitus secondary to cartilage damage, crackling associated with hypermobility, or clonking caused by a loose body or irregular surfaces such as severe damage. Audible tendon friction rubs may be heard in patients with systemic sclerosis.

The examination is documented most easily on a homunculus. A standardized approach is recommended to denote joint swelling, joint tenderness, and restricted movement and to describe deformities (Fig. 29.3, Table 29.6).

Stress

Making a diagnosis requires integration of the history and findings on examination with knowledge of the possible causes and results of appropriate investigations. The likely diagnoses should have been identified from the history and examination. Pattern recognition plays a key role. Knowing what is likely at different stages of life in different individuals and looking for clues throughout the consultation are important. Because musculoskeletal conditions are common, multiple pathologic processes are possible. Investigations may be necessary to confirm the diagnosis and to assess disease status for a plan of management to be made.

Joint stability should be assessed by stressing a joint. Stability may be abnormal because of generalized hypermobility, ligament rupture subsequent to trauma or inflammation, capsular inflammation, or loss of articular cartilage and changes in bone as a result of OA or RA.

Documentation The history and examination need to be documented. The history should form a clear story that another clinician can read, assess, and interpret.

INTERPRETATION

CHAPTER 29  History and physical examination

237

BOX 29.6  CLINICAL SIGNS OF MUSCULOSKELETAL CONDITIONS

FIG. 29.1  Testing for warmth by using the back of one’s hand.

■ Attitude ■ Deformity ■ Swelling ■ Skin changes ■ Muscle wasting ■ Tenderness ■ Restricted movement ■ Crepitus ■ Warmth ■ Muscle weakness ■ Instability ■ Limited function Table 29.5

System for Examination of the Musculoskeletal System Look a

At rest for: Swelling Deformity Wasting Attitude Skin During movement Tenderness Swelling Movement—crepitus Temperature Active Passive Resistance Stability

b

Feel

c

d

FIG. 29.2  Testing for swelling. (a) The bulge sign in the knee. The back of the hand gently pushes the fluid from one side of the knee to the other to fill out the “dimples” on either side of the patella. This is most helpful in detecting small knee effusions. (b) The patellar tap. One hand is used to cup the patella and compress the suprapatellar pouch, and the fingers of the other hand press down on the patella to feel for cross-fluctuation. (c and d) Swelling or fluctuation of the small joints of the hand. Detect cross-fluctuation at the joint line with the index fingers and thumbs by squeezing and feeling each side of the joint (as illustrated) or by squeezing and feeling from side to side with one index finger and thumb and squeezing and feeling from the palmar to the dorsal aspect with the other index finger and thumb (“interlocking C”).

Patterns within the different syndromes are considered. Within these the different pathogenic mechanisms need to be reflected on (Box 29.7) to ensure all possible causes are considered.

Move

Stress

Table 29.6

Common Deformities Kyphosis Scoliosis Dislocation Subluxation Fixed flexion Valgus Varus

Forward curvature of the thoracic spine Lateral curvature of the spine Articulating surfaces displaced so that they are no longer in contact with one another Partial dislocation Loss of extension so that the joint is permanently flexed A lower limb deformity in which the distal part is directed away from the midline (e.g., hallux valgus) A lower limb deformity in which the distal part is directed toward the midline (e.g., genu varum)

Joint problems Joint problems are inflammatory or noninflammatory. It is important to be able to identify whether a joint problem is inflammatory by the characteristics of symptoms and by examination (Table 29.9). Early diagnosis of inflammatory joint disease is important to achieve best outcomes from treatment. Systemic markers of inflammation, such as the erythrocyte sedimentation rate or C-reactive protein, may be raised. An arthropathy may affect single joints (monoarthritis), a few joints (oligoarthritis up to four joints), or many joints (polyarthritis). It can be symmetric or asymmetric and peripheral or central (axial). Onset can be acute or gradual with an additive, intermittent, or migratory temporal pattern. It may be of recent onset (acute) or have persisted for 6 weeks or more (chronic). Patterns are suggestive of different diagnoses (Tables 29.10 to 29.16). An acute monoarthritis must be considered as possible septic arthritis and diagnostic aspiration is often necessary, although there are several other possible causes (see Table 29.12). RA typically follows an additive peripheral, symmetric course with polyarticular involvement developing over several weeks and persisting, but the joint symptoms of parvovirus infection may also be symmetric and peripheral but develop rapidly over a few days and then slowly improve (see Table 29.15). A lower limb oligoarthritis, such as knees and ankles, is seen in HLA-B27–associated peripheral spondyloarthropathies. An asymmetric oligoarthritis affecting various interphalangeal joints of the hands, especially some distal interphalangeal joints, and sometimes with diffuse swelling of a digit, is characteristic of psoriatic arthritis (see Table 29.14). Periarticular involvement needs to be distinguished. In sarcoid and hypertrophic pulmonary osteoarthropathy the tenderness is around the

joint margin. In benign joint hypermobility syndrome, there is joint pain from periarticular structures with no evidence of inflammation.

Regional pain problems Regional pain problems may be periarticular, neurogenic, referred pain, or articular. Periarticular pain is characterized by local or regional distribution. It typically affects the shoulder and elbow, and there is selectivity of painful movements. Active mobilization is much more painful than passive; there is no passive range limitation. Palpation of the structure is painful, and specific distention or resisted movements are painful. Neurogenic pain is characterized by distribution in a dermatome or peripheral nerve territory and dysesthetic nature of pain. The most common sites are sciatica, carpal tunnel syndrome, and ulnar syndrome. It is associated with a normal local osteoarticular examination with local alterations in the neurologic examination (late onset), exacerbation with mobilization of the spine (in radiculopathies), and Tinel sign (in nerve entrapment) may be positive. Referred pain is characterized by local or regional distribution, and uncharacteristic rhythm, a dysesthetic nature (neurogenic pain), associated symptoms (neighboring joints, viscera, neurologic changes), and a normal local examination.

Generalized pain problems Fibromyalgia is characterized by pain “all over” with a diffuse distribution with little focus in the joints. Pain may be migratory and worse after exercise. The distribution is usually inconsistent with polyarthropathy. The

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SECTION 3  Approach to the Patient

Table 29.7

ANNOTATING THE EXAMINATION FINDINGS

Associated Skin Lesions Region

Types of Skin Lesions

Associated Conditions

Torso and limbs

Livedo reticularis

SLE, antiphospholipid syndrome, vasculitis Sign of external heat applied to relieve pain Lyme arthritis Leukocytoclastic vasculitis Psoriatic arthritis Acute sarcoid Heberden nodes, RA, gout, hyperlipidemia, SLE, rheumatic fever, polyarteritis nodosa, multicentric histiocytosis, sarcoidosis Vasculitis, Behçet disease, Crohn's disease Limited cutaneous systemic sclerosis SLE Psoriatic arthritis Dermatomyositis

Erythema ab igne Erythema migrans Palpable purpura Psoriasis Erythema nodosum Nodules

Ulcers Calcinosis cutis Face and mouth

Butterfly rash Psoriasis Heliotrope discoloration Oral ulcers Telangiectasia

Nails

Clubbing Pitting Onycholysis Splinter hemorrhages

Hands

Raynaud phenomenon Nail fold capillary abnormalities Palmar erythema Gottron papules Telangiectasia Sclerodactyly

Feet

Vasculitic lesions Keratoderma blennorrhagica

SLE, reactive arthritis, Behçet disease Limited cutaneous systemic sclerosis Hypertrophic pulmonary osteoarthropathy Psoriatic arthritis Psoriatic arthritis Small-vessel vasculitis, endocarditis SLE, scleroderma, mixed connective tissue disease Scleroderma, dermatomyositis Active RA, SLE Dermatomyositis Limited cutaneous systemic sclerosis Limited cutaneous systemic sclerosis RA, connective tissue diseases Reactive arthritis

FIG. 29.3 A homunculus can be used to annotate abnormal findings during examination.

BOX 29.7 PATHOGENIC MECHANISMS OF RHEUMATIC AND

MUSCULOSKELETAL CONDITIONS

■ Traumatic ■ Vascular/ischaemic ■ Neurologic ■ Infectious ■ Degenerative ■ Immune mediated ■ Metabolic ■ Inherited/developmental/congenital ■ Neoplastic ■ Psychological

Table 29.9

Joint Problems: Features of Inflammatory Joint Disease vs Osteoarthritis Inflammatory History ■ ■

RA, Rheumatoid arthritis; SLE, systemic lupus erythematosus.

Osteoarthritis

■ ■ ■

Worse in the morning Improves with movement Pain at rest; no pain-free position Prolonged morning stiffness (30 minutes) Stiffness after rest >5 minutes

■

Firm, rubbery swelling Spindle shaped swelling Pain along the joint margins No crepitus (or fine crepitus) Signs of inflammation Extraarticular signs are common Any joint

■

■ ■ ■ ■

Examination ■

Table 29.8

■

Possible Causes of Tenderness

■

Site

Possible Cause

■

Muscular: localized Muscular: generalized Joint line: generalized Joint line: localized

Myofascial lesion Fibromyalgia, myositis Arthropathy, capsular disease Abnormality of intracapsular structure, e.g., medial knee joint line tenderness with a meniscal tear Bursitis, enthesopathy, sarcoid Bone pathology: osteoporotic fracture or invasive lesion Bone pathology: osteoporotic fracture or invasive lesion

Periarticular Bone Vertebral

■ ■ ■

■ ■ ■ ■ ■ ■

Worse in the evening Worsens with movement Eases at rest; pain-free positions Short morning stiffness (99% DNA antibodies in 60%–75% HLA-B27 in ~90%

Sacroiliitis Vertebral squaring

Gout

Recurrent attacks

Osteoarthritis

Pain ± swelling ± limited motion

Systemic sclerosis

Skin tightness proximal to metacarpophalangeal joints Facial skin tighteningRaynaud phenomenon Muscle weakness ± pain

Inflammation WBC count, 5000–20,000/mm3 Negatively birefringent crystals on microscopy Noninflammatory WBC count 90% with HEp-2 cells

CPK elevated in 80%, ANA and myositisspecific antibodies

Erosions, cysts Joint space narrowing Osteophytes ± Pulmonary fibrosis ± Esophageal dysmotility ± Calcinosis Not helpful

Mild inflammation

Nonspecific

ACPA, Anticitrullinated peptide antibodies; ANA, antinuclear antibodies; CPK, creatine phosphokinase; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor; WBC, white blood cell count. Adapted from Pincus T. Laboratory tests in rheumatic disease. In: Klippel JH, Dieppe PA, editors. Rheumatology. 2nd ed. London: Mosby International; 1997, pp. 10.1–10.8.

RED BLOOD CELLS Anemia in rheumatic diseases most commonly reflects decreased production of red blood cells in the bone marrow caused by continued inflammation, with increased hepcidin production leading to disturbed iron metabolism. Anemia of chronic inflammation (ACI, formerly known as anemia of chronic disease) is commonly normocytic and normochromic; however, microcytic hypochromic anemia also can be associated with chronic inflammation. Microcytic hypochromic anemia is more commonly seen with iron deficiency and other conditions such as thalassemia and lead poisoning. Macrocytic anemia, commonly caused by vitamin B12 deficiency, folate deficiency, liver disease, and hypothyroidism, is not common in rheumatologic conditions except with methotrexate treatment. Hemolytic anemia occurs in active SLE with detection of antierythrocyte antibodies and in other immune complex–mediated conditions. Anemia caused by chronic or acute gastrointestinal bleeding is also a frequent adverse effect of NSAIDs, with glucocorticosteroids contributing to an increased risk.

BIOCHEMICAL TESTING LIVER FUNCTION TESTS Liver function tests should be ordered before and after initiation of treatment with certain antirheumatic drugs (including NSAIDs as well as conventional and biologic and targeted synthetic DMARDs) to monitor for adverse effects. Measurement of aspartate aminotransferase and alanine aminotransferase is included in guidelines or recommendations for monitoring treatment with all immunosuppressive medications.6 Usually a DMARD should be stopped if aminotransferase levels increase above three times the upper limit of

normal (ULN). A concomitant increase of serum total bilirubin above twice the ULN without findings of cholestasis indicates potentially life-threatening drug-induced liver injury (Hy’s law). Albumin levels can also be measured when chronic liver disease or damage to the liver from medications is suspected. There is evidence to suggest that low-dose methotrexate therapy in RA is less liver toxic as previously suggested and safe if monitored according to guidelines.7, 8

ALKALINE PHOSPHATASE Alkaline phosphatase is made mostly in the liver and in bone, with some produced in the intestines and kidneys and by the placenta in pregnant women. Conditions that cause rapid bone growth (puberty), bone disease (osteomalacia or Paget disease), hyperparathyroidism, or liver cell damage can lead to increases in alkaline phosphatase levels. Values of 1.5 to 3.0 times the ULN are consistent with a hepatocellular cause (viral infection, drug toxicity, alcohol), but values more than 3.0 times the upper limit of normal are usually associated with biliary involvement. Bone involvement can be found at any alkaline phosphatase level. The source of the alkaline phosphatase elevation often can be determined by measuring the gamma-glutamyl transferase (GGT), which is elevated in liver disease but normal in bone disease.

KIDNEY FUNCTION TESTS AND URINALYSIS Kidney function tests are routinely performed before and after initiation of treatment with antirheumatic drugs, including NSAIDs, to monitor for adverse effects. For this purpose, serum creatinine levels or estimated glomerular filtration rate (eGFR) provides sufficient information. Of note, disturbed kidney function is associated with a high risk of methotrexate

CHAPTER 30  Laboratory tests in rheumatic disorders accumulation, causing toxic and potentially life-threatening effects. Also, for several other drugs including, e.g., allopurinol a dose adjustment is required in patients with reduced kidney function. This is of special interest, because like in gouty arthritis medical treatment has to take into account that a reduced kidney function, which is often associated with the disease itself, can cause increased toxicity, e.g., of NSAIDs or allopurinol, and thus will limit therapeutic options. Systemic autoimmune rheumatic diseases, such as SLE, and systemic vasculitides are frequently associated with kidney involvement, causing glomerular and interstitial nephritis. In cases of suspected nephritic or nephrotic syndrome, urine tests and kidney biopsy are standard procedures. Urinalysis is also useful for monitoring of kidney involvement and should include detection and quantification of proteins as well as of hematuria and leukocyturia. Furthermore, microscopic detection of urinary casts (e.g., protein or cellular cylindrical structures) is a finding in glomerulonephritis as a frequent organ manifestation in different rheumatic diseases.

Uric acid Uric acid measurement is commonly included in the workup of patients with arthritis, and serum levels are elevated in 90% of patients with gout. Yet, healthy people can have elevated levels as well, and the definitive diagnosis of gout depends on the demonstration of uric acid crystals in synovial fluid (Fig. 30.1). The goal of urate–lowering therapy is to reduce the risk of gouty attacks and to avoid tophaceous gout. For this purpose, treatment targets have been predefined according to uric acid serum levels of below 6 mg/dL or 5 mg/dL, respectively.9

Calcium and vitamin D Determination of calcium and vitamin D levels is part of the evaluation for osteoporosis and high or low bone turnover states and may be considered in patients at risk of these conditions and for monitoring of treatment. Calcium absorption, use, and excretion are regulated and stabilized by a feedback loop involving parathyroid hormone and vitamin D. Conditions and diseases that disrupt calcium regulation can cause inappropriate acute or chronic elevations or decreases in serum calcium and lead to symptoms of hypercalcemia or hypocalcemia. In rheumatology, whereas hypercalcemia is often associated with sarcoidosis, paraneoplastic conditions, immobilization, and vitamin D intoxication, hypocalcemia is a typical finding in vitamin D deficiency, rhabdomyolysis, hypoparathyroidism, and renal tubular acidosis. In the past 25 years, more than 50 metabolites of vitamin D have been described. To date, only a few of these have been quantified in blood, but this has widened our understanding of the pathologic role that altered vitamin D metabolism plays in the development of diseases of calcium homeostasis. Currently, awareness is growing of the prevalence of vitamin D insufficiency in the general population in association with an increased risk of several diseases. Two metabolites—25-hydroxyvitamin D and 1, 25-dihydroxyvitamin D—have received the most attention. The need for measuring serum levels of 1, 25-dihydroxyvitamin D is limited, and this metabolite therefore should not be considered as part of the standard vitamin D testing regimen. On the other hand, serum levels of 25-hydroxyvitamin D provide the single best assessment of vitamin D status, and thus measurement of this metabolite should be the only vitamin D assay typically performed.10

Acute-phase reactants The acute-phase response occurs in a wide variety of inflammatory conditions, including various infections, trauma, malignancies, inflammatory rheumatic disorders, and certain immune reactions to drugs.11 Currently, the most widely used laboratory tests to monitor inflammation are the

243

erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level. Of note, ESR levels are usually physiologically higher in women than men and increase with age and during pregnancy. CRP levels in particular have been reported to be higher among obese patients. The acute-phase proteins are mainly produced by hepatocytes upon stimulation by cytokines (e.g., interleukin-6, interleukin-1, and tumor necrosis factor). The most important acute-phase proteins whose levels increase during inflammation (positive reactants) are CRP, fibrinogen, S100 proteins, ferritin, serum amyloid protein A, and several complement components, especially C3. In inflammatory conditions, increased plasma levels of fibrinogen and immunoglobulins as well as a frequently associated anemia can increase the ESR. In patients with polycythemia or chronic lymphocytic leukemia, a lower ESR is typical. Serial measurements of ESR and CRP are valuable for monitoring the level of inflammation in patients with disorders such as RA. In Still disease, high elevated ferritin levels and S100 proteins are additionally used as diagnostic markers, but also for evaluation of disease activity.12 Less than 10 percent of patients with polymyalgia rheumatica (PMR) show signs of clinical disease activity but have normal CRP and ESR values.13 In addition, up to 40% of patients with RA have a normal ESR and/or CRP level at initial presentation.14 In each instance, the clinical picture should be the determining factor in decision making regarding treatment. It is essential to note that ESR is an indirect measure of acute-phase protein concentrations. Although CRP concentrations may increase and decrease very rapidly, ESR values change slowly upon control of inflammation. With few exceptions, almost all patients with PMR and temporal arteritis have an elevated ESR or CRP (or both) at the time of diagnosis. In patients receiving immunosuppressive treatment, CRP levels may not show an adequate increase when infection is present. Clinicians should be aware of this problem, especially upon treatment with the interleukin-6 receptor antagonists (tocilizumab and sarilumab), where despite an infection CRP may be normal, and should here rely on clinical examination and imaging tools.

SEROLOGIC TESTING AUTOANTIBODIES Testing for autoantibodies is frequently used in the diagnosis of rheumatic conditions and sometimes for monitoring of disease activity. Some of these autoantibodies are more specific for one disease, and others can be found in several diseases. Research into autoantibodies has yielded considerable information about the pathogenesis of various rheumatic conditions, but serologic testing for autoantibodies in clinical practice generally remains more an adjunct to diagnosis and management rather than a precise clinical guide.

Rheumatoid factor Rheumatoid factor (RF) is the traditional designation for autoantibodies directed at the Fcγ chains of IgG molecules. In clinical practice, laboratories tend to test only for IgM RF, but RF can belong to all major immunoglobulin classes (IgG, IgA, IgM) and in some cases IgD and IgE as well. In peripheral circulation, however, the main immunoglobulin classes of RF that can be easily detected are IgA and IgM RFs. Today enzyme-linked immunosorbent assay (ELISA) and nephelometric assays have become the most common methods for quantifying RF. IgM RF is produced in many chronic inflammatory conditions (long-standing infections such as bacterial endocarditis, hepatitis B and C, tuberculosis, and chronic bronchitis but also in fibrosing alveolitis and silicosis). Thus RF is not specific for a particular rheumatic disease such as RA. It can also be seen in 5% to 10% of older adults in the normal population. The main indication for RF testing in adults is supporting the clinical diagnosis of RA or Sjögren syndrome. The specificity of RF in differentiating RA from other autoimmune conditions is limited, however. Higher RF titers are a poor prognostic factor in patients with RA and associated with more aggressive and erosive disease. Of note, 20% to 30% of patients with RA test negative for RF and yet have a clinical picture with a potentially poor prognosis when not treated. RF may appear up to several years before the onset of clinical RA. With effective treatment, RF titers can decrease, which is especially typical for B cell–directed therapy with rituximab.

Antibodies to citrullinated protein and peptide antigens

FIG. 30.1  Uric acid crystals in synovial fluid.

In 1964, antibodies directed to keratohyaline granules of human buccal mucosa cells were described as a specific marker for RA. They were termed antiperinuclear factor (APF). Several years later, antibodies reacting with upper mucosal cells of the esophagus, so-called antikeratin antibodies (AKAs), were found that had a prevalence in and specificity for RA similar

244

SECTION 3  Approach to the Patient

Table 30.3

Comparison of Anticitrullinated Peptide Antibodies and Rheumatoid Factor Tests in Terms of Positive and Negative Predictive Values CCP2 Number of patients (RA/control) 1316/1697

PPV (%) 91.2

CCP3

NPV (%) 78.4

PPV (%) 84.9

NPV (%) 79.8

MCV PPV (%) 80.4

NPV (%) 81.5

RF PPV (%) 75.9

NPV (%) 75.3

CCP, Cyclic citrullinated peptide; MCV, mutated citrullinated vimentin; NPV, negative predictive value; PPV, positive predictive value. Adapted from Pruijn GJ, Wiik A, van Venrooij WJ. The use of citrullinated peptides and proteins for the diagnosis of rheumatoid arthritis. Arthritis Res Ther 2010;12:203.

Table 30.4

Sensitivity of Antinuclear Antibodies in Autoimmune and Nonrheumatic Diseases Sensitivity (%) Autoimmune disease

Systemic lupus erythematosus Systemic sclerosis Mixed connective tissue disease Polymyositis or dermatomyositis Rheumatoid arthritis Rheumatoid vasculitis Sjögren syndrome Drug-induced lupus Discoid lupus Pauciarticular juvenile chronic arthritis

95–100 60–80 100 60 50 30–50 40–70 90 15 70

FIG. 30.2  Antinuclear antibody homogeneous staining.

Nonrheumatic diseases

Hashimoto thyroiditis Graves disease Autoimmune hepatitis Primary pulmonary hypertension

45 50 50 40

to those of APF. In the late 1990s, anticitrullinated vimentin (anti-Sa) antibodies were described in Canada, and anticitrullinated peptide antibodies (ACPAs) were described in The Netherlands and France. All of these antibodies (APF, AKA, anti-Sa, ACPA) have now been shown to target citrullinated parts of proteins such as filaggrin, alpha-enolase, vimentin, and fibrin. Citrullination is the result of deimination of arginine residues in these proteins by activation of Ca2+-dependent peptidylarginine deiminase enzymes during inflammation-induced apoptosis (programmed cell death). Leakage of these active enzymes into cells or onto synovial structures causes citrullination of proteins in many types of synovial inflammation. However, typically, only RA patients and some PsA patients react to such modified proteins by producing significant amounts of ACPAs. This is likely to depend on the specific presentation of citrullinated peptides to T cells by shared epitope motifs on human leukocyte antigen (HLA)-DR molecules. The diagnostic performance of ACPAs is superior to RF because they can be detected with a higher specificity and moderate sensitivity for RA using citrullinated proteins or peptides in ELISA.15 Nevertheless, it should be noted that RF as well as ACPA positivity are criteria for RA and that testing for both markers is important. Furthermore, the current classification criteria for RA take also into account the titer of RF and ACPA with up to three out of six criteria points in case of high elevated antibodies (above 3 times the ULN).16 The use of a cyclic citrullinated peptide (CCP2 and CCP3) has become the most widely used surrogate antigen for detection of ACPA. Other identified citrullinated autoantigens in RA, such as citrullinated vimentin or mutated citrullinated vimentin (MCV), can also be used for detection of ACPA (Table 30.3). Several studies have demonstrated the presence of ACPAs up to a decade before the onset of clinical disease.17 When found in patients with early undifferentiated arthritis, ACPAs predict later development of classic erosive RA. They are especially prevalent in RF-positive patients but can be found in around 25% of RF-negative RA patients as well.18 The ACPA test is helpful in discriminating between RA and psoriasis with erosive arthritis and between RA and hepatitis C–associated polyarthritis. Accumulating data suggest that RA patients seropositive for ACPAs or RF may respond better to certain biologics, including rituximab and abatacept. An association between ACPA positivity, HLA-DR alleles, and smoking has been shown in different cohorts.19 Other modifications of antigens by, e.g., carbamylation have been described to induce an autoantibody response in RA. However, they are not part of the standard diagnostic procedures so far showing a rather low specificity for RA if other disease groups20 are tested.

FIG. 30.3  Antinuclear antibody speckled staining.

Antinuclear antibodies ANA testing serves as a screening tool for systemic autoimmune rheumatic diseases. However, ANAs are seen in individuals with many autoimmune conditions as well as in many healthy people and lack specificity for any one particular disease (Table 30.4). They are generally detected by indirect immunofluorescent (IIF) techniques using monolayers of HEp-2 cells. Subsequently, differentiation of a positive ANA result should be performed using solid-phase immunoassays such as ELISA. ANAs are reported in terms of titers (e.g., 1 : 160, which is usually also the cutoff for positive results) and staining patterns (e.g., homogeneous or speckled). The presence of ANAs is a serologic hallmark of autoimmune rheumatic disorders such as SLE, Sjögren syndrome, mixed connective tissue disease, systemic sclerosis, and undifferentiated connective tissue disease, as well as of autoimmune hepatitis. However, the mere presence of these antibodies does not signify disease because healthy people (especially family members of patients with autoimmune diseases, older adults, and patients using drugs such as sulfasalazine, isoniazid, and TNF-inhibitors) can show clinically irrelevant positive ANA reactivity. A high titer increases the likelihood that the presence of antibodies is related to an autoimmune disease. In such cases, further evaluation with testing for the specific antigenic target such as anti-double-stranded DNA (dsDNA), anti-Ro (SS-A), anti-La (SS-B), anti-Smith (Sm), and anti-ribonucleoprotein (RNP) is indicated. In patients in whom a diagnosis cannot be made based on clinical symptoms, watchful waiting is recommended. ANAs also produce a wide range of staining patterns on Hep-2 cells, which should guide the further serologic differentiation (Figs. 30.2 to 30.4). The International Consensus on ANA Patterns (ICAP) initiative has previously reached consensus on the nomenclature and definitions of HEp-2 IIFA patterns.21

CHAPTER 30  Laboratory tests in rheumatic disorders

245

Autoantibodies in idiopathic inflammatory myopathies The spectrum of antibodies in idiopathic inflammatory myopathies has been significantly extended over the past years and can be separated in myositis-specific antibodies and myositis-associated antibodies. These antibodies are detectable in approximately 80% of patients and can contribute to the diagnosis and stratification of subgroups of idiopathic inflammatory myopathies. Furthermore, some antibodies can serve as predictive markers for organ manifestations, risk of cancer, and overall prognosis of disease.23 They are described in more detail in Chapter 158.

Antiphospholipid antibodies

FIG. 30.4  Antinuclear antibody centromere staining.

Anti-double-stranded DNA antibodies Anti-DNA antibodies target complexes of single- or double-stranded DNA and protein, producing a homogeneous pattern in ANA IIF with positively reacting chromosomes in metaphase. Although anti-dsDNA antibodies are a specific marker for SLE, anti-single-stranded DNA (ssDNA) antibodies represent a nonspecific finding. A positive result for anti-dsDNA antibodies in ANA or ELISA screening must be confirmed by Crithidia luciliae IIF or Farr assay, which provide higher specificity. Anti-dsDNA antibody testing is very specific (95%) but not as sensitive (70%) for SLE, which makes the test result part of the classification criteria for SLE.22 Anti-dsDNA antibodies also may have a pathogenic role in lupus nephritis and are commonly associated with disease activity. The usual picture in active lupus nephritis is increased anti-dsDNA antibody along with decreased serum levels C3 and C4, with levels of all tending to normalize with control of active kidney disease.

Anti-Sm and anti-U1 ribonucleoprotein antibodies Anti-Sm and anti-U1 RNP antibodies are directed against the spliceosome and produce a coarse speckled pattern in ANA IIF, with the nucleoli spared. These antibodies can be confirmed using solid-phase immunoassays such as ELISA. Anti-Sm antibodies are found almost exclusively in SLE patients, with a sensitivity of 10% to 40%, and are part of the EULAR/ ACR classification criteria. A negative result is not helpful in ruling out SLE, but the presence of these antibodies is a very strong piece of evidence of possible SLE. The presence of anti-U1 RNP antibodies, especially at high titers, is very typical for mixed connective tissue disease and is a prerequisite for diagnosis. Furthermore, anti-U1 RNP antibodies, usually at lower titers, are found in 40% to 60% of SLE patients.

Anti-Ro (SS-A) and anti-La (SS-B) antibodies The targets of anti-Ro (SS-A) and anti-La (SS-B) antibodies are nuclear and cytoplasmic RNPs. These antibodies produce a fine speckled pattern in ANA IIF, with staining of the nucleoli as well. Anti-Ro and anti-La antibodies are part of the classification criteria for Sjögren syndrome but also are frequently detectable in SLE patients. They have been associated with subacute cutaneous lupus and photosensitivity as well as lung involvement in systemic autoimmune diseases. Anti-Ro and anti-La antibodies have also been associated with neonatal lupus and congenital heart block because they cross the placental barrier. Therefore during pregnancy in women with positive tests for anti-Ro antibodies, the fetus should be screened for congenital heart block by ultrasonography, and newborns of anti-Ro antibody-positive mothers should avoid sunlight exposure during the first weeks of life.

Anticentromere and anti-Scl-70 antibodies Anticentromere and anti-Scl-70 autoantibodies are the specific and most frequent markers for systemic sclerosis, each detectable in up to 40% of patients. Anticentromere antibodies produce a typical pattern in ANA IIF by staining the centromere region of chromosomes. The target of antiScl-70 is topoisomerase I, and it shows a nucleolar and nucleoplasmatic staining as well as positively reacting with chromosomes in metaphase. The presence of anti-Scl-70 antibodies should be confirmed using solid phase immunoassays, but the ANA pattern of anticentromere antibodies is pathognomonic. Interestingly, these two antibody types rarely occur in the same patient and are associated with distinct clinical pictures. Anticentromere antibodies are more frequently observed in the context of localized systemic sclerosis and pulmonary hypertension. Patients who test positive for anti-Scl-70 typically have diffuse systemic sclerosis and pulmonary parenchymal involvement.

Antiphospholipid antibodies bind to certain serum proteins complexed to phospholipid molecules.24 The assays most widely used to detect antiphospholipid antibodies are the anticardiolipin assay and the lupus anticoagulant functional test. One also can screen for functionally procoagulant antiphospholipid antibodies by measuring the activated partial thromboplastin time, which is abnormally prolonged in their presence. Antiphospholipid antibodies were originally detected when false-positive serologic results for syphilis were found using the Wassermann reaction. Subsequently, positive reactivity on the anticardiolipin ELISA and the lupus anticoagulant test were shown to depend on binding of autoantibodies to a serum cofactor, which in the case of the anticardiolipin ELISA is β2-glycoprotein I and in the lupus anticoagulant assay may be either β2-glycoprotein I or prothrombin. Anticardiolipin antibodies are detected by ELISA using cardiolipin-coated microtiter plates that are then flooded with diluted bovine serum to secure binding of bovine proteins to the phospholipid. The most important phospholipid-binding protein attaching to the cardiolipin is β2-glycoprotein I, which acts as a cofactor in the test. Autoantibodies to β2-glycoprotein I and to the cardiolipin–β2-glycoprotein I complex give rise to positive results of importance for diagnosing a procoagulant state, but antibodies directed at the cardiolipin itself show no such relationship. Antibodies to the naked cardiolipin appear transiently in several infections and permanently in syphilis. The antibodies may belong to all three major immunoglobulin classes, but IgG anticardiolipin antibodies are those most closely related to procoagulant activity and thus the presence of lupus anticoagulant activity. To be able to discriminate between diagnostically important anticardiolipin antibodies, it is now common to search for specific anti–β2-glycoprotein I antibodies using ELISA plates coated with purified β2-glycoprotein I protein. The presence of anti–β2-glycoprotein I antibodies correlates better with a positive lupus anticoagulant test result and with manifestations of antiphospholipid syndrome. Lupus anticoagulant is an inappropriate name for the procoagulant autoantibodies because they appear not only in SLE but also in other autoimmune diseases and in so-called primary antiphospholipid syndrome. Patients with primary antiphospholipid syndrome experience venous or arterial thrombotic events, recurrent fetal loss, and thrombocytopenia in the absence of clinical features of another chronic inflammatory rheumatic disorder (see Chapter 147). The name also is misleading because lupus anticoagulants are not anticoagulants but procoagulants. They block the assembly of the prothrombinase complex, which gives rise to prolonged results on coagulation assays in vitro (e.g., prolonged activated partial thromboplastin time, dilute Russell viper venom time, and kaolin clotting time). This abnormality cannot be corrected by mixing the patient plasma 1 : 1 with normal plasma, but this mixing corrects clotting properties in patients with coagulation factor deficiencies.

Antineutrophil cytoplasmic antibodies Antineutrophil cytoplasmic antibodies (ANCAs) represent a subgroup of neutrophil-specific autoantibodies. They are commonly directed to the azurophil granule proteins myeloperoxidase (MPO) and proteinase 3 (PR3). ANCAs are characteristic of patients with necrotizing vasculitides such as granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (see Chapter 164). In IIF assays, ANCA directed at PR3 typically gives rise to a coarse granular fluorescence pattern in the cytoplasm of neutrophils and monocytes using ethanol-fixed leukocytes and is therefore called cytoplasmic ANCA (c-ANCA) (Fig. 30.5). In contrast, MPO-ANCA produces a perinuclear staining pattern on neutrophils and monocytes (p-ANCA) (Fig. 30.6). A positive result on an IIF screening test for p-ANCA or c-ANCA should be confirmed using a specific ELISA using MPO and PR3 as antigens. Since the newest generation of ELISAs against MPO and PR3 show excellent diagnostic performance, a direct testing without the need of screening by IIF is recommended in the new guidelines.25 The usefulness of ANCAs in monitoring disease activity in granulomatosis with polyangiitis has been controversial.26,27 They are useful in diagnosing ANCA-associated vasculitides but may not be that helpful in individual patients in predicting remission or relapse, and their measurement is not currently recommended for these reasons.

246

SECTION 3  Approach to the Patient

FIG. 30.5  Cytoplasmic staining pattern of antineutrophil cytoplasmic antibodies.

FIG. 30.6  Perinuclear staining pattern of antineutrophil cytoplasmic antibodies.

COMPLEMENT The most frequent laboratory parameters used for judging complement activation are the serum protein levels of C3 and C4, although these values are of limited use because they represent increased production during inflammation (acting as positive acute-phase reactants) and sometimes also increased consumption by immune complexes. Total hemolytic complement (CH50) is a functional assay used to measure the intactness and consumption of the entire classic pathway; however, it is rarely used nowadays because of its technical complexity. Decreased complement levels are useful in the setting of lupus nephritis, in which low levels are associated with persistent nephritis and normalization is associated with better outcomes. Hypocomplementemia is also a feature of preeclampsia and eclampsia, which is an important point to remember when caring for pregnant patients with SLE with and without antiphospholipid syndrome.

CONCLUSION Laboratory tests are useful tools for diagnosis of systemic autoimmune rheumatic diseases and for monitoring of adverse events related to medication use in some rheumatic conditions. Laboratory results are considered in combination with clinical signs and symptoms and should not replace a thorough history and physical examination in the diagnostic evaluation. As always, any test that will not change the diagnosis, prognosis, or treatment of a rheumatic condition should not be performed.

REFERENCES 1.

Reid MC, Lane DA, Feinstein AR. Academic calculations versus clinical judgments: practicing physicians’ use of quantitative measures of test accuracy. Am J Med. 1998;104:374–380. 2. Pincus T. A pragmatic approach to cost-effective use of laboratory tests and imaging procedures in patients with musculoskeletal symptoms. Prim Care. 1993;20:795–814. 3. Pincus T. Laboratory tests in rheumatic disease. In: Klippel JH, Dieppe PA, eds. Rheumatology. 2nd ed London: Mosby International; 1997:10.1–10.8. 4. Yazici Y, Erkan D, Paget SA. Monitoring by rheumatologists for methotrexate-, etanercept-, infliximab-, and anakinra-associated adverse events. Arthritis Rheum. 2003;48:2769–2772. 5. Mahabir VK, Ross C, Popovic S, et al. A blinded study of bone marrow examinations in patients with primary immune thrombocytopenia. Eur J Haematol. 2013;90:121–126. https://doi.org/10.1111/ejh.12041. 6. Yazici Y, Erkan D, Paget SA. Monitoring for methotrexate hepatic toxicity in rheumatoid arthritis patients: is it time to update the guidelines? J Rheumatol. 2002;29:1586–1589. 7. Yazici Y, Sokka T, Kautiainen H, et al. Long-term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely due to laboratory abnormalities. Ann Rheum Dis. 2005;64:207–211.

8. Mazaud C, Fardet L. Relative risk of and determinants for adverse events of methotrexate prescribed at a low dose: a systematic review and meta-analysis of randomized placebo-controlled trials. Br J Dermatol. 2017 Oct;177(4):978–986. https://doi.org/10.1111/bjd.15377. Epub 2017 Aug 30. PMID: 28182264. 9. Richette P, Doherty M, Pascual E, et al. EULAR evidence-based recommendations for the management of gout. Annals of the Rheumatic Diseases. 2017;76:29–42. 10. Zerwekh JE. Blood biomarkers of vitamin D status. Am J Clin Nutr. 2008;87:S1087–S1091. 11. Gabay C, Kushner I. Acute phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448–454. 12. Feist E, Mitrovic S.Fautrel B. Mechanisms, biomarkers and targets for adult-onset Still’s disease. Nat Rev Rheumatol. 2018;14:603–618. 13. Keenan RT, Swearingen CJ, Yazici Y. Erythrocyte sedimentation rate and C-reactive protein levels are poorly correlated with clinical measures of disease activity in rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis patients. Clin Exp Rheumatol. 2008;26:814–819. 14. Wolfe F, Michaud K. The clinical and research significance of the erythrocyte sedimentation rate. J Rheumatol. 1994;21:1227–1237. 15. van Venrooij WJ, van Beers JJ, Pruijn GJ. Anti-CCP antibodies: the past, the present and the future. Nat Rev Rheumatol. 2011;7:391–398. 16. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–2581. 17. Rantapää-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies to cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48:2741–2749. 18. Ford JA, Liu X, Marshall AA, et al. Impact of cyclic citrullinated peptide antibody level on progression to rheumatoid arthritis in clinically tested cyclic citrullinated peptide antibody–positive patients without rheumatoid arthritis. Arthritis Care & Research. 2019;71(12):1583–1592. 19. Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54:38–46. 20. Li X, Wang Z, Yi H, et al. Diagnostic accuracy of anti-carbamylated protein antibodies in rheumatoid arthritis: a systematic review and meta-analysis. Clin Lab. 2019;65(12) 21. Damoiseaux J, Andrade LEC, Carballo OG, et al. Clinical relevance of HEp-2 indirect immunofluorescent patterns: the International Consensus on ANA patterns (ICAP) perspective. Ann Rheum Dis. 2019;78(7):879–889. Epub 2019 Mar 12. 22. Aringer M, 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019;78(9):1151– 1159. Epub 2019 Aug 5. Review. 23. Stuhlmüller B, Schneider U, González-González JB, Feist E, Disease specific autoantibodies in idiopathic inflammatory myopathies. Front Neurol. 2019;8(10):438 eCollection 2019. Review. 24. Roubey RAS. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other antiphospholipid autoantibodies. Blood.. 1994;84:2854–2867. 25. Bossuyt X, Cohen Tervaert JW, Arimura Y, et al. Position paper: Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. Nat Rev Rheumatol. 2017;13(11):683–692. Epub 2017 Sep 14. Review. 26. Stegeman CA. Predictive value of antineutrophil cytoplasmic antibodies in small-vessel vasculitis: is the glass half full or half empty? J Rheumatol. 2005;32:2075–2077. 27. Finkielman JD, Merkel PA, Schroeder D, et al. Antiproteinase 3 antineutrophil cyto plasmic antibodies and disease activity in Wegener granulomatosis. Ann Intern Med. 2007;147:611–619.

Aspiration and injection of joints and periarticular tissue and intralesional therapy Esperanza Naredo • Ingrid Möller

Key Points ■ Synovial aspiration is a basic bedside diagnostic tool in rheumatology. ■ Major diagnostic errors can be made by simply assuming the nature of an effusion. ■ Corticosteroid injection and infiltration and viscosupplementation are basic treatment tools in rheumatology, orthopedics, physiatry, and general medicine. These procedures pose minimal risk to patients when performed properly. ■ Synoviorthesis, or medical synovectomy, may be achieved by the intraarticular injection of sclerosing agents or radioactive material but requires specialized knowledge. ■ There are emerging results on the efficacy of new medications and procedures (e.g., platelet-rich plasma, stem cell therapy, prolotherapy) for osteoarthritis and soft tissue lesions. ■ Rheumatologists trained in musculoskeletal ultrasonography are able to perform, at low cost and minimal risk to patients, accurate interventional procedures. ■ Ultrasound (US) is a valuable bedside tool for guiding accurate and safe musculoskeletal fluid aspiration and perilesional or intralesional injections. US provides confirmation of the clinical diagnosis and the indication for injection. Realtime US enables us to place the needle correctly, deliver medication accurately, and visualize the drug during and after the procedure.

INDICATIONS FOR ASPIRATING OR INJECTING MUSCULOSKELETAL TISSUES ASPIRATION OF FLUID OR DIAGNOSTIC OR THERAPEUTIC PURPOSES Joint aspiration has a number of major indications. In patients in whom infection, crystal, or blood is the suspected cause of monoarthritis or a bursal or tendon sheath lesion, aspiration and synovial fluid analysis are essential and required for diagnosis.1–3 In patients with tense joint effusions, aspiration of synovial fluid provides prompt relief of pain and permits the patient to move or bear weight on the affected joint. Finally, in hemarthrosis or septic arthritis, the blood and pus within a synovial cavity may be damaging to the joint cartilage and synovial membrane, so evacuation of the fluid is necessary to prevent permanent joint damage. Large articular effusions should be drained as fully as possible to decrease pressure, improve synovial circulation, and prevent muscle atrophy. Synovial fluid analysis is discussed in Chapter 32.

KEY PRACTICE ISSUES General principles for musculoskeletal (MSK) injection practice are displayed in Table 31.1.

Procedure Aspiration or injection of joints or soft tissues is an outpatient office procedure. Table 31.2 shows the equipment required for MSK aspiration and injections. A US system should also be available for US-guided procedures. The procedure must be explained fully to the patient. Universal precautions focused on sterilization must be followed during the procedure.

External landmark-guided aspiration The patient should be in a supine position for lower extremity procedures and in a sitting position in a chair with armrests for upper extremity procedures. Anatomic landmarks need to be identified by palpation and the needle site marked. The skin must then be cleaned carefully with antiseptic agents. For local anesthesia, the skin and subcutaneous tissue are infiltrated with 1% or 2% lidocaine without epinephrine (adrenaline) via a small-bore needle down to the level of the periarticular lesion or joint capsule. However, experienced physicians may use topical ethyl chloride or no anesthetic at all. With proper technique, the needle passes freely through the extraarticular tissues, and a “pop” may be felt as the needle enters the joint. The ease with which fluid can

31

be withdrawn depends on the size of needle used, the viscosity of the fluid, and the presence of any fibrin clots or “rice bodies” in the joint fluid. Free flow of fluid is often suddenly interrupted because of clogging of the end of the needle by the synovial membrane or debris. Rotating the needle, withdrawing it slightly, or even reinjecting a little of the fluid will often help unclog the needle. If corticosteroids or other substances are to be injected, this should be done through the same needle without removing it from the joint.

Ultrasound-guided aspiration and injection US can be a valuable bedside tool for guiding MSK fluid aspiration and perilesional or intralesional injections accurately and safely.4–6 US provides confirmation of the clinical diagnosis and the indication for injection. The characteristics of joint effusions (e.g., extension, solid or fluid content, internal synovial hypertrophy) that should be aspirated are visualized with US. This information is very useful for planning the best access to the fluid while avoiding synovial hypertrophy or solid material inside the fluid and for selecting the appropriate needle for the procedure. In addition, US allows us to select the joints that will potentially benefit more from a corticosteroid injection because of its greater inflammatory activity.7 Real-time US enables correct placement of the needle and accurate delivery of any medication by visualizing the drug suspension during and after the procedure. Injections into anatomic structures adjacent to the intended target (e.g., vessels, nerves, subcutaneous fat) can be avoided because they are easily identified with US. Furthermore, US can be used to monitor therapeutic response to musculoskeletal interventional procedures complementarily to clinical assessment.8 The learning time for US-guided injections is usually short. Several studies have demonstrated a greater accuracy of US-guided aspiration and injections in different joints and periarticular structures compared to injections guided by external anatomic landmarks.9 Although the impact of accurate needle placement on the therapeutic response to local corticosteroid injection needs further elucidation,10 it seems clear that US guidance, if available, can maximize accuracy of the injection into the intended target and minimize adverse effects related to the procedure. The capability of US to guide injections is based on the easily detectable hyperechoic appearance of metals such as needles and other puncture devices. The needle is visualized as a bright hyperechogenic line, often with a posterior reverberation artifact, when it is directed parallel to the long axis of the contact surface of the transducer (i.e., probe) and perpendicular to the US beam (Fig. 31.1). When the transducer is placed transverse to the route of the needle, only the tip of the needle is detected as a bright hyperechogenic focus as it reaches the target under the probe. The size of the needle does not significantly influence its visualization. US-guided injections should be carried out by following six steps: 1. US assessment of the clinically pathologic area and confirmation of the clinical diagnosis and indication for injection. 2. Planning of the injection route: the shortest, easiest, and safest to successfully achieve the target. 3. Measurement of the skin-target skin distance to properly choose the length of the needle. 4. Sterilization of the patient’s skin and probe. This can be effectively achieved with a careful cleaning of the probe and skin using conventional antiseptic agents (e.g., chlorhexidine). Sterile gel or a sterile sleeve for the probe with acoustic gel within it can also be used.11 5. Skin puncture under US guidance. 6. Confirmation of correct fluid aspiration or drug location (or both) with US before removing the needle. Two methods of guiding musculoskeletal needle placement with US are used: 1. Skin marking or indirect method (Fig. 31.2). With this method, US is used to select the potentially most successful puncture site over the target but not to guide progression of the needle; and 2. Needle guidance under direct US control (Fig. 31.3, a and b). This method consists of a continuous monitoring of progression of the needle under direct US visualization. Aspiration of fluid (Fig. 31.3, c to e) and injection of medication 247

SECTION 3  Approach to the Patient

248 Table 31.1

General Principles for Musculoskeletal Injections Preprocedure

Preprocedure

Preprocedure Preprocedure

Preprocedure

During procedure During procedure During procedure Postprocedure

Postprocedure

Postprocedure

The patient must be informed of all the details, benefits, and risks of the procedure. Patient’s informed consent should be obtained. The anatomic landmarks of the target area should be identified before injection. In ultrasound (US)-guided injections, the best approach to the target should be chosen before injection. Select the needle with appropriate length to reach the target. Select the finest needle appropriate for the density of the expected aspirated liquid or the injected medication. The patient’s skin in the area to be injected, the practitioner’s hands, and the US probe (if applicable) should be sterilized. Use different needles for drawing the medication and injecting it into the target structure. Avoid injection into tendon, ligament, or nerve substance or into vessels. Use US guidance, if available for deep or complex anatomic areas. Report the details of the injection, i.e., route used, quantity and aspect of the aspirated fluid, injected medication, adverse effects suffered by the patient during or after the procedure in the patient´s clinical records. Keep a minimum interval between injections and perform a maximum number of them depending on the clinical response, the anatomic area, and the injected drug. Explain to the patient that they should contact the medical team if they present with potential infection signs (fever, inflammatory changes, or severe pain) in the injected area after the procedure.

Table 31.2

Equipment Required for Joint and Soft Tissue Injectionsa Procedure

Details

Skin preparation

Antiseptic solution (povidone–iodine, chlorhexidine), alcohol swabs, 4 × 4 gauze pads 1% or 2% lidocaine without epinephrine No. 23–27 for local anesthetic, 18 gauge for largeto moderate-sized joints (e.g., knees, shoulders, ankles), no. 23–27 for small joints (e.g., wrists, metacarpophalangeal joints) 3 or 5 mL for anesthetic-steroid injection and 10–50 mL for joint aspiration (sterile steroid–prefilled syringes are preferable when available) Gloves, forceps for removing needles from the syringe, specimen tubes and plates for culture and fluid analysis

Local anesthetic Needles

Syringes

Miscellaneous

a

All the supplies required should be assembled in advance. Importantly, the needle must be long enough to reach the intended place and have a caliber adequate for the nature of the fluid. Although standard needle lengths work well in thin patients, longer needles and even a spinal needle may be required in obese patients. On the other hand, a 1-mL syringe with a half-inch no. 27 needle is particularly useful for infiltrating superficial structures such as the interphalangeal, metacarpophalangeal, and metatarsophalangeal joints; the digital flexor tendon sheaths; the carpal tunnel; de Quervain disease; and the elbow joint through the lateral approach. Purulent effusions require no. 18 or 16 needles. Failure to fully drain a septic joint indicates large debris or loculation and calls for tidal lavage, arthroscopy, or arthrotomy. All material should be new and sealed when used; do not use the rest of opened vials.

can be seen in real time. Most ultrasonographers carry out direct US-guided injections via a freehand technique. A needle guide can also be installed on the transducer to hold and direct the needle for injecting deep lesions. However, these devices make the procedure more time consuming and expensive and the approach less flexible.

AFTERCARE A simple adhesive plaster (tape) is applied at the injection site for a few hours. In most cases, it is sensible for patients to rest or at least not to

SDB

FIG. 31.1  Ultrasound-guided injection of the subdeltoid bursa. The needle appears as a hyperreflective line with posterior reverberation artifact (arrows) inside a hypoechoic subdeltoid bursitis. SDB, Subdeltoid bursa.

overuse the affected joint for 24 to 48 hours after a therapeutic injection to minimize leakage of the therapeutic agent after lower extremity procedures and improve the antiinflammatory response.12

CONTRAINDICATIONS There are few absolute contraindications to joint or soft tissue aspiration and injection; if infection is suspected, fluid should always be aspirated from a joint. For other indications, the procedure should be avoided if the overlying skin or subcutaneous tissue is infected or if bacteremia is suspected. Joint aspiration and injections are considered low-bleeding risk procedures.13 Nevertheless, the presence of a significant bleeding disorder or diathesis or severe thrombocytopenia may also preclude joint aspiration. However, if it is deemed necessary for diagnosis or therapy, the procedure may be carried out after appropriate coverage for the bleeding disorder. Neither warfarin anticoagulation with international normalized ratios in the therapeutic range nor use of direct oral anticoagulants are contraindications to joint or soft tissue aspiration or injection.14,15 Aspiration or medication injection in a joint before or after a joint replacement surgical procedure may be performed although this decision is often best left to surgeons. An umbrella review concluded that there was limited evidence that intraarticular corticosteroid injections prior to arthroplasty did not increase the risk of subsequent infections postoperatively.16

CORTICOSTEROID INJECTIONS Corticosteroid injections are frequently used to achieve a local antiinflammatory response. Indications for their use include persistent inflammation at a single site in immune-mediated inflammatory arthritis or microcrystalline arthropathies, osteoarthritis (OA), or inflamed periarticular structures (e.g., bursitis, tenosynovitis).17 Although there is a paucity of comparative data on the efficacy of different corticosteroids for injections,18 synovial joints and other cavities (e.g., bursae, cysts) should generally be injected with a long-acting crystalline form of corticosteroid such as triamcinolone hexacetonide or methylprednisolone acetate. These crystals persist longer in the fluid than do mixtures of depot and soluble betamethasone19 and thereby allow continued local release into the targeted area. Only a relatively small proportion escapes into the general circulation, but during the first 24 hours after injection, patients may experience flushing or other evidence of a corticosteroid “pulse.”20 For periarticular injections, particularly subcutaneous bursae and de Quervain tenosynovitis, methylprednisolone acetate should be used because the less soluble (and therefore more potent) triamcinolone hexacetonide is likely to induce skin atrophy. Local anesthetics such as lidocaine or bupivacaine may be administered mixed with corticosteroids in the same syringe in an attempt to reduce postprocedure discomfort.

CHAPTER 31  Aspiration and injection of joints and periarticular tissue and intralesional therapy

249

FIG. 31.2  (a) Ultrasound-guided indirect method of injection into the right tibiotalar joint. An extended paper clip is displaced between the probe and the skin until its tip is imaged at the center of the target. The puncture point is marked in the patient’s skin with the clip. (b) The needle is inserted perpendicular to the skin.

a

b

SDB bt

c

bg

SDB bt

bg

d fh

SDB bt

fn

a

b

e

bg

FIG. 31.3  (a) Ultrasound-guided direct method of injection of the right hip joint. The needle is inserted adjacent to the transducer and directed to the anterior recess of the hip. (b) On the ultrasound image, the tip of the needle (arrowheads) has a hyperechogenic appearance inside the hip effusion. The needle (arrow) appears hyperechogenic in the iliopsoas muscle. fh, Femoral head; fn, femoral neck. (c) Ultrasound-guided injection of subdeltoid bursitis. (d and e) Successful fluid aspiration can be visualized in real time. Arrowheads indicate needle tips. bg, Bicipital groove; bt, biceps tendon; SDB, subdeltoid bursa. Corticosteroid doses vary with the structure injected. For each of the procedures discussed, a dose range based on the use of methylprednisolone acetate is shown in each section. If the more potent triamcinolone hexacetonide is used, the lower dose of the indicated range should be chosen. Intracavitary position of the needle can be ascertained by withdrawing some joint fluid or checking to see whether the cavity distends as fluid is injected. In soft tissues, correct positioning may be ascertained by elimination of pain with a preceding lidocaine infiltration. However, if available and in procedures in which needle misplacement is common, US guidance gives the best results.21,22 Resting or at least avoiding overuse of the injected site for 24 to 48 hours after the procedure is generally recommended.12 The most common indications for aspiration and injection of the musculoskeletal system are presented in this chapter.

Complications of corticosteroid injections23 ■

Local bleeding. In patients without a bleeding diathesis, pressing the puncture site with sterile gauze for about 1 minute—or longer in those

■ ■

■

■

taking prophylactic aspirin—stops the bleeding. In procedures on the upper extremity, arm elevation prevents venous bleeding. Facial flushing. Flushing occurs in perhaps 40% of cases. Transient and inconsequential, it may nevertheless worry unwarned patients. Postinjection flare. Corticosteroid crystal–induced synovitis occurs in approximately 5% of intraarticular injections. Pain appears several hours after the procedure and may last from a few hours to 1 day. Persistent pain and mounting swelling may indicate infection; these joints should be reaspirated for Gram stain and aerobic and anaerobic culture. Skin atrophy. This complication occurs frequently, particularly in older individuals and with superficial infiltrations. The condition is characterized by cigarette paper–like skin, recurrent ecchymosis, and chronic pressure pain. Fat atrophy. This complication may occur with repeated fatty tissue infiltration, such as for Morton neuroma and proximal plantar enthesopathy.

250 ■

■

■

■

■

■

■ ■

SECTION 3  Approach to the Patient Skin hypopigmentation. Superficial corticosteroid infiltrations such as for de Quervain tenosynovitis often result in a hypopigmented patch, which may be quite disfiguring in people with dark skin. Embolia cutis, livedoid dermatitis, or Nicolau syndrome. A rare adverse reaction to drug injections, including corticosteroids, this complication is characterized by microembolic obstruction of a dermal artery, which causes a livedoid lesion and necrotic ulcers. Pain is felt around the injection site followed by a livedoid and hemorrhagic patch, and finally necrosis of the skin, subcutaneous fat, and muscle occurs. Infection. The reported rate of septic arthritis after corticosteroid injection has been on the order of 5 cases per 100,000 procedures when the corticosteroid is aspirated from a vial and fewer than 1 case per 100,000 procedures when prefilled syringes are used.24 Patients who have severe immunodeficiency problems, as well as those with implants, may be at greater risk. It is important to not reuse leftovers of open vials because of staphylococcal contamination. Tendon rupture. A ruptured tendon after a corticosteroid injection may indicate abuse of the procedure, intratendinous injection, or coincidental rupture caused by the very condition that led to the injection. Conditions that result in spontaneous tendon rupture include dorsal wrist tenosynovitis and posterior tibialis tenosynovitis in patients with rheumatoid arthritis (RA); degenerative changes in the supraspinatus, long biceps, or Achilles tendon; chronic corticosteroid use; fluoroquinolone-induced Achilles tendinopathy; uremia; hyperparathyroidism; and systemic lupus erythematosus. Corticosteroid arthropathy. Abuse of intraarticular injections may result in a Charcot-like arthropathy similar to that described with calcium pyrophosphate crystal deposition disease. Nerve damage. With knowledge of regional anatomy, this complication should largely be avoided. However, because anatomic variations are frequent, insertion of the needle should always be done cautiously. Osteonecrosis. This is a reported complication of articular or soft tissue corticosteroid infiltration abuse.25 Systemic complications. Corticosteroid injections cause pituitary inhibition, which recovers in 1 to 2 weeks,26 and in patients with diabetes, transient hyperglycemia lasting 2 to 3 days. Diabetic patients with elevated levels of glycated hemoglobin (A1c) should be strictly monitored after these injections.27 Patients with diabetes mellitus, particular those who are taking insulin, should be counseled to check their blood glucose levels at a minimum of twice daily for up to 48 hours post intraarticular injection because of an expected rise in blood glucose levels.28 Anaphylactic shock, albeit exceedingly rare, may also occur.29

OTHER THERAPEUTIC INJECTIONS VISCOSUPPLEMENTATION Viscosupplementation is the term that describes the use of intraarticular hyaluronates. Two types of agents are in use. One is hylan G-F 20, a high-molecular-weight preparation (molecular weight of 6,000,000). The other type includes lower-molecular-weight hyaluronan preparations in the range of 800,000 to 2,000,000. Viscosupplementation is often effective in relieving pain in patients with OA.30,31 When compared with intraarticular corticosteroids, the beneficial effect of viscosupplementation is that it has delayed action but lasts longer.32 The relative merits of hylan G-F 20 and the lower-molecular-weight compounds are still in dispute.33 Although these agents were initially used for OA of the knee, other joints such as the trapeziometacarpal joint,34 the shoulder, the hip, and the ankle have all been treated with benefit. Viscosupplementation is associated with several risks. The most common adverse effects are joint swelling and arthralgia. However, postinjection pain, not necessarily associated with a significant effusion, has been common in the authors’ experience. Another complication is a pseudo–septic effusion associated with pyrexia.35 These reactions require hospital admission and intravenous antibiotics pending the results of culture. A granulomatous reaction has also been reported.36 A further risk with viscosupplementation is an allergic reaction in patients with avian protein allergy (e.g., products, feathers). The usual indications for viscosupplementation include (1) patients who cannot tolerate oral antiinflammatory medications and whose pain is unrelieved with analgesics and (2) those with advanced OA who refuse or are not suitable candidates for surgery. The medication and administration costs of viscosupplementation are considerable. However, a Canadian cost analysis has shown superiority of viscosupplementation over appropriate care without viscosupplementation.37

SYNOVIORTHESIS Synoviorthesis, or medical synovectomy, may be achieved with the intraarticular injection of chemicals such as osmic acid, rifampicin, and rifamycin or radioactive colloids such as yttrium-90 (90Y), erbium-169 (169Er), dysprosium-165 (165Dy), and gold-198 (198Au), among others. The procedure may be used in patients with RA, OA, pigmented villonodular synovitis,38 and other chronic effusive conditions, as well as in those with hemophilia to terminate recurrent hemarthrosis.39 Chemical agents are believed to be less efficacious than radioactive colloids, and among these, beta-emitting radioisotopes such as 90Y, 169Er, and 165Dy are preferred over gamma-emitting radioisotopes such as 198Au, which cause total body irradiation. Few randomized controlled trials of radioactive and chemical synoviorthesis have been conducted.40 Adverse effects of radioactive synoviorthesis are uncommon. A possible untoward local effect is a burning sensation in the needle track. This may be prevented by injecting a corticosteroid suspension while slowly removing the injecting needle. A greater concern has been a possible oncogenic effect of the radioactive colloid. However, although chromosomal damage has been found rather frequently in peripheral blood after these procedures, a 30-year Finnish follow-up study of 90Y synoviorthesis in more than 1000 patients failed to show excess cancer deaths.41 Thus radioactive synoviorthesis, a low-risk, relatively low-cost outpatient procedure that minimally disrupts the patient’s activities, is a plausible alternative to surgical synovectomy in carefully selected patients. In hemophilia, according to experts, failure of three consecutive radioactive synoviorthesis procedures is an indication for open or arthroscopic synovectomy.

OTHER INJECTIONS In recent years, many diverse medications became available for intraarticular or periarticular injections. Although there has been a growing literature production, their evidence-based efficacy is still insufficient or controversial, especially in the mid and long term. Among them, platelet-rich plasma is being used increasingly to ameliorate pain in patients with OA42,43 and to improve symptoms and potentially facilitate healing in those with tendinopathy.44 Botulinum toxin has shown inconclusive results for the relief of chronic refractory muscle pain.45 Collagenase Clostridium histolyticum may be a minimally invasive alternative to surgery for selected patients with Dupuytren contracture.46 Regarding prolotherapy (e.g., dextrose, saline), there is limited evidence for its efficacy and safety in treating tendon and ligament lesions and OA.47,48 The use of intraarticular or periarticular injection of ozone for pain relief has occasionally been described.49 Recently, intraarticular injection of stem cells (bone marrow aspirate, adipose-derived, placental-derived) has been proposed as a regenerative therapy for OA therapy.50 Finally, peripheral nerve blockades for regional pain relief are increasingly used in rheumatology.51 The next section of this chapter focuses on the most frequent procedures involving corticosteroid injection from an anatomic perspective.

WRIST AND HAND FINGER AND METACARPOPHALANGEAL JOINTS Indications. Active Bouchard nodes, RA,52 psoriatic arthritis (PsA). US guidance is optional. Corticosteroid dose. 10 to 15 mg methylprednisolone acetate (no. 25 or 27 needle). Approach. Dorsolateral (radial or ulnar) with the digit in semiflexion (Fig. 31.4 and Figs. e31.1 and e31.2). Note that in this and other clinical pictures, the skin had been sterilized with alcohol and the needle seen in place was for injection of local anesthetic before injection of the steroid. Multiple joints may be injected during the same session. Precautions. Do not overdistend the joint or joints. Fluid tends to back up; apply firm pressure with sterile gauze for at least 2 minutes after the procedure. Complications. Joint hyperlaxity, capsular calcification (frequent but inconsequential).

FIRST CARPOMETACARPAL JOINT Indications. Painful OA. The efficacy of steroid injection has been disputed.53 Viscosupplementation may be useful as an alternative to surgery.54 US guidance is optional. Corticosteroid dose. 15 to 20 mg methylprednisolone acetate (no. 25 or 27 needle).

CHAPTER 31  Aspiration and injection of joints and periarticular tissue and intralesional therapy

251

Approach. A common entry site is at the anatomic snuffbox while flexing the thumb across the palm, which optimally exposes the joint just proximal to the protruding base of the first metacarpal (Fig. 31.5). A palmar approach is generally used to inject this joint under US guidance. Precautions. Avoid the radial artery as it traverses the anatomic snuffbox. Complications. None.

WRIST (RADIOCARPAL AND MIDCARPAL JOINTS, DISTAL RADIOULNAR JOINT)

a

Indications. For diagnosis of acute arthritis. Most cases of acute wrist arthritis are due to acute pyrophosphate arthritis, gout, and septic arthritis. For injection in patients with RA, other sterile arthropathies, and OA, US guidance is preferred. US allows identification of which wrist joint (e.g., radiocarpal, midcarpal, and/or radioulnar) is more inflamed or has more fluid, which is important in determining the injection target. Corticosteroid dose. 30 to 40 mg methylprednisolone acetate (no. 25 or 27 needle). Aspiration should be attempted before injection. For aspiration alone, use a no. 20 or 18 needle. Approach with blind injections. The radiocarpal joint is approached dorsally just distal to the Lister tubercle (a bony prominence in the dorsal distal end of the radius) or at the midcarpal joint 1 cm ulnar and 5 mm distal to the Lister tubercle (Figs. e31.3 and e31.4). The distal radioulnar joint is approached from the dorsal-ulnar aspect (Figs. e31.5 and e31.6). The wrist should be slightly palmar-flexed to assist in the procedure. Precautions. No neurovascular structures of concern are located at this site. Complications. None.

TRIGGER FINGER AND TRIGGER THUMB

b

FIG. 31.4  (a) Injection of the right fourth proximal interphalangeal joint in a patient with osteoarthritis. (b) The needle (red arrow) enters from the dorsal-radial aspect of the proximal interphalangeal joint going through the skin and the joint capsule to reach the joint recess. 1, Proximal phalanx; 2, middle phalanx; 3, flexor digitorum tendon. (Fig. 31.4, b Courtesy of M. Miguel, University of Barcelona, Spain.)

FIG. 31.5  Injection of the left trapeziometacarpal joint in a patient with osteoarthritis.

Indications. Only 30% of trigger fingers resolve spontaneously, and injections are highly efficacious.55 A lower success rate of injections is seen in patients with diabetes. US guidance is optional. Approach. Just distal to proximal palmar crease (index) (Fig. 31.6), between the proximal and distal creases in the long finger (Fig. e31.7), and just distal to the distal crease in the ring and little fingers (Fig. e31.8) with the needle held at a 45-degree distal inclination; just proximal to the digital crease and aimed at sesamoids of the thumb (Fig. 31.7). Corticosteroid dose. 10 to 15 mg methylprednisolone acetate usually mixed with 1 to 2 mL lidocaine (no. 25 or 27 needle). Precautions. Avoid intratendinous injection. Intrasheath injection is not a requirement for success.56 Up to three injections given 3 weeks apart are allowed. Complications. Focal palmar fat atrophy.

FIG. 31.6  Injection of a right index trigger finger.

CHAPTER 31  Aspiration and injection of joints and periarticular tissue and intralesional therapy FIG. E31.1  (a) Injection of third metacarpophalangeal joint in a patient with rheumatoid arthritis. (b) The needle (red arrow) enters the metacarpophalangeal joint space from the dorsal-ulnar side of the joint capsule through skin; the blue indicates the injected dye diffusion into the joint. 1, Metacarpal head; 2, extensor mechanisms of the finger. (Fig. E31.1, b Courtesy of M. Miguel, University of Barcelona, Spain.) a

FIG. E31.2  Injection of interphalangeal joint of the thumb adjacent to a Heberden node.

b

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SECTION 3  Approach to the Patient

DIGITAL FLEXOR TENOSYNOVITIS Indications. RA, PsA, and other inflammatory conditions. Because the injection must be intrasheath for flexor tenosynovitis, US guidance is preferred (Fig. 31.8, Fig. e31.9). Corticosteroid dose. 15 to 20 mg methylprednisolone acetate usually mixed with 1 to 2 mL lidocaine (no. 25 or 27 needle). Approach. If US is unavailable, inject as for trigger finger. Precautions. Avoid intratendinous injection. Complications. As with trigger finger, tendon rupture occurs occasionally.

and a 45-degree lateral inclination. The corticosteroid is injected into the proximal extension of the ulnar bursa. Precautions. Paresthesias indicate median nerve engagement; reposition the needle. Reciprocal needle motion with gentle finger motion indicates tendon engagement; reposition the needle. A wrist splint in neutral is a useful adjunct to the injection. Complications. Pain, which may last 1 to 3 days, and a transient increase in paresthesias. The patient should be instructed to use an ice pack intermittently, 5 minutes on and 5 off, at the first hint of pain.

CARPAL TUNNEL SYNDROME57

DE QUERVAIN TENOSYNOVITIS59

Indications. Injection is indicated for all causes of carpal tunnel syndrome except acute cases (hypoesthesia, severe pain, and tense bulging) caused by synovitis, fracture, hemorrhage, infection, and carpal tunnel syndrome in late pregnancy. US guidance is optional for routine cases but is a must for unilateral cases to rule out a mass lesion.58 Corticosteroid dose. 20 to 30 mg methylprednisolone acetate, straight or mixed with 2 to 3 mL lidocaine (no. 25 or 27 needle). Approach. About 10 mm proximal to the distal wrist crease and just medial to the palmaris longus tendon (Fig. 31.9 and Fig. e31.10).37 If the palmaris longus is absent (14% of people), use a midline approach. The needle is inserted to a depth of 0.8 to 1 cm at a 45-degree distal inclination

Indications. Steroid injection is the treatment of choice for this condition. US guidance is optional (Video 31.1). Corticosteroid dose. 15 to 20 mg methylprednisolone acetate (no. 25 or 27 needle). Approach. The needle is aimed toward the radial styloid, which underlies the sheath (Fig. 31.10). The needle is then pulled back by the millimeter and injection is attempted. Successful injections distend the sheath of the abductor pollicis longus or extensor pollicis brevis (or both). Up to three injections given 3 weeks apart are allowed. Precautions. The corticosteroid must remain within the sheath. Complications. Skin hypopigmentation and skin atrophy.

FIG. 31.7  Injection of a right trigger thumb.

FIG. 31.9  Injection for right carpal tunnel syndrome.

t

a

S

b

FIG. 31.8  (a) With the hand supinated and the finger extended, the needle is introduced from distal to proximal to target the tendon sheath indicated by the red arrow. The skin and the subcutaneous fat will be in the path of the needle. 1, Metacarpal bone. 2, flexor tendon. (b) Ultrasound-guided injection of a flexor digitorum tenosynovitis (same patient as in Fig. e31.9), the drug is seen hyperechoic after the procedure. S, Steroid; t, flexor tendon. (Fig. 31.8, a Courtesy of M. Miguel, University of Barcelona, Spain.)

FIG. 31.10  Injection for right de Quervain tenosynovitis.

SECTION 3  Approach to the Patient

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FIG. E31.3  Aspiration of the radiocarpal joint for gout, radial view.

FIG. E31.4  Aspiration of the radiocarpal joint for gout, dorsal view.

FIG. E31.5  With the wrist slightly flexed, the needle (red arrow) penetrates between the fourth (4) and the fifth (5) extensor compartments at the dorsal radio ulnar joint crossing through the extensor retinaculum. 1, Radius; 2, ulna; 3, extensor pollicis longus. (Courtesy of M. Miguel, University of Barcelona, Spain.)

S

S

u ulna

a

b

FIG. E31.6  (a) Ultrasound image of the distal radioulnar joint in a patient with rheumatoid arthritis. Synovitis (S) is shown distending the capsule (arrows). (b) Ultrasound-guided injection of the above distal radioulnar synovitis; the needle is seen hyperechoic (arrows) inside the synovial hypertrophy. u, Ulna.

CHAPTER 31  Aspiration and injection of joints and periarticular tissue and intralesional therapy

FIG. E31.8  Injection of a right ring trigger finger.

FIG. E31.7  Injection of a right middle trigger finger.

FIG. E31.9  Ultrasound-guided direct injection for flexor tenosynovitis of the hand.

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253

FIG. 31.11 Ultrasound-guided injection of a ganglion cyst at the dorsal aspect of the wrist with the needle parallel to the long axis of the transducer (a) or perpendicular to the long axis of the transducer (b). The hyperechoic needle (a; arrowhead) or the tip of the needle (b; arrowhead) is seen inside the lesion.

a

b

WRIST EXTENSOR TENOSYNOVITIS Indications. Sustained tenosynovitis in patients with RA and PsA, microcrystalline tenosynovitis. Failure of one injection is an indication for tenosynovectomy. Corticosteroid dose. 15 to 20 mg methylprednisolone acetate (no. 25 or 27 needle). Approach. A direct US-guided injection is preferred (Figs. e31.11 and e31.12). Complications. The extensor digital tendons are prone to spontaneous rupture in patients with RA. An intratendinous injection probably enhances this tendency. Whether to inject an extensor tendon sheath or proceed to tenosynovectomy should be discussed with a hand surgeon.

GANGLIA Indications. Local corticosteroids are highly effective in the treatment of ganglia. Ganglia within the carpal tunnel, those that impinge on neurovascular structures, and those larger than 3 cm in diameter should be injected under US guidance60 or treated surgically. US guidance for ganglia injections is especially valuable with deeply located lesions or when they are close to other structures that may be punctured incidentally (e.g., tendons, peripheral nerves or vessels) (Fig. e31.13 and Fig. 31.11). Corticosteroid dose. Depends on the lesion; usually 15 to 20 mg methylprednisolone acetate (no. 20 or 18 needle; thinner needles may become clogged). Approach. The needle is aimed at the center of the lesion, which is aspirated before injection. Ganglia contain a viscous, translucent fluid. Fluid with other characteristics indicates that the lesion is not a ganglion; the fluid should therefore be cultured and inspected for crystals. Precautions. With ganglia in the wrist and anatomic snuffbox, rule out radial artery aneurysm, which mimics a ganglion. These lesions are expansile with the pulse, as opposed to the focal pulsation caused by a normal adjacent radial artery. Complications. None.

a

ELBOW REGION ELBOW (JOINT) Indications. Aspiration for acute arthritis, injection for RA, and PsA. Corticosteroid dose. 30 to 40 mg methylprednisolone acetate (no. 22, 25, or 27 needle). Aspiration should be attempted before injection. For aspiration alone, use a no. 20 or 18 needle, depending on the suspected diagnosis. US guidance is optional. Approach for blind injections. Two entries are commonly used; for both entries, the elbow is held flexed at 90 degrees. —Inferolateral approach. The midpoint cleft between the tip of the olecranon and the lateral epicondyle is palpated. The needle is then inserted perpendicularly and aimed at the center of the joint. —Lateral approach. The radiocapitellar joint may be entered from the side just proximal to the radial head. The needle is passed perpendicular to the skin between the two bones (Fig. 31.12). If palpation-guided aspiration of the elbow joint is not successful, US-guided arthrocentesis can be carried out from an anterior or posterior recess,

b

FIG. 31.12  (a) Lateral (radiocapitellar) injection of the left elbow in a patient with rheumatoid arthritis. The patient remains with the elbow in a semiflexed position; (b) The needle penetrates from the radial aspect of the joint between the olecranon and humerus at the level of the olecranon fossa. The blue dye shows the location of the articular recess after the injection. 1, Olecranon bone; 2, humeral bone. (Fig. 31.12, b Courtesy of M. Miguel, University of Barcelona, Spain.)

CHAPTER 31  Aspiration and injection of joints and periarticular tissue and intralesional therapy

FIG. E31.10  The tendons used as landmarks for injection into the carpal tunnel are seen clearly in this patient. To the left of the needle, past the vein, two tendons are seen: the palmaris longus and, radial to this, the flexor carpi radialis.

FIG. E31.11  The needle is inserted adjacent to the transducer and directed to the sheath of the fourth extensor compartment of the wrist.

lu tr

sc

FIG. E31.12  Same patient as in Fig. e31.11. On the ultrasound image, the needle (arrowhead) is introduced into the hypoechoic extensor tenosynovitis. lu, Lunate; sc, scaphoid; tr, triquetrum.

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FIG. E31.13  Transverse ultrasound image of a scapholunate ganglion.

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SECTION 3  Approach to the Patient

depending on the location and characteristics of the effusion. The brachial artery and median and radial nerves can easily be identified and avoided with the anterior needle route. Precautions. No neurovascular structures are located in the vicinity. Complications. None.

OLECRANON BURSA Indications. For the diagnosis of effusion and for the treatment of refractory aseptic bursitis (traumatic or microcrystalline). A negative bursal fluid culture is required before steroid injection. US guidance is optional. Corticosteroid dose. 20 mg methylprednisolone acetate (no. 20 or 22 needle). Empty the bursa before injection. Approach. Lateral through normal skin and aimed at the center of the bursa (Fig. e31.14). Precautions. Taps at the tip of the bursa may create a chronic leak. Medial entries may damage the ulnar nerve. Complications. None.

LATERAL EPICONDYLAR SYNDROME, OR TENNIS ELBOW, AND MEDIAL EPICONDYLAR SYNDROME, OR GOLFER’S ELBOW61,62 Indications. Failure of conservative treatment. To shorten the symptomatic period (with the caveat that the long-term outcome may be worse in injected than in uninjected patients). US guidance is optional. Corticosteroid dose. 10 to 20 mg methylprednisolone acetate (no. 25 or 27 needle). Approach for the lateral epicondyle. At the most tender point (Fig. 31.13), pass the needle until contact with the periosteum is made and infiltrate with 1 mL lidocaine. Failure to eradicate pain on resisted wrist dorsiflexion indicates the wrong injection site; reposition the needle and reinfiltrate with lidocaine. The corticosteroid should be infiltrated deeply at the enthesis and radially within the proximal part of the tendon. Approach for the medial epicondyle. Aim the needle toward the distal portion of the medial epicondyle where the wrist flexor muscles insert. Avoid injecting the posterior surface of the epicondyle to stay away from the ulnar nerve (Fig. e31.15).42 Precautions. Avoid injecting too superficially. Complications. Transient increase in pain in 20% to 40% of patients.

SHOULDER REGION SHOULDER (GLENOHUMERAL JOINT)

Approach for blind injection. Two entries are described: the posterior approach, which is preferred by the authors, and the anterior approach. —Posterior approach (Fig. 31.14 and Figs. e31.16 and e31.17). With the patient sitting, the posterior margin of the acromion is palpated. The needle is then inserted posteroanteriorly 1 cm below and 1 cm medial to the posterior corner of the acromion and aimed toward the coracoid process until bone is touched at the articular space. —Anterior approach. Again, the patient should be sitting with the arm hanging at the side of the body, elbow flexed 90 degrees, and forearm in the sagittal plane. The needle is inserted anteroposteriorly 1 cm distal and 1 cm lateral to the coracoid process. When the bone is touched, the forearm is very gently and passively brought into internal rotation as the needle is pushed into the articular space. The glenohumeral joint is usually injected from a posterior approach under US guidance. The needle is directed to the posterior synovial recess located at the superior angle of the posterior labrum. Precautions. Use a chair with armrests; watch for fainting. Complications. Vasovagal syndrome. Misplaced anterior injections may encounter neurovascular structures.

ACROMIOCLAVICULAR JOINT Indications. Aspiration for acute arthritis; injection for OA, RA, and spondyloarthritis. US guidance is optional. Corticosteroid dose. 10 to 20 mg methylprednisolone acetate (no. 25 or 27 needle). Aspiration should be attempted before injection. For aspiration alone, use a no. 20 needle. Approach. Aim the needle perpendicular to the skin into the articular cleft; aspirate or inject to distend the joint (Fig. e31.18). Precautions. The procedure is difficult because the acromioclavicular joint space is narrow and has a partial meniscus. Complications. None.

SUBACROMIAL BURSA Indications. Injection may be indicated for rotator cuff tendinopathy and inflammatory and microcrystalline bursitis. US guidance is highly desirable (Figs. e31.19 and e31.20; Video 31.2). Corticosteroid dose. 30 to 40 mg methylprednisolone acetate (no. 22 or 25 needle). Approach for blind injection. The needle is inserted laterally near the posterior angle of the acromion and aimed anteromedially while ensuring that it passes under the anterior half of the acromion. Easy flow and bulging outlining the bursa indicate bursal injection.

Indications. Aspiration for acute arthritis; injection for RA, spondyloarthritis, and the initial stages of frozen shoulder63; viscosupplementation for OA. US guidance is necessary for the latter indication and desirable for all of them. Corticosteroid dose. 40 to 80 mg methylprednisolone acetate (no. 22 needle). Aspiration should be attempted before injection. For frozen shoulder, injection into the joint may be difficult because of the capsular restriction. For aspiration alone, use a no. 20 or larger needle.

FIG. 31.13  Injection for right tennis elbow (lateral epicondylar syndrome).

FIG. 31.14  Posterior approach to the right shoulder in a patient with a frozen shoulder.

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FIG. E31.14  Lateral needle entry for olecranon bursitis.

FIG. E31.15  Injection for right golfer’s elbow (medial epicondylar syndrome).

CHAPTER 31  Aspiration and injection of joints and periarticular tissue and intralesional therapy Precautions. None. Complications. None. Note: Only about 50% of blind subacromial bursa injections fall on target.

ROTATOR CUFF CALCIFIC TENDINOPATHY In patients with calcific tendinitis of the rotator cuff who do not respond to blind corticosteroid injections, US-guided puncture of the calcifications combined with local corticosteroid injection can be a successful therapeutic alternative.64 The needle should be directed to the subdeltoid bursa under continuous US guidance. After the bursa is anesthetized with lidocaine, the needle is introduced through the tendon until the calcium deposit is reached. Fragmentation and aspiration of at least part of the calcium deposit and later bursal and peritendinous corticosteroid injection are carried out. Calcification lavage can be facilitated by using two needles for the procedure.

LONG HEAD OF THE BICEPS BRACHII TENDON Ultrasonography allows accurate fluid aspiration and peritendinous injection in biceps tenosynovitis (i.e., inflammatory or microcrystalline arthritis of the glenohumeral joints) or biceps tendinopathy.65

HIP REGION HIP JOINT66 Indications. Diagnosis of septic arthritis, including the differential diagnosis of septic arthritis versus aseptic loosening in a prosthetic hip; viscosupplementation. US guidance is required. Corticosteroid dose. Although the procedure is generally performed for diagnosis, there are proponents of steroid injection or, preferably, viscosupplementation for advanced hip osteoarthritis. The dose is 40 to 60 mg methylprednisolone acetate mixed with 3 mL of 1% lidocaine (no. 22 needle). Aspiration should be attempted before injection. Approach. US guidance is required (Figs. 31.3 and 31.15). Precautions. The danger of injuring the femoral neurovascular bundle is averted by guidance with US. Complications. None.

255

Corticosteroid dose. 20 to 40 mg methylprednisolone acetate usually mixed with 5 mL of 1% lidocaine (no. 22, 1.5-inch needle; a longer needle may be required for obese patients). Approach. With the patient lying on the opposite side, the greater trochanter is identified by distal-to-proximal palpation along the femur. The point of maximal tenderness is usually located at the posterior corner of the trochanter. The needle is inserted vertically until contact is made with the periosteum. The mixture of corticosteroid and lidocaine should then be infiltrated radially to cover the base of a cone 3 cm in diameter, half on bone and half in the proximal soft tissues (Fig. e31.21).48 Precautions. The needle should be of sufficient length to reach bone. Complications. None.

KNEE REGION KNEE (JOINT) Indications. For diagnosis of any joint effusion; for corticosteroid injection in patients with RA, spondyloarthritis, OA, and, occasionally, crystal-induced synovitis. For viscosupplementation, US guidance is optional68 Corticosteroid dose. 40 to 80 mg methylprednisolone acetate (no. 22 needle). Aspiration should be attempted before injection. For aspiration alone use a no. 20 or 18 needle depending on clinical suspicion. Approach. Lateral, with the needle aimed at the patellar undersurface midway between the upper and lower poles of the patella (Fig. 31.16, a and b). When clinical attempts to aspirate a knee effusion are unsuccessful, confirmation of synovitis and guidance of the procedure can

ILIOPSOAS BURSA Indications. Painful iliopsoas bursitis and bursal distention causing neurovascular compression. Corticosteroid dose. 20 to 40 mg methylprednisolone acetate mixed with 3 mL of 1% lidocaine (no. 22 needle). Aspiration should be attempted before injection. Approach. US guidance, as for the hip. Precautions. As for the hip. Complications. None.

TROCHANTERIC SYNDROME Indications. Lateral hip pain with trochanteric tenderness.67 US guidance is optional. However, US allows differential diagnosis between trochanteric bursitis and gluteus tendinopathy-enthesopathy and, if present, facilitates injection inside the bursa.

FIG. 31.15  Anatomic image showing the femoral head (1), the femoral neck (2), and the labrum (3). The arrow represents the needle direction, from distal to proximal and from lateral to medial avoiding the femoral neurovascular bundle. (Courtesy of M. Miguel, University of Barcelona, Spain.)

LR

p

Ifc

a

b

c

d

FIG. 31.16  (a) Knee injection, lateral approach, for right knee osteoarthritis. (b) The needle is introduced between the quadriceps tendon and the iliotibial tract band through the skin, the deep fascia of the thigh, and the joint capsule. (c) Ultrasound-guided direct method of injection into the knee. The needle is inserted adjacent to the transducer and directed to the lateral recess of the knee. (d) Ultrasound-guided injection into the lateral recess of the knee. The needle has a hyperechoic appearance (arrowheads) inside the lateral recess, which is distended by synovitis. lfc, Lateral femoral condyle; LR, lateral recess; p, patella. (Fig. 31.16, b Courtesy of M. Miguel, University of Barcelona, Spain.)

CHAPTER 31  Aspiration and injection of joints and periarticular tissue and intralesional therapy

FIG. E31.16  Posterior approach to the right shoulder, back view.

FIG. E31.17  Posterior approach to the right shoulder, superior-lateral view.

FIG. E31.18  Injection of a painful acromioclavicular joint in a patient with osteoarthritis.

FIG. E31.19  Ultrasound-guided direct injection into the subacromial bursa.

SDB

t

bg

FIG. E31.20  Same patient as in Fig. e44.19. The needle (arrowhead) is hyperechogenic with a posterior reverberation artifact inside the subdeltoid bursitis (SDB). bg, Bicipital groove; t, biceps tendon.

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SECTION 3  Approach to the Patient

be achieved with US. The parapatellar recesses are more accessible to US-guided injection than the suprapatellar recess is (see Fig. 31.16, c and d). Precautions. Beware of superimposed septic arthritis in patients with RA. Postpone injection of an acutely inflamed joint until a negative synovial fluid culture result becomes available. Complications. None.

BAKER CYST With very large cysts, direct aspiration through a large-bore needle followed by instillation of a corticosteroid is appropriate. US guidance is highly desirable (Fig. 31.17). US-guided aspiration, fenestration, and injection has been shown to be effective and safe for symptomatic popliteal cysts.69

MEDIAL KNEE PAIN AND PES ANSERINUS SYNDROME Indications. Pain in the pes anserinus area.70 US guidance is optional. Corticosteroid dose. 20 mg methylprednisolone acetate usually mixed with 2 to 3 mL lidocaine (no. 22 needle).

Approach. The injection site is best determined by following the medial tendinous border of the thigh (semitendinosus tendon), with the knee in semiflexion, to the tibia, where a mark is placed. The knee is then brought to extension and the needle inserted perpendicularly until contact with the tibia (Fig. 31.18). An area 3 cm in diameter is infiltrated adjacent to the periosteum. Precautions. Paresthesias extending along the medial aspect of leg indicate engagement of the saphenous nerve; reposition the needle. Complications. None.

ANKLE AND FOOT ANKLE (JOINT) Indications. As for the knee. US guidance is preferable71 (see Fig. 31.2). Corticosteroid dose. 40 to 60 mg methylprednisolone acetate (no. 22 or 25 needle). Aspiration should be attempted before injection. For aspiration alone use a no. 20 needle. Approach for blind injection. With the patient supine on the examination table, seek the cleft between the tibia and talus by gently flexing and extending the foot. Insert the needle vertically medial to the anterior tibialis tendon (Fig. e31.22). The lateral and medial tibiotalar recesses, with avoidance of vessels and tendons, are the usual routes for US-guided injections into the ankle. Precautions. Avoid the dorsalis pedis artery. Complications. None.

SUBTALAR JOINT Indications. As for the knee. US guidance is optional. Corticosteroid dose. 20 to 30 mg methylprednisolone acetate (no. 22 needle). Aspiration should be attempted before injection. For aspiration alone use a no. 20 needle. Approach. By gently inverting and everting the foot, find the soft cleft (sinus tarsi) anterior to the lateral malleolus. Insert the needle perpendicularly toward the tip of the medial malleolus. Aspiration of fluid proves an articular insertion. Inject under low pressure (Fig. e31.23)50. Precautions. This procedure should be performed only by health professionals with a thorough knowledge of anatomy. Complications. None.

BC

METATARSOPHALANGEAL JOINTS mfc

FIG. 31.17  Ultrasound-guided injection of a Baker cyst. The needle (arrowheads) has a hyperechoic appearance inside the Baker cyst (BC). mfc, Posterior aspect of the medial femoral condyle.

FIG. 31.18  Injection for right pes anserinus syndrome.

Indications. Aspiration for the diagnosis of gout (usually the first metatarsophalangeal joint). Injection for hallux rigidus, RA, and spondyloarthritis. US guidance is optional. Corticosteroid dose. 10 to 20 mg methylprednisolone acetate (no. 22, 25, or 27 needle). Attempt aspiration before injection. For aspiration alone use a no. 22 needle.

FIG. 31.19  Aspiration of the left first metatarsophalangeal joint for gout.

256.e1

SECTION 3  Approach to the Patient

FIG. E31.21  Steroid injection for trochanteric syndrome.

CHAPTER 31  Aspiration and injection of joints and periarticular tissue and intralesional therapy Approach for blind injection. Dorsal, lateral, or medial to the extensor tendon. Slight passive plantar flexion facilitates the procedure (Fig. 31.19 and Figs. e31.24 and e31.25). Precautions. None. Complications. None.

RETROCALCANEAL BURSA Indications. Refractory Achilles tendon enthesis organ inflammation in spondyloarthritis, RA. Whenever possible, this procedure should be performed under US guidance (Fig. 31.20). Corticosteroid dose. 15 to 20 mg methylprednisolone acetate (no. 22, 25, or 27 needle or butterfly). Aspiration should be attempted before injection. The presence of fluid (usually a trace) proves intrabursal location of the needle. Approach for blind injection. Posterior approach.72 The patient lies prone on the examination table with the foot outside the mattress. Allow calf relaxation. A 13-mm no. 27 insulin needle may be best suited for this procedure. The needle is advanced vertical to the skin, transtendinously, and aimed at the posterior superior calcaneal angle. Precautions. This procedure should be performed only by health professionals with a thorough knowledge of anatomy. Complications. Tendon rupture is possible, and more than one reinjection is discouraged.

POSTERIOR TIBIALIS TENDON (PTT), PERONEAL TENDON, EXTENSOR AND FLEXOR TENDON SHEATH

257

Approach for blind procedure. Medial, needle parallel to the plantar skin 2 cm deep to the plantar surface. Aim the needle into the medial plantar tubercle of the calcaneus. Resilience indicates a fascial location. Relocate the needle, and inject deeply and superficially to the fibrous fascia (Fig. e31.26). Precautions. This procedure should be performed only by health professionals with a thorough knowledge of anatomy. Complications. Repeated infiltrations result in fat atrophy and pressure-induced plantar heel pain. Rupture of the plantar fascia may also occur. Discourage more than one reinjection (2 to 3 weeks after the initial injection).

INTERMETATARSAL BURSAE Indications. Intermetatarsal bursitis in patients with RA (two or more toes spread apart). US guidance is optional. Corticosteroid dose. 20 mg methylprednisolone acetate (no. 25 or 27 needle). Approach. Dorsal to plantar with the needle aimed toward the space in between the metatarsal heads (Figs. e31.27 and e31.28). Precautions. Plantar fat atrophy is minimized by using an insulin needle. Complications. None.

MORTON NEUROMA76 Indications. Morton neuroma. US guidance is optional. Corticosteroid dose. 20 mg methylprednisolone acetate mixed with 1 mL lidocaine (no. 22 or 25 needle).

Indications. Tenosynovitis in patients with RA and spondyloarthritis; tarsal tunnel syndrome. US guidance is highly desirable (Fig. 31.21; Video 31.3). Corticosteroid dose. 15 to 20 mg methylprednisolone acetate (no. 22 or 25 needle). Approach for blind injection (PTT as example). The patient lies supine with the injected leg resting on the contralateral knee. Have the patient invert the foot to identify the posterior tibialis tendon, which tents the skin. The needle is inserted tangentially, three fingerbreadths proximal to the tip of the medial malleolus. Inject under low pressure. Fluid may be seen and felt distending the sheath. Precautions. Aspirate first to make sure that the posterior tibial artery has not been punctured. Plantar paresthesias indicate engagement of the posterior tibial nerve. This procedure should be performed only by health professionals with a thorough knowledge of anatomy. Complications. The posterior tibialis tendon is prone to spontaneous rupture in patients with RA. A misplaced (intratendinous) injection probably enhances this tendency.

TS tpt

mm

PLANTAR FASCIA CALCANEAL ENTHESIS73,74 Indications. Refractory plantar fasciitis in patients with spondyloarthritis. US guidance is highly desirable. Plantar fascia rupture and fat pad atrophy may be serious complications of this injection; US guidance should monitor the position of the needle deep to the plantar fascia to prevent plantar fascia rupture and fat pad atrophy.75 Corticosteroid dose. 20 to 30 mg methylprednisolone acetate diluted with 2 mL lidocaine (no. 22 needle).

FIG. 31.21  Ultrasound-guided direct injection for tenosynovitis of the tibialis posterior tendon. The needle (arrowhead) is inserted within the distended tendon sheath (TS). mm, Medial malleolus; tpt, tibialis posterior tendon.

FIG. 31.20  (a) Ultrasound-guided

cal B

a

b

direct injection into the retrocalcaneal bursa. The needle is inserted adjacent to the transducer and perpendicular to its long axis. (b) On the ultrasound image, the tip of the needle (arrow) is hyperechogenic inside the retrocalcaneal bursitis. B, Bursa; cal, calcaneus.

CHAPTER 31  Aspiration and injection of joints and periarticular tissue and intralesional therapy

a

257.e1

b

FIG. E31.22  (a) Aspiration of the right tibiotalar (ankle) joint in a patient with gout. (b) The arrow represents the direction of the needle for the injection at the anterior ankle, avoiding the neurovascular bundle of the dorsalis pedis artery and the deep peroneal nerve. The path of the needle when across the skin and the extensor retinaculum is through the capsule and the intracapsular fat pad of the ankle joint. The needle angulation is approximately 45 degrees to the tarsal bones. The patient remains with the knee flexed and the sole of the foot resting on the bed. 1, Tibialis anterior tendon; 2, extensor hallucis longus tendon; 3, extensor digitorum longus tendon. (Fig. 31.22, b Courtesy of M. Miguel, University of Barcelona, Spain.)

FIG. E31.23  Injection of the talocalcaneal joint (subtalar) in a patient with rheumatoid

FIG. E31.24  Aspiration of second metatarsophalangeal joint for gout.

arthritis.

FIG. E31.25  Aspiration of fifth metatarsophalangeal joint for gout.

SECTION 3  Approach to the Patient

257.e2

a

b

FIG. E31.26  (a) Injection for calcaneal plantar fascia enthesopathy. (b) Plantar fascia injection is done from medial to lateral at the level of the medial plantar tuberosity of the calcaneus. The arrow shows the needle direction. 1, Plantar fascia; 2, calcaneus bone. (Fig. 31.26, b Courtesy of M. Miguel, University of Barcelona, Spain.)

FIG. E31.27  Intermetatarsal bursitis in a patient with rheumatoid arthritis. The third and fourth toes are spread apart along with soft tissue tenderness between the metatarsal heads.

FIG. E31.28 Same patient as in Fig. e31.27. For steroid injection, the needle is inserted vertically into the intermetatarsal space.

FIG. E31.29  Corticosteroid injection of a rheumatoid nodule (see text for technique).

258

SECTION 3  Approach to the Patient

FIG. 31.22  Injection for Morton neuroma, right foot, third web space. Approach for blind procedure. Through the web space on the plantar side (Fig. 31.22). The needle is advanced in a distal-to-proximal direction and aimed at the neuroma (technique taught to one of the authors by Lilia Andrade-Ortega, MD, Mexico City). Precautions. Inject under low pressure. This procedure should be performed by health professionals with a thorough knowledge of anatomy. Complications. None expected; up to two reinjections 2 to 3 weeks apart are allowed.

INTRALESIONAL CORTICOSTEROID TREATMENT Intralesional corticosteroid treatment is sometimes used for discoid lupus,77 medical treatment of rheumatoid nodules78 (Fig. e31.29), nodular fasciitis, occasionally Sweet syndrome,79 granulomatous disease (including Crohn’s disease) affecting the oral cavity,80 tracheal granulomas in patients with antineutrophil cytoplasmic antibody–positive granulomatous vasculitis,81 and eosinophilic granuloma of the skin.82

ACKNOWLEDGMENTS We thank our patients for generously allowing us to take pictures during aspiration or injection procedures for the benefit of others. We also thank Ana Cruz, MD, and Felix Cabero, MD, from the Department of Rheumatology of the Hospital Universitario Severo Ochoa for their help in obtaining pictures of the US-guided injection methods. The authors would like to acknowledge the contributions of Dr. Juan Canoso, who was the author of this chapter in previous editions, and Dr. Marina Rull, who was coauthor of this chapter in previous editions.

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32

Synovial fluid analysis Klaus P. Machold

Key Points ■ Healthy joints contain only minimal amounts of synovial fluid (SF); in disease, the SF increases in volume and can be aspirated. ■ Normal SF is hypocellular. Changes in the number and type of cells, noncellular particles, and molecular biomarkers in SF reflect the pathogenesis of the arthropathy. ■ SF microscopy, which detects cells and particles, is a simple, inexpensive, and accurate test that yields information of diagnostic and prognostic significance. ■ Cellular and molecular biomarkers of disease processes are becoming increasingly studied in SF and may bring about improvements in understanding, recognition, and management of joint disease.

Synovial membranes, which cover the inside of joint capsules, tendon sheaths, and bursae, produce synovial fluid (SF). Physiologically, the amount of fluid within a diarthrodial joint space is minimal. Estimates of physiologic volume in healthy probands’ knees are in the range of 4–9 mL.1,2 As Dougados noted in 1996,3 “Arthrocentesis has to be considered as a part of the clinical examination. A reasonable amount of aspirated synovial fluid is the best argument in favor of an objective articular disorder.” SF is a plasma-derived fluid supplemented with high-molecular-weight molecules; synoviocytes are thought to produce proteoglycan 4 (PRG4, lubricin), hyaluronan (HA), and surface-active phospholipids (SAPL).4–7 Chondrocytes in the superficial layer of articular cartilage produce lubricin as well. These molecules possess viscosity-enhancing properties. In addition, a few cells such as macrophages (usually 95%, of septic arthritis.

Not all bacterial infections lead to septic arthritis.20 Gram-positive cocci (e.g., Staphylococcus aureus and Streptococcus pyogenes and pneumoniae) account for up to 80% of causes of septic arthritis. The remainder of bacteria are Gram-negative organisms such as Neisseria gonorrhoeae and gram-negative bacilli, Pseudomonas aeruginosa, and Escherichia coli, the latter being frequently identified in cases of septic arthritis in immunosuppressed patients. Haemophilus influenzae, S. aureus, and group A streptococci have been the most common in children younger than 2 years of age.20,21 In septic arthritis, microscopic examination of SF may allow identification but not classification of microbes beyond gram-positive or -negative cocci or bacilli. Unfortunately, the relative paucity of organisms leaves initial cytologic examination of little benefit in many cases,22 so, considering the possibly dire consequences of delayed treatment, even in cases of negative results of cytospin examination, antibiotic treatment and possibly surgical joint treatment should be initiated promptly if suspicion of septic arthritis is reasonably high. Microbiologic culture in these circumstances is also important; however, falsely negative results may be seen.23 Despite these caveats, in an acutely inflamed joint SF microscopy can be used as a rapid screening test for organisms and to exclude other causes such as a crystal arthropathy or reactive arthritis. Additional criteria may, in the absence of identifiable organisms, be helpful in identifying patients with a high probability of having infection: criteria such as ragocyte count greater than 95%, total nucleated cell count greater than >20,000 cells/mm3, or polymorphs greater than 90% of nucleated cells; in these circumstances, examination of Gram-stained cytocentrifuge preparations should be performed and SF and blood samples be sent for culture. With increasing prevalence of total or partial joint replacements, interest in diagnosing joint prosthesis infections (JPI) is also rising. In an international consensus, preliminary thresholds for cell counts and cytologic characteristics have been defined.23 A joint count of >10,000/mm3 and a polymorphonuclear cell percentage of >90% are considered a criterion for acute JPI; in chronic JPI (>90 days), the thresholds are given as 3000/mm3 and >80%, respectively. This classification was refined in 2018, incorporating SF alpha-defensin as well as serum D-dimer, CRP, and ESR.23 Additional markers, such as SF calprotectin and others, may help refine accuracy of diagnosis of JPI and septic arthritis.24,25 Several bacterial joint pathogens (e.g., Mycobacteria spp. [including atypical forms], Neisseria, and Salmonella) do not cause septic arthritis. These can be identified in the synovial fluid both by culture and direct microscopic examination of appropriately stained cytologic preparations, e.g., ZiehlNeelsen’s stain.

CYTOCENTRIFUGE PREPARATION

NONBACTERIAL INFECTIONS

SF cytologic analysis and staining have to be conducted on monolayers made using a cytocentrifuge; smears are not suitable for this purpose. Optimal preparations are made by diluting the fluid to 400 cells/mm3 with isotonic saline and staining with a Giemsa stain. When septic arthritis is suspected, it is desirable to find organisms in a more concentrated sample,

Fungal infections are diagnosed by the same approaches suggested for bacteria. By contrast, viral infections are more difficult to diagnose, although an interest in the arthritides associated with HIV infection has shown the diagnostic importance of some features such as coexistence of a septic and a reactive arthritis in the same joint that are seen in no other disorder.

FIG. 32.9  A greenish-yellow precipitate of hematoidin phagocytosed by a g­ ranulocyte. (Andres M, Pascual E. Arthritis Rheumatol 2017; 69: 836.)

observed (Fig. 32.9). Its pathogenic significance, apart from indicating an older bloody effusion, is uncertain.18 Table 32.1 gives an overview of common and less common crystals identifiable in synovial fluid.

NONCRYSTALLINE PARTICULATE MATTER Many noncrystalline particles may be found in SF: fragments of cartilage, such as chondrocytes or fibrillary material are found in osteoarthritis; in cruciate ligament tear, ligament fibrils may be seen; polyethylene- or metal-containing (micro-) granules may be found in prosthesis wear; foreign bodies (wood, plant thorns, soil, etc.) after penetrating trauma. For more detailed descriptions of detection and appearance of these and other noncellular and noncrystalline SF contents, see Freemont and Denton (1991).8

RAGOCYTES

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SECTION 3  Approach to the Patient

Table 32.1

Characteristics of Common Crystals/Particles Found in Microscopic Analysis of SF Crystal/Particle

Occurrence

Shape

Birefringence/“Elongation”

Urate (MSU) Calcium pyrophosphate (CPP) Basic cationic phosphate (BCP), e.g., apatite Cholesterol Glucocorticoids Starch Oxalate Hematoidin Lipids

MSU-arthropathy/gout “Pseudogout”/chondrocalcinosis, OA Destructive OA, “Milwaukee-Shoulder” syndrome “Old” effusion (RA, OA) Joint injections Artifact, e.g., from gloves Dialysis arthropathy Chronic joint hemorrhage Joint fracture, soft tissue trauma

Needle Needle, rhomboid, rod-like Variable, often submicroscopic

Strongly negative Weakly positive When stained with Alizarin red

Flat plates with notched edges Variable “Maltese cross” Bipyramidal, irregular, rods Variable Circular bubbles, needles, occasionally Maltese crosses

Variable Strongly negative or strongly positive Strong Strong Positive Strong

Biomarkers of disease processes such as culture of pathogens or detection of alpha-defensin should complement the bedside microscopic analysis.

REFERENCES 1. 2. 3. 4. 5.

6.

FIG. 32.10  Ragocytes. (Freemont AJ, Denton J. Atlas of Synovial Fluid Cytopathology.

7.

Springer Science and Business Media, B.V.; 1991.)

8.

SYNOVIAL FLUID CYTOLOGY

9.

Many different cell types are found within SF, reflecting the differing pathogenic mechanisms. Despite numerous attempts to identify “disease specific” cells or cell patterns, SF cytology offers only clues towards the underlying process that do not have enough clinically valuable specificity. Cell recognition in SF preparations is based largely on morphologic criteria. Cytochemical or immunocytochemical analyses, despite having shown disease-related changes in several forms of arthritis in experimental setups, have not been proven to be of practical diagnostic value. This is partly attributable to problems in performing immunocytochemistry on cytocentrifuge preparations. In inflammatory arthropathies such as RA, psoriatic arthritis, and reactive arthritis26 polymorphs dominate the cytologic picture. In septic arthritis the nucleated cells are usually >95% neutrophils and ragocytes account for more than 95% of these. In noninflammatory arthropathies lymphocytes, macrophages, and synoviocytes are the most commonly encountered cells. Several case reports and case series have reported that, in systemic lupus erythematosus, a lymphocytic predominance and, occasionally, LE cells can be found. Macrophages are the predominant cell (>80% of nucleated cells) in viral arthritis, Milwaukee shoulder, some forms of chronic pyrophosphate arthritis, pigmented villonodular synovitis, and prosthetic-debris–induced arthropathy. Macrophages that have phagocytosed apoptotic polymorphs (cytophagocytic mononuclear cells [CPMs], formerly called Reiter’s cells) have been first identified in reactive arthritis27 but are also found in other forms of inflammatory arthritides.28,29

SUMMARY In healthy joints, minimal amounts of synovial fluid (SF) are present. Increased volume of SF is indicative of disease. Normal SF has very low cellularity (usually 3 months’ duration). The course of uveitis is described as acute, recurrent, or chronic. Acute uveitis has a sudden onset with a limited duration, as in acute anterior uveitis (AAU) seen with seronegative spondyloarthritis. Recurrent uveitis describes a course of multiple attacks of sudden onset and limited duration alternating with periods of remission when the uveitis is inactive and the patient is not receiving therapy for the disease. Chronic uveitis typically has an insidious onset and a persistent duration, with disease relapse promptly on discontinuing therapy. Chronic anterior uveitis (CAU) includes the uveitis associated with juvenile idiopathic arthritis (JIA).1,2 Tubulointerstitial nephritis and uveitis syndrome (TINU) presents as an acute bilateral anterior uveitis but may evolve into a chronic anterior or, rarely, a chronic panuveitis.3 Most intermediate, posterior, and panuveitis typically have a chronic course and are unassociated with a rheumatic disease; nevertheless there are several well-recognized associations, including intermediate and panuveitis with sarcoidosis, intermediate uveitis with Lyme disease, and panuveitis with retinal vasculitis with Behçet disease. Patients with AAU typically have a red, painful, photophobic eye. Slitlamp examination reveals inflammatory cells in the anterior chamber. These cells may be deposited on the posterior corneal endothelium and are called keratic precipitates. The cellular inflammation in the anterior chamber may be so severe that it produces a hypopyon or layering of inflammatory cells within the anterior chamber. Exudation of protein into the anterior chamber, known as flare, may also be seen and can be so marked that a fibrin clot forms in the anterior chamber. A complication of anterior uveitis is the formation of adhesions between the posterior iris and the anterior lens

35

surface (posterior synechiae). Posterior synechiae may frequently persist after the inflammation has settled (Fig. 35.2). Anterior uveitis may also lead to the development of peripheral anterior synechiae or scar tissue that forms between the peripheral iris and the posterior cornea. The anterior synechiae may be so extensive that the drainage angle of the eye becomes blocked, which can cause an increase in intraocular pressure and secondary glaucoma. Typically, AAU affects one eye at a time, although uncommonly both eyes may be affected simultaneously. Even though only one eye is affected at a time, both eyes may experience attacks, in which case the uveitis is termed recurrent, unilateral alternating AAU.1,2 Acute anterior uveitis is most commonly associated with seronegative spondyloarthritis.1,4 The estimated annual incidence of AAU is 8.2 new cases per 100,000 population.5 Approximately half of these patients express the HLA-B27 antigen, and 60% will have a diagnosis of seronegative spondyloarthritis.4,6 The Assessment of Spondyloarthritis International Society (ASAS) classified seronegative arthritis as axial spondyloarthritis (axial SpA) and nonaxial spondyloarthritis.7 Axial SpA includes ankylosing spondylitis (AS) and nonradiographic spondyloarthritis. Nonaxial spondyloarthritis includes peripheral arthritis and/or enthesitis and/or dactylitis more commonly associated with inflammatory bowel disease (IBD), reactive arthritis, and psoriatic arthritis (PsA).1,4,6–15 AAU occurs in 25% to 40% of patients with axial SpA.8–10 Conversely, studies of patients with AAU have reported that axial SpA is present in 18% to 34%.1,10 AAU is said to occur in 5% to 20% of patients with reactive arthritis at the initial episode and in up to 50% of these patients at long-term follow-up.8,9 Of patients with arthritis related to IBD, those with axial SpA associated with IBD appear to be at greatest risk for the development of AAU. Spondylitis occurs in 20% of patients with Crohn disease and in 10% to 15% of patients with ulcerative colitis.11 Approximately 50% to 70% of patients with spondylitis associated with IBD are HLA-B27 positive.11,13 Of the HLA-B27-positive patients with IBD, AAU will develop in 50%.6,11,13 Among patients with PsA, AAU occurs in approximately 7% to 10%.9,10,12,14 Although unilateral, alternating AAU is the most typical type of uveitis associated with seronegative spondyloarthritis, chronic and bilateral uveitis also occurs occasionally and may be seen more frequently in women with IBD or with PsA.9,12,13,15 The exact role of HLA-B27 expression in the development of spondyloarthropathy and uveitis is yet to be elucidated. Differences in antigen presentation are thought to contribute to the development of inflammatory disease, possibly by presentation of an “arthritogenic” (or “uveitogenic”) peptide. An etiologic role for exposure to intracellular bacteria such as Yersinia, Shigella, Salmonella, and Chlamydia spp. has also been proposed based on the known role these bacteria play in triggering reactive arthritis.16 Chronic anterior uveitis occurs less frequently than AAU and may be seen with several disorders. The rheumatic disease most commonly associated with CAU is JIA.17,18 Approximately 12% to 17% of children with JIA have uveitis.18,19 A population-based study performed in Finland reported the mean annual incidence and prevalence rates for JIA-associated uveitis to be 0.2 and 2.4 cases per 100,000 population, respectively.20 Although recurrent AAU is seen with enthesitis-related arthritis, the HLA-B27-associated subgroup of JIA, CAU is more commonly associated with JIA and is seen with antinuclear antibody (ANA)-positive disease in 70% to 90% of patients, 78% to 90% have oligoarticular disease, and if the age at the time of presentation is less than 4 years, frequencies are reported to be approximately 30%.21,22 Even though CAU has traditionally been reported in patients with ANA-positive oligoarticular disease, one study has suggested a similar frequency in those with ANA-positive oligoarticular persistent, oligoarticular extended, and polyarticular disease, thus suggesting that the presence of ANA and not the type of arthritis may be the key risk factor for CAU.22 Although it has traditionally been believed that cases of JIA-related CAU occur more frequently in girls, one retrospective study of 90 children with JIA found no sex difference in the risk for development of CAU.18 CAU in patients with JIA tends to be insidious and minimally symptomatic (“white eye” uveitis; Fig. 35.3); therefore it is recommended that patients with ANApositive JIA be evaluated every 3 months in an effort to detect the uveitis 281

SECTION 3  Approach to the Patient

282 Table 35.1

Ocular Involvement in Rheumatic Disease Ocular Manifestation

Risk of Vision Loss

Rheumatic Disease

Dry eyes (keratoconjunctivitis sicca)

Low

Keratitis

Moderate

Episcleritis

Low

Scleritis

Moderate

Rheumatoid arthritis, primary and secondary Sjogren’s syndrome, systemic sclerosis, systemic lupus erythematous, sarcoidosis Rheumatoid arthritis, ANCA-associated vasculitides, Sjogren’s syndrome Rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematous Rheumatoid arthritis, vasculitides ~50% are ANCA positive, relapsing polychondritis, polyarteritis nodosa, inflammatory bowel disease

Uveitis Acute anterior uveitis

Low

Chronic anterior uveitis

Moderate to high

Intermediate uveitis

Moderate

Posterior uveitis Panuveitis Retinal vascular Retinal vasculitis Vasoocclusive disease

High High

Orbital inflammation Ischemic optic neuropathy

Low High

High High

Seronegative spondyloarthritis, Behçet disease, sarcoidosis, tubulointerstitial nephritis, and uveitis syndrome Juvenile idiopathic arthritis, sarcoidosis, inflammatory bowel disease, cryoglobulinemia Sarcoidosis, tubulointerstitial nephritis and uveitis syndrome, inflammatory bowel disease, Behçet disease Sarcoidosis, Behçet disease Behçet disease, sarcoidosis Behçet disease, ANCA-associated vasculitides, sarcoidosis Systemic lupus erythematous, ANCA-associated vasculitides, polyarteritis nodosa ANCA-associated vasculitides, dermatomyositis, polymyositis Giant cell arteritis, systemic lupus erythematous, other systemic vasculitides

ARTHRITIS AND THE EYE Sclera Retina Conjunctiva Pars plana Vitreous body Anterior chamber Cornea

Lens

Iris Optic nerve Ciliary body Limbus

Posterior synechiae

Choroid Ocular muscle

FIG. 35.1  The structural elements of the eye that may be primarily involved in rheumatic disease processes.

early.23 Uveitis precedes the onset of arthritis in approximately 6% of cases. Two thirds of patients have bilateral disease, and in patients with unilateral disease, uveitis often develops in the other eye within 1 year of diagnosis.1 The median time between the onset of arthritis and the development of uveitis has been estimated to be 2 years (range, simultaneous development to 10 years).1,10 Studies have reported both a decrease in prevalence and frequency of complications from JIA uveitis over time. A prospective, cross-sectional study from Germany including 18,555 patients with JIA between 2002 and 2013 found a significant decrease in uveitis prevalence from 13.0% to 11.6%.24 There were also significant decreases in uveitis complications from 33.6% to 23.9% (approximately a one-third reduction). Over the same time period, there were increases in use of synthetic disease-modifying antirheumatic drugs (DMARDs) (39.8%–21.8%). Another study compared a cohort of patients with JIA-associated uveitis from 1990 to 1993 with a 2000 to 2003 cohort and found a frequency of complications of 35% and 21%, respectively.25 This reduction in reported complications and incidence

FIG. 35.2  Wide-beam slit-lamp view of “old” posterior synechiae (adhesions between the iris and lens) causing distortion of the pupil.

of uveitis may be related to earlier use of systemic immunomodulatory therapy to treat joint disease. This is further supported by data that looked at a cohort of JIA patients with disease duration less than 1 year.26 Compared with those with no DMARD treatment in the year before uveitis onset, the risk of uveitis was significantly decreased by methotrexate and tumor necrosis factor (TNF) inhibitors. Sight-threatening ocular complications may develop in patients with CAU, with band keratopathy and cataract each occurring in up to one third of patients.1,19,20,27–37 Secondary glaucoma occurs in 10% to 20% of patients

CHAPTER 35  Ocular manifestations of rheumatic diseases

FIG. 35.3  Chronic uveitis in a patient with oligoarticular juvenile idiopathic arthritis: “white eye” uveitis.

with JIA-associated uveitis and is a poor prognostic finding.27,28,30–32,38,39 Posterior synechiae are common.27,31,38 Other complications include macular edema in 8% to 10% of cases and phthisis in 4% to 10%. Although blindness developed in 40% of patients reported in early series, more recent series have reported a better prognosis, with blindness occurring in about 10%.19,27,28,32,38,39 The improved prognosis appears to be due to earlier detection, better treatment, and better surgical management of the associated complications.31,33,35 Nevertheless, about 25% of patients with JIA-associated CAU will have some degree of visual impairment. Furthermore, because the uveitis may persist into adulthood, these individuals remain at risk for ocular complications from uveitis for decades. Thus it is imperative to maintain treatment target at grade 0 inflammation.36 Ocular inflammation occurs in approximately 26% to 38% of patients with sarcoidosis.40,41 Anterior uveitis is the most common ocular manifestation of sarcoidosis40 and can present with either acute or chronic course. The activity and severity of the ocular disease does not necessarily parallel the activity of the systemic disease. Clinical features suggestive of sarcoid-associated uveitis include granulomatous inflammation characterized by mutton-fat keratic precipitates in Arlt’s triangle and characteristic iris nodules called Koeppe nodules on the pupillary border, Bussaca nodules in the iris stroma, and Berlin nodules in the anterior chamber angle. These features, while suggestive of ocular sarcoidosis, are not pathognomonic for sarcoid uveitis, as they can be seen in other granulomatous uveitides. Sarcoid uveitis also may be associated with structural complications including cataract, posterior synechiae, and cystoid macular edema. The approach to treating sarcoid-associated uveitis can range from topical corticosteroids to regional or systemic corticosteroids and immunosuppressive therapy depending on the disease severity and extent of associated structural complications. Uveitis is a primary manifestation of Behçet disease.37,42 The uveitis in Behçet disease may be anterior uveitis (56%–79% of cases, depending on the series), intermediate uveitis (18%–66% of cases), posterior uveitis (3%– 29% of cases), or panuveitis with retinal vasculitis (29%–41% of cases).1,37 The presence of retinal vasculitis confers a poor prognosis for vision and is described further in the section on retinal vascular disease. Anterior uveitis with or without hypopyon is the most common ocular finding in Behçet disease. Although studies from the 1960s and early 1970s reported hypopyon uveitis in up to 88% of patients, more recent studies have shown a decreased frequency of hypopyon to as low as 9%.1,37,43 This reported decrease probably represents earlier diagnosis and more aggressive therapy. The uveitis associated with Behçet disease is typically bilateral. In one series, 81% of patients had bilateral uveitis after 1 year and 93% by 2 years.37,42–44 Bilateral CAU may also occur with other uncommon causes such as essential mixed cryoglobulinemia,45 hypocomplementemic urticarial vasculitis syndrome (HUVS),43 and familial juvenile systemic granulomatosis (FJSG).46–48 Essential mixed cryoglobulinemia, or type II cryoglobulinemia, is a small-vessel vasculitis that may result in palpable purpura, arthralgias or arthritis, lymphadenopathy, hepatosplenomegaly, peripheral neuropathy,

283

and hypocomplementemia.49 Renal disease may also be seen in up to 60% of patients with essential mixed cryoglobulinemia.48 Most cases of essential mixed cryoglobulinemia are associated with hepatitis C virus (HCV) infection, with an estimated 85% to 95% of patients having circulating antibodies to HCV.49,50 The diagnosis is made by the presence of cutaneous small-vessel vasculitis confirmed by biopsy and the presence of serum cryoglobulins in a patient with the typical clinical features. An uncommon systemic small-vessel vasculitis, HUVS is characterized by recurrent urticarial lesions associated with cutaneous vasculitis, constitutional symptoms, arthralgias or arthritis, angioedema, and glomerulonephritis.51 The joint and kidney disease may be indistinguishable from that found in systemic lupus erythematosus (SLE) and, in fact, low ANA titers are often detected in patients with HUVS.51 The diagnosis of HUVS is suggested in a patient with recurrent urticaria accompanied by leukocytoclastic vasculitis, constitutional symptoms, arthralgias, and hypocomplementemia. Continuous granular deposition of immunoreactants along the basement membrane zone seen on skin biopsy specimens via a direct immunofluorescence technique helps confirm the diagnosis.52 Ocular inflammation has been reported in HUVS and includes conjunctivitis, episcleritis, anterior uveitis, and diffuse anterior scleritis.51,52 Familial juvenile systemic granulomatosis (www.omim.org/entry/ 186580), also known as Jabs syndrome or Blau syndrome, is an uncommon autosomal dominant genetic disease characterized by granulomatous polysynovitis, rash, vascular disease, and uveitis.46,47,53 The syndrome is caused by mutations in the NOD2 (CARD15) gene, which is involved in apoptosis. The uveitis associated with FJSG may be bilateral CAU46,53 or a chronic panuveitis with multifocal choroiditis.47 FJSG and CAU are often misdiagnosed as JIA or pediatric sarcoidosis. Ocular complications such as cataract and macular edema are common.47 Patients may require aggressive medical therapy to control the uveitis, including immunosuppressive drugs such as methotrexate or mycophenolate mofetil47 and/or biologics such as TNF-alpha inhibitors, interleukin 1β receptor antagonist anakinra, and specifically canakinumab, which have shown to be effective for disease control.54

MANAGEMENT Anterior uveitis usually responds to topical corticosteroids, which suppress the inflammatory response, and mydriatics, which prevent sequelae of the disease such as posterior synechiae. For the initial attack of uveitis, corticosteroid drops may be required on an hourly basis while the patient is awake. Topical corticosteroids have good penetration into the anterior chamber and are therefore useful in treating anterior uveitis. However, because they have limited penetration to the back of the eye, topical corticosteroids are inadequate for intermediate, posterior, or panuveitis. Periocular and intraocular corticosteroid injections may provide higher concentrations of corticosteroids in the eye and are useful in treating intermediate uveitis and cystoid macular edema, a common vision-threatening complication resulting from uveitis. There are now implantable agents such as the dexamethasone and fluocinolone intravitreal implants and the fluocinolone acetonide sutured implant that can be used to achieve high corticosteroid concentrations within the eye for an extended period of time, especially for eye-limited intermediate, posterior, or panuveitis. However, results from 7 years of extended follow-up of patients on Multicenter Uveitis Steroid Treatment (MUST) trial show that patients randomized to receive systemic therapy (oral corticosteroids and immunosuppressive agents) when used appropriately had better visual acuity than those randomized to receive intravitreal fluocinolone acetonide sutured implant with no evident increased risk of systemic side effects compared to regional corticosteroid therapy, except for greater antibiotic use for infections. In fact, regional corticosteroid therapy was associated with ocular complications like cataract, glaucoma, and surgery-related complications like retinal detachment.55 For patients who cannot tolerate local corticosteroid therapy or have active systemic inflammation, oral corticosteroid therapy is used. Patients with severe acute episodic uveitis may occasionally need treatment with a short course of oral prednisone in addition to intensive topical corticosteroids, as in the case of severe AAU. In patients with noninfectious intermediate, posterior, panuveitis, or anterior uveitis unresponsive to topical corticosteroids, high-dose prednisone (e.g., 1 mg/kg/day) is administered until the inflammation is suppressed, followed by tapering to a lower dose, ideally less than 7.5 mg/day. Even with a low daily dose of prednisone at 7.5 mg/day for 15 years or 5 mg/day for 22 years or beyond, studies in rheumatoid arthritis suggest that there is an increased risk of cardiovascular disease and cardiovascular mortality with large cumulative doses of prednisone.56,57 If long-term prednisone at a dose of >7.5 mg/day is needed to suppress the inflammation or in cases where systemic corticosteroids are insufficient

284

SECTION 3  Approach to the Patient

to control more severe forms of uveitis, immunosuppressive drug therapy may be required.1,36,58 Various agents, including antimetabolites, calcineurin inhibitors, alkylating agents, and, more recently, biologics, have been used to treat ocular inflammation successfully. Infliximab and adalimumab have been recommended as first-line immunosuppressive agents for the treatment of ocular manifestations of Behçet disease and second-line agents for JIA-associated uveitis.59 Chronic uveitis in children who have persistent inflammation despite topical corticosteroid therapy often requires treatment with systemic agents such as methotrexate or biologics such as infliximab or adalimumab to control the disease.27–29,39,60 A cross-sectional study of 2748 children with JIA managed by a pediatric rheumatologist demonstrated that approximately 75% had received therapy with a DMARD and 45% had received biological therapy.29,60 The presence of uveitis was strongly associated with use of a DMARD (odds ratio = 5.2, 95% confidence interval [CI], 3.6–7.6), with 88% of children with uveitis receiving methotrexate and 57% receiving TNF-alpha inhibitors.28 These findings parallel the recommendations of the American College of Rheumatology and the conclusions of an expert panel of the American Uveitis Society that generally recommended a trial of a nonbiologic DMARD such as methotrexate prior to the initiation of TNF-alpha inhibitors. As such, biologic DMARDs such as infliximab or adalimumab are considered as a second line of therapy for JIA-associated uveitis.59 The SYCAMORE trial, a randomized, placebo-controlled trial among children and adolescents 2 years of age or older with active JIA-associated uveitis, demonstrated that addition of adalimumab to a stable weekly dose of methotrexate resulted in a significantly delayed time to treatment failure (defined by multicomponent intraocular inflammation score) compared to placebo and methotrexate (hazard ratio = 0.25; 95% CI, 0.12–0.49; P < .0001).61 Coadministration of methotrexate may improve efficacy of infliximab or adalimumab by suppressing the formation of antidrug antibodies,62 which are associated with reduced serum drug levels and diminished clinical response.63,64 Other TNF-alpha inhibitors, abatacept, and tocilizumab (an IL-6 inhibitor) have all been suggested as possibly effective options in systemic JIA-associated uveitis in small cases series.65

FIG. 35.4  Diffuse and nodular scleritis involving predominantly the upper temporal quadrant of the globe.

SCLERAL DISEASE Scleral disease may be classified as episcleritis or scleritis. Episcleritis is associated with discomfort rather than pain, more superficial ocular inflammation, and less frequent ocular complications, and it typically has a less frequent association with systemic disease.66 The clinical findings depend on whether only the episclera is involved or whether deeper tissue involvement is present. Episcleritis may be nodular or simple and is usually a self-limited condition that often resolves without treatment. Resolution of the inflammation may be expedited by the use of topical corticosteroids. In severe or recurrent cases, nonsteroidal antiinflammatory drugs (NSAIDs) may be administered to suppress the inflammation. Slit-lamp examination is required to differentiate this condition from other causes of “red eye,” such as conjunctivitis and anterior uveitis.36,59,66,67 Scleritis is often characterized by pain, deeper inflammation, and edema of the sclera. It is more frequently associated with ocular complications and in approximately 50% of cases accompanies a systemic inflammatory disease or infection.59,66–68 Unlike episcleritis, which is typically self-limited and remits spontaneously, scleritis generally requires therapy. Scleritis may be classified as diffuse anterior, nodular anterior (Fig. 35.4), posterior, or necrotizing (Fig. 35.5). Scleromalacia perforans is a separate category with an insidious but destructive scleral process that is seen in patients with long-standing rheumatoid arthritis (RA). Any of the previously mentioned types of scleritis may be found in association with RA, although diffuse anterior scleritis is most common.66 Approximately 10% of patients with scleritis have an associated infection, such as varicella zoster virus, herpes simplex virus, syphilis, Lyme disease in endemic areas, or, rarely, tuberculosis presenting as a characteristic caseating nodular scleritis.67 Patients with scleritis appear to have a higher frequency of rheumatic disease.69 Forty percent of patients with scleritis have a rheumatic disease, the most frequent of which is RA.67 Scleritis affects an estimated 1% to 6% of patients with RA.67,70,71 Although estimates of the frequency of scleritis in patients with RA have been as high as 6%, large series have shown that approximately 1% of patients with RA have scleritis.66,71 Patients with RA and scleritis tend to have longer duration, more severe disease course, and a higher prevalence of extraarticular disease.68,70,71 One study of patients with necrotizing scleritis or necrotizing keratitis and RA suggested an increased mortality rate in these patients.70 The second most frequent systemic disorder associated with scleritis is antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis; other associated diseases include SLE, IBD, relapsing polychondritis, polyarteritis

FIG. 35.5  Necrotizing scleritis in a patient with severe rheumatoid arthritis. nodosa, and SpA.59,66–68 Any type of vasculitis may be present with scleritis, but half of the cases of vasculitis-associated scleritis are caused by ANCAassociated vasculitis.67 Furthermore, in half of patients with vasculitis and scleritis, scleritis is the initial feature of the disease.67 Scleritis is common in ANCA-associated vasculitis, in which it occurs in 16% to 38% of patients, and it is either the first or second most frequent ocular feature, depending on the series.36,71–74 The scleritis can be of any type, particularly diffuse anterior or necrotizing scleritis. Marginal corneal ulcers are often seen in association with the scleritis (necrotizing sclerokeratitis) and occasionally without scleritis (see the section “Corneal Disease”).70,73 Posterior scleritis has also been reported.1 All types of scleritis have been associated with IBD, including necrotizing scleritis and posterior scleritis.75,76 The scleral inflammation may parallel the activity of the underlying bowel disease.75 Scleral involvement is the most common ocular manifestation of relapsing polychondritis and occurs in approximately 35% to 41% of patients.77,78 Most often, diffuse anterior scleritis is common, but recurrent episcleritis, necrotizing scleritis, or posterior scleritis may also be seen. An association between scleritis and ankylosing spondylitis and other forms of seronegative SpA has been reported.67

MANAGEMENT Patients with episcleritis can be treated by observation, artificial tear solutions, and short courses of topical corticosteroids because the disease is often self-limited. Scleritis typically requires systemic therapy and may call

CHAPTER 35  Ocular manifestations of rheumatic diseases for treatment directed at controlling the underlying systemic disease, as in vasculitis.59,66–69,74 NSAIDs, particularly flurbiprofen or indomethacin as first choice, are effective in the initial management of anterior scleritis in approximately one third of patients.66 If NSAID therapy fails to control the anterior scleritis or if posterior or necrotizing scleritis is present, oral prednisone therapy starting at 1 mg/kg per day is needed.58,66,79 For cases in which oral prednisone does not control the scleritis or when it cannot be tapered to an acceptably low daily dose (7.5 mg/day or less), a corticosteroid-sparing immunosuppressive agent may be required.58,66 Approximately one third of patients with scleritis, often those with associated systemic disease, require immunosuppressive drug therapy; historically, cyclophosphamide was the drug used most often, particularly for severe, necrotizing disease, but its use has declined due to safety concerns and available alternatives.66,79 Antimetabolites such as mycophenolate mofetil or methotrexate or biologics such as TNF-alpha inhibitors are reported to be effective.80,81 In particular, necrotizing scleritis and peripheral ulcerative keratitis are harbingers of severe rheumatoid arthritis or systemic vasculitis and often portend increased risk of mortality unless prompt aggressive immunosuppressive treatment is initiated.59,70,71 Rituximab82 and tocilizumab83 have demonstrated efficacy in controlling treatment refractory scleritis. For ANCA-associated vasculitis-related scleritis, rituximab is particularly effective with an acceptable safety profile and has largely replaced cyclophosphamide.84

RETINAL VASCULAR DISEASE Retinal vasculitis is defined as inflammation of the retinal vessels accompanied by intraocular inflammation with or without retinal vessel occlusion. Although most ophthalmologists do not distinguish among the different types of retinal vascular disease, we distinguish retinal vasculitis from the occlusive vasculopathies such as the antiphospholipid antibody syndrome associated with SLE (where no intraocular inflammation is present). Retinal vasculitis may involve the retinal arteries, capillaries, or veins, and it may cause significant visual loss.85,86 Retinal vasculitis can be seen in the systemic vasculitides, but it is an uncommon complication except for Behçet disease, in which retinal vasculitis is the most frequent ocular complication in some series.36,85–88 In Behçet disease, inflammation may involve both veins and arteries and result in arterial occlusion and retinal necrosis (Fig. 35.6). Occasionally, secondary neovascularization and tractional retinal detachment may develop.86–88 The natural history of ocular Behçet disease without treatment is poor. The majority of untreated patients will lose all or part of their vision within 5 years, with 74% of eyes in one series having vision worse than 20/200.87 For eyes that deteriorated to no light perception, vision declined to this level over a period of 3.6 years.42,87 With treatment, clinical outcomes have improved but remain somewhat guarded, with the rate of any ocular complication estimated to be 0.45 per eye-year and rates of vision loss to the 20/200 level or worse being approximately 10% per eye-year.38 Corticosteroid therapy appears to delay progression of the disease but does not alter the ultimate outcome; therefore immunosuppressive drug therapy is used for the treatment of patients with retinal vasculitis complicating Behçet disease.36,58 Initially, chlorambucil was used, typically at a dose of 0.1 to 0.2 mg/kg/day.58,89–95 Uncontrolled case series of chlorambucil therapy for Behçet disease have shown long-term, drug-free remissions after 2 years of

a

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treatment.66,89,90 Fewer published data are available for cyclophosphamide as treatment of patients with ocular Behçet disease, but some clinicians have found it to be as effective as chlorambucil and easier to use.66 Cyclosporine and azathioprine have also been reported to be effective in the treatment of patients with ocular Behçet disease, and they have been shown to be efficacious in randomized clinical trials.66,93–96 However, nearly 25% of patients treated with azathioprine either had no benefit in terms of the frequency and severity of ocular attacks or required additional therapy, and only 50% of patients treated with cyclosporine had a good response.66,93,95,96 Studies of patients with ocular Behçet disease treated with infliximab have suggested that it is an effective therapy at the dose of 5 mg/kg per infusion or higher.97,98 Outcomes with adalimumab have also been favorable in the treatment of patients with Behçet retinal vasculitis. A systematic review by an expert panel of the American Uveitis Society recommends a regimen including anti-TNF therapy with either infliximab or adalimumab as a first line of therapy for Behçet disease.59 Microvascular vasoocclusive disease can also affect the retinal vasculature. In SLE, the retinal capillaries are involved and primarily result in cotton-wool spots or microinfarcts of the nerve fiber layer of the retina.99 The prevalence of retinopathy varies widely depending on the patient population studied, from 3% of ambulatory outpatients to 28% of hospitalized patients with SLE having retinal vascular findings.100,101 These findings occur in the absence of intraocular inflammation. More extensive retinal and vasoocclusive disease can occur with active SLE or as a result of antiphospholipid antibody syndrome (Fig. 35.7).100–102 This more

FIG. 35.7  Acute, severe, retinal vasoocclusive disease affecting the upper temporal retinal vessels. A large number of hemorrhages and white choroidal and retinal infiltrates are present.

b

FIG. 35.6  Fundus photographs from a patient with Behçet disease demonstrating retinal vasculitis. (a) Early macular lesion. (b) Progressive disease 1 month later. (From Thome JE, Jabs DA. Rheumatic diseases. In: Ryan SJ, editor. The retina. 4th ed. London: Elsevier; 2006, p. 1383–408.)

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SECTION 3  Approach to the Patient

severe retinal vasoocclusive disease occurs in fewer than 1% of patients with SLE, appears to be associated with central nervous system lupus,101 and includes central retinal artery occlusion, central retinal vein occlusion, branch artery occlusion, and diffuse retinal vasoocclusive disease (Fig. 35.8).102 With severe retinal vascular disease, the prognosis for vision is poor, and retinal neovascularization commonly develops. Even less common than retinopathy is lupus choroidopathy (Fig. 35.9).103 The clinical changes seen in patients with lupus choroidopathy involve serous elevations of the retina or detachments of the retinal pigment epithelium. These clinical findings are associated with a systemic vascular disease, either hypertension from lupus nephritis or systemic vasculitis.103 Treatment of the underlying systemic disease with systemic corticosteroids and immunosuppressive agents if needed and control of the hypertension can lead to resolution of the serous retinal detachments.103 Central retinal artery occlusions can be seen in patients with polyarteritis nodosa (PAN) and with giant cell arteritis (GCA), although arteritic ischemic optic neuropathy is a more classic finding.36,85,86,104 Arteriovenous anastomoses result from shunting of blood from artery to vein without an intervening capillary bed. They are seen commonly in the midperiphery of the retina in patients with Takayasu arteritis.1,36,105–107 The arteriovenous anastomoses can shunt blood away from the peripheral retina, which occasionally leads to areas of retinal nonperfusion with subsequent neovascularization of the retina and vitreous hemorrhage.1,105–107 In addition to systemic immunosuppression, pan-retinal photocoagulation may be helpful in controlling inflammation associated with retinal vasculitis and preventing secondary retinal neovascularization.108

FIG. 35.8 Fundus photograph demonstrating diffuse vasoocclusive disease in a patient with systemic lupus erythematosus. (From Jabs DA, Fine SL, Hochberg MC, et al. Severe retinal vaso-occlusive disease in systemic lupus erythematosus. Arch Ophthalmol 1986;104:558–563.)

OPTIC NERVE DISEASE Optic nerve dysfunction associated with rheumatic disease includes ischemic optic neuropathy and optic neuritis.36 The characteristic features of ischemic optic neuropathy are painless sudden loss of vision, decreased color vision, and classically an altitudinal visual field defect. A relative afferent pupillary defect is present in the affected eye. The loss of visual acuity and visual field is usually permanent, and the optic nerve head becomes atrophic and pale (e.g., optic nerve pallor) over time. In some cases of ischemic optic neuropathy, however, partial recovery of visual acuity has been noted after large doses of pulse intravenous (IV) corticosteroids (e.g., 1 g/ day of methylprednisolone for 3 days).109,110 Although ischemic optic neuropathy may occur with any type of vasculitis, as well as with SLE,111 it is seen most commonly in patients with GCA.112 Optic neuritis is characterized by acute or subacute visual loss associated with retrobulbar pain, especially with movement of the affected eye. Examination of the eye reveals decreased vision, a relative afferent pupillary defect, decreased color vision, and visual field loss. The optic nerve head may be swollen or appear normal initially, depending on whether the optic neuritis is at the level of the optic nerve head (inside the eye) or along the retrobulbar nerve (behind the eye). Visual symptoms result from optic nerve demyelination. Unlike ischemic optic neuropathy, up to 95% of patients with optic neuritis have visual acuity of 20/40 or better 1 year after the event.36 Optic neuritis is most typically associated with multiple sclerosis and responds to pulse IV corticosteroids, with more rapid improvement of vision. Optic neuritis may also occur in SLE; such patients typically have a steroid-responsive but also steroid-dependent process and typically require immunosuppressive drug therapy to reduce the risk of recurrence and subsequent visual loss.1 Anti-TNF alpha agents are contraindicated in the presence of demyelinating disorders such as multiple sclerosis as steroid-sparing immunosuppressive therapy as they resurface or worsen demyelination.113 Traditionally systemic corticosteroids have been the cornerstone of treatment for GCA. Extended therapy is required with typical durations of treatment ranging from 18 to 24 months to prevent recurrence. In some patients, long-term low-dose corticosteroid treatment has been required. Growing evidence suggests that immunosuppressive medications may have a beneficial role in preventing relapse and may help prevent contralateral eye involvement in GCA, including clinical trial data involving tocilizumab.114 A randomized, placebo-controlled study of 251 patients with GCA reported that treatment with weekly or biweekly tocilizumab in conjunction with corticosteroid taper over a 26-week period was superior to placebo plus corticosteroid taper over either 26 or 52 weeks in achieving sustained disease remission. 56% of patients in the weekly tocilizumab group and 53% of patients in the biweekly tocilizumab group achieved sustained remission by 52 weeks compared to 14% and 18% of patients who underwent the 26-week and 52-week prednisone taper, respectively. Tocilizumab was approved for use by the United States Food and Drug Administration as a therapy for GCA. There are limited data comparing the relative efficacy of tocilizumab versus other immunosuppressive medications used to treat GCA such as methotrexate, adalimumab, or ustekinumab in inducing remission and preventing disease recurrence in GCA.115 The multicenter randomized clinical trial MEthotrexate versus TOcilizumab for treatment of Giant cell Arteritis (METOGiA) suggested that cost-effective methotrexate failed to be comparable to tocilizumab effectiveness.

ORBITAL DISEASE

FIG. 35.9  Fundus photograph of a patient with choroidopathy and systemic lupus erythematosus. (From Jabs DA, Hanneken AM, Schachat AP, Fine SL. Choroidopathy in systemic lupus erythematosus. Arch Ophthalmol 1988;106:230–234.)

Orbital inflammation in patients with rheumatic disease may include primary inflammation of the orbital tissue (e.g., orbital pseudotumor or orbital inflammatory syndrome), inflammation of the extraocular muscles (e.g., orbital myositis), or contiguous spread of inflammation from the sinuses. Orbital inflammatory disease occurs most frequently in individuals with ANCA-associated vasculitis and sarcoidosis.116–118 The most common initial sign of orbital disease is proptosis or anterior displacement of the eye caused by a space-occupying lesion or inflammatory process. Associated symptoms and signs include pain, blurred vision, and diplopia (double vision) as a result of restriction of eye movement, chemosis, and eyelid swelling. In ANCA-associated vasculitis, orbital involvement is common and occurs in 15% to 50% of patients, and in some series, it is the most common form of ophthalmic involvement.116–118 Orbital disease may be an extension of granulomatous inflammation from the sinus into the orbit. Such inflammation can lead to compartment syndrome within the orbit, resulting in compressive optic neuropathy and subsequent irreversible visual loss.117,118

CHAPTER 35  Ocular manifestations of rheumatic diseases Systemic corticosteroids or immunosuppressive drug therapy aimed at controlling the underlying disease can decrease proptosis, improve mobility, and reduce associated symptoms, as well as improve visual acuity. Rarely, orbital decompression may be necessary if the inflammatory process has caused proptosis severe enough to compromise the optic nerve (orbital apex syndrome). The orbital disease accompanying ANCA-associated vasculitis typically requires immunosuppression and may be difficult to control. The use of biologic therapies including infliximab and rituximab has demonstrated efficacy in suppressing orbital inflammatory disease.119

CORNEAL DISEASE Corneal manifestations of rheumatologic disease include forms of keratitis (inflammation in the cornea) and dry eye disease, or keratoconjunctivitis sicca (KCS; described in the next section). Keratitis is classified as interstitial keratitis (IK) or peripheral ulcerative keratitis (PUK). The diagnosis of IK includes diffuse stromal keratitis, sclerosing keratitis, and deep keratitis. PUK is also known as marginal keratitis, marginal corneal ulceration, or limbal guttering. Limbal vasculitis may also be seen as a rare manifestation and is not discussed further here. Keratitis may occur on its own or in association with scleritis, in which case it is termed sclerokeratitis. Although PUK and sclerokeratitis are often associated with rheumatic disease, infectious causes such as herpes simplex and syphilis also need to be considered. Interstitial keratitis is characterized by nonsuppurative inflammation, usually with vascularization of the corneal stroma. It is generally caused by an immunologic response to an infectious agent (e.g., syphilis) but occasionally occurs in systemic disease, with the most common cause being Cogan syndrome.120 It also may occur as a common corneal complication of scleritis.58,67,77 The pericorneal or limbal inflammation is accompanied by peripheral corneal vessels that advance across the central cornea, preceded by superficial stromal opacities. In nodular scleritis, the corneal involvement may be restricted to one segment, but in diffuse scleritis the entire cornea may be involved, with a dense corneal leukoma being produced. Symptoms of IK include pain, tearing, photophobia, and conjunctival injection. The IK associated with Cogan syndrome typically responds to topical corticosteroid therapy. Clinically, PUK typically manifests with pain, though this is not always the case. Peripheral corneal infiltrates may develop. Epithelial breakdown of the cornea occurs followed by corneal ulceration and stromal thinning, which may progress circumferentially and then centrally (Fig. 35.10).121–123 If left untreated, the lesion progresses and results in corneal perforation and loss of vision. Bacterial corneal infection must be excluded first, particularly in patients with compromised corneal epithelia (e.g., KCS secondary to Sjögren syndrome). PUK typically occurs in patients with RA or vasculitis and often involves the lower half of the cornea with furrowing of the corneal periphery (Fig. 35.11). The development of PUK in patients with RA has been linked to immunologically mediated small-vessel vasculitis of the pericorneal vessels and is associated with advanced RA, elevated rheumatoid factor titers, and increased risk for mortality.70 PUK has also been reported to occur in patients with other connective tissue disorders such as ANCA-associated vasculitis, relapsing polychondritis, SLE, and progressive systemic sclerosis.36

FIG. 35.10  Active corneal ulceration with corneal infiltrates at the “leading edge” of an ulcer and associated conjunctival injection.

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Treatment of patients with PUK is aimed at the underlying disease and often requires the use of high-dose systemic corticosteroids and immunosuppressive medications to arrest the disease process and prevent progressive corneal thinning and perforation. Given the potential role of inflammatory cytokines such as TNF-alpha in the pathogenesis of PUK,124 TNF-alpha inhibitors such as infliximab or adalimumab may be beneficial for the treatment of refractory PUK, although the data are limited and published evidence is based on case reports and case series.125,126 Local therapy such as the use of cyanoacrylate adhesive glue, amniotic membranes, and corneal or scleral patch grafts is often needed to prevent perforation and to maintain tectonic support of the globe.122,127–129 However, these measures will eventually fail if the underlying inflammation is not controlled. Very small central corneal perforations ( 0.5, current prednisolone use, and RA duration > 10 years), all of which independently contribute to risk. There is conflicting evidence in respect of RA disease management and coronary risk. Bili et al.50 performed a retrospective drug exposure analysis to interrogate the association between tumor necrosis factor alpha (TNF-α), other DMARDs, and no DMARD exposure and incident cardiovascular events in an incident RA population. They observed a 55% reduction in risk of incident CAD in patients using TNF-α inhibitors compared to patients using nonbiologic DMARDs. In contrast, Sharma et al.51 observed a reduction of CAD with hydroxychloroquine (HCQ, a non-DMARD in the previous study50) in a retrospective analysis of 1266 patients with RA of whom 547 had ever had HCQ exposure. They found that CV events were reduced in those ever receiving HCQ (relative risk = 0.6; (0.41–0.94) after adjustment for CV risk. However, in this study,51 immortality bias was not controlled for. A randomized placebo-controlled trial of atorvastatin 40 mg daily vs placebo in 200 patients with SLE failed to show a difference in progression of coronary artery calcification, carotid intima media thickness, or carotid plaque.52 By contrast, statin use was associated with reduced mortality and cardiovascular events in a nested case control study of 4095 patients with SLE and hyperlipidemia.53 The previous conflicting evidence in respect of lipids and obesity probably explains the poor compliance with guidance advice. In their assessment of coronary risk factor management at a lupus clinic, Demas and colleagues54 found that fewer than 3% of patients had all five coronary risk factors assessed within the preceding year, and only a quarter had four of five recommended assessments performed. A review of the literature looking at the antiinflammatory effects of statins on CAD found that there is firm evidence that statins have a positive effect on the reduction of inflammation. While the magnitude of effect may differ with various types of statins, all statins examined were shown to lower the levels of inflammatory markers, especially C-reactive protein (CRP) levels, and inhibit inflammation in CAD.55 Antiphospholipid syndrome is rather different from the other inflammatory autoimmune diseases in that it is associated with arterial and venous thrombosis. Several studies have shown that thrombotic CAD can lead to myocardial infarction, although this is less common than venous thrombosis (3% of 1000 patients with antiphospholipid syndrome experienced myocardial infarction, whereas 32% of patients had deep vein thrombosis).56 In the systemic vasculitides, especially antineutrophil cytoplasmic antibody–associated diseases such as granulomatosis with polyangiitis (Wegener granulomatosis) and microscopic polyangiitis, there is an excess of deaths due to cardiovascular causes. Flossman et al. showed that in 535 patients randomized to four clinical trials of antineutrophil cytoplasmic antibody vasculitis, after the first year, 26% of deaths were attributable to cardiovascular disease.57

ATYPICAL CORONARY DISEASE IN SARDs Mucocutaneous lymphadenopathy, also known as Kawasaki disease, is the SARD primarily associated with specific coronary lesions.58 This condition typically affects young male children less than 5 years of age but has also been reported in adults without classical dermatologic lesions.59 The administration of intravenous immunoglobulin (IVIG) while the disease is active helped reduce the prevalence of coronary aneurysms from 20% to 5%.58 However, IVIG is not universally successful, and for those who never develop aneurysms, the risk of persistent vasculitis is not yet clear. Hence, specialists advise long-term follow-up in these patients.60 In later stages, thin-walled aneurysms and secondary stenotic lesions dominate, and stenting of these lesions is considered safe and practical.61 Behçet’s syndrome primarily causes dilation of pulmonary vessels, possibly through inflammation of the vasa vasorum (Fig. 36.1). There is also, however, an association with coronary aneurysms, which develop in overt disease activity and are improved by immunosuppressive therapy.62 Takayasu arteritis can cause angina and heart failure secondary to involvement of the coronary ostia in aortic disease, but generally smaller vessels such as the coronary arteries are spared.63 IgG4-RD is a heterogenous fibroinflammatory multiorgan disease associated with elevated IgG4 levels. The clinical manifestations are protean, and attempts are being made to codify these.64 Coronary involvement is not uncommon and includes stenotic disease (which may require intervention),

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SECTION 3  Approach to the Patient Mousseaux et al.70 found that LGE within the LV on CMR in patients with scleroderma was an independent risk factor for a major adverse cardiac event such as myocardial infarction, pulmonary arterial hypertension, heart failure, or cardiovascular death (HR = 3.74; 95% CI, 1.09–13.5; P = .028). Myocarditis is also a key etiological factor in scleroderma cardiomyopathy. Mavrogeni et al.71 demonstrated that silent myocarditis is found in a considerable percentage of patients with scleroderma without clinical cardiac symptoms and without elevated CRP, erythrocyte sedimentation rate, or further clinical disease characteristics. CMR has a role to play in diagnosing silent myocarditis. Treatment with immunosuppressants frequently normalized CMR signs of myocarditis at 6 months.71 This is key in preventing progressive cardiac damage.

FIG. 36.1  Pulmonary artery aneurysm shown on computed tomographic pulmonary angiogram in a patient with Behçet syndrome and pulmonary hypertension (arrow).

FIG 36.2  Coronary aneurysms on computed tomography coronary angiography in a patient with IgG4-RD (green arrows).

HYPERTENSION Gout and hyperuricemia have the strongest association with hypertension.72 In in vitro studies, uric acid is a powerful pro-oxidant in the intracellular environment,73 causing endothelial dysfunction74 and inflammation. In humans, intervention to reduce uric acid levels appears to ameliorate hypertension.75 Metaanalysis of available controlled studies from 2011 indicate that there is no excessive hypertension observed in patients with RA compared to the control group76; this is also supported by a large registry from the south of England.77 However, recent studies published in 2019 suggest that individuals with SARDs, such as RA and SLE, especially have an increased prevalence of hypertension that is associated with a higher risk for CVD. In SLE, hypertension control is critical in order to maintain kidney function and prevent kidney failure.78 In patients with RA who also have hypertension, an increased risk of CV events is observed,77,79 and the typical consequences of hypertension, atrial fibrillation, and stroke have also been found to be significantly more common.80 A metaanalysis of TNF-α trials shows that when compared to controls, anti-TNF therapy significantly increased the risk of developing hypertension. Concerningly, the incidence of hypertension in this group of patients with RA was doubled.81 Continued monitoring of blood pressure in patients on anti-TNF therapy is advised.

aneurysms (which may progressively enlarge despite disease control), and perivascular inflammatory masses (Fig. 36.2).16

HEART FAILURE AND DIRECT MYOCARDIAL INVOLVEMENT

CORONARY ARTERITIS

There is a growing number of population-based studies estimating the incidence, prevalence, and prognosis of heart failure in RA. While it is unarguable that RA is associated with a greater risk of heart failure, it is not all related to myocardial infarction. The cumulative incidence of heart failure (HF) not due to ischemic heart disease was remarkably high in RA. The relative risk of heart failure (2:1) is driven mainly by heart failure with preserved ejection fraction (HFpEF).82 Proposed causes include amyloidosis, nonsteroidal antiinflammatory drug (NSAID) use, glucocorticoid therapy, IHD, and direct myocardial involvement.83 Two studies have demonstrated that the prevalence of heart failure in RA increases with age, disease duration, and severity.84,85 The E/A ratio (a measure of diastolic dysfunction) on echocardiography was comparable with healthy controls in low RA disease activity; however, it decreased with increased age and disease severity. A reduction in E/A ratio may be the first sign of diastolic dysfunction in patients with RA. The presentation of heart failure may be subtle, given preserved systolic function, but is associated with a worse prognosis in the 6 months following acute exacerbations.86 The presence of overt heart failure entails a higher association with morbidity and mortality in this patient group; screening and early risk management may have a prognostic benefit. From the rheumatologic perspective, the salient points are that echocardiography is relatively insensitive as a tool for diagnosing RA-associated heart failure (assessment of diastolic dysfunction lacks specificity), and angiotensin-converting enzyme inhibition and β-blockade are not beneficial in HFpEF. On echocardiography, an enlarged left atrium may be the only feature (and this can also be caused by prolonged atrial fibrillation). CMR, however, has shown potential in capturing early tissue changes in heart failure in RA such as myocardial inflammation and myocardial perfusion defects due to macrovascular (coronary artery disease) or microvascular (vasculitis) disease. This is very useful in evaluating patients in early asymptomatic stages, allowing treatment targeting the heart to be given when it can be most effective.87 Cardiac failure should be very common in scleroderma, given up to 70% of patients have histologic evidence of cardiac involvement on postmortem examination68 and a similar percentage of patients exhibit abnormalities on

Conditions such as eosinophilic granulomatosis with polyangiitis (eGPA), granulomatosis with polyangiitis (GPA), and polyarteritis nodosa can cause intramyocardial coronary arteritis,65 although the latter can also cause coronary artery aneurysms.66 Cardiac involvement in eGPA remains the major determinant of mortality in this condition.67 A study of 65 patients67 with eGPA suggests that myocarditis and reduced left ventricular ejection fraction at presentation are predictive of adverse events related to heart failure. The study found that while noncorticosteroid immunosuppression may represent an effective therapy to help limit myocardial damage and prevent heart failure, inadequate duration of noncorticosteroid immunosuppression correlated directly with higher myocardial damage. Myocardial damage was characterized with late gadolinium enhancement (LGE) on CMR.

FUNCTIONAL CORONARY ARTERY DISORDERS Systemic sclerosis, also known as scleroderma, is thought to impair intramyocardial vascular tone, leading to ischemia-reperfusion injury, which is classically observed on histological lesions of contraction band necrosis and replacement fibrosis.68 However, comparative histologic studies have indicated that such lesions are only modestly more common in patients with scleroderma than in the normal population. Additionally, the clinical manifestations are less common than the histological findings, making the clinical significance of such findings uncertain.12,68 Systematic evaluation of CMR findings in patients with scleroderma with histopathologically confirmed myocardial involvement allowed Krumm et al.69 to define five categories: (1) pericardial effusion, (2) ventricular kinesic pattern (LV and RV hypokinesia, dyskinesia, dyssynchrony, and diastolic restriction), (3) reduced LV-EF or RV-EF, (4) positive LGE or pathologic inversion time localizer, and (5) right ventricular dilatation. Pathology in any three categories signified myocardial involvement. Thus, CMR is increasingly recognized as an integral tool to assess the extent of myocardial involvement in patients with scleroderma.

CHAPTER 36  The cardiovascular system in rheumatic disease CMR.88 However, clinically systolic LV dysfunction is rather uncommon,89 and overt HFpEF is encountered in only a minority. Although systolic heart failure is seen occasionally in the context of renal crisis or in association with myocarditis,90 most commonly cardiac involvement remains subclinical unless there is an associated cardiac stress. Right-sided heart failure secondary to pulmonary hypertension is the most common reason that patients with scleroderma have symptoms and signs of heart failure. Cardiologists are sensitized to the possibility of sarcoid cardiac involvement because of the association with sudden cardiac death (SCD) and heart block, not so much because of the occurrence of heart failure. Nevertheless, a byproduct of this is an awareness of the possibility of sarcoid as an underlying diagnosis when a patient has myocarditis or restrictive cardiomyopathy. The prevalence of cardiac involvement in sarcoid depends on the series chosen. While postmortem series suggest that 30% of patients have granulomas in the heart, the diagnosis is uncommon when patients are alive, indicating subclinical disease, as in the case of scleroderma.91 Clinical prevalence lies between 5%92 and 40%.93 There is considerable variation in the diagnostic criteria for cardiac sarcoidosis94; a metaanalysis95 of gross pathological images from autopsy and cardiac transplantation cases found certain features of myocardial involvement that occurred frequently (LV subepicardial, LV multifocal, septal, and RV free wall involvement) could aid diagnosis and prognostication of patients. Heart failure may present as part of an active inflammatory sarcoidassociated myocarditis, with persistent troponin leakage and evidence of diffuse myocardial edema and midwall fibrosis on CMR. Steroids and occasionally more aggressive immunosuppression (such as mycophenolate) are the mainstay of therapy. Early intervention with therapy should be initiated to avoid reduction of the ejection fraction to less than 40%, and given the association with ventricular arrhythmias, consideration should be given to use of a life vest or implantation of a defibrillator to deal with unpredictable arrhythmias during the initial phase of therapy.93,96 Alternatively, patients may have heart failure of more insidious onset, often associated with very large atria and features of restriction. This form of heart failure is difficult to treat and only diuretics appear to have any role in management. As detailed above under coronary arteritis, Churg–Strauss syndrome/ eGPA frequently leads to impaired cardiac function and symptomatic heart failure, particularly if nonsteroid immunosuppression is not used early in the disease course.97 While microvascular ischemia is thought to be the main driver, endomyocarditis on biopsy is also found in some series.98 Once heart failure is present, standard therapy is appropriate; however, prevention theoretically should now be possible by monitoring troponin levels when treating patients with these conditions aggressively with prolonged immunosuppression if there are any concerns about cardiac involvement. Current teaching is that heart failure in SLE is most likely the result of standard dilated cardiomyopathy or coronary disease rather than direct lupus or antimalarial drug toxicity.99 Certainly, given the increased frequency of coronary disease, computed tomographic angiography seems a sensible first investigation in patients with systolic heart failure. CMR often shows evidence of myocardial edema and late gadolinium enhancement (Fig. 36.3), but whether this differentiates myocarditis from hydroxychloroquine toxicity has not been established, and myocardial biopsy with electron microscopic evaluation for myeloid bodies100 should be considered if other clinical features of disease activity are absent or there are features of hypertrophy. Lupus-related myocarditis can be detected in patients with pleuropericardial chest pain using clinical and laboratory methods, especially with the wide availability

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of troponin and N-terminal-pro-brain natriuretic peptide (NT-proBNP) and increasing availability of CMR.101 Speckle tracking echocardiography on patients with clinical lupus myocarditis found global longitudinal strain (GLS) correlated with regional and global left ventricular function. This combined with diastolic parameters allows speckle tracking echocardiography to detect subclinical left ventricular dysfunction in patients with SLE.102 Heart failure is thought to be common in inflammatory myopathies; however, the quality of registry data makes this uncertain.103 The finding of subclinical myocardial involvement in autopsy studies, backed by suggestions of a high cardiac mortality, indicate that cardiac failure may be underdiagnosed. Available data suggest that a process of lymphocytic infiltration similar to that observed in the skeletal muscle may affect the heart and that cardiac lesions may progress despite steroid therapy.104 With more widespread use of troponin and NT-proBNP testing as well as CMR, the picture should clarify in the coming decade. To date we have just the report from Hunan in China, suggesting that mortality remains modest and usually due to infection rather than cardiac causes.105

VALVULAR HEART DISEASE Ask cardiologists about rheumatologic conditions that cause valvular heart disease, and they will recall Libman–Sacks endocarditis as a matter of historical interest and offer ankylosing spondylitis as a contributor to aortic valve disease. Such impressions are in part testament to the efficacy of current management of SARDs and in part reflection of cardiologic disinterest in subclinical valvular lesions. Although clinically overt valve disease is now rare in SLE, echocardiographic studies suggest that involvement remains common, with 40% of patients exhibiting minor abnormalities on transthoracic echocardiographic studies and 70% on transesophageal echocardiographic studies, including vegetations in over 30%.6 Valvular lesions identified only on transesophageal echocardiography can be influenced by immunosuppressive therapy. A correlation between valvular lesions in SLE and stroke has been found with microembolization as the proposed mechanism.106 It is increasingly recognized that the presence of antiphospholipid antibodies in patients with SLE is more likely to be associated with cardiac valve disease, predominantly the mitral and aortic valve, rather than with Libman–Sacks endocarditis.107 While immunosuppressants, especially with corticosteroids, are a common and effective strategy to treat lesions in SLE by decreasing inflammation, such immunosuppressive therapy also increases the probability of fibrosis and scarring, causing further valvular damage.108 However, no large, systematic studies have been done on immunosuppressive or antiinflammatory treatments of valve diseases. In ankylosing spondylitis, aortitis is thought to occur during late stages of the disease and may be quite common. Generally, only thickening of the aortic wall is evident; however, this may lead to aneurysm formation, thickening and retraction of the aortic or mitral valve leaflets causing regurgitation, and/or fibrosis of the upper septum, leading to conduction abnormalities. As with all largely subclinical processes, more detailed investigations lead to higher reported prevalence rates, and with transesophageal echocardiographic evaluation, root and valve abnormalities are found to be more than threefold more common in patients with ankylosing spondylitis than in control populations.109 Currently, scleroderma is not considered a major cause of valvular heart disease, but modest thickening of the leaflets with shortening of the chordae tendineae is common in echocardiographic studies, as is mild regurgitation. In the authors’ experience, most patients who require intervention for valve lesions have aortic stenosis, although at this time it is not evident that the prevalence exceeds that in the normal population.

PERICARDITIS

FIG. 36.3  Extensive diffuse myocardial edema in a patient with sarcoid-associated acute myocarditis. Cardiac magnetic resonance image showing late gadolinium enhancement (green arrow pointing to mottled gray appearance of left ventricular myocardium).

Pericarditis typically presenting with fever and pleuritic/positional chest pain and pericardial effusions typically presenting with dyspnea and fatigue are the most common types of pericardial involvement with SARDs but quite rare overall and not the primary complaint. SLE is the rheumatologic condition classically associated with typical symptomatic pericarditis, with up to one-fourth of patients having a syndrome of positional chest pain, fever, tachycardia, and/or pericardial rub, and >50% of patients have been reported to have a pericardial effusion on echocardiography, although this may be asymptomatic.110–112 Pericardial involvement may precede the clinical signs of SLE.113 SLE is difficult to diagnose and often misdiagnosed in the years preceding the diagnosis. A study of Taiwan’s National Health Insurance Research Database found that patients utilized ambulatory care services significantly more in the year preceding diagnosis of SLE compared to controls, generally for respiratory and digestive systems.114

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All types of pericardial involvement have been described, most commonly fibrinous pericarditis, and the pathologic basis appears to be inflammatory depositions (immunoglobulin, C1q, C3) in the walls of pericardial vessels.115 Treatment is adequate control of lupus activity. It is remarkable how quickly even large pericardial effusions improve with corticosteroid therapy. Direct intervention for pericardial effusions is very rarely required. Pericardial effusions are also common in scleroderma; however, clinical pericarditis is uncommon. Autopsy studies reveal frequent and diverse pathologic features, including fibrinous and fibrous pericarditis, adhesions, and effusions.116 Clinically, effusions are most relevant when they are associated with pulmonary hypertension, in which they provide evidence of RV decompensation, and when they are associated with an active myocarditis,117 which requires treatment in its own right. In the setting of pulmonary hypertension, pericardial drainage should usually be avoided; it does not normally improve hemodynamics and can result in worsening of right-sided heart failure due to sudden reduction in free wall support. It is RV dominance that causes the apparent compression of the left ventricle that has been reported, rather than tamponade. Clinical pericarditis is uncommon in RA ( 7 years), and withdrawal of antimalarial therapy does not necessarily lead to recovery, with nearly one-third of patients succumbing. In the treatment of gout, febuxostat is associated with higher all-cause mortality and cardiovascular mortality than allopurinol and it now carries a US Food and Drug Administration boxed warning alert.191

CONCLUSION It may be concluded that all aspects of cardiac function may be affected either directly or indirectly in SARDs. While knowledge gaps remain, there has been significant progress over the past few years, improving our understanding of the cardiac contribution to adverse outcomes in these populations and the importance of multidisciplinary discussion and management. Dedicated combined cardiology–rheumatology clinics are increasingly relevant to identify and manage cardiac involvement early in patient cohorts with SARDs and to monitor for possible cardiac toxicity, as DMARDs with uncertain cardiovascular safety proliferate.

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131. Carvalheiras G, Faria R, Braga J, et al. Fetal outcome in autoimmune diseases. Autoimmun Rev. 2012;11:A520–A530. 132. Bernardo P, Conforti ML, Bellando-Randone S, et al. Implantable cardioverter defibrillator prevents sudden cardiac death in systemic sclerosis. J Rheumatol. 2011;38:1617–1621. 133. Henes JC, Koetter I, Horger M, et al. Autologous stem cell transplantation with thiotepa-based conditioning in patients with systemic sclerosis and cardiac manifestations. Rheumatology. 2014;53:919–922. 134. Mueller KA, Mueller II, Eppler D, et al. Clinical and histopathological features of patients with systemic sclerosis undergoing endomyocardial biopsy. PLoS ONE. 2015;10(5):e0126707. 135. Dumitru R, Bissell L-A, Erhayiem B, et al., Cardiovascular outcomes in systemic sclerosis with abnormal cardiovascular MRI and serum cardiac biomarkers, RMD Open, 7 (3), 2021, doi:10.1136 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524374/pdf/rmdopen2021-001689.pdf, 34663635. 136. Lindhardsen J, Ahlehoff O, Gislason GH, et al. Risk of atrial fibrillation and stroke in rheumatoid arthritis: Danish nationwide cohort study. BMJ. 2012;344:e1257. 137. Kim SC, Liu J, Solomon DH. The risk of atrial fibrillation in patients with rheumatoid arthritis. Annals of the rheumatic diseases. 2014;73(6):1091–1095. 138. Bazzani C, Cavazzani I, Ceribelli A, et al. Cardiological features of idiopathic inflammatory myopathies. J Cardiovasc Med. 2010;11:906–911. 139. Dik VK, Peters MJ, Dijkmans PA, et al. The relationship between disease-related characteristics and conduction disturbances in ankylosing spondylitis. Scand J Rheumatol. 2010;39:38–41. 140. Ljung L, Sundström B, Smeds J, Ketonen M, Forsblad-d’Elia H. Patterns of comorbidity and disease characteristics among patients with ankylosing spondylitis—a cross-sectional study. Clin Rheumatol. 2018;37(3):647–653. 141. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53:1801913. 142. Chatterjee S. Pulmonary hypertension in systemic sclerosis. Semin Arthritis Rheum. 2011;41:19–37. 143. Condliffe R, Kiely DG, Peacock AJ, et al. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med. 2009;179:151–157. 144. Condliffe R, Howard LS. Connective tissue disease-associated pulmonary arterial hypertension. F1000Prime Reports. 2015;7:06. 145. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis. 2007;66(7):940–944. 146. Hernández-Oropeza JL, Rodríguez-Reyna TS, Carrillo-Pérez DL, et al. Pulmonary vasoreactivity and phenotypes in pulmonary arterial hypertension associated to connective tissue diseases. Rev Inves Clin. 2018;70:82–87. 147. Dobarro D, Schreiber B, Handler C, et al. Pulmonary hypertension in sarcoidosis. Clinical characteristics, haemodynamics and treatment in a single centre experience over 11 years and meta-analysis of the published data. Am J Cardiol. 2013;111:278–285. 148. Condliffe R, Kiely DG, Peacock AJ, et al. Connective tissue disease–associated pul monary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med. 2009;179:151–157. 149. Montani D, Henry J, O’Connell C, et al. Association between rheumatoid arthritis and pulmonary hypertension: data from the French Pulmonary Hypertension Registry. Respiration. 2018;95(4):244–250. 150. Kobak S, Kalkan S, Kirilmaz B, Orman M, Ercan E. Pulmonary arterial hypertension in patients with primary Sjögren’s Syndrome. Autoimmune Dis. 2014;2014:710401. 151. Mukerjee St. D, George D, Knight C, Davar J, et al. Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis. Rheumatology. 2004;43:461–466. 152. Nihtyanova SI, Schreiber BE, Ong VH, et al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol. 2014;66(6):1625–1635. 153. Nicola PJ, Maradit-Kremers H, Roger VL, et al. The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum. 2005;52:412–420. 154. Mueller KA, Mueller II, Eppler D, et al. Clinical and histopathological features of patients with systemic sclerosis undergoing endomyocardial biopsy. PLoS ONE. 2015;10(5):e0126707. 155. Lv TT, Wang P, Guan SY, et al. Prevalence of pulmonary hypertension in systemic lupus erythematosus: a meta-analysis. Ir J Med Sci. 2018;187(3):723–730. 156. Gaine S, Chin K, Coghlan G, et al. Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. Eur Respir J. 2017;50(2):1602493. 157. Pan J, Lei L, Zhao C. Comparison between the efficacy of combination therapy and monotherapy in connective tissue disease associated pulmonary arterial hypertension: a systematic review and meta-analysis. Clin Exp Rheumatol. 2018;1095:1102. 158. Coghlan JG, Galie N, Barbera JA, et al. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease–associated pulmonary arterial hypertension (CTDPAH): subgroup analysis from the AMBITION trial. Ann Rheum Dis. 2017;76(7):1219–1227. 159. Gaine S, Chin K, Coghlan G, et al. Selexipag for the treatment of connective tissue disease– associated pulmonary arterial hypertension. Eur Respir J. 2017;50:1602493. 160. Coghlan JG, Galiè N, Barberà JA, et al. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTDPAH): subgroup analysis from the AMBITION trial. Ann Rheum Dis. 2017;76(7):1219–1227. 161. Khanna D, Zhao C, Saggar R, et al. Long-term outcomes in patients with connective tissue disease–associated pulmonary arterial hypertension in the modern treatment era: meta-analyses of randomized, controlled trials and observational registries. Arthritis Rheumatol, 2021;73(5):837–847. 162. Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007;115:1634–1642. 163. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375:2519–2529.

164. Bally M, Dendukuri N, Rich B, et al. Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data. BMJ. 2017;357:j1909. 165. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. New England Journal of Medicine. 2019 Feb 21;380(8):752–762. 166. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019. 167. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–1131. 168. De la Forest M, Brugneaux J, Utard G, Salliot C. SAT0141 safety of anti-TNFS in RA patients in real life: results from a systematic literature review and meta-analyses from biologic registers. Ann Rheum Dis. 2015;74(Suppl 2). 169. Low AS, Symmons DP, Lunt M, et al. Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76(4):654–660. 170. Rezik M, Mattina D. Severe cardiomyopathy secondary to anti-TNF therapy for Crohn’s disease. J Am Coll Cardiol. 2016;67(13_S). 171. Singh JA, Furst DE, Bharat A, et al. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64(5):625–639. 172. Baniaamam M, Paulus WJ, Blanken AB, Nurmohamed MT. The effect of biological DMARDs on the risk of congestive heart failure in rheumatoid arthritis: a systematic review. Expert Opin Biol Ther. 2018;18(5):585–594. 173. Conti F; Atzeni F; Massaro L, et al., The influence of comorbidities on the efficacy of tumour necrosis factor inhibitors, and the effect of tumour necrosis factor inhibitors on comorbidities in rheumatoid arthritis: report from a National Consensus Conference, Rheumatology, 2018; vii11–vii22. 174. Gabay C, McInnes IB, Kavanaugh A, et al. Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis. Ann Rheum Dis. 2015, doi: 10.1136/annrheumdis-2015-207872. 175. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet. 2012;379(9822):1214–1224. 176. Kobayashi Y, Kobayashi H, Giles JT, Hirano M, Nakajima Y, Takei M. Association of tocilizumab treatment with changes in measures of regional left ventricular function in rheumatoid arthritis, as assessed by cardiac magnetic resonance imaging. Int J Rheum Dis. 2015. http://doi.org/10.1111/1756-185X.12632. 177. Kobayashi H, Kobayashi Y, Giles JT, Yoneyama K, Nakajima Y, Takei M. Tocilizumab treatment increases left ventricular ejection fraction and decreases left ventricular mass index in patients with rheumatoid arthritis without cardiac symptoms: assessed using 3.0 Tesla cardiac magnetic resonance imaging. J Rheumatol. 2014;41(10):1916–1921. 178. Giles JT, Sattar N, Gabriel S, et al. Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomised controlled trial. Arthritis Rheumatol. 2020;72(1):31–40. 179. Souto A, Salgado E, Maneiro JR, Mera A, Carmona L, Gómez-Reino JJ. Lipid profile changes in patients with chronic inflammatory arthritis treated with biologic agents and tofacitinib in randomized clinical trials: a systematic review and meta-analysis. Arthritis Rheumatol. 2015;67(1):117–127. 180. McInnes IB, Kim HY, Lee SH, et al. Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a randomised study*. Ann Rheum Dis. 2014;73(1):124–131. 181. Xie W, Huang Y, Xiao S, Sun X, Fan Y, Zhang Z. Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Ann Rheum Dis. 2019;78(8):1048–1054. 182. Qiu C, Zhao X, She L, Shi Z, Deng Z, Tan L, Tu X, Jiang S, Tang B. Baricitinib induces LDL-C and HDL-C increases in rheumatoid arthritis: a meta-analysis of randomized controlled trials. Lipids Health Dis. 2019 Feb 18;18(1):54. 183. Scott IC, Hider SL, Scott DL. Thromboembolism with Janus kinase (JAK) inhibitors for rheumatoid arthritis: how real is the risk? Drug Saf. 2018 Jul;41(7):645–653. 183a. Ytterberg SR, Deepak LB, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386:316–326. 183b. Kragstrup TW, Glintborg B, Svensson AL, et al. Waiting for JAK inhibitor safety data. RMD Open. 2022;8:e002236. 184. Lehane PB, et al., Effect of concomitant statins on rituximab efficacy in patients with rheumatoid arthritis, Ann Rheum Dis, 2014. 185. Ke C, Khosla A, Davis MK, Hague C, Toma M. A case of coronary vasospasm after repeat rituximab infusion. Case Rep Cardiol. 2015. 186. Lv S, Liu Y, Zou Z, et al., The impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol. 2014;33(1):69–76. 187. Myasoedova E, Gabriel SE, Green AB, Matteson EL, Crowson CS. The impact of statin use on lipid levels in statin-naive patients with rheumatoid arthritis (RA) vs non-RA subjects: results from a population-based study. Arthritis Care Res. 2013;65(10):1592. 188. Liu D, Li X, Zhang Y, et al., Chloroquine and hydroxychloroquine are associated with reduced cardiovascular risk: a systematic review and meta-analysis. Drug Des Dev Ther. 2018;12:1685–1695. 189. Yang D, Leong P, Sia S, Wang Y, Cheng-Chung Wei J. Long-term hydroxychloroquine therapy and risk of coronary artery disease in patients with systemic lupus erythematosus. J Clin Med. 2019;8(6):796. 190. Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf. 2018;41(10):919–931. 191. White WB, Saag KG, Becker MA, et al., Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med, 2018;378(13):1200–1210.

The lungs in rheumatic disease Tracy J. Doyle • Ivan O. Rosas • Paul F. Dellaripa

Key Points ■ All components of the respiratory system can be involved in the lung manifestations of rheumatologic diseases. ■ Interstitial lung disease (ILD) is one of the most challenging lung complications because of its progressive nature, variable response to therapy, and poor prognosis. ■ ILD may precede more common features of rheumatologic disease by several years, or some patients may have ILD with features of an autoimmune disease without meeting criteria for a specific connective tissue disease, which has been termed interstitial pneumonia with autoimmune features (IPAF). ■ High-resolution computed tomography is helpful in differentiating ILD patterns. Surgical biopsy may be required. ■ Rapidly progressive diffuse lung disease mimicking acute respiratory distress syndrome can occur, particularly in patients with the MDA5 antibody. ■ Pneumonitis caused by drugs or opportunistic infection can confound the diagnosis of ILD. ■ To date, treatment approaches target the dominant pattern of disease.

INTRODUCTION Pulmonary manifestations of rheumatic diseases are among the most significant challenges for practicing rheumatologists. Interstitial lung disease (ILD), one of the most challenging lung complications, is the main focus of this chapter. Other major areas of lung involvement, including airway, pleural, and vascular diseases, are discussed under the specific rheumatic diseases in which they occur.

INTERSTITIAL LUNG DISEASE ILD presents a major challenge in the management of patients with rheumatic diseases because of its progressive nature, variable response to therapy, and poor prognosis. It can be associated with scleroderma (systemic sclerosis [SSc] form), rheumatoid arthritis (RA), dermatomyositis or polymyositis, or mixed connective tissue disease and less frequently with systemic lupus erythematosus (SLE) and Sjögren syndrome. ILD may precede the development of a specific rheumatic syndrome or present as part of a poorly defined or undifferentiated rheumatic syndrome that the rheumatologist may be asked to evaluate to rule out autoimmune disease. In some cases, ILD will be the principal manifestation, known as interstitial pneumonia with autoimmune features (IPAF).1 The prognosis is variable and associated with the histopathologic pattern noted in an open lung biopsy. Outcomes tend to be better in ILD associated with rheumatic disease than in the idiopathic interstitial pneumonias, except for the usual interstitial pneumonia pattern, which carries a worse prognosis and resembles that of idiopathic pulmonary fibrosis (IPF).2,3

PATHOLOGIC AND RADIOLOGIC FEATURES IN INTERSTITIAL LUNG DISEASE An understanding of the histopathologic classification of ILD is important because different histologic subtypes portend different prognoses and treatment should be tailored appropriately. The two most common types of ILD associated with rheumatic diseases are nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP), followed by lymphocytic interstitial pneumonia (LIP), cryptogenic organizing pneumonia (COP), and, less frequently, diffuse alveolar damage (DAD) (Table 37.1). Nonspecific interstitial pneumonia is the histopathologic lung pattern seen most frequently in patients affected with most rheumatic diseases.4 It is characterized by a uniform, homogeneous pattern with variable degrees of inflammation (cellular NSIP) or fibrosis (fibrotic NSIP) and a noted paucity of fibroblastic foci on pathologic examination (Fig. 37.1). Typically, ground-glass opacities are noted and can be associated with a reticular pattern and traction

37

bronchiectasis but a lack of honeycombing on chest computed tomography (CT) scan (Fig. 37.2). Usual interstitial pneumonia, the classic pathologic lesion observed in IPF, is often seen in patients with RA but can also be seen in patients with SSc and other rheumatic syndromes. UIP is associated with a patchy heterogeneous process with fibrotic areas interposed with normal or near-normal lung and is notable for characteristic fibroblastic foci (Fig. 37.3). The presence of honeycombing (cystic spaces within clearly definable walls) on high-resolution chest computed tomography (HRCT) in a predominately subpleural distribution with architectural distortion and traction bronchiectasis is pathognomonic for UIP (Figs. 37.4 and 37.5). The presence of UIP in RA portends a worse prognosis than other histopathologic patterns.4 Less common forms of ILD include: 1. COP, formerly known as bronchiolitis obliterans organizing pneumonia (BOOP), predominately involves the distal airways (acini and respiratory bronchioles). The classic finding on CT is the reverse halo sign, or atoll sign (Fig. 37.6), characterized by a central ground-glass opacity surrounded by denser consolidation in the shape of a crescent, although lower lobe patchy consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening can commonly be seen. It is associated with many rheumatic diseases, and the presence of COP, specifically, should prompt the search for an underlying rheumatologic process such as SLE, RA, and, most notably, the antisynthetase syndrome or dermatomyositis. 2. LIP is characterized by extensive lymphocytic infiltration associated with peribronchial lymphoid follicles. Lower lobe–predominant groundglass opacities, centrilobular nodules, and interstitial thickening are frequently seen on CT. It is most often seen in Sjögren syndrome and RA and may be a feature of ILD in undifferentiated forms of autoimmune disease as well. 3. DAD can occur de novo or in patients with preexisting lung disease and is notable for the development of hyaline membranes on pathology and bilateral patchy ground-glass opacities with airspace consolidation on CT scan, similar to what is seen in the acute respiratory distress syndrome (ARDS). It can develop in a variety of rheumatic syndromes, including polymyositis/dermatomyositis, MDA5, and SLE, and is usually associated with severe respiratory failure and overall poor prognosis.

EVALUATION OF PATIENTS WITH INTERSTITIAL LUNG DISEASE IN THE RHEUMATIC DISEASES Given that many rheumatic diseases have a high incidence of ILD, individuals with this condition should be routinely assessed for respiratory symptoms (cough, dyspnea) and bibasilar crackles on lung examination. Any concern for ILD should prompt additional workup as detailed below. Conversely, because ILD may be the first manifestation of a CTD, individuals with a new diagnosis of ILD should be screened for an underlying CTD, including history, physical examination with capillary microscopy, and select autoantibodies (e.g., antinuclear antibody, rheumatoid factor, cyclic citrullinated peptide, and myositis panel). The initial pulmonary assessment includes baseline HRCT, pulmonary function testing, and echocardiography if pulmonary hypertension is suspected. Based on data in SSc, assessment using an algorithm combining findings on pulmonary function tests, including use of routine spirometry and gas transfer, and HRCT can aid in prognostication and decisions regarding treatment.5,6 A broader understanding of which additional factors are important prognostically, such as genetic factors, is an important area of ongoing research.7

RADIOGRAPHIC STUDIES Chest radiography is not particularly sensitive in detecting mild forms of ILD, but it may be useful in identifying other lung manifestations of 299

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Table 37.1

Histologic and Radiographic Features of Interstitial Lung Disease Subtypes Subtype of ILD

Pathologic Features

Nonspecific interstitial pneumonia Usual interstitial pneumonia

Uniform, homogeneous pattern with variable degrees of inflammation Fibrotic areas interposed with normal or nearnormal lung; fibroblastic foci Inflammation in distal airways

Cryptogenic organizing pneumonia Lymphocytic interstitial pneumonia

Extensive lymphocytic infiltration associated with peribronchial lymphoid follicles

Diffuse alveolar damage

Hyaline membranes

Radiographic Features

*

Ground-glass opacities

Honeycombing in a subpleural distribution Central groundglass opacity surrounded by denser consolidation Lower lobe– predominant groundglass opacities; centrilobular nodules and interstitial thickening Bilateral patchy ground-glass opacities with airspace consolidation

FIG. 37.3  This 40× view shows characteristic features of usual interstitial pneumonia (UIP) with the presence of normal lung (asterisk) next to fibrotic lung, which illustrates the temporal heterogeneity of UIP. Fibroblastic foci, commonly seen in UIP, are indicated by the arrows.

FIG. 37.4  Computed tomographic scan of the chest shows the pattern associated with usual interstitial pneumonia (UIP). Note the peripheral coarse honeycomb pattern that is the hallmark of UIP.

FIG. 37.1  This 40× view shows homogeneous inflammation and fibrosis of the interstitium of the lung characteristic of nonspecific interstitial pneumonia. (Courtesy of Lynette Sholl, MD, Brigham and Women’s Hospital.)

FIG. 37.5  High-resolution computed tomographic scan of the chest shows fibrotic changes in a subpleural distribution with honeycombing consistent with usual interstitial pneumonia.

method to detect and quantify the extent and severity of fibrosis, particularly in the research setting.8

PULMONARY FUNCTION TESTING FIG. 37.2  High-resolution computed tomographic scan of the chest shows bilateral ground-glass opacities without honeycombing in a patient with dermatomyositis, which is consistent with nonspecific interstitial pneumonia.

rheumatic disease, such as pleural effusions or nodules, and in excluding conditions such as congestive heart failure and pneumonia. HRCT of the chest is the imaging modality of choice in detecting ILD and is particularly useful for detecting subclinical disease. There is a correlation between the histopathologic patterns and radiographic appearance on chest CT in both NSIP (inflammatory ground-glass opacities) and UIP (honeycombing in a subpleural distribution) patterns but likely a higher correlation with the UIP pattern. Computer-aided quantitative scoring of CT scans is emerging as a

Interstitial lung disease is characterized by the presence of restriction on spirometry (reduced forced vital capacity [FVC]), a low total lung capacity (TLC) on plethysmography, a low carbon monoxide diffusion capacity of the lung (DLCO), and desaturation with ambulatory oximetry. The 6-minute walk test (6MWT) is a useful and simple test that can suggest interstitial or pulmonary vascular disease but may also be affected by the underlying autoimmune disease, especially in those with Raynauds or musculoskeletal limits to ambulation.9

BRONCHOSCOPY The main role of bronchoscopy and bronchoalveolar lavage (BAL) in ILD is to determine the presence of infection, particularly given that many patients with CTD are immunosuppressed. BAL analysis for cell differentials and

CHAPTER 37  The lungs in rheumatic disease

FIG. 37.6 Axial high-resolution computed tomographic scan in patient with Jo-1associated interstitial lung disease demonstrates dense left lower lobe peribronchial bandlike consolidation (arrow) and right lower lobe peribronchial ground glass associated with architectural distortion. Imaging findings are highly suggestive of organizing pneumonitis and confirmed on lung biopsy. (Courtesy of Rachna Madan, MD, Brigham and Women’s Hospital.)

specific cell type predominance is unlikely to be diagnostic by itself, but it can support a diagnosis or narrow a differential. Based on the Scleroderma Lung Study, BAL analysis did not serve as an independent predictor of disease progression or response to treatment.10 While the yield of traditional transbronchial biopsy in diagnosing most ILDs is low, the use of cryobiopsy for the diagnosis of diffuse parenchymal lung disease has a reported diagnostic yield of 70% to 80%.11 In addition, in rare instances, an alternative diagnosis is established (i.e., granulomatous disease).

SURGICAL LUNG BIOPSY In many cases, when the disease pattern on HRCT clearly favors one diagnosis and the clinical features are characteristic, lung biopsy may not be necessary or advisable. However, when the clinical presentation is atypical or poorly differentiated, lung biopsy may offer important information that can influence treatment decisions.

ANCILLARY STUDIES Patients with ILD are at risk for pulmonary hypertension and should be evaluated with a transthoracic echocardiogram and possibly a right heart catheterization if they have either a disproportionately low DLCO or an underlying rheumatic disease in which pulmonary hypertension is common, such as SSc or SLE. Early recognition is important given the numerous therapeutic options available to treat pulmonary hypertension, which may enhance survival and quality of life. In addition, there is growing evidence that gastroesophageal reflux (GER) and silent aspiration may be risk factors for the development and exacerbation of ILD, particularly in SSc.12 As such, all new patients with ILD should be evaluated for these disorders and should be considered for medical or surgical intervention, although no prospective data exist to definitely guide therapy.

LUNG INVOLVEMENT IN RHEUMATIC DISEASES SYSTEMIC SCLEROSIS Pulmonary disease is the leading cause of mortality and morbidity in patients with SSc. ILD is the most common pulmonary manifestation, with a prevalence of up to 90% depending on the subtype and definition of scleroderma; clinically significant ILD occurs more commonly in diffuse disease than in limited disease and is more severe in African Americans, patients with higher skin scores, and those with the antitopoisomerase antibody.13 ILD can also occur in patients without cutaneous involvement of scleroderma, known as sine scleroderma.14 Most of the morbidity and progression of ILD in diffuse SSc occurs in the first 4 to 5 years, although ILD may continue to progress slowly over time. The predominant pathologic pattern seen is fibrotic NSIP followed by UIP; rarely, COP and DAD may be seen.1,15 The pathogenesis of the fibrosis is not fully understood, but transforming growth factor-β, platelet-derived growth factor, and endothelin-1, among other cytokines, chemokines, and mediators, play important roles in disease progression.16

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If significant inflammatory ILD associated with SSc appears to be progressive, then a trial of cytotoxic or other immune-modulating therapy with or without steroids (low dose) may be considered. Prospective clinical trials using cyclophosphamide (CYC) showed very modest benefit in terms of forced vital capacity (FVC),14,15 but these benefits must be weighed against the risk of significant toxicity. Recent data suggest that mycophenolate has similar improvements in FVC compared with CYC,17 and novel approaches include Rituxan, tocilizumab, and stem cell transplantation.18–21 In fibrotic disease, nintedanib has been demonstrated to slow the annual rate of decline in FVC.22 Finally, lung transplantation in selected patients must always be considered in patients with progressive lung disease. Other complications such as aspiration pneumonia and pulmonary hypertension can occur separately or concomitantly with ILD in SSc and should be treated concurrently. Aspiration related to esophageal dysmotility is seen commonly and may play a role in either the pathogenesis or exacerbation of ILD in SSc.23 Although no prospective trials have measured progression of lung function in response to control of GER, it may be beneficial to minimize the risk of GER by using high-dose proton pump inhibitors or to consider antireflux surgery in patients with evident ILD. In some patients, severe pulmonary hypertension and ILD can occur concurrently, which is among the most challenging scenarios in terms of prognosis and therapy.

RHEUMATOID ARTHRITIS With the successful implementation of disease-modifying antirheumatic drugs (DMARDs) and biologics geared toward management of articular disease, lung disease has become one of the leading causes of death in patients with RA and is the only extraarticular complication of RA increasing in prevalence.24,25 The most significant pulmonary complication is RA-associated ILD. Clinically evident disease occurs in nearly 10% of the RA population based on national data, with an additional 20% to 50% of participants having evidence of subclinical disease on CT scan.26 There is mounting evidence that although subclinical disease often goes unrecognized, the patient may already have respiratory symptoms and functional decrements.27 Importantly, disease progression has been observed in this type of patient, which suggests that clinically significant pulmonary fibrosis is likely to develop in a subset of patients affected with subclinical RA-ILD.28 The histopathologic patterns most commonly seen in RA-ILD are UIP and NSIP, with the UIP pattern portending a progressive phenotype with worse prognosis.29,30 Risk factors for the spectrum of RA-ILD include older age, male sex, smoking history, and higher titer RF and anti-CCP.31,32 Increased mortality in RA-ILD is associated with older age, male sex, UIP pattern, and low baseline lung function or a significant decline in lung function at follow-up.33 The incidence of RA-ILD has a bimodal distribution, with a majority of patients developing ILD a decade after the onset of articular manifestations and a minority of patients developing clinically apparent disease shortly after the development of articular disease.28,34 Although the significance of anti–cyclic citrullinated peptide antibodies and citrullination in patients with ILD without clinically evident RA is uncertain, there is a small subset of patients in which lung involvement is the first disease manifestation of RA. In general, RA-ILD with this atypical presentation is similar in clinical course, response to treatment, and prognosis to other RA-ILD.35 These diverse clinical phenotypes suggest that genetic factors and environmental determinants (e.g., smoking) are potential disease modifiers that influence outcomes. Treatment of RA-ILD should be based on the underlying histologic pattern; inflammatory disease often responds to immunosuppression, and progressive fibrotic disease should be treated with nintedanib,36 and the UIP pattern with pirfenidone if TRAIL1 (Phase II Study of Pirfenidone in Patients with RAILD, NCT02808871) confirms that it is as effective in RA-ILD as in IPF. Bronchiectasis or bronchiolectasis is observed in up to 30% of patients with RA studied with chest CT.37 Similarly, obliterative bronchiolitis is more common in RA than in other rheumatologic diseases. Although the prevalence of obliterative bronchiolitis is low, the prognosis is poor because of the lack of effective treatments, and lung transplantation may be required to prolong survival and improve quality of life. Other forms of bronchiolar involvement may show an obstructive clinical picture and mosaicism on CT scan similar to that seen in obliterative bronchiolitis but have a better overall prognosis and may be amenable to immunomodulating therapy. Some studies have demonstrated early inflammatory airway involvement in CCP+ subjects without inflammatory arthritis, suggesting that the lung may be an initiating site of RA-related autoimmune injury.38 Rheumatoid arthritis pulmonary nodules are commonly observed as an incidental finding on chest CT or less frequently in an open lung biopsy.39 Nodule cavitation may result in hemoptysis or pneumothorax through the rupture of subpleural nodules. Caplan syndrome consists of RA nodules

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associated with coal miner’s pneumoconiosis. Pleural disease is also common in RA, and pleuritic pain occurs at some time in at least 20% of patients. Pleural disease is common in RA and can typically result in pleural effusions with a characteristic low glucose (3.5 g/day, low serum albumin, and elevated cholesterol levels Elevated plasma creatinine, microscopic hematuria, RBC casts Rapidly rising plasma creatinine level, falling GFR, hematuria, RBC casts Proteinuria, ± low serum albumin, microscopic hematuria Elevated plasma creatinine, proteinuria, hematuria, ± RBC casts Elevated plasma creatinine, sterile pyuria (WBCs), microscopic hematuria Elevated plasma creatinine, reduced GFR ± urinary abnormalities Plasma creatinine >6 mg/dL, GFR 3.2.98 Post-hoc analyses suggested equivalent clinical responses to adalimumab whether immediate or delayed; clinical and functional outcomes were superior with initial adalimumab plus MTX at week 26, but no significant differences remained at weeks 52 and 78. Initial adalimumab plus MTX was superior radiographically, but this was marginal (72% vs 86% had no radiographic progression at weeks 52 and 78), and minimal progression was seen after 26 weeks in any group, whether treated with immediate adalimumab, treated with delayed adalimumab, or able to remain on MTX monotherapy.99 Similarly, post-hoc analyses of the OPTIMA and PREMIER trials suggested similar rates (~25%) of comprehensive disease control (clinical remission, normalization of function, absence of radiographic progression) after 1 year of adalimumab plus MTX, whether initial therapy or after MTX-IR.100 The VEDERA study (a pragmatic, open-label RCT) offers additional exploratory insights into the earliest stages of disease (mean symptom duration 20 weeks). Patients were randomized to initial MTX/etanercept combination therapy or MTX monotherapy with addition of SFZ and HCQ up to week 20 if DAS28-ESR ≥ 3.2 and escalation to MTX/etanercept at week 24 if DAS28ESR ≥ 2.6 (glucocorticoid bridging permitted in both arms).4 DAS28-ESR remission rates at week 48 were 52% and 38%, respectively (odds ratio = 1.6; 95% CI, 0.8 to 3.5; primary outcome not met, largely owing to lower than expected remission rates with early etanercept). Planned exploratory analyses suggested response to delayed etanercept (post-MTX-IR) might be diminished compared with early etanercept (odds ratio = 2.84 for remission following 24 weeks exposure to etanercept; 95% CI, 0.8 to 9.6; baseline DAS28 reset to week 24 for delayed etanercept), raising the question of whether a subgroup of patients might benefit from b/tsDMARDs as firstline therapy. In summary, the data clearly show that b/tsDMARDs (combined with MTX, or as monotherapy for tocilizumab and JAKi) are superior to MTX monotherapy as initial treatment in early RA when compared head to head at the population level. However, divergent early clinical responses become almost identical over longer time frames with T2T, and effective glucocorticoid bridging seems to mitigate the effect size. While there is some suggestion that delaying biologic initiation until after MTX-IR could impact potential response, immediate b/tsDMARD combination therapy for all patients risks overtreating good responders to MTX. This is relevant from a safety perspective (for example, serious infection rates, while similar in the individual trials discussed above, are higher with b/tsDMARDs according to metaanalyses)101 and a health economic perspective, as historically bDMARDs have been vastly more expensive than csDMARDs. The advent of biosimilars, however, and a more positive cost landscape may justify reappraisal of this approach in a proportion of patients. B/tsDMARDs have a particularly profound impact on radiographic progression, but whether marginal improvements achieved with immediate b/tsDMARDs (compared with MTX, glucocorticoid bridging, and T2T) are of longer-term clinical relevance (e.g., on function, pain, etc.) remains unclear. If more ambitious outcomes are to be achieved in RA, such as true drug-free remission (discussed below), initial b/tsDMARDs might play a key role.

BIOLOGIC DMARD INDUCTION FOLLOWED BY TAPERING The goal of “drug-free remission” has driven a number of studies evaluating remission induction in early RA using bDMARD therapy followed by tapering or withdrawal (i.e., “step-down” rather than “step-up” strategies). Generally, shorter-duration disease and more established remission

periods are associated with greater success rates of bDMARD tapering and/ or cessation. In the HIT-HARD RCT, patients were randomized to MTX monotherapy or immediate adalimumab/MTX combination, with adalimumab stopped after 24 weeks.102 DAS28 scores, ACR70 responses, remission rates, and function were all superior with combination therapy at 24 weeks, but clinical outcomes subsequently converged and were no longer significantly different at 48 weeks, although radiographic progression remained lower with adalimumab. In the OPTIMA trial (introduced above), patients randomized to initial adalimumab plus MTX who had qualifying responses at 26 weeks (DAS28 4 months and 3 and tyrosine kinase 2 Inhibits Janus kinase 3>1,2 and tyrosine kinase 2 Inhibits Janus kinase 1,3 >2

2 mg once daily 5 mg twice daily; 11 mg XR once daily 15 mg once daily

IR to >1 TNFi IR to >1 TNFi IR to >1 TNFi

Abatacept

CTLA-4 immunoglobulin that inhibits T-cell costimulation

Anakinra

No failures required; use as monotherapy or combination with DMARDs other than TNFi Failed >1 DMARD

IL-6 receptor inhibitors n Sarilumab n Tocilizumab

Recombinant human IL-1 type I receptor antagonist; Competitively inhibits IL-1B and 1 alpha Human monoclonal antibody that inhibits soluble and membrane-bound IL-6 receptors Humanized antibody that inhibits IL-6 receptor

IV: 500 mg (100 kg) Subcut: 125 mg weekly Subcut: 100 mg/day

Subcut: 200 mg once every 2 weeks IV: 4 mg/kg every 4 weeks, up to 8 mg/kg Subcut: 162 mg every 2 weeks to every week

IR or intolerance to 1>DMARDs IR to 1> DMARD

TNF inhibitors n Adalimumab n Certolizumab n Etanercept n Golimumab n Infliximab

All inhibit TNF-α Fully human antibody Pegylated humanized antibody Soluble receptor Humanized antibody Chimeric (human–mouse) antibody

No specific failures required No specific failures required No specific failures requiredb No specific failures requiredc No specific failures requiredc

Rituximab

Chimeric (human–mouse) mAb against CD20; depletes CD20+ B cells. May reduce antigen presentation to T cells by B cells

40 mg every other week 200 mg every other week 50 mg once weekly 50 mg once monthly 3 mg/kg every 8 weeks, up to 10 mg/kg every 4 weeks Two 1000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks

n n n

Baricitinib Tofacitinib Upadacitinib

bDMARDs

Biosimilar DMARDsa n SB4 (Benepali) Originator: etanercept; inhibits TNF-α n Etanercept-szzs (Erelzi) n Etanercept-ykro (Eticovo) n Infliximab-dyyb (Inflectra) Originator: infliximab; inhibits TNF-α n Infliximab-qbtx (Ixifi) n Infliximab abda (Renflexis) n Infliximab-axxq (Avsola) n Adalimumab-atto (Amjevita) Originator: adalimumab; inhibits TNF-α n Adalimumab-abdm (Cyltezo) n Adaliumab-adaz (Hyrimoz) n Adalimumab-bwwd (Hadlima) n Adalimumab-afzb (Abrilada)

IR to 1> TNFis; use +MTX

50 mg once weekly 50 mg once weekly 50 mg once weekly 3 mg/kg every 8 weeks, up to 10 mg/kg every 4 weeks

40 mg every other week

bDMARD, Biologic disease-modifying antirheumatic drug; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DMARD, disease-modifying antirheumatic drug; EMA, European Medicines Agency; FDA, Food and Drug Administration; IL-1, interleukin-1; IL-6, interleukin-6; IR, inadequate response; mAb, monoclonal antibody; NTD, none to date; TNF-α, tumor necrosis factor-α; tsDMARD, targeted synthetic disease-modifying antirheumatic drug. a

Information accessed from https://www.accessdata.fda.gov Use +/– MTX Use +MTX

b c

resources and patient comorbidity profile, while acknowledging the value that patients place on more rapid onset of action of TNFi. Temporary use of a glucocorticoid as adjunctive therapy to hasten reduction in disease activity may sometimes be deemed necessary. However, constant review of the indication and employment of the lowest dose for the shortest duration possible are recommended, given that a dose-dependent (>7.5 mg daily or cumulative dose >40 gm) increase in all-cause mortality21 has been observed with glucocorticoids.

COMPARATIVE EFFICACY OF TARGETED DMARDs (tDMARDs) The next conundrum facing clinicians is identifying the optimal second tDMARD following failure of a first tDMARD. When tDMARD choices were more limited, options for patients who had inadequate response to a first TNFi (in combination with a csDMARD) included either a second TNFi or a limited number of tDMARDs with a different mechanism (i.e., non-TNFi

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SECTION 7  Rheumatoid Arthritis

Table 101.2

Comparative Efficacy of Disease-Modifying Antirheumatic Drugs From Head-to-Head Randomized Clinical Trials in Established Patients With RA Study Population

Intervention vs Comparator

MTX IRs

Triple therapy (MTX, SSZ, and HCQ) vs Etanercept 50 mg weekly + MTX

Triple therapy noninferior to etanercept + MTX, as measured by change in DAS 28 baseline vs week 48 Trial acronym: RACAT15

MTX IRs

Abatacept + MTX vs Adalimumab 40 mg biweekly + MTX

Noninferiority of abatacept vs adalimumab, as measured by ACR 20 at year 1 Trial acronym: AMPLE27

MTX IRs or intolerant or discontinued

Tocilizumab 8 mg/kg IV monthly monotherapy vs Adalimumab 40 mg biweekly monotherapy

Tocilizumab superior to adalimumab, as measured by change in DAS28ESR from baseline to week 24 Trial acronym: ADACTA25

MTX IRs

Tofacitinib 5 mg twice daily monotherapy vs Tofacitinib 5 mg twice daily + MTX vs Adalimumab 40 mg biweekly + MTX

Tofacitinib + MTX noninferior to adalimumab + MTX, as measured by ACR 50 at month 6 Tofacitinib monotherapy did not meet noninferiority criteria against either tofacitinib + MTX or adalimumab + MTX Trial acronym: ORAL STRATEGY28

MTX IRs

Upadacitinib 15 mg once daily +MTX vs Adalimumab 40 mg biweekly +MTX

Upadacitinib + MTX superior to adalimumab + MTX, as measured by DAS28-CRP < 3.2 at week 12 Trial acronym: SELECT-COMPARE29

csDMARD IRs

IV rituximab 1 g on day 1 and 15 and after 26 weeks if persistent disease activity (DAS28-ESR > 3.2) vs Adalimumab 40 mg biweekly or etanercept 50 mg weekly

Rituximab is noninferior to TNF inhibitors, as measured by change in DAS28-ESR over 12 months

Sarilumab 200 mg every 2 weeks monotherapy vs Adalimumab 40 mg biweekly monotherapy

Sarilumab superior to adalimumab, as measured by change in DAS28-ESR from baseline to week 24 Trial acronym: MONARCH26

MTX IRs

Primary Outcome and Conclusions

Trial acronym: ORBIT30

csDMARD, Conventional synthetic disease-modifying antirheumatic drug; HCQ, hydroxychloroquine; IV, intravenous; MTX, methotrexate; MTX-IR, MTX inadequate responder; SSZ, sulfasalazine.

tDMARD). Observational studies reported that low disease activity or remission could be achieved in up to 40% of patients after switching from one TNFi to a second TNFi,22 without significant differences in ACR 20/50/70 responses between second TNFi and non-TNFi tDMARD switched groups.23 However, significantly higher rates of nonpersistence were reported in the TNFi cycling group compared to mechanism switchers.24 Echoing this, the updated ACR guidelines8 recommend class switching of tDMARD in patients who are not at target on maximally tolerated MTX but acknowledge the low certainty of evidence supporting this statement and allow for variability in physician practices and patient preferences. With the continued expansion of the number and mechanisms of RA-targeted DMARDs on the market, options for both a first and second tDMARD have increased, including baricitinib, tofacitinib, and upadacitinib. Thus, a TNFi need no longer be the first choice for a tDMARD following inadequate response to MTx. The most recent 2021 ACR RA guidelines8 do conditionally recommend bDMARD or tsDMARDs in those not meeting disease targets on methotrexate. However, taking into account new safety signals that emerged regarding tofacitinib from the ORAL-Surveillance ­trial,24a FDA restricted the use of all approved tsDMARDs to RA patients with inadequate response or intolerance to one or more TNF inhibitors. Likewise, options for inadequate responders to a first TNFi have broadened substantially. Selection of both first and second tDMARDs would be best guided by head-to-head comparative effectiveness data from randomized controlled trials (RCTs). But such trials are very few in number, they have been performed primarily in patients who were tDMARD naïve, and their designs and inclusion/exclusion criteria differ markedly from trial to trial. These RCTs in csDMARD-experienced patients are outlined in Table 101.2 and can be briefly summarized as follows: (1) tocilizumab monotherapy was superior to adalimumab monotherapy; (2) sarilumab monotherapy was superior to adalimumab monotherapy; (3) abatacept + MTX was noninferior to adalimumab + MTX; (4) tofacitinib + MTX was noninferior to adalimumab + MTX; (5) upadacitinib + MTX was superior to adalimumab + MTX; and (6) rituximab was noninferior to TNFi.25–30 Based on these data, the 2019 EULAR guidelines7 note a possible advantage of an interleukin 6 (IL-6) receptor or JAKi monotherapy31 over other tDMARD monotherapy. RCTs comparing newer tDMARDs and TNFis are in progress.32 Unfortunately, to date, no clinical, laboratory, or radiographic parameters have been identified that reliably predict an initial or sustained response to a specific tDMARD. Therefore a trial-and-error approach is necessary but informed by clinical judgment, patient preferences, cost, and adverse event profiles.

TREATMENT WITHDRAWAL Until a cure for RA is identified, lifetime treatment is almost always needed. However, withdrawal of DMARDs, particularly tDMARDs, may be desirable from the standpoint of cost and risk reduction if such withdrawal does not trigger a flare. These considerations have prompted investigation into the sustainability of RA remission upon DMARD withdrawal. In general, studies have compared maintaining DMARDs vs dose or interval tapering vs complete withdrawal of DMARDs. In the RETRO study,33 patients in stable DAS28 remission were randomized to continue at full doses vs taper doses by 50% vs taper followed by complete withdrawal of all DMARDs; relapse rates were 15.8%, 38.8%, and 51.9%, respectively. In another study by Emery et al.,34 patients who had achieved sustained remission on etanercept 50 mg + MTX were randomized to etanercept 25 mg + MTX vs MTX alone vs withdrawal of both; rates of sustained remission at 39 weeks postrandomization were 63%, 40%, and 23%, respectively. Of note, no significant differences in radiographic progression were noted among the groups. Similar results were observed by Smolen et al.35 In this study, patients who had achieved LDAS with MTX and etanercept 50 mg were randomized to maintaining full doses vs etanercept 25 + MTX vs MTX only. The percentages of patients in whom LDAS was sustained were 82.6%, 79.1%, and 42.6%, respectively. In contrast, Ibrahim et al.36 reported that reduction of etanercept or adalimumab doses by 66% significantly increased the risk of flare compared to maintenance of full dose (adjusted hazard ratio [HR] = 3.47; 95% confidence interval [CI], 1.26, 9.58; p = 0.016). An alternative strategy to dose tapering is to increase the interval of dosing. In contrast to the dose taper studies, in the DRESS study,37 flare rates did not significantly differ in the regular dosing group compared to the increased interval dosing group. Although withdrawal data are limited in non-TNFi tDMARDs, rates of persistent remission after stopping tocilizumab were reported in the 13% to 55% range.38 Increasing the dosing interval for tocilizumab to 6 weeks, or decreasing the dose for abatacept, was not associated with an increase in clinical disease activity or flare.39,40 Additionally, dose reduction of baricitinib was associated with earlier and more frequent relapse.41 In summary, while there is some variability from study to study, taper to withdrawal or abrupt withdrawal of DMARDs, in general, substantially increases the risk of flare, while reducing the dose or increasing the dosing interval may not induce flare. Although data are limited, it is reassuring that, in one study, 91% of those who flared when a TNFi was tapered or withdrawn were able to regain low disease activity with resumption of TNFi treatment.42

CHAPTER 101  Management of rheumatoid arthritis in patients with prior exposure to csDMARDs Variables associated with better relapse-free survival and with regaining remission with retreatment include shorter disease duration, lower HAQ and DAS28 scores prior to withdrawal,43–45 lower pretreatment CRP41 and ESR,42 and the absence of RF43 and ACPAs.33 Because of the significant risk of flaring upon taper or withdrawal of DMARDs, the 2021 ACR treatment guidelines8 conditionally recommend continuation of current DMARDs at current doses over taper or discontinuation. However, if taper or discontinuation is considered, recommendations for taper or discontinuation assume that all patients will remain on at least one DMARD and that they will have been in low disease activity or remission for at least 6 months prior to initiation of taper. These guidelines further advise that (1) dose reduction is preferable to gradual discontinuation, (2) gradual discontinuation is preferable to abrupt discontinuation, and (3) gradual discontinuation of MTX is preferable to discontinuation of a tDMARD in patients taking both MTX and a tDMARD. The 2019 EULAR guidelines7 recommend sustained remission as a prerequisite to tapering, sequential tapering of steroids first, followed by tDMARDs, and taper and/or discontinuation of the remaining csDMARD(s) in select patients. Ultimately, the decision to withdraw therapy is made together between the patient and clinician.

GENERAL SAFETY MONITORING OF DMARD THERAPIES The introduction of an RA treatment regimen should encompass a thoughtful discussion of medication risk with the patient. ACR guidelines8 recommend safety monitoring including bloodwork every 4 to 6 weeks after initiating a DMARD(s) or after a dose adjustment. When a stable therapeutic regimen is achieved, safety monitoring can be extended to every 3 months. Table 101.3 outlines several common adverse effects of approved DMARDs. These are discussed in detail in Chapters 63 to 73. While Chapters 63 and 64 focus on csDMARDs, the safety focus in this chapter is on tDMARDs.

NON-CLASS-SPECIFIC ADVERSE EVENTS WITH TARGETED THERAPIES Infections and immunizations Serious infections are a concern with tDMARD therapy. The patient’s baseline infection risk should be evaluated and active chronic infections treated before initiating tDMARD therapy. Predictors of increased infection risk in patients with RA include longer RA disease duration, treatment with a tDMARD with or without csDMARDs,46 age, elevated baseline HAQ score,

comorbid diseases, history of infection,47 and steroid use.48 If a patient develops a moderate to severe infection while on DMARD treatment, typically the csDMARDs such as MTX are continued or discontinued at the discretion of the treating physician while the tDMARD is held until the course of antimicrobial therapy is completed. In those with active disease despite csDMARD monotherapy, the ACR 2021 guidelines8 recommend adding other csDMARDs over tDMARDs in cases of serious infection(s) within the previous 12 months. In a review of RCTs, patients treated with a TNFi added to background csDMARD had either a two- to sixfold higher rate of serious infections or no increase in risk compared to those who remained on the csDMARD alone.5,15,16 Postapproval observational data, examining a broader array of tDMARDs, reported HRs for serious infections ranging between 1.1 to 1.8 for tDMARDs vs csDMARDs, without differences across individual tDMARDs.49 Opportunistic infections, including reactivation of Mycobacterium tuberculosis, warrant special attention. In animal models of latent tuberculosis,50,51 neutralization of TNF caused reactivation and widespread dissemination of M. tuberculosis, ultimately leading to death. In a metaanalysis of 29 RCTs, treatment with each of the originator TNFis was associated with a higher rate of M. tuberculosis infection compared to control treatment (placebo or methotrexate) (odds ratio [OR] = 1.94; 95% CI, 1.10, 3.44; p = 0.02), but rates did not differ among individual TNFis.51 Recommendations for screening and treatment have been extrapolated to all tDMARDs, such that any patient who is being considered for treatment should be screened for latent and active tuberculosis (TB). The 2015 ACR guidelines52 advise that active TB must be treated to completion, and latent TB treated for at least 1 month, before starting a tDMARD therapy. Updated ACR guidelines8 for treatment of patients with RA with moderate to high disease activity who have nontuberculous mycobacterial (NTM) infection advise: (1) csDMARDs are recommended over tDMARDs and (2) if a tDMARD is required, abatacept is conditionally preferred over other tDMARDS. An extensive review of infections in rheumatic disease patients can be found in Section 9. For patients with RA with comorbid hepatitis B or C infections who have completed or are currently receiving hepatitis treatment, the ACR guidelines52 allow for use of the same RA DMARD(s) as in patients unexposed to hepatitis B or C. Additionally, in those with natural immunity from prior exposure, RA treatment can be continued with regular viral load monitoring. However, in patients with untreated chronic hepatitis B, antiviral treatment must be initiated before DMARD therapy. Updated ACR guidelines,8 in tandem with the American Association for the Study of Liver Diseases guidelines,53 recommend prophylactic antiviral treatment (over frequent laboratory monitoring) for (1) patients who are hepatitis B core antibody and surface antigen positive and are initiating any tDMARD and (2) patients who are hepatitis B core antibody positive (regardless of hepatitis B virus

Table 101.3

Overview of Important Safety Considerations of Food and Drug Administration/European Medicines Agency–Approved Rheumatoid Arthritis DiseaseModifying Antirheumatic Drugs DMARD Category csDMARDs: Hydroxychloroquine Leflunomide Methotrexate Sulfasalazine bDMARDs TNF inhibitors Abatacept IL-6 inhibitors n Tocilizumab n Sarilumab Rituximab tsDMARDs Tofacitinib Baricitinib Upadacitinib

Notable Potential Adverse Effectsa GI upset, skin discoloration, eye toxicity, myopathy, aplastic anemia GI upset, bone marrow toxicity, infections, alopecia, abnormal liver enzymes, hypertension, interstitial lung disease, weight loss GI upset, mucosal ulcers, alopecia, hepatotoxicity, bone marrow toxicity, pneumonitis, infections, EBV-mediated lymphoma, fatigue, nodules GI upset, severe allergic reactions, bone marrow toxicity, contraindicated in G6PD deficiency, infections, renal toxicity Injection site or infusion reaction, serious and opportunistic infections, reactivation of TB, skin cancer, heart failure, pneumonitis, druginduced lupus, psoriasis, demyelinating syndrome GI upset, injection site or infusion reaction, serious infections, reactivation of TB, exacerbation of COPD Injection site or infusion reaction, serious and opportunistic infections, reactivation of TB, GI perforation, hypercholesterolemia, transaminitis, neutropenia Neutropenia, increased ALT, injection site erythema, upper respiratory infections, urinary tract infections Infusion reactions, serious allergic reactions, serious and opportunistic infections, hypogammaglobulinemia, hepatitis, progressive multifocal leukoencephalopathy, bone marrow toxicity, pulmonary toxicity, cardiac toxicity GI upset, serious and opportunistic infections, herpes zoster, reactivation of TB, transaminitis, elevated creatinine, cancers, GI perforation, leukopenia, hypercholesterolemia, major adverse cardiovascular events (MACE), deep venous thrombosis, and pulmonary embolism Upper respiratory tract infections, nausea, herpes simplex, herpes zoster, neutropenia, liver enzyme elevations, lipid elevations, creatinine elevations, malignancies, deep venous thrombosis and pulmonary embolism, major adverse cardiovascular events Pneumonia, cellulitis, herpes zoster, neutropenia, lymphopenia, anemia, liver enzyme elevations, lipid elevations, GI perforation, malignancies, deep venous thrombosis and pulmonary embolism, major adverse cardiovascular events

ALT, Alanine transaminase; bDMARD, biologic disease-modifying antirheumatic drug; COPD, chronic obstructive pulmonary disease; csDMARD, conventional synthetic disease-modifying antirheumatic drug; DMARD, disease-modifying antirheumatic drug; EBV, Epstein–Barr virus; G6PD, glucose-6-phosphate dehydrogenase; GI, gastrointestinal; TB, tuberculosis; TNF, tumor necrosis factor; tsDMARD, targeted synthetic disease-modifying antirheumatic drug. a

863

Note that this list of adverse effects is not complete. For a full list, please refer to manufacturers’ inserts or FDA/EMA websites.

864

SECTION 7  Rheumatoid Arthritis

surface antigen status) and are initiating rituximab. On the other hand, frequent laboratory monitoring was recommended over prophylactic treatment in those initiating any tDMARD other than rituximab who are hepatitis B core antibody positive but surface antigen negative. For untreated chronic hepatitis C infections, nonhepatotoxic csDMARDs (SSZ or HCQ) are preferred, but TNFis may be used because this class of agent has not consistently been associated with increased hepatitis C virus replication.54 This has become a nonissue in areas in which hepatitis C antiviral therapy is available; patients who are hepatitis C positive should receive curative hepatitis C antiviral therapy. Unfortunately, little is known about management of RA in patients with human immunodeficiency virus (HIV), but small case series in individuals with HIV with other autoimmune illnesses suggest safety with use of HCQ, SSZ, and etanercept.55 Because of the immunosuppressive nature of RA DMARDs, vaccination is an important preventive measure to reduce risk of infection. The ACR52 and EULAR guidelines56 recommend yearly influenza vaccination as well as appropriate vaccination for pneumococcal pneumonia and hepatitis B virus. While host responses to influenza vaccination are not significantly reduced by most DMARDs, humoral responses are reduced in the presence of rituximab57; therefore EULAR guidelines56 recommend vaccination before initiation of this DMARD. Additionally, methotrexate is held 2 weeks after influenza vaccination, as studies58,59 demonstrate higher influenza vaccine response when methotrexate is held (without flares of RA disease). Live vaccines such as varicella and yellow fever should be avoided during treatment with immunosuppressants. Varicella zoster virus (VZV) vaccine is recommended to prevent VZV reactivation and should be considered for patients with RA who are 50 years of age or older.52 If the live attenuated vaccine is used, the vaccine can be administered in the presence of MTX (≤0.4 mg/kg/week) and corticosteroids (3 g/dL or an absolute hemoglobin level of 7.5 mg per day) was independently and significantly associated with prolonged TTP.87 In male patients with RA, testosterone and luteinizing hormone levels were lower than those in healthy individuals.88 MTX use in male patients with inflammatory bowel disease (IBD) was associated with a significant increase in sperm DNA fragmentation and oxidative stress adducts in comparison to controls, despite normal sperm numbers.89 SSZ use in men with IBD has been reported to cause transient oligospermia, as well as abnormal morphology and reduce motility, with recovery time varying between 1 and 3 months after discontinuation.90 However, there are no reports of postconception teratogenicity following paternal exposures to RA medications; therefore continuation of HCQ and TNFis is strongly recommended, and MTX, leflunomide, SSZ, and NSAIDs conditionally recommended, in the 2020 ACR reproductive health guidelines.91 Pregnancy. Several concerns with pregnancy in women with RA exist. While RA was historically thought to go into remission during pregnancy, modern studies indicate that only 27% of patients with RA achieve remission during pregnancy.92 Achievement of remission was more likely in those with low disease activity in the first trimester.93 In terms of the effects of RA on fetal outcomes, RA confers modestly higher risks of preterm delivery, stillbirth, and lower birth weight compared to patients with RA.94 The effects of DMARDs on fetal outcomes are arguably one of the most pressing concerns. New 2020 ACR reproductive health guidelines91 strongly recommend continuing SSZ and HCQ and conditionally recommend prednisone (taper to less than 20 mg/day in conjunction with pregnancy-compatible medications) preconception through breastfeeding. Additionally, it is strongly recommended to discontinue MTX within 3 months prior to planned conception and to implement cholestyramine-based washout preconception for leflunomide users if metabolite levels are detectable and/or pregnancy is confirmed.95 Additionally, these guidelines91 strongly recommend continuing certolizumab preconception through breastfeeding, while for the other TNFis (infliximab, etanercept, adalimumab, golimumab), it is conditionally recommended to continue through conception and first and second trimesters and discontinue in the third trimester several half-lives prior to delivery and then strongly recommended to continue during breastfeeding. Reassuringly, an insignificant elevation in the risk of congenital anomalies compared to pregnant controls was reported in a meta analysis of 13 pooled studies of pregnant TNFi users with various autoimmune diseases.96 Moreover, no significant differences were noted in live birth, preterm birth, or congenital anomalies between patients with RA who were TNFi users vs nonusers.96 Although limited in number, among women exposed to tocilizumab or tofacitinib, the frequencies of congenital malformations and/or spontaneous abortions were comparable to those in the general population.97,98 In summary, pregnancy planning in a woman with RA requires an individualized discussion with the patient regarding the impact of RA on fertility, the benefits of achieving control of disease prior to pregnancy, and importance of discontinuation or washout of known teratogenic DMARD therapy well before pregnancy.

COMORBID DISEASE RA may affect extraarticular organs such as the lung but may also lead to the development or exacerbation of comorbidities such as cardiovascular disease (CVD). In addition, preexisting comorbid conditions can impact DMARD selection. Chapter 42 discusses multiple comorbidities as they relate to rheumatic diseases. Here we will briefly discuss CVD and pulmonary disease as they relate to RA and its management.

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CARDIOVASCULAR DISEASE RA confers up to 1.5-fold increased risk of developing CVD when compared with age- and gender-matched non-RA controls.99 The elevated risk of developing CVD in RA is hypothesized to be due to robust systemic and vascular inflammation, steroids, and an enhanced prevalence of traditional CV risk factors.100 The potential impact of RA DMARDs on this enhanced CVD risk is currently being elucidated. Two studies in the general population had mixed results. In the CANTOS trial,101 patients treated with the IL-1 inhibitor canakinumab had a reduced rate of major adverse cardiac events (MACEs) compared to placebo-treated patients (HR = 0.85; 95% CI, 0.74– 0.98; p = 0.021). In contrast, in the CIRT study,102 low-dose methotrexate (15–20 mg weekly) was not associated with a lower rate of MACEs compared to placebo (HR = 0.96; 95% CI, 0.79–1.16). It should be noted that in CANTOS, but not in CIRT, an elevated hsCRP was an entry requirement. Because a long-term placebo-controlled trial with MACE outcomes cannot be conducted in RA for ethical reasons, data on DMARDs in RA are limited to comparative studies of different DMARDs. In a metaanalysis of observational and randomized studies in RA, methotrexate users had a lower rate of CV events compared to nonusers (relative risk [RR] = 0.72; 95% CI, 0.57–0.91; p = 0.007).103 CV event rates were also lower in TNFi recipients compared to nonrecipients (RR = 0.70; 95% CI, 0.54–0.90; p = 0.005).103 In a metaanalysis of 14 observational studies comparing MACE in TNFi users vs non-TNFi tDMARD users,104 tocilizumab was associated with a lower risk (OR = 0.59; CI, 0.34–1.00; p = 0.05), while csDMARDs (including MTX) were associated with a higher risk (OR = 1.58; CI, 1.16–2.15; p = 0.00). This observation regarding tocilizumab is cogent, as treatment with tocilizumab was associated with larger increases in lipid levels relative to csDMARDs and other tDMARDs.25,105 Other studies suggest that the potent antiinflammatory effects of tocilizumab may counterbalance lipid elevations.103 Moreover, in an RCT comparing tocilizumab to etanercept, there was no difference in rates of MACE.106 As JAK kinase inhibitor treatment has also been associated with elevations in lipid levels, interest grew in RCTs comparing MACE in JAKi compared to non-JAKi DMARDs. The recently published ORAL Surveillance trial24a demonstrated an increased risk of MACE in tofacitinib (5 mg or 10 mg) users compared to TNFi: HR = 1.33; CI: 0.91–1.94, which did not meet noninferiority criteria. Therefore, the use of tofacitinib in RA patients with older age, smoking, and/or other prevalent CV risk factors mandates caution and careful balance of risk and benefit for the patient. With regard to heart failure, TNF has been implicated as a major factor in its pathogenesis,108–110 yet inhibition of TNF was paradoxically associated with worsening heart failure and death in non-RA patients with advanced heart failure.111,112 In contrast, in patients with RA, a series of small, mostly retrospective studies of TNFi users did not reveal a statistically significantly increased risk compared to csDMARD users; in fact, some reported a lower rate of heart failure.113–115 In contrast, another study reported an increased risk of heart failure in TNFi users compared to MTX users.116 In a rigorous observational study, using a propensity score–matched Cox proportional regression model, Solomon et al.117 reported that there was no elevated risk of heart failure among TNFi users compared to csDMARD users (HR = 0.84; CI, 0.62–1.12). Given the absence of high-quality clinical trial data on the effect of TNFis on heart failure in RA, the 2021 ACR guidelines8 conditionally recommend that, in patients with RA with NYHA class III heart failure or higher who require a tDMARD for control of disease activity, addition of a non-TNFi tDMARD is preferred over a TNFi. Likewise, for patients with RA who develop heart failure while receiving a TNFi, consideration should be given to switching the TNFi to a non-TNFi tDMARD. Ultimately, the rheumatologist can play a significant role in mitigating CV risk by treating RA disease to remission, controlling conventional cardiovascular risk factors, and limiting steroid use.

INTERSTITIAL LUNG DISEASE Interstitial lung disease (ILD) is a known complication of RA. The prevalence of ILD in early RA is variable (1%–58%) depending on ascertainment and study methodology.118 RA DMARDs, while effective for the arthritis of RA, are not generally effective in treating the ILD. In fact, several DMARDs, including MTX, leflunomide, SSZ, AZA, TCZ, and TNFis, have been suggested to cause new or worsening pulmonary symptoms in a small percentage of patients with RA, although most reports are case series, case reports, or small uncontrolled open-label treatment studies.119 MTX can cause an acute hypersensitivity pneumonitis, although rarely and usually early in treatment, but its use was not associated with the development of incident ILD in two RA inception cohorts (OR = 0.85; 95% CI, 0.49–1.49; p = 0.578).120 While MTX can be avoided in patients with RA-ILD if other

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DMARDs successfully control disease activity, some patients with difficult-to-treat RA may require its use. In fact, acknowledging the historic importance of MTX as an anchor drug in RA, the recent ACR guidelines8 conditionally recommend use of MTX over other DMARDs in patients with preexisting airway or parenchymal lung disease but emphasize the need for an informed discussion with patients about the increased risk of pneumonitis prior to initiation of therapy. Small open-label observational studies suggest that selected DMARDs may improve ILD parameters in some patients. In a noncontrolled open-label study of abatacept, improvements in ILD imaging parameters in 36.4% and in diffusing capacity in 25% of patients with RA-ILD were reported.80 A retrospective review of patients with RA-ILD who received rituximab revealed stability of lung function in 52% and improvement in diffusing capacity in 16%.121 Use of mycophenolate mofetil, an agent with known antifibrotic effects, has also been associated with significant improvement in forced vital capacity and diffusing capacity in autoimmune ILD.122 Unfortunately, mycophenolate mofetil is not regarded as an effective therapy for RA synovitis; thus, an additional therapy for the joint component is required. Recently, treatment of patients with autoimmune ILD (12.7% of whom were patients with RA) with the tyrosine kinase inhibitor nintedanib was associated with a lower annual decline in FVC compared to placebo123 (INBUILD). INBUILD is the only placebo-controlled RCT to date that has enrolled patients with RA-ILD. Nintedanib is now approved for patients with autoimmune ILD with a progressive phenotype, offering hope for patients with RA-ILD.

CONCLUSIONS The treatment of RA has evolved considerably in recent decades with an explosion in effective therapies and more in the pipeline. Tight control of disease activity is critical to avoid debilitating long-term consequences of RA. RA management guidelines from the ACR and EULAR are available to help guide physicians through management decisions. Additional factors such as the comparative efficacy and safety of particular DMARDs, patient comorbid conditions, and desire for pregnancy are all important to consider before initiating or modifying a treatment regimen. Investigators have been interested in the ability to withdraw DMARD therapy when disease targets have been achieved; however, many patients have disease relapse after DMARD withdrawal, requiring reinitiation of treatment. With sustained remission or low disease activity, however, the likelihood of most patients with RA living lives with minimal to no RA-associated disability is high. Unfortunately, no biomarkers have been identified that can reliably predict response to a particular DMARD; however, this problem is actively under investigation. Additionally, the high cost of targeted DMARDs is prohibitive for some patients. As a result, the development of molecules with quality, safety, and efficacy comparable to those of currently available biotherapeutic agents, termed biosimilars (see Chapter 75,) are well under way with several recent approvals (see Table 101.1).

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94. Nørgaard M, Larsson H, Pedersen L, et al. Rheumatoid arthritis and birth outcomes: a Danish and Swedish nationwide prevalence study. J Intern Med. 2010;268(4):329–337. 95. Götestam Skorpen C, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75(5):795–810. 96. Komaki F, Komaki Y, Micic D, Ido A, Sakuraba A. Outcome of pregnancy and neonatal complications with anti-tumor necrosis factor-α use in females with immune mediated diseases; a systematic review and meta-analysis. J Autoimmun. 2017;76:38–52. 97. Hoeltzenbein M, Beck E, Rajwanshi R, et al. Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data. Semin Arthritis Rheum. 2016;46(2):238–245. 98. Clowse MEB, Feldman SR, Isaacs JD, et al. Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis. Drug Saf. 2016;39(8):755–762. 99. Avina-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2012;71(9):1524–1529. 100. Dougados M, Soubrier M, Antunez A, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis. 2014;73(1):62–68. 101. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–1131. 102. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019;380(8):752–762. 103. Roubille C, Richer V, Starnino T, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74(3):480–489. 104. Singh S, Fumery M, Singh AG, et al. Comparative risk of cardiovascular events with biologic and synthetic disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res. March 15, 2019:acr.23875 Published online. 105. McInnes IB, Thompson L, Giles JT, et al. Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Ann Rheum Dis. 2015;74(4):694–702. 106. Giles JT, Sattar N, Gabriel S, et al. Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol. August 30, 2019:art.41095 Published online. 107. Kremer JM, Genovese MC, Keystone E, et al. Effects of baricitinib on lipid, apolipoprotein, and lipoprotein particle profiles in a phase IIb study of patients with active rheumatoid arthritis. Arthritis Rheumatol. 2017;69(5):943–952. 108. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure, NEJM. Accessed January 1, 2020. https://www.nejm.org/doi/10.1056/NEJM199007263230405?url_ ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov

109. Tracey KJ, Beutler B, Lowry SF, et al. Shock and tissue injury induced by recombinant human cachectin. Science. 1986;234(4775):470–474. 110. Bozkurt, SB Kribbs, FJ Clubb, et al., Pathophysiologically relevant concentrations of tumor necrosis factor-α promote progressive left ventricular dysfunction and remodeling in rats. 11. 111. Mann DL, McMurray JJV, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004;109(13):1594–1602. 112. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure: results of the AntiTNF Therapy Against Congestive Heart failure (ATTACH) trial. Circulation. 2003;107(25): 3133–3140. 113. Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis. Rheumatology. 2005;44(5):677–680. 114. Listing J, Strangfeld A, Kekow J, et al. Does tumor necrosis factor α inhibition pro mote or prevent heart failure in patients with rheumatoid arthritis? Arthritis Rheum. 2008;58(3):667–677. 115. Wolfe F, Michaud K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti–tumor necrosis factor therapy. Am J Med. 2004;116(5):305–311. 116. Setoguchi S, Schneeweiss S, Avorn J, et al. Tumor necrosis factor-α antagonist use and heart failure in elderly patients with rheumatoid arthritis. Am Heart J. 2008;156(2):336–341. 117. Solomon DH, Rassen JA, Kuriya B, et al. Heart failure risk among patients with rheumatoid arthritis starting a TNF antagonist. Ann Rheum Dis. 2013;72(11):1813–1818. 118. Spagnolo P, Lee JS, Sverzellati N, Rossi G, Cottin V. The lung in rheumatoid arthritis: focus on interstitial lung disease. Arthritis Rheumatol. 2018;70(10):1544–1554. 119. Roubille C, Haraoui B. Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum. 2014;43(5):613–626. 120. Kiely P, Busby AD, Nikiphorou E, et al. Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts. BMJ Open. 2019;9(5):e028466. 121. Md Yusof MY, Kabia A, Darby M, et al. Effect of rituximab on the progression of rheumatoid arthritis–related interstitial lung disease: 10 years’ experience at a single centre. Rheumatology. 2017;56(8):1348–1357. 122. Fischer A, Brown KK, Du Bois RM, et al. Mycophenolate mofetil improves lung function in connective tissue disease–associated interstitial lung disease. J Rheumatol. 2013;40(5):640–646. 123. Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–1727.

Multidisciplinary nonpharmacologic approach to rheumatoid arthritis Turid Heiberg • Anne-Lene Sand-Svartrud • Rikke Helene Moe • Tore K. Kvien

Key Points n Therapeutic approaches and in particular individual management plans should be based on shared decisions between the patient and the multidisciplinary team. n Multidisciplinary team care is a complex multimodal treatment approach targeting complex disease consequences when single interventions are not sufficient. n Cognitive-behavioral therapy improves important outcomes, especially when offered at an early stage of the disease. n Recommendations for patient education have been published, and patient education should be an integral part of standard care, to improve clinical outcomes. n Recommendations for rheumatology nursing have been published and agreed upon across Europe, but they are not yet widely implemented in clinical practice. n Physical activity is important to maintain movement and strength and is generally recommended both to strengthen physical health and coping. n Exercise improves function, fitness, and strength and is safe. n Exercise should be individually tailored and adjusted to changes in fitness, comorbidity, and joint damage. n Exercise can contribute to reducing the increased risk of cardiovascular disease. n Orthoses, insoles, assistive devices, and shoes can be used to obtain activity and participation. n Proposed diets for persons with RA should be based on general healthy dietary advice. n Preventing work disability is important and more effective than correcting work disability after work loss, and multidisciplinary nonpharmacologic interventions at an early stage should be considered.

INTRODUCTION Over the past decades, new treatment options as well as new treatment strategies have improved prognosis and quality of life in people with rheumatoid arthritis (RA). Still, most patients will experience pain, fatigue, and loss of function and benefit from therapeutic interventions from a multidisciplinary team of health professionals. The expectations for level of participation in society have also been raised with the new opportunities for improvement and achievement of better health. A consumer-centered approach is now widely applied in disease management. Individual goals and treatment plans are jointly set by the patient and the multidisciplinary team. Core functions of this team are described in Table 102.1. Even if each profession has different areas of expertise, a common goal will always be to reduce and control disease activity, to maintain or improve function and work ability, and to enhance coping strategies and the quality of life of the patient and his or her family. Therapeutic approaches and in particular individual management plans should be based on a shared decision between the patient and the management team. Published recommendations for disease management often divide the recommendations into pharmacologic, nonpharmacologic, and surgical interventions. Health professionals primarily work with nonpharmacologic interventions, which, however, do not exclude advice, counseling, and monitoring related to drug therapies.1 The nonpharmacologic interventions are relevant both for preventive, therapeutic, and rehabilitative approaches, but we do not distinguish between these approaches in this chapter, since there are clear overlaps, especially between secondary and tertiary prevention and rehabilitation. It is also important that nonpharmacologic interventions usually have a wide focus on several aspects of the disease and that relevant outcome assessment instruments accordingly should reflect dimensions that are relevant to patients as, for example, the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire.2 This chapter focuses on the evidence for nonpharmacologic interventions and also discusses different therapeutic approaches. We focus mainly on documentation from studies performed in patients with RA. However, in some areas, few studies are available in RA, and information from nonpharmacologic interventions in other joint diseases can also have some relevance for RA.3

102

COPING—BALANCING NEEDS AND RESOURCES RA, like many other chronic diseases, may require that the patient changes ways of caring for themselves to meet the needs of everyday living. This adaptation may focus on both physical, mental and social well-being skills, as well as pain, fatigue, and sleep. Coping with these disease-related problems can be both an activity and an outcome. Coping as an activity can be regarded as a therapeutic use of resources. As an outcome, coping is a priority dimension to patients. Exploring patients’ needs and assessing patients’ own resources is central for identification of resources that can be mobilized, strengthened, or compensated for to address unmet health-related needs.4 Spending time with patients provides opportunities to teach and empower patients about managing the disease and understanding treatment, which may impact treatment adherence in patients.4,5 Nurses are regarded to be in a position to coordinate care within the multidisciplinary setting, which is seen as beneficial for disease management.6 There is a broad agreement across Europe on recommendations for a set of rheumatology nursing management.1 However, these recommendations are not widely implemented in clinical practice.5 Important approaches to address coping by strengthening personal resources are cognitive-behavioral therapy (CBT) and mindfulness, especially when administered early in the disease.7 The outcomes where CBT seems to have the most important impact are on pain management and fatigue. However, secondary outcomes like coping, disability, sleep, and self-efficacy also improve.8 Mindfulness seems to address mental challenges, more specifically depression and psychological distress.9 Disease and symptom management based on patient-preferred outcomes should be performed in a timely manner. Elements that focus on aspects like self-efficacy and active coping behavior seem to increase the likelihood of a positive effect on symptoms and health status. Coping can be optimized through focusing on positive aspects of the situation, learning self-management skills, and acknowledging emotions (Fig. 102.1).10 The use of telehealth and/or nurse-led telephone services can enhance continuity of care and ongoing support as also mandated in many countries during the COVID-19 pandemic.

PATIENT EDUCATION AND COUNSELING The EULAR recommendations for patient education (Box 102.1) emphasize that patient education should be an integral part of standard care.11 The primary targets of patient education are outcomes that are important to the patients and increased patient involvement in the management of the disease. Patients want and are entitled to get the information that they need, and content and delivery should be individually tailored. Patient education is the foundation of self-management and shared decision making. A 1-year intervention, using a self-care promoting problem-based learning program showed increased empowerment, and the patients implemented lifestyle changes related to the program.12 Self-efficacy has been an important outcome in coping and has been associated to other disease-related variables. Psychosocial issues must be addressed to reduce anxiety and depression that may limit self-efficacy. Educational activities had a positive impact on self-efficacy, and disease-related variables usually improved as well.13 Education improves self-management, function, strength, self-efficacy, satisfaction with care, and clinical outcomes. Approaches like group education, guided exercise training, as well as nurse-led counseling are both clinically effective and also cost effective.14 Almost all persons with RA use medications, and in a Norwegian study, up to 60% of patients with RA or polyarthritis reported using five or more drugs when admitted to a hospital.15 Not surprisingly, issues concerning medication and side effects are frequently raised in studies exploring unmet health care needs in this patient population. Clinical pharmacists are

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Table 102.1

Core Functions of the Potential Members of a Multidisciplinary Team Profession

Core Functions

Clinical pharmacist Nurse

The clinical pharmacist identifies, solves, and prevents drug-related problems such as unnecessary drug use, nonoptimal drug or dosage, need for additional drug, interaction between drugs, adverse drug reactions, and need for more information or therapy discussion. The nurse assists the patient in coping with health-related needs, when disease or treatment require altered use of resources. Nurses focus on activities that the patient would perform unaided given relevant resources like strength, motivation, or knowledge. The nurse functions by mobilizing, strengthening, or compensating the patient’s own resources. The nutritionist/dietician assesses, diagnoses, and treats nutrition-related problems and gives practical guidance regarding diets. He or she treats a range of medical conditions with dietary therapy on the basis of current literature, scientific evidence, best practices, and the individual needs of the person. The occupational therapist evaluates the impact of rheumatic diseases on function and performance of daily tasks and valued life roles, using interviews, observation, and standardized assessments. Personal goals, interests, and resources are screened to determine if adjustments are necessary to enhance the person’s abilities. Core tasks are ergonomic principles and activity pacing, therapeutic exercise, and activity programs, provision of orthoses and assistive technology, and environmental and task modifications. An orthopedic surgeon trained in the treatment of people with rheumatoid arthritis will be responsible for performance of surgical procedures and, together with the patient, rheumatologist, and relevant team members, will establish a plan for surgical procedures coordinated with the timing of other interventions. The foot specialist evaluates the foot and ankle in order to define deformities, instabilities, and painful areas. Custom-made insoles and orthopedic shoes are common interventions in pain relief and stabilization of an unstable and/or painful rheumatoid foot and ankle. Paddings or orthoses can be applied to prevent or correct deformities, reduce pain, or increase function. Lightweight and soft materials with an easy closure system are preferred. The role of the clinical psychologist is to optimize the patient and family in managing emotional and psychological stress and to assist living and coping with a chronic disease. The clinical psychologist provides a wide range of interventions designed to enhance coping, including cognitive therapy, pain, sleep, and stress management; sexual and relationship counseling; and psychotherapy. The psychologist may also have a consultation role with the interdisciplinary team. Based on assessments of physical fitness and functional status, the physical therapist uses therapeutic exercises and manual techniques to improve patients’ muscle strength, joint mobility, and cardiovascular function. Physical modalities such as heat, cold, electrical therapy, and hydrotherapy may also be used to achieve temporary pain relief and reduce muscle spasm, in preparing the patient for exercise and activity. The rheumatologist is primarily responsible for diagnosis and the total disease management. His or her main responsibility is usually pharmacologic interventions and disease monitoring. The rheumatologist will work with the patient and members of the multidisciplinary team to identify needs for nonpharmacologic interventions. Social workers play a role in preventing and solving personal problems and problems regarding networks of interpersonal relation in the family and outside the family. They also address economic problems and limitations regarding education, work, and/or a professional career.

Nutritionist/ dietician Occupational therapist

Orthopedic surgeon Podiatrist/or foot specialist

Psychologist

Physical therapist

Rheumatologist

Social worker

as it reflects the opposite of what should be communicated; the importance of staying active and exercise to maintain movement and strength.

EXERCISE THERAPY

FIG. 102.1 To optimize coping, people with rheumatoid arthritis should remain as active as reasonably possible, acknowledge and express their emotions in a way that allows them to take control of their lives, engage in self-management, and try focusing on potential positive outcomes.

educated to identify and prevent drug-related problems.15 Counseling with pharmacists should thus be available on an individual basis, as well as in group-based patient education programs. Protecting the joints as a passive coping strategy was frequently used previously; however, modern rheumatology today has an overall more active approach to treating RA. Studies of educational programs (including information about assistive devices, orthosis, or adjustments to enable activity and participation) using standard methods of education and training have shown little or no effect. The term “joint protection” should now be avoided

People with RA often have reduced muscle strength, endurance, and aerobic capacity compared with age-matched controls.16 Due to fear of aggravating disease activity and symptoms, people with RA were in earlier times advised to limit their amount of physical activity and protect their joints during exercise. However, deconditioning and low muscle strength predicts earlier mortality.17 Increased physical activity and exercise can be used alongside pharmacologic and physical therapies to effectively alleviate RA symptoms. Physical activity is defined as any bodily movement that causes increased energy expenditure, has major beneficial health outcomes, and is associated with better physical and mental health, prevention of disease, and reduced risk of all-cause mortality. People with RA suffer from decreased levels of physical activity despite that it has been shown to be safe, has favorable effects on joint structures, and can improve function and disease-related outcomes.18–21 People with RA have an increased risk of cardiovascular disease compared to the normal population, which represents an excess burden of morbidity and mortality.22 Exercise can contribute to reducing this risk. A systematic review of 14 RCTs including 1040 RA patients found that cardiorespiratory aerobic exercise improved physical function (HAQ score), pain, and quality of life, and the authors concluded that cardiorespiratory exercise appeared safe for people with RA.23 Two other reviews have highlighted the dearth of studies on the effects of exercise on cardiovascular outcomes and provided strong evidence that exercise of various modes is effective in improving disease-related characteristics and functioning in RA. They also addressed how to manage exercise in the treatment of people with RA, including cardiovascular comorbidity, and summarized the antiatherogenic and antiinflammatory effects of exercise.20,24 A metaanalysis demonstrated the beneficial effects of exercise on inflammation.25 Another metaanalysis including 10 RCTs with a total of 547 patients evaluated the efficacy of resistance exercises in RA patients and found that such training was safe and beneficial. Several outcomes of muscle strength and function were improved, and subgroup analyses revealed a

CHAPTER 102  Multidisciplinary nonpharmacologic approach to rheumatoid arthritis

871

BOX 102.1 RECOMMENDATIONS FOR PARENT EDUCATION FOR

PEOPLE WITH INFLAMMATORY ARTHRITIS1

Overarching principles 1. Patient education is a planned interactive learning process designed to support and enable people to manage their life with inflammatory arthritis and optimize their health and well-being 2. Communication and shared decision making between people with inflammatory arthritis and their healthcare professionals are essential for effective patient education

Recommendations 1. Patient education should be provided for people with inflammatory arthritis as an integral part of standard care in order to increase patient involvement in disease management and health promotion 2. All people with inflammatory arthritis should have access to and be offered patient education throughout the course of their disease including as a minimum; at diagnosis, at pharmacological treatment change, and when required by the patient’s physical or psychological condition 3. The content and delivery of patient education should be individually tailored and needs-based for people with inflammatory arthritis 4. Patient education in inflammatory arthritis should include individual and/ or group sessions, which can be provided through face-to-face or online interactions, and supplemented by phone calls, written or multimedia material 5. Patient education programs in inflammatory arthritis should have a theoretical framework and be evidence-based, such as self-management, cognitive behavioral therapy, or stress management 6. The effectiveness of patient education in inflammatory arthritis should be evaluated and outcomes used must reflect the objectives of the patient education program 7. Patient education in inflammatory arthritis should be delivered by competent health professionals and/or by trained patients, if appropriate, in a multidisciplinary team 8. Providers of patient education in inflammatory arthritis should have access to and undertake specific training in order to obtain and maintain knowledge and skills 1

Reproduced with permission from the Annals of the Rheumatic Diseases.

trend towards higher efficacy with higher-intensity programs.26 A systematic review including six primary studies on aquatic exercises for people with RA described evidence for improving pain and health status in the short term, compared with none or various other interventions.27,28 The effects of hand-specific exercises are often reported separately from general exercise studies. An RCT (the SARAH trial) included 490 RA patients who were followed for 4 and 12 months and showed improved function from a daily strengthening and stretching exercise program, compared to usual care, with no serious adverse events.29 A systematic review concluded that intensive hand exercise programs are well tolerated and can improve hand function in terms of decreased pain and increased strength, with a trend towards more improvements with higher intensity and longer duration.30 A Cochrane review including seven studies indicated only slight improvements of hand exercises on hand function due to risk of bias.31 Exercise improves functional ability, aerobic capacity and strength, is safe, and without negative effects on pain and disease activity in patients with both early and established RA. The magnitude of effect is dependent on various general and individual factors. The type of exercise should include both aerobic and strengthening exercises and be tailored to individual patient preferences, as there is a lack of evidence on the optimal mode of exercise delivery (Fig. 102.2); however, exercise at higher intensities is associated with stronger beneficial effects.25,32–34 Recommendations for physical activity and exercise for people with RA is similar to those for the normal population but should be individually tailored according to fitness, symptoms, comorbidity, and joint damage.20,33 It is important that health professionals promote physical activity and guide patients in achieving and maintaining a healthy lifestyle.21 Standards of care35 suggest people with RA to be educated about the beneficial effects of exercise and how to improve and maintain their fitness.

HANDS-ON TECHNIQUES AND PHYSICAL MODALITIES Hands-on techniques and different physical modalities are important components of the nonpharmacologic care for people with RA. It is common to use

FIG. 102.2  Exercise improves functional ability, aerobic capacity and strength, and is safe in people with both early and established rheumatoid arthritis. A treadmill gives the opportunity to adjust speed and inclination and can be useful for high intensity cardiorespiratory training.

these treatment alternatives for pain control and increased joint mobility in addition to exercise. These techniques include, for example, joint mobilization or manipulative techniques, electrotherapy, thermal agents, and balneotherapy. People with limited range of motion in peripheral joints may benefit from passive mobilization, but in general, the evidence for hands-on techniques is limited. However, one novel randomized crossover trial treated 12 participants with RA with joint mobilization and found comparable improvements on outcomes like pain, tender and swollen joints, and joint space narrowing for both the treated and contralateral hand.36 Some physical modalities, like transcutaneous electrical nerve stimulation (TENS), therapeutic ultrasound, low-level laser therapy, and thermotherapy have been recommended for the management of RA.37 TENS is used for pain control or muscle stimulation, and there are conflicting results on the effects on pain in patients with RA.38 Low-level laser therapy can be considered for short-term treatment for relief of pain and morning stiffness, particularly since it has few side effects.39 Ultrasound, combined with other treatment modalities (exercises, faradic current, and wax baths), has not been found to be beneficial in a systematic review. However, single studies, mostly of poor quality, have indicated that ultrasound alone on the hand may have beneficial effect on grip strength, wrist motion, morning stiffness, and number of affected joints. No harmful effects have been reported.40 A systematic review including six studies (257 individuals) showed that cryotherapy (superficial cooling) can improve pain.41 Superficial heat can also be used as palliative therapy, and paraffin wax baths combined with exercises can be used to relieve short-term effects for arthritic hands, but the evidence for efficacy is weak. There is also insufficient evidence whether balneotherapy (thermal bathing) is more effective than no treatment or compared to other interventions. Although studies may report positive findings, they may frequently suffer from poor methodology, and the results must be interpreted with caution.28

ORTHOSES, INSOLES, AND SHOES The wrists and fingers are frequently affected joints in people with RA. Working wrist orthoses, resting splints for the wrist and hand, and splints

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to correct for specific deformities are three commonly used hand orthoses in RA. A mixed methods systematic review of working splints concluded that these splints reduce pain and improve grip in RA, but the effect on function is unclear.42 Recommendations regarding the use of resting hand splints to reduce pain and swelling could not be given based on current evidence, but patients in one of the two included primary studies preferred wearing the splints to not wearing them.43 Based on data from one RCT evaluating the clinical effectiveness of static resting splints including 120 patients, the use of these splints in early RA is strongly discouraged.44 Small custom-made splints have been shown to correct deformities and improve pain45 while specially designed silver ring splints may improve dexterity in patients with swan neck or boutonnière deformities.46 Foot problems are also frequent in RA47 and may alter walking patterns and thereby the biomechanics of the entire lower extremity. People with RA are therefore advised to use appropriate footwear, such as lightweight shoes. Often, a combination of orthopedic shoes, orthoses, paddings, and insoles are applied. In general, current research supports use of these interventions. The results of a systematic review of interventions for foot problems in RA indicates that extra-depth shoes have beneficial effects on pain and function and that the benefit is greater if combined with orthoses.48 In another review, some evidence indicated that custom foot orthoses can reduce pain and forefoot plantar pressures, but there was inconclusive evidence for the effects on foot function, walking speed, gait, or reduced progression of hallux valgus deformities.47 However, studies are not definite regarding which type of shoes or foot orthoses is most effective.

ASSISTIVE TECHNOLOGY Assistive technology is prescribed and used as means to reduce pain and compensate for impairment and environmental demands, and it is a frequent self-help strategy reported by persons with RA.49 It includes a wide range of products, from low-tech devices to technologically complex equipment, some of which is designed for the general population, whereas others are developed to meet the needs of people with functional limitations or disabilities. Studies indicate that assistive devices are still helpful to persons with arthritis, despite the improvement in pharmacologic management.50 However, even if provision of assistive devices is a widely used multidisciplinary intervention, there is a general lack of studies evaluating the effect of such devices.49 Limited high-quality evidence is available for the use of assistive devices in RA. One reason for the small number of studies and low level of formal evidence may be that the effect of some assistive devices seems rather obvious, such as the benefit of using raised seats, grab bars, or canes or crutches to ease safe transfer or mobility.

NUTRITION People with RA may try to replace their traditional food with special diets.51 The most common diets are vegetarian (usually eliminating meat and fish), vegan (eliminating meat, fish, eggs, and milk), Mediterranean (including small amounts of meat and more fish, fruits, vegetables, and olive oil), and elemental or elimination diets. Elemental diets are usually liquid diets that contain nutrients that are broken down to make digestion easier, whereas elimination diets are used to exclude foods that might potentially worsen the disease. A systematic review of dietary interventions in RA concluded that effects of diet on pain, stiffness, and physical function were uncertain.51 The impact of obesity in RA is complex.52 Body mass index (BMI) is usually used as a marker of obesity in epidemiologic research. It seems to be clear that an increasing BMI increases the risk of development of RA, in particular in women. Further, obesity is associated with a disease phenotype characterized by more pain and reduced functional ability. This association can potentially be mediated through production of adipokines. It has also been shown that increasing BMI is related to poorer response when using both biologic and synthetic DMARDs. However, it is intriguing that obesity also seems to protect against radiographic progression.52 RA is associated with an increased risk of cardiovascular morbidity and mortality. It is generally agreed that the management of cardiovascular risk include a focus both on the inflammatory activity and on conventional risk factors. Obesity is one of these conventional risk factors53 and should be targeted in a risk management plan.22 Many proposed dietary interventions for RA patients are in line with what may be considered a healthy diet, with a focus on fiber, fruits, vegetables, antioxidants, fish, moderate amounts of lean meat, and reduction of saturated fat and sugar. In general, persons with RA should therefore be given the same advice as the general population, which is to follow a healthy diet, avoid certain foods that may cause allergies or intolerance, and consult a nutritionist if they want to try any special diet.

INTERVENTIONS PREVENTING JOB LOSS AND WORK DISABILITY Despite early aggressive treatment and the introduction of biologic treatments, RA is still associated with a significant burden of illness, and reducing the prevalence of work loss remains an important and major challenge. To enable persons with RA to maintain or return to work, a variety of nonpharmacologic interventions and vocational rehabilitation programs have been developed. Prevention of work disability is more effective than correction of work disability after work loss, and the occurrence of complete sick leave is found to be an independent risk factor for job loss in patients with chronic arthritis who have a disease-related problem at work.54 Keysor et al. conducted an RCT where employed persons with rheumatic disease at risk for job loss were randomized to a work disability prevention program (n = 143) compared to a control group (n = 144) receiving written materials about disability employment issues and resources. This study showed that job loss was reduced in the intervention group, but also that work loss and work limitations were higher than expected, suggesting an unmet need in this population.55 The work disability prevention program (developed in the United States) is found to be credible, acceptable, and deliverable in modified form, in a context with different social security system, employment law, and rehabilitation services (the United Kingdom).56 Recommended content in a vocational program is a structured assessment of health-related workplace barriers and possible solutions related to agreed priority problems. Further, interventions may include job accommodations, a work site visit, ergonomic advices, assistive devices, or improved coping skills.55,56 This evidence indicates that more attention should be directed towards rapid identification and treatment of persons at risk of being work disabled.

MULTIDISCIPLINARY TEAM CARE Multidisciplinary team care and rehabilitation in patients with RA aims at maintaining or improving physical, psychological, and social functioning and health. This is a complex, multimodal treatment approach aimed at targeting complex disease consequences for which single interventions are not sufficient.57 Access to a multidisciplinary team is considered as a part of the standard care for patients with RA in many countries. However, access to services from health professionals differs and may be influenced not only by socioeconomic factors and funding but also by factors such as doctor’s awareness and knowledge about health professional’s treatment opportunities and the availability of health professionals. The configuration of multidisciplinary teams and mode of delivery of multidisciplinary team care programs varies both between and within countries. A comparative study looking at the content of team care across countries and settings in Northern Europe points out some commonalities: the team usually includes a medical doctor, nurse, physiotherapist, occupational therapist, and social worker. Care is formally coordinated by a rehabilitation plan including individual goals. In several settings, nurses will be a main coordinator of team care. The patient should be included in developing the plan, and the multidisciplinary interventions should be directed towards helping the patient achieve these goals.58 Setting goals and following a rehabilitation plan are considered key components of arthritis team care rehabilitation.59 Although there is no disease-specific research on the effect of setting goals for patients with RA, there is some low-quality evidence that goal setting may improve outcomes for adults receiving rehabilitation for acquired disability; particularly, results from structured goal setting appears to favor positive effects for psychosocial outcomes (i.e., health-related quality of life, emotional status, and self-efficacy).60 A metaanalysis evaluating multidisciplinary team care in RA patients was published in 2016. There is limited effect of multidisciplinary team care on disability, disease activity, and quality of life at all time points compared to controls, and there is still a paucity of high-quality evidence evaluating multidisciplinary team care in people with RA.61 Seven of the 10 included RCTs in this metaanalysis were published before the year 2000. Since then the RA population has changed as a consequence of improved pharmacologic treatment, which has led to changes in the primary aim and focus of multidisciplinary team care and rehabilitation. In the nineties, the primary focus of multidisciplinary team rehabilitation in RA was on preventing disability in primary ADL-activities due to reduced joint function and pain. Today most RA-patients manage ADL without difficulties and very few are in need of personal assistance.62 As a consequence of this, the goals, content, and focus of RA multidisciplinary team care rehabilitation today should be to help the patient to obtain and maintain full participation and optimal quality of life guided by individual rehabilitation goals reflecting a biopsychosocial

CHAPTER 102  Multidisciplinary nonpharmacologic approach to rheumatoid arthritis understanding of function. In addition, it is important to have a particular focus on the subgroup of patients that, despite well-managed inflammatory parameters, report high pain and impaired function early in their disease course. Health care providers should be aware of this subgroup of patients since they have an increased risk of being in the most disabled tertile of RA patients several years later.63

DIGITAL HEALTH INTERVENTIONS An increasing number of interventions are delivered via digital and mobile technologies, such as websites or smartphones. These trends influence several nonpharmacologic interventions for people with RA, such as internet-based cognitive-behavioral therapy, telemedicine delivery of patient education, and online support groups, as well as digital interventions on physical activity and use of wearable activity trackers, mobile apps, and various self-monitoring services. The use of digital technology across many areas of medicine has been further enhanced during the global COVID-19 pandemic.

ACKNOWLEDGMENT The authors would like to acknowledge the contributions of Professor Ingvild Kjeken, Professor Hanne Dagfinrud, and PhD Mari Klokkerud, who were coauthors of this chapter in previous editions.

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Bergstra SA, Murgia A, Te Velde AF, et al. A systematic review into the effectiveness of hand exercise therapy in the treatment of rheumatoid arthritis. Clin Rheumatol. 2014;33(11):1539–1548. 31. Williams MA, Srikesavan C, Heine PJ, et al. Exercise for rheumatoid arthritis of the hand. Cochrane Database Syst Rev. 2018;7:Cd003832. 32. Hurkmans E, van der Giesen FJ, Vliet Vlieland TP, et al. Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis. Cochrane Database Syst Rev. 2009;4:Cd006853. 33. Pedersen BK, Saltin B. Exercise as medicine—evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports. 2015;25(Suppl 3):1–72. 34. Swardh E, Brodin N. Effects of aerobic and muscle strengthening exercise in adults with rheumatoid arthritis: a narrative review summarising a chapter in physical activity in the prevention and treatment of disease (FYSS 2016). 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Casimiro L, Brosseau L, Robinson V, et al. Therapeutic ultrasound for the treatment of rheumatoid arthritis. Cochrane Database Syst Rev. 2002(3):Cd003787. 41. Guillot X, Tordi N, Mourot L, et al. Cryotherapy in inflammatory rheumatic diseases: a systematic review. Expert Rev Clin Immunol. 2014;10(2):281–294. 42. Ramsey L, Winder RJ, McVeigh JG. The effectiveness of working wrist splints in adults with rheumatoid arthritis: a mixed methods systematic review. J Rehabil Med. 2014;46(6):481–492. 43. Egan M, Brosseau L, Farmer M, et al. Splints/orthoses in the treatment of rheumatoid arthritis. Cochrane Database Syst Rev. 2003(1):Cd004018. 44. Adams J, Burridge J, Mullee M, et al. The clinical effectiveness of static resting splints in early rheumatoid arthritis: a randomized controlled trial. Rheumatology (Oxford). 2008;47(10):1548–1553. 45. Silva PG, Lombardi Jr. I, Breitschwerdt C, et al. 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SECTION 7  Rheumatoid Arthritis

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Section

8

PEDIATRIC RHEUMATOLOGY

Evaluation of children with rheumatologic complaints Nora G. Singer • Karen B. Onel

Key Points ■ A systematic approach should be used to assess symptoms of musculoskeletal and rheumatic diseases in children. ■ The physical examination is used to distinguish between inflammatory rheumatic and mechanical musculoskeletal diseases of children. ■ Specific clinical maneuvers can be used to identify the range of musculoskeletal disorders in children. ■ Pediatric rheumatologists should be familiar with disorders typically treated by pediatric orthopedists that may present for evaluation; prompt recognition and evaluation with appropriate referral are key.

HISTORY TAKING FOR THE MUSCULOSKELETAL SYSTEM IN CHILDREN GENERAL APPROACH For children of all ages, direct honest communication at an age-appropriate level establishes trust and provides expectant guidance for what will happen during the examination. Talking first to the parents of very young children while the children are held in a parent’s lap may reduce their fear both of the unknown and of pain. Telling a child what is required establishes trust in the long term even though it may be stressful. How much history is provided by the parents or by the children themselves depends on the age of the child; adolescents should be engaged to provide their own history and invited at some point to be alone in the examination room without their parents. Disparity in the historical narratives provided by the patient and the parent should be noted and may provide clues to the underlying problems. Genuine mistakes, inaccurate recall, or errors of interpretation may be manifestations of a serious underlying issue, such as abuse. Child abuse at any level (physical, psychological, or sexual) may present as rheumatic complaints, particularly musculoskeletal pain.

CONSTITUTIONAL FEATURES Most chronic inflammatory diseases are accompanied by a constellation of relatively nonspecific but potentially important constitutional features, such as lethargy or fatigue, mood change, irritability, reduced appetite, and weakness. Fever is a prominent feature of inflammation and may be typical, as in the evening fevers of systemic arthritis, or episodic, as in periodic fever syndromes. More chaotic or less localizing fever may be seen in disorders such in systemic lupus erythematosus or macrophage activation syndrome with systemic-onset juvenile idiopathic arthritis or the more recently identified COVID 19-triggered multisystem inflammatory syndrome in children (MIS-C). Whereas complaints of muscle weakness are common in inflammatory myopathy, complaints of muscle pain may be more profound in infectious and postinfectious inflammatory myopathy (e.g., pyomyositis, influenza-associated myopathy) and may be seen in juvenile dermatomyositis. Whereas absence of weakness may point toward complex regional or

103

generalized pain disorders, proximal muscle weakness typifies inflammatory or steroid-induced myopathy. Impaired linear growth and weight loss are often seen in the presence of systemic inflammation.

JOINT PAIN Joint pain as a symptom should be assessed as to whether it interferes with function (e.g., walking, running, or writing), aggravating and relieving factors, diurnal variation, and progression. Pain reporting can be improved through use of an age-appropriate visual analog scale such as one with happy and sad faces and may also be detected by observing a child’s pain avoidance behavior (e.g., limping in the absence of pain complaints, loss of motor milestones previously attained). Enlisting the parent’s assessment of pain complaints is important. Dramatic complaints of musculoskeletal pain by either the parent or the patient seemingly out of proportion to the physical findings may be reported because of the “bother” or affective (psychological) component of pain. Pain associated with inflammation tends to be mild to moderate in intensity and rarely present at rest (Table 103.1), but the pain of infection is, in general, severe. Liquid tumors (leukemia, lymphoma, and neuroblastoma) may present with severe periarticular pain.

JOINT SWELLING AND STIFFNESS A history of joint swelling should be assessed and confirmed during the physical examination (see later). Joint stiffness, or the reporting of reduced, uncomfortable range of joint movement, seems to be at its worst on awakening in the mornings and improves throughout the day in inflammatory arthritis. “Gelling” may occur after prolonged inactivity, such as sitting in a car or at a desk. Understanding the spectrum of musculoskeletal disorders that occur in different age groups is helpful in focusing the clinician on a working diagnosis because childhood musculoskeletal diseases may be identified in part by the age at which symptoms appear. The acronym ARTHRITIS, proposed by Taunton Southwood, is a helpful mnemonic (Box 103.1). The most important noninflammatory disorders and the typical age at which they occur are described in this chapter and are listed in Table 103.2, along with the symptoms with which they may present and important clinical features that help to distinguish them.

EXAMINATION OF THE MUSCULOSKELETAL SYSTEM GENERAL EXAMINATION The child’s general condition and appearance, reviewing her or his growth and percentiles, skin color and condition, overall nutritional status, muscle bulk, vital signs (temperature, blood pressure), and joint movement when playing can help in forming an overall assessment of whether the child is well or sick (Table 103.3). Careful assessment of the eyes and peripheral pulses should also be included as part of the routine physical examination of these children. 875

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SECTION 8  Pediatric Rheumatology BOX 103.1 AN APPROACH TO THE DIFFERENTIAL DIAGNOSIS OF

Table 103.1

RHEUMATIC CLINICAL FEATURES IN CHILDREN AND YOUNG PEOPLE

Relative Contribution of Musculoskeletal Clinical Features in Differential Diagnosis in Children Inflammatory Disease Paina Joint stiffness Joint swelling Joint instability Sleep disturbance Physical signsb

+/− ++ +++ +/− +/− ++

Mechanical Disorder + +/− +/− ++ − +

Amplified Pain Disorders +++ + +/− +/− ++ +/−

May depend on both the age of the child and the age appropriateness of the tool used to measure pain. Changes in temperature may be found in inflammatory disease and in amplified pain disorders but are more frequently accompanied by complaints of dysesthesia in the latter.

a

b

Avascular necrosis, orthopedic diseases (e.g., slipped upper femoral epiphysis, osteochondritis) Reactive arthritis Trauma associated, including nonaccidental injury and hypermobility Hematologic: bleeding diatheses, hemoglobinopathies Rickets and other metabolic and endocrine diseases: diabetes and thyroid diseases Infection of bone or joint Tumor, leukemia, neuroblastoma Idiopathic or psychosomatic disorders, including musculoskeletal pain amplification syndromes Systemic connective tissue diseases: multisystem inflammation of muscle, skin, or blood vessels

Table 103.2

Noninflammatory Musculoskeletal Disorders: Symptom Combinations and Pivotal Clinical Features “Typical” Symptom Combinations

Pivotal Clinical Features

Possible Diagnoses

“Clunk” on hip movement screening, limping in an older infant Nocturnal awakening with leg pain in a young child Sudden limping in an otherwise well young child Joint effusion with or without pain

Asymmetric upper leg skinfolds, limited hip abduction Normal child

Developmental dysplasia of the hip

Hip pain in a preadolescent (boys more than girls) Hip pain in an obese preadolescent boy Hip pain and limp in adolescent girl “Snapping” hip

Loss of joint range, pain on motion, may be bilateral Unilateral hip restriction Unilateral pain and stiffness Sensation of internal or external hip

Localized pain

Point tenderness with or without localized swelling Pain with use of stairs (ascending or descending), stiffness Tenderness over the tibial tuberosity Tenderness over the inferior pole of the patella

Anterior knee pain

Lateral knee pain

Medial knee pain

Unilateral restricted hip movement Effusion with hemorrhagic fluid on aspiration

Pain over the patellar tendon or quadriceps tendon Pain where the iliotibial band courses over the lateral femoral epicondyle; also may radiate proximally into the iliotibial band Pain over the lateral joint line, possible positive finding on McMurray test Intermittent pain and effusion with or without locking, usually increased with activity Popping or snapping medially when extending from flexion Pain inferior to medial joint line or tibia

JOINT ASSESSMENT Conducting a standardized joint examination minimizes the risk of omission (a side-to-side comparison should always be made). Head-to-toe joint examination commonly is performed so that one will remember to examine all joints; starting by examining the extremities may be less threatening to young children. Suggested steps in the joint examination include: 1. Look: Inspect the position of the joint at rest and its surface anatomy, contours, color, scar, size, and muscle bulk, as well as limb length. 2. Feel: Palpate for skin warmth, joint swelling, and tenderness. Swelling includes any increase in joint size that alters the normal surface markings of the joint. Swelling may be due to intraarticular effusion, periarticular fluid, soft tissue changes (edema; joint capsule thickening;

“Growing pains” Osteoid osteoma Toxic synovitis Hemarthrosis after trauma or if recurrent Pigmented villonodular synovitis Legg-Calvé-Perthes disease Slipped upper femoral epiphysis Idiopathic chondrolysis Internal movement of the iliopsoas muscle over the iliopectineal eminence, lesser trochanter, or anterior superior iliac spine; external movement of the iliotibial band over the greater trochanter hip Stress fracture Patellofemoral syndromes Osgood-Schlatter disease (apophysitis of the tibial tuberosity) Sinding-Larsen-Johansson syndrome Apophysitis of the inferior pole of the patella Extensor tendinitis Iliotibial band syndrome

Lateral meniscal injury Osteochondritis dissecans Medial plica syndrome Pes anserine bursitis

inflammation of muscle, ligament, or subcutaneous or cutaneous tissues), or bony hypertrophy. Joint margin tenderness or tenderness and inflammation at the site of tendon insertion into bone or ligament, fascia, or joint capsule may indicate the presence of enthesitis. 3. Move: Include motion by the examiner (passive range of motion) and by the patient (active range of motion), noting any pain or irritability on motion, especially at the end range of joint motion. 4. Test: Assess joint stability, particularly for the stability ligaments of the knee (cruciate and collateral ligaments), and assess for pain referable to other joint structures such as the menisci and associated structures such as the iliotibial bands and bursa. In young children, beginning the examination with the toes and feet is the least upsetting. Examining the most painful areas at the end of the examination often facilitates performing a complete examination.

CHAPTER 103  Evaluation of children with rheumatologic complaints

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FIG. 103.1  Asymmetric mouth opening and an abnormally small oral aperture caused by mandibular hypoplasia and temporomandibular joint arthritis in a young adult who has had juvenile idiopathic arthritis since the age of 1 year. Table 103.3

Functional Musculoskeletal Examination Position

Musculoskeletal Features Examined

Sitting cross-legged

Hip abduction, external rotation and flexion, knee flexion Leg extension, back extension, lower limb muscle power Anterior spinal curvature, scoliosis Hip and knee flexion, hand and wrist function Shoulder and elbow range of movement Gait phases: stance, toe off, swing, heel strike Toe extension, ankle plantar flexion, muscle power Ankle dorsiflexion, knee extension, pain at enthesis Elbow extension, shoulder power Finger flexion Wrist extension, elbow flexion, finger extension Shoulder flexion Cervical spine rotation

Rising to stand straight Bending forward Removing shoes and socks Removing top Walking normally Tiptoe walking Heel walking Hands pronated, arms extended Making a fist “Hands praying” position Arms above the head, reaching Looking over each shoulder

FIG. 103.2  “Burying the fingers.” Being able to perform the maneuver suggests the presence of normal flexion at the second through fifth metacarpophalangeal (MCP) joints, proximal interphalangeal joints, and distal interphalangeal joints. Some examiners have children make a full fist and assess the first MCP and interphalangeal joint at the same time.

disruption of the proximal radioulnar joint. To assess the glenohumeral joint, palpate the joint margin with the humerus abducted to 90 degrees and rotated internally and externally (using the forearm as a lever down and up, respectively). The acromioclavicular and sternoclavicular joints should be palpated for tenderness and swelling.

Cervical spine and temporomandibular joints

Hands and wrists

Detection of limitation or loss of motion in the cervical spine and temporomandibular joints may raise the possibility of systemic arthritis, even if the child does not have complaints specifically referable to these joints (e.g., a teenager with ankylosing spondylitis as a cause of hip joint space narrowing may complain of hip pain but also have restricted neck motion). Lateral rotation and extension are most likely to be lost early if the cervical spine is affected by arthritis. Rotation can be evaluated by asking the patient to place the chin on each shoulder. The normal extension range on tipping the head back is greater than 20 degrees. Having the child place the ear on the shoulder allows assessment of lateral flexion. The face should be inspected for asymmetry or mandibular hypoplasia (Fig. 103.1). The temporomandibular joints can be palpated just anterior to the tragus of the ear, where tenderness may be demonstrated and asymmetric movement detected, particularly on asking the patient to open the mouth widely (see Fig. 103.1). An oral aperture below 40 mm is considered to be abnormal.

Hand and wrist examination begins with the child sitting up with his or her hands held out in front of the body. Begin by inspecting the dorsal aspect of the hands and fingers and eliciting active finger flexion by asking the child to “make fists” and “bury the fingernails” (Fig. 103.2) (nail pitting may predate or accompany psoriasis). Joint swelling can be palpated with the hands in a prone position, and joint margin tenderness and passive range of joint movement are also noted. Rotation of the wrists at the distal radioulnar joint allows inspection of the palmar surfaces of the hands and fingers. Active finger flexion at the interphalangeal joints should normally result in the fingertips making contact with the palms overlying the metacarpal joints. By using the “prayer” position with the palms placed together, finger flexion or wrist extension deformities can be detected, which has the advantage of highlighting asymmetry at the wrists and small joints of the hand.

Elbows and shoulders The elbows are extended fully with hands reaching toward the ceiling (sometimes called reaching for the sky, which also demonstrates shoulder flexion) and then are lowered in an extended position to allow palpation of the olecranon bursa itself (which rarely swells in children except in injury or infection) and either side of the olecranon process. Functional elbow flexion can be demonstrated by placing the hands to the mouth. Pronation and supination of hands with the elbows at 90 degrees of flexion may reveal

Hips Detection of intraarticular effusion requires advanced imaging (ultrasonography or magnetic resonance imaging [MRI]). Screening for hip disease on examination is accomplished by passive internal and external rotation with the hip and knee flexed at 90 degrees; at least 45 degrees of internal rotation can usually be elicited in a normal child’s hip. Extension range, which is normally 30 degrees beyond neutral when the patient is lying prone, tends to be lost early in hip arthritis, but loss of flexion in the hip generally indicates more advanced disease. Entheses to be examined include the greater trochanter and anterior superior iliac spines.

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SECTION 8  Pediatric Rheumatology

Knees Loss of vastus medialis muscle bulk or bulk in the gastrocnemius may result from muscle atrophy caused by reduced use or guarding of a painful joint. Subtle loss of knee extension may be seen using relaxed passive extension of both knees by lifting the patient’s feet gently up off the table (Fig. 103.3). Mild swelling obscuring the medial and lateral contours of the patella can

be confirmed by palpating and inspecting for a synovial fluid wave or bulge sign (medial compression followed by lateral “reexpression” of the swelling) and by balloting the patella. Joint margin tenderness is often maximal just medial to the lower patellar border. Key points for palpation of entheses are at the tibial tuberosity and the 2, 6, and 10 o’clock positions around the patella. Knee locking or giving way may indicate a mechanical disorder and requires assessment of knee stability. The most useful examination techniques for medial and lateral collateral ligament integrity are the application of gentle valgus and varus pressure, respectively, on the knee (while the knee is held in 5 degrees of flexion), which may result in abnormal abduction or adduction (Fig. 103.4). The anterior cruciate ligament is also vulnerable to sports injuries in children and young people; that, and the posterior cruciate, can be assessed using anterior and posterior drawer tests. These and other tests to elicit derangement or tightness of structures in and around the knee are listed in Table 103.4.

Feet and ankles

FIG. 103.3  Relaxed passive extension of the knees. The right knee has subtle loss of relaxed passive extension indicating loss of joint range secondary to juvenile idiopathic arthritis.

With the child supine, observe the leg lengths carefully for any discrepancy. Asking the patient to curl his or her toes allows observation of flexion and extension metatarsal and interphalangeal joint movement. Carefully squeeze the metatarsophalangeal joints in such a manner as not to cause alarm, and if tenderness is noted, assess each metatarsophalangeal joint for synovitis by gently palpating the joint margins while moving the joint through its range of motion. Examine the midtarsal joints by stabilizing the calcaneus while inverting and everting the forefoot. Assess the subtalar joints by inverting and everting the calcaneus (hindfoot) and the ankle (tibiotalar) joints by dorsiflexion and plantarflexion at the ankle to detect synovitis. Synovitis is

FIG. 103.4  Valgus stressing (a) and varus stressing (b) performed to detect any abnormalities in the medial and lateral collateral ligaments of the knee.

a

b

Table 103.4 Maneuvers That May be Used to Diagnose Mechanical Disorders of the Knee Maneuver Name

Structure(s) Tested

Description

Patellar apprehension

Patella (laxity)

Lachman

Anterior cruciate ligament (ACL) (integrity)

Anterior drawer

ACL

McMurray

Menisci

Valgus stress

Medial collateral ligament (MCL)

Varus stress

Lateral collateral ligament (LCL)

Posterior drawer Ober test

Posterior collateral ligament Iliotibial bands

Thomas test

Quadriceps (flexibility)

The knee is placed in relaxed flexion (30 degrees), and the patella is subluxed laterally using gentle pressure (not so much pressure that it could displace the patella). The knee is flexed to 20 degrees; the examiner holds the distal thigh above the knee, pressing down with that hand while simultaneously grasping the tibia with the other hand and pulling it forward. Excess motion or no sharp stop compared with the other side indicates possible injury to the ACL. The knee is flexed to 90 degrees with foot stabilizing the knee. The proximal tibia is held with both hands with the thumbs in front reaching circumferentially; the tibia is displaced anteriorly. Excess laxity compared with the other side is considered a positive finding, although asymmetric pain and any abnormal movement should be noted. With a thumb and fingers placed over the medial and lateral joint line, the knee is moved through range of motion by holding the foot with the other hand and applying medial or lateral rotational pressure. The knee is extended passively and the procedure repeated to detect pain at the joint line. Pain, sometimes accompanied by a “thunk,” suggests the presence of meniscal abnormality. With the knee extended, the upper hand is placed above the knee laterally and the lower hand over the gastrocnemius on the medial aspect. Pressure is applied outward on the calf, and laxity and pain are noted if the MCL is not functioning normally. With the knee extended, the upper hand is placed above the knee medially and the lower hand over the gastrocnemius laterally. Pressure is applied inward on the calf, and laxity and pain are noted if the LCL is not functioning normally. Performed in the same manner as the anterior drawer test except that the tibia is forced posteriorly. The patient is placed on the nonpainful side. The affected hip is placed in a slightly extended position with the hip flexed and pain or limitation is observed when the affected leg is no longer held in the air by the examiner but instead returns to the surface. A hand is placed under the lumbar lordosis, and the patient is asked to flex one knee to the chest; if the other hip flexes, tightness of the quadriceps is suggested.

CHAPTER 103  Evaluation of children with rheumatologic complaints sometimes appreciated only when observed posteriorly; observation from the posterior view also allows detection of Achilles tendon thickening. To detect enthesitis, palpate for tenderness at the insertion of the plantar fascia to the metatarsal heads, fifth metatarsal base, calcaneus, and Achilles tendon insertion into the posterior aspect of the calcaneus.

Spine and gait The spine is best examined with the patient standing on bare feet and viewed from behind. Observe the position of the feet for loss of medial longitudinal arch contour (pes planus) and the hindfoot for overpronation, which suggests hypermobility (Fig. 103.5). Check that the pelvis is horizontal; leglength discrepancy is best detected clinically when the patient is standing. Assess for scoliosis by noting the symmetry of the spine in standing and gentle forward flexion (Fig. 103.6). Palpation over the sacroiliac joints may reveal tenderness, although this maneuver may be insensitive for detection

FIG. 103.5  Overpronation of both ankles associated with hypermobility.

879

of inflammation. Checking particularly for abnormal flattening of the lumbar spine, which might suggest spondylitis, is important. Pain on hyperextension of the spine, which puts the only synovial joints (the apophyseal joints) in the spine on the stretch, can be seen in sacroiliac joint disease or spondylolysis. The gait should be assessed when the patient is wearing shorts and walking with bare feet. Note is made of each of the gait phases (heel-strike, stance, toe-off, and swing phases), with observation for antalgic gait, a Trendelenburg abnormality (a waddling gait caused by weakness of hip stability muscles), and any other asymmetry.

DIFFERENTIAL DIAGNOSIS In children, the history is of principal importance in distinguishing whether the complaints or physical findings are more likely related to congenital or acquired abnormalities of the developing musculoskeletal system or caused by autoinflammatory or autoimmune disorders with tissue-specific manifestations. In children, overdiagnosis of mechanical musculoskeletal “disorders,” such as the variations in normal alignment in the growing skeleton, can be avoided through recognition of normal findings during an examination. Prompt recognition of abnormalities is key because delay in the diagnosis of either inflammatory disease or mechanical disorders may also delay appropriate and timely therapy. Transient musculoskeletal complaints are common in children and adolescents and are often associated with sports-related conditions or nonrheumatologic disease. When present, systemic symptoms such as fever, rash, headache, listlessness or lethargy, limping, weakness, or anorexia, which may be transient or chronic, should lead the examiner away from primary mechanical and noninflammatory disorders as the cause of the complaints. Knowledge of features that may distinguish inflammatory from noninflammatory conditions (see Table 103.1) and a fundamental understanding of the spectrum of pediatric diseases that primarily involve other body systems but are known to have musculoskeletal manifestations (Table 103.5) also help to focus the diagnostic strategy. Clinical reasoning using the constellation of symptoms and signs produce more accurate diagnosis rather than depending on isolated symptoms or laboratory examinations to arrive at a correct diagnosis. Disease features such as peripheral joint swelling increase the likelihood of a rheumatic diagnosis, but demonstration of joint instability, pain with maneuvers to isolate specific structures, predominant night time pain, pain largely associated with activities, and the absence of local inflammation or systemic symptoms are more suggestive of noninflammatory rheumatic disease (see Table 103.4).

SEPTIC ARTHRITIS Septic or infectious arthritis is a serious infection that should be recognized promptly because it can rapidly lead to joint destruction, sometimes within 24 hours of onset. Monoarticular disease is much more common than polyarticular disease in infections with most organisms, except Neisseria infection, especially gonococcal arthritis in teenagers, especially when the oropharynx has been infected. The hip joint is the most commonly septic joint in young children, and septic arthritis more frequently affects boys than girls. Staphylococcus aureus is now the most common bacterium causing septic arthritis; routine use of Haemophilus influenzae vaccine has drastically reduced the incidence of H. influenzae–related invasive disease. Kingella kingae is an increasingly identified cause of musculoskeletal infections in young children.1,2 Children with infected joints generally look unwell and may have a “toxic” appearance, with high fever and severe pain limiting the Table 103.5

Some Major Pediatric Diseases That May Have Musculoskeletal Manifestations

FIG. 103.6  Gentle forward flexion of the spine in a preadolescent boy with normal examination findings.

Disease

Musculoskeletal Manifestation

Cystic fibrosis Down syndrome Diabetes Hypothyroidism/hyperthyroidism Hemophilia Hemoglobinopathies Pancreatitis Inflammatory bowel disease

Large- and small-joint arthropathy Carpal osteolysis Cheiroarthropathy Musculoskeletal pain Intraarticular and muscle hemorrhage Avascular necrosis, septic arthritis Osteolytic lesions Erythema nodosum, large-joint arthritis, spondyloarthritis Hypertrophic osteoarthropathy Metastases, hypertrophic osteoarthropathy

Cyanotic congenital heart disease Malignancies

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SECTION 8  Pediatric Rheumatology

ability to bend the affected joint. Septic arthritis often results from hematogenous spread but may also occur after a puncture wound or infected skin lesions (e.g., chickenpox). In young children, it may result from spread from adjacent osteomyelitis into joints where the capsule inserts below the epiphyseal growth plate; coexistent osteomyelitis occurs in up to 15% of affected children. Aspiration of the affected joint space for culture, fluid analysis (the definitive test), and drawing of blood for cultures are best performed before the initiation of intravenous antibiotics unless doing so would delay therapy unacceptably. Notably, Kingella kingae may be difficult identify by culture and signs of inflammation may be quite mild.

REACTIVE OR POSTINFECTIOUS ARTHRITIS Reactive arthritis is the most common form of arthritis in childhood and is defined as time-limited joint swelling (usually lasting less than 6 weeks) after (or rarely accompanying) evidence of extraarticular infection. The enteric bacteria (Salmonella, Shigella, Campylobacter, and Yersinia spp.) are implicated in most pediatric cases of reactive arthritis. Arthritis after infection with parvovirus B19, influenza viruses, coxsackie viruses, Mycoplasma spp., or Borrelia spp. or after infection with or vaccination against rubella virus or herpesviruses is also seen. Acute rheumatic fever and poststreptococcal reactive arthritis may be classified within the broader category of reactive arthritis. New pathogens such as arthritis from chikungunya and possibly zika may be seen but appear in adults to have a greater likelihood of evolving into a chronic persistent arthritis.

MUSCULOSKELETAL SYNDROMES AND BENIGN LIMB PAINS Hypermobility syndrome is one of the most common noninflammatory diagnoses in children and is discussed in Chapter 217. Benign limb pains, also known as growing pains, occur in 10% of children between the ages of 4 and 14 years. Children typically awaken at night with deep thigh or calf pain that responds to analgesics, massage, and heat, and there may be a family history of similar problems in one of the parents. Normal findings on physical examination along with a history of normal activity after the episode resolves are helpful in distinguishing benign limb pain from a more serious cause of night pain (e.g., osteoid osteoma or malignancy-associated limb pain). No further workup is needed if there is a typical history and absence of any physical abnormalities. Growing pains frequently remit, although intermittent night pain may continue for many years.3

involvement, and often the other hip is asymptomatic.5 When bilateral, the hips are usually in different stages of disease. Ischemia is thought to occur within the femoral epiphysis, but damage may be cumulative with more than one episode of ischemia leading to the observed avascular necrosis. Revascularization and reossification follow over 18 to 36 months, and the goal of treatment is to have the femoral head remodel in a spherical fashion within the acetabulum. Mutation in the COL2A1 gene (which encodes a precursor of the type II collagen α1 chain) has been associated with LCP disease.5,6 The severity of hip involvement and long-term risk are similar in boys and girls; fever and elevated inflammatory parameters are typically absent.

Imaging Initial radiographic findings may be normal, but radiographs eventually show increased density in the femoral head, which subsequently becomes fragmented (Fig. 103.8) during revascularization and irregular, which results in superior and lateral subluxation. On radiographs, four stages of the pathologic process can be identified: initial, fragmentation, healing, and reossification. Healing is manifested by new bone formation and reossification, with or without residual deformity. Changes in the acetabulum are important in the long term6,7; several radiographic classification systems for LCP disease exist and are based either on the extent of involvement of the femoral head (Stulberg classification)8 or on the height of the lateral epiphysis on anteroposterior radiographs (lateral pillar classification system).9 In LCP disease, the amount of femoral head involvement and the degree of lateral subluxation are such important prognostic factors that they are best assessed by MRI to determine the extent and location of involvement in the femoral head and the degree of lateral subluxation.10–12 Before the advent of MRI, technetium-based bone scanning was the gold standard for evaluation of this disease; reduced uptake occurs initially followed by foci of increased accumulation in the femoral head as revascularization occurs. Bone scanning may still be useful when MRI scans cannot be obtained (Fig. 103.9).

REGIONAL SYNDROMES: HIP TRANSIENT (TOXIC) SYNOVITIS (IRRITABLE HIP) Toxic synovitis (TS) is the most common cause of acute hip pain in children ages 2 to 12 years and often follows or occurs at the time as a viral infection. Sudden onset of pain in the hip and a reluctance to weight bear in the young child or a limp in the older one is the most common presentation. There is typically decreased range of motion on examination; the hip is held in external rotation, which is the position of greatest comfort, and pain may be referred to the knee. Fever may be present, but affected children do not appear overly ill. The neutrophil count and levels of acute-phase reactants may be normal or slightly elevated; radiographs are normal, but a small joint effusion is frequently apparent on ultrasound evaluation (Fig. 103.7). TS must be distinguished from septic arthritis, high fever, severe illness, pain at rest, and minimal or no movement at the hip, the latter which confers marked elevation in neutrophil counts and acute-phase reactants and frequent association with positive blood culture results. Aspiration of the hip joint in TS allows infection to be excluded and may temporarily relieve most or all of the symptoms. Management of transient synovitis is with nonsteroidal antiinflammatory drugs (NSAIDs); rest or activity is recommended as tolerated. Occasionally transient synovitis precedes the presentation of Legg-Calvé-Perthes (LCP) disease or slipped capital femoral epiphysis

FIG. 103.7  Ultrasound image in a patient with irritable hip (transient synovitis of the hip) demonstrating effusion.

LEGG-CALVÉ-PERTHES DISEASE Legg-Calvé-Perthes disease was described independently by Legg, Calvé, Perthes, and Waldenström.4 It is an idiopathic hip disorder hypothesized to be caused by reduced vascular flow to the affected area. It is more common in boys than in girls with a peak incidence between 4 and 10 years of age; the onset is insidious with the disorder manifesting as a limp or persistent hip or knee pain. Up to 13% of children have bilateral

FIG. 103.8  Avascular necrosis of the right hip.

CHAPTER 103  Evaluation of children with rheumatologic complaints Magnetic resonance imaging adds additional anatomic visualization in LCP disease. The presence of a subchondral fracture line on MRI predicts eventual necrosis better than it does the extent of necrosis, but the sphericity of the femoral head is also an important predictor of long-term outcome. Gadolinium-enhanced subtraction MRI can improve sensitivity in early diagnosis of LCP disease and may be used to monitor subluxation.11,13 Synovitis was observed by MRI in 72 patients with LCP disease, with a correlation between the severity of the synovitis and the severity of the necrosis.11 Cartilaginous physeal and metaphyseal abnormalities are common and frequently are associated with growth arrest.

881

Pathophysiology Ischemic necrosis precedes collapse of the head and subsequent repair of the femoral capital epiphysis. The initial event is silent clinically, and with collapse and repair of the bone, pain and limitation of motion, particularly abduction and internal rotation, develop to varying degrees. The extent of subsequent growth disturbance of the proximal femur where the epiphyseal and physeal cartilage are located depends on the extent of the avascular event. The pathogenesis involves a disruption or interruption of the blood supply to the femoral head (Fig. 103.10). Thrombophilia (enhanced ability to form clots), hypofibrinolysis (decreased clot breakdown), or both may contribute to the pathogenesis of LCP disease; LCP disease with thrombophilia secondary to protein C and S deficiency as well as Leiden V mutation has been reported.14 More recent information suggests that polymorphism in methylenetetrahydrofolate reductase (MTHFR) and polymorphisms in platelet glycoprotein IIb/IIIa associate with severity of LCP disease whereas factor V Leiden mutations do not.14,15 The incidence of LCP appears to be declining, but the precise factors contributing to the decline remain unknown.16

Treatment Children with mild LCP disease often do not require intervention but instead can be observed and managed symptomatically with activity restriction and physical therapy. This low-risk group includes children who maintain good hip motion (at least 30 degrees of abduction) or who are younger than 6 years of age. However, about 60% require mechanical treatment, which is based on the principle of containment of the femoral head within the acetabulum so that, during healing, the head is molded by the acetabulum. Obtaining the maximal sphericity of the femoral head is the goal to ensure acetabular development and containment.17 Containment is accomplished by bracing or by surgical intervention using an innominate (Salter) osteotomy, femoral osteotomy, or combination of the two. The role of bisphosphonate therapy in limiting damage by reducing osteoclast and remodeling is still under investigation.

a

Prognosis The overall prognosis is good, particularly in those younger than 6 years of age with less than half of the epiphysis involved. When more than 50% of the epiphysis is affected and the child is older than 6 years, deformity of the femoral head and metaphyseal damage are more likely, resulting in secondary osteoarthritis in adult life. In more severe disease, the femoral head needs to be covered by the acetabulum to act as a mold for the reossifying of the epiphysis maintaining some degree of sphericity.

b

FIG. 103.9 Pelvic radiograph and technetium bone scintiscan for an 8-year-old with Legg-Calvé-Perthes (LCP) disease. (a) The child has early involvement of the right hip, with relatively subtle changes apparent on the radiograph. (b) The bone scintiscan, however, shows complete blood loss in the right femoral head, consistent with osteonecrosis. The left hip shows classic, more advanced stages of LCP disease (in the revascularization phase), with return of normal blood flow visible on the scintiscan.

Long-term follow-up A review of 20- to 40-year follow-up studies found that 70% to 90% of patients are active and pain free, regardless of treatment.18 Growth studies in children followed longitudinally show that affected children are slightly shorter at birth and that they remain shorter over the entire growth period. The femoral head and neck deformity can lead to a “functional retroversion,” causing an externally rotated gait.19

ARTERIAL SUPPLY TO THE FEMORAL HEAD Retinacular artery

Joint cartilage Greater trochanter

Femoral neck Lateral circumflex femoral artery

Epiphyseal Capsule of plate hip joint

Medial circumflex femoral artery

Retinaculum or reflected synovial layer of capsule

FIG. 103.10  Normal blood supply to the femoral head in a 4-year-old child. A blockage of this blood supply, which is yet not fully understood, leads to Legg-CalvéPerthes disease.

.

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SECTION 8  Pediatric Rheumatology

SLIPPED CAPITAL FEMORAL EPIPHYSES Slipped capital femoral epiphyses (SCFE) is most likely to occur in preteen and early teenaged boys; its overall incidence in the general population is 0.7 to 3.4 per 100,000.20,21 Boys are affected at least two to five times more frequently than girls. The peak age at onset is 11.5 years in girls and 13 years in boys.22 Acute SCFE occurs up to 10% to 15% of the time.23 In SCFE, whereas the term acute refers to the interval between the onset of pain and presentation to the practitioner (10,000 μg/L), high soluble transferrin receptor (sCD25), and hemophagocytosis in the bone marrow, spinal fluid, liver, and/or spleen. The European League Against Rheumatism/American College of Radiology (EULAR/ACR)-approved criteria for MAS in systemic JIA are shown in Box 105.1.6 Left untreated, the mortality rate is high (50% in earlier series). Prompt treatment with anti-­ interleukin 1 drugs and corticosteroids reduces mortality, and recent reports show an 8% mortality rate.19,20

OLIGOARTHRITIS, PERSISTENT AND EXTENDED

b

FIG. 105.2  Hip arthritis in systemic juvenile idiopathic arthritis. (a) Hip joint space narrowing bilaterally. (b) There was recovery of joint space 2 years later (standing view).

a

Arthritis in a child with fewer than five actively affected joints during the first 6 months of the disease course fits into the most common category of oligoarticular JIA, unless specific exclusion criteria are present (see later). Oligoarthritis may be further divided into persistent or extended according to the number of joints involved after the first 6 months. At least one-third of children develop extended oligoarticular disease with five or more joints involved during the disease course.21 The majority of children with oligoarticular JIA are younger than 5 years of age at presentation, with a peak onset between 1 and 3 years of age. Oligoarticular JIA occurs more frequently in girls, with a female-tomale ratio of 2 : 1 for the persistent category and 5 : 1 for the extended category. Commonly, such children are brought to the physician because of a limp4 with few or no constitutional signs or symptoms; complaints of pain are less frequent. In the majority of cases, laboratory findings show little or no increase in CRP, ESR, or thrombocytes. If only one joint is involved and the joint is painful and red, a more likely diagnosis is septic arthritis, especially if the onset is abrupt, the child has a fever, or there is a marked inflammatory response. At onset the knee is the most commonly affected joint (Fig. 105.8), followed by the ankle and then either the small joints of the hand or the elbow. Involvement of the TMJ and cervical spine is also

b

FIG. 105.3  Magnetic resonance images of a swollen ankle in a 5-year-old boy. In addition to talocrural arthritis, joint fluid and synovitis are present in the subtalar and the talonavicular joint (arrows). There is bone marrow edema of the talus on the short tau inversion recovery image (a). Fat-suppressed T1 image after administration of intravenous contrast (b) shows tenosynovitis (arrows).

CHAPTER 105  Clinical features of juvenile idiopathic arthritis

897

ULTRASOUND IMAGES OF THE WRIST

rc

rc mc

Radius

Lun

mc Radius

Cap

Proximal

Distal

a

Lun

Cap

Proximal

Distal

b

c

FIG. 105.4  (a) Schematic of the normal thin dorsal recesses of the radiocarpal (rc) and midcarpal (mc) joints, pointing distally. (b) Schematic of hypertrophic thickened synovial recesses of the radiocarpal and midcarpal joints. (c) Dorsal sagittal ultrasonographic scan of a hypoechoic thickened radiocarpal recess. Cap, Capitate bone; Lun, lunate bone. (From Laurell L, Court-Payen M, Nielsen S, et al. Ultrasonography and color Doppler in juvenile idiopathic arthritis: diagnosis and follow-up of ultrasound-guided steroid injection in the wrist region. A descriptive interventional study. Pediatr Rheumatol 2012;10:11)

Table 105.3

Characteristics of the Various Categories of Juvenile Idiopathic Arthritis Category

Age at Onset

Affected Joints

Systemic Features

Major Complications

Oligoarticular persistent

Early childhood

No

Chronic uveitis Local growth disturbances

Oligoarticular extended

Early childhood

No

Chronic uveitis Local growth disturbances

Polyarticular RF negative Polyarticular RF positive Systemic

Throughout childhood Teenage years

Large joints, asymmetric (knee, ankle, wrist, elbow, temporomandibular, cervical spine) Same as above, but more than four joints involved after the first 6 months of disease Any, often symmetric, often small joints

Malaise (subfebrile)

Chronic uveitis Local growth disturbances Local growth disturbances and articular damage Acute: macrophage activation syndrome Chronic: general growth disturbance, amyloidosis Psoriasis Local growth disturbances Acute symptomatic uveitis

Throughout childhood

Psoriatic

Late childhood

Enthesitis-related

Late childhood

Any, usually symmetric and involving small joints Any (not necessarily at disease onset)

Spine, lower extremities, distal interphalangeal joints, dactylitis Spine, sacroiliac, lower extremities, thoracic cage joints

Malaise (subfebrile) High fever, rash, polyserositis, marked acute-phase response

Inflammatory bowel disease

RF, Rheumatoid factor.

common, but involvement of other joints occurs less frequently. Arthritis limited to the hip is extremely rare in this category and, if present, the diagnosis should be questioned. The immunofluorescence ANA test yields positive results in 40% to 85% of children with oligoarticular JIA, both persistent and extended, and a positive ANA is associated with chronic asymptomatic anterior uveitis. The association with uveitis is particularly strong for preschool girls with ANA positive arthritis, regardless of number of active joints.22

POLYARTHRITIS Approximately 25% of children with JIA have polyarticular onset involving five or more joints during the first 6 months of disease. Two categories of polyarthritis are defined depending on the existence of persistent serum IgM RF.

Rheumatoid factor–negative polyarticular juvenile idiopathic arthritis In RF-negative polyarticular JIA, the joints tend to be symmetrically involved, with the knees, wrists, and ankles being most commonly affected. In the hands, the metacarpophalangeal and proximal interphalangeal joints are involved, and flexor tenosynovitis is common (Fig. 105.9). The TMJ and cervical spine are often affected, and occasionally patients have torticollis. Hip and shoulder may be involved. Systemic features such as fatigue, lowgrade fevers, mild hepatosplenomegaly, and anemia may occur.

Rheumatoid factor–positive polyarticular juvenile idiopathic arthritis Teenagers with early symmetrical small joints involvement, unremitting inflammatory activity, nodules similar to those seen in adult rheumatoid arthritis (RA), and early development of erosions on radiographs are more likely to have ACPAs and IgM RF, disease persistence, and poor outcome. Systemic features are rare, except for fatigue and anemia. The clinical presentation and the genetic profile of this category are very similar to those of seropositive adult RA,23 and most patients are female. Symmetric involvement of the small joints is typical, including the metacarpophalangeal, metatarsophalangeal, and proximal interphalangeal joints, as well as sometimes the distal interphalangeal joints. Large joints tend to be involved only in association with small-joint involvement. Flexor tenosynovitis is common and often results in trigger fingers.

PSORIATIC ARTHRITIS Dactylitis, nail pitting, distal interphalangeal arthritis, and asymmetric RF-negative peripheral arthritis are typical findings in juvenile as well as adult psoriatic arthritis. Arthralgia and joint contractures may be a more prominent feature than clinically overt arthritis. A significant proportion of children may develop inflammatory back disease, including spondyloarthritis and sacroiliitis. Results of an ANA immunofluorescence test were positive in one-third of children fulfilling the ILAR criteria for psoriatic arthritis in an epidemiologic study from Scandinavia.24 Juvenile psoriatic arthritis is

SECTION 8  Pediatric Rheumatology

898

FEVER IN SYSTEMIC-ONSET JIA 42 41

Temperature (C)

40 39 38 37 36

02 06 10 14 18 22 02 06 10 14 18 22 02 06 10 14 18 22 02 06 10 14 18 22

FIG. 105.7  Radiograph of a 3-year-old child with systemic juvenile idiopathic arthritis who had pericardial effusion at presentation.

Time (hours)

FIG. 105.5  An example of the typical fever curve seen in systemic juvenile idiopathic

BOX 105.1 EULAR/ACR 2016 CRITERIA FOR THE CLASSIFICATION

OF MACROPHAGE ACTIVATION SYNDROME IN PATIENTS WITH SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS

arthritis (JIA).

A febrile patient with known or suspected systemic JIA is classified as having macrophage activation syndrome if the following criteria are meta: • Ferritin >684  μg/L • And any two of the following: • Platelet count ≤181 × 109/L • Aspartate aminotransferase >48 units/L (0.8 μkat/L) • Triglycerides >1.56  g/L • Fibrinogen ≤3.6  g/L  Laboratory abnormalities should not be otherwise explained by the patient’s condition, such as concomitant immune-mediated thrombocytopenia, infectious hepatitis, visceral leishmaniasis, or familial hyperlipidemia. ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; JIA, juvenile idiopathic arthritis. From Ravelli A, Minoia F, Davi S, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2016;75(3):481–9 and Arthritis Rheumatol. 2016 Mar;68(3):566–76. doi: 10.1002/art.39332. Epub 2016 Feb 9. a

a

b

FIG. 105.6 The rash of systemic juvenile idiopathic arthritis. Larger lesions are becoming confluent (a). This must be differentiated from erythema marginatum (b), characteristic of the rash seen in rheumatic fever.

a heterogeneous category, and the discussion on whether psoriasis should define a distinct disease category in JIA is ongoing.25

ENTHESITIS-RELATED ARTHRITIS Enthesitis-related arthritis (ERA) affects more boys than girls and presents most commonly after the age of 9 years.26 Arthritis typically involves the lower extremities, most commonly the knees, ankles, tarsal joints, and hip.27 Enthesitis, defined by the ILAR as “tenderness at the insertion of the tendon, ligament, joint capsule or fascia to bone,”3 occurs frequently and is commonly seen as plantar fasciitis, Achilles tendinitis, and patellar tendon enthesitis. Enthesitis can be difficult to differentiate from arthritis. Inflammatory back pain is often seen, defined as “lumbosacral spinal pain at rest with morning stiffness that improves on movement.”3 Many of these children have sacroiliitis and may later develop spondyloarthritis (Fig. 105.10). The ERA category incorporates those conditions traditionally viewed as spondyloarthritis in adults, including juvenile ankylosing spondylitis and the syndrome of seronegative enthesopathy and arthropathy (SEA syndrome).27

ERA is difficult to diagnose correctly during childhood because some of the features defining the category typically develop over many years of disease, which causes frustration for the patient, family, and physician. The full clinical picture might not be seen until adulthood. Also, this is a category in which pain, especially diffuse back pain, might be the initial symptom bringing the teenager to seek medical advice. The association with HLA-B27 is strong, and those with HLA-B27, a family history of spondyloarthritis, and definite arthritis are more likely to develop spondyloarthritis at follow-up. Uveitis, usually acute and symptomatic, occurs in 15% to 25% of children with ERA. Another major feature can be severe hip disease, requiring early total hip replacement. In this category, inflammatory bowel disease (IBD) must be considered if there is diarrhea, persistent fever associated with the arthritis, poor growth, or delayed puberty.

UNDIFFERENTIATED ARTHRITIS Undifferentiated arthritis is a rather unsatisfactorily defined category that results from the goal of the present ILAR classification to form homogeneous categories to facilitate research. Psoriasis, enthesitis, sacroiliitis with inflammatory bowel disease, and first-degree relatives with psoriasis or ankylosing spondylitis are exclusion criteria for other categories, as described in Chapter 104.3 Cases are excluded from the other categories because they fulfill criteria for two or more categories or for no category because of exclusion criteria. In a Scandinavian epidemiologic study using the present ILAR criteria, about 15% of JIA cases belonged to the undifferentiated category.28 Almost all of these children had oligoarthritis, extended or persistent, or enthesitis-related arthritis, and the main reason for exclusion was a first-degree relative with psoriasis or fulfillment of the criteria for more than one category.

CHAPTER 105  Clinical features of juvenile idiopathic arthritis

SPECIAL PROBLEMS OF ARTHRITIS IN CHILDREN Children and adolescents with rheumatic diseases have specific problems that do not pertain to adults. Delayed physical development as shown by growth and puberty may occur in all childhood rheumatic diseases. Growth disturbances can be local or general and may result in permanent sequela. The chronic, asymptomatic uveitis associated to childhood arthritis is specific to children. All of these manifestations are dealt with in more details in the next sections.

MULTIDIMENSIONAL OUTCOME JIA may have considerable impact on physical function and psychosocial well-being throughout childhood and into adult life. To what degree today’s early, more intensive, and tailored treatment improves outcome remains to be seen. Outcome is a multidimensional phenomenon that needs to be viewed from many perspectives. Most studies have focused on traditional disease-centered outcomes, including mortality, disease activity and duration, remission, physical disability, and structural damage. To get a true picture of the impact of JIA from a patient-centered approach, a broader perspective must be adopted, including quality of life issues such as pain and fatigue, psychosocial health, participation, and socioeconomic attainments.29 Important prerequisites when studying disease outcome include using common classification criteria to ensure that we measure the same disease and validated outcome measures to ensure that we measure the same outcome. The Juvenile Arthritis Disease Activity Score (JADAS) is such a

899

validated measure of disease activity.30–33 It is a simple composite score consisting of the patient/parent and physician global assessment, the number of involved joints, and the ESR or CRP level. The ACR core set of improvement is based on mainly the same variables.34 The Juvenile Arthritis Damage Index (JADI) is a validated tool aiming to score long-term articular and extraarticular damage.35 New tools to monitor disease activity and predict outcome are likely to allow individually tailored early treatment aiming to decrease joint destruction and improve long-term outcome.12,36,37 Before we continue to discuss long-term outcome in JIA, it is important to remember that today’s outcome studies will always reflect yesterday’s treatment practice. We will never be able to study long-term outcome of the most updated standard of care.

MORTALITY, CANCER, AND SEVERE MORBIDITY The most recent studies show no increased mortality in JIA, but in certain categories and in historic reports, standardized mortality ratios ranged from three to five times that of the normal population.38,39 A small but significantly increased risk of lymphoproliferative malignancies is found in large epidemiologic studies of JIA but no additional risk attributable to the increasing use of biologic disease-modifying antirheumatic drugs (DMARDs).40,41 The

POSSIBLE COURSE OF ENTHESITIS-RELATED ARTHRITIS Active synovitis

Right hip replacement

Left total hip replacement

Right hip Left hip Sacroiliitis No back limitation noted

Left elbow Left hip Right toe Heels

Right toe Tendinitis

Knee 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Age (years)

FIG. 105.8  Oligoarticular juvenile idiopathic arthritis in a 2-year-old girl with arthritis

FIG. 105.10  Disease course and joint involvement in enthesitis-related arthritis in an

in her left knee.

HLA-B27-positive boy. JIA, Juvenile idiopathic arthritis.

FIG. 105.9  Finger joint involvement. (a) Symmetric involvement of metacarpophalangeal and proximal interphalangeal (PIP) joints typical of polyarticular juvenile idiopathic arthritis (JIA) in a 9-year-old girl. (b) More advanced changes can evolve over time with joint deviations, as in this teenaged boy. (c) Asymmetric arthritis with swelling and extension deficit in the fourth PIP joint in a young girl with oligoarticular JIA. (Courtesy Ellen Nordal.)

a

b

c

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SECTION 8  Pediatric Rheumatology

increased risk of cardiovascular disease seen in adult RA has not been verified in children, but there are indications of blood vessel endothelial dysfunction42 and increased arterial stiffness compared with controls.42,43 Today amyloidosis is an extremely rare complication of systemic JIA, owing to more effective antiinflammatory therapy. Amyloidosis should be suspected in patients with persistent disease activity who develop proteinuria and a rising ESR with falling hemoglobin and serum albumin levels.

has been shown that early disease-modifying antirheumatic drug treatment, including biologics, is associated with better outcomes, supporting the concept of a “window of opportunity” where the natural disease outcome may be modified.64,65

CONTINUOUS ACTIVITY, INACTIVITY, AND REMISSION

Joint destruction with radiographic changes, especially in the hip and wrist, was seen in 25% after 10 years’ disease duration in studies from the prebiologic era.66,67 Even if the risk of joint destruction is much lower today, children with JIA still have increased risk of local growth disturbances not seen in adults.

A common misconception has been that most childhood arthritis disappears in adulthood. Duration of disease, risk of flares, and chance of remission may be more important outcome dimensions than life-threatening but very rare consequences. It is challenging to define remission in diseases that are characterized by flares and quiescence. It was a great achievement when Wallace defined clinical remission, disease activity, and inactivity in JIA.44,45 Unfortunately, it becomes increasingly more obvious that remission is not the same as being cured and that many pediatric rheumatic conditions will flare even after long-term remission.44,46 While the Wallace criteria are important for definition of inactivity and remission, the JADAS score30–33 may be used to quantify disease activity and change in activity over time. Since 2000, several studies on long-term outcome of JIA have been published (Table 105.4). Most are retrospective and/or hospital-based studies (see Table 105.4),21,47–57 but a few are population-based (see Table 105.4).21,57 All studies demonstrate that 40% to 70% of the patients are not in remission off medication after more than 10 years of disease. Most of these studies have been performed in the prebiologic era, but the Nordic study published in 2019 started inclusion in 1997, and 30% of the participants had been treated with biologics during the study, a fact that did not change the high number of patients not in remission at the end of the study period.21

RISK FACTORS FOR CONTINUOUS ACTIVITY AND DAMAGE The outcome of JIA depends on the disease phenotype. Remission rate is highest in persistent oligoarticular arthritis (50%–80%), lower in extended oligoarticular and polyarticular disease (20%–30%), and especially low in the polyarticular RF positive category.21,32,58 Remission rates in studies of systemic disease are more variable (0%–80%), with higher remission rates in population-based studies.21,47 The long-term remission rates in enthesitis-related arthritis and juvenile psoriatic arthritis seem to be low (0%–30% and 30%–40%, respectively),51,57,59,60 and HLA-B27 seems to predict a more chronic disease course.10 The most consistent risk factors for continued disease activity, disability, and joint damage in JIA are polyarticular and extended oligoarticular disease, especially in females; elevated inflammatory markers at onset; and positive RF. New knowledge of risk factors and biomarkers may in the future be used in prediction models of outcome to guide clinical decision making.12,36,61,62 Attainment of disease inactivity at least once in the first 5 years is found to be associated with less long-term joint damage and a trend toward less functional impairment.57,63 More recently it

ARTICULAR AND SKELETAL DAMAGE Joint destruction

Local growth disturbances Local factors that influence bone growth include proinflammatory cytokines that stimulate osteoblasts to increase epiphyseal growth but also stimulate maturation and closure of the epiphysis if inflammation is long-standing. The knee, ankle, and hand are most commonly involved, but on rare occasions joints such as the cricoarytenoid may be involved, resulting in hoarseness, permanent voice changes, and laryngeal stricture.68

Knee The most frequent site of overgrowth is the inflamed knee. The result is leglength inequality, with the longer leg on the side of the involved knee (see Fig. 105.8).69 Valgus deformity and atrophy of the muscles in the affected thigh might be seen as a complication of long-standing knee arthritis, especially in the youngest children. Occasionally, the inflammation results in early epiphyseal closure, causing a permanently shorter leg on the side of the involved knee (Fig. 105.11).

Ankle Valgus deformity in the ankle is a common sequela of arthritis in the talocrural, subtalar, or tarsal joints (Fig. 105.12). These changes may be reversible in a growing child if the arthritis responds to treatment. Temporary correction of the deformity by orthopedic soles is usually helpful.

Wrist and hand In contrast to the knee, many growth disturbances seen radiographically in the wrist are not observed clinically. The wrist can show increased bone age (see Fig. 105.1) and carpal bone fusion with long-standing involvement. Brachydactyly can occur in the fingers or toes as a result of early epiphyseal closure (see Fig. 105.1). In polyarticular disease, especially if RF positive, radiologic abnormalities of the wrist and hand may already be seen at the time of diagnosis.

Hip Growth abnormalities in the hip include lack of growth of the iliac bone and a coxa valga deformity with widening of the femoral neck or premature fusion leading to stunting of the femoral neck (Fig. 105.2).

Table 105.4

Long-Term Studies on Outcome of Juvenile Idiopathic Arthritis: Disease Activity and Disability Study (Author, Year, Country)

Participants (n)

Disease Duration, Mean/ Mediana (Years)

Active Disease: Not in Remission Off Medication (%)

Disability: HAQ/C-HAQ >0 (%)

Zak and Pedersen, 2000, Denmark49 Oen et al., 2002, Canada50 Minden et al., 2002, Germany51 Packham and Hall, 2002, UK52 Fantini et al., 2003, Italy53 Foster et al., 2003, UK55 Arkela-Kautiainen et al., 2005, Finland54 Bertilsson et al.,b 2013, Sweden57 Dimopoulou et al., 2017, Greece56 Tollisen et al.,b 2018, Norway47 Tollisen et al.,b 2019, Norway48 Glerup et al.,b 2019, Nordic countries21

65 392 215 246 683 82 123

26 11a 17a 28 10 21a 16

37 44 55 54 67 39 65

46 55 39 — — — —

86 102 176 96 434

17 17 30 19 18

60 76.5 57 59 67c

46 47 47 46 28

C-HAQ, Childhood Health Assessment Questionnaire; HAQ, Health Assessment Questionnaire. a Median years. b Prospective study. c 52% had JADAS ≥1.

CHAPTER 105  Clinical features of juvenile idiopathic arthritis

a

901

b

FIG. 105.11  Oligoarticular juvenile idiopathic arthritis with arthritis in the right ankle. (a) A shorter leg length from the knee to the ankle is seen. (b) The right foot is smaller, with underdevelopment of the right forefoot caused by disuse.

FIG. 105.13  Systemic juvenile idiopathic arthritis in a child who had a polyarticular course. Her neck shows apophyseal fusion of C2 to C4 and undergrowth of the adjacent vertebrae.

adults with JIA.75,76 Some have also shown increased prevalence of vertebral fractures.77 However, little is known about the bone health in JIA in the biologic era, and very little is known about the risk of fractures in older age.

ENDOCRINE DAMAGE Endocrine damage with consequences for growth and puberty is of special concern in children with JIA.

General growth disturbance

TMJ arthritis is reported in 40% to 70% of children with JIA.70 It occurs in all categories and may be overlooked because arthritis may be asymptomatic or young children may have difficulties describing symptoms. Clinical signs of mandibular dysfunction are pain, reduced opening of the mouth, TMJ crepitations, and restricted horizontal movements.71 Even a thorough clinical examination might not reveal the early signs of condylar lesions, which can present early, progress insidiously, and might lead to malocclusion and severely altered craniofacial profile.72 Unilateral TMJ disease can result in deviation to the affected side of the jaw on opening the mouth, resulting in facial asymmetry caused by mandibular hypoplasia (Fig. 105.14). Regular evaluation of all children with JIA by a pedodontist or orthodontist is recommended to enable early detection and intervention.73

General growth disturbance has been observed and is related to active disease intensity and duration. During quiescent periods of the disease, height can return to normal in 2 to 3 years if premature closure of the epiphysis did not occur. The cause of delayed growth is multifactorial, and the precise mechanisms of the effects of inflammatory cytokines, glucocorticosteroids, and malnutrition on systemic and local growth factors are still unclear.78 Studies have suggested that decreased caloric intake, increased metabolic needs beyond recommended daily requirements, or lack of essential vitamins may result in decreased weight and growth velocity. Corticosteroids also inhibit growth but usually not skeletal maturation (Fig. 105.15). Growth retardation is likely to occur with corticosteroid doses higher than prednisolone 5 mg/m2/day (corresponding to Prednisone at about 0.125 mg/kg/day) for 6 months or longer, but individual tolerance varies.79 Studies on final height in patients with JIA are few and indicate no major reduction in height, but subsets of patients might still end up with a final height considerably below their target height.80 Studies have shown that 5% to 10% of children with JIA are estimated to be growth restricted,51,81,82 mainly patients with unremitting systemic, polyarticular, or extended oligoarticular disease. Treatment to target inactive disease with disease-modifying antirheumatic drugs and biological drugs may stabilize and even improve growth velocity in JIA.80,82 Careful monitoring of the growth of the child with JIA is mandatory during follow-up, and when reduced growth is assessed, treatment optimization, as well as dietary status and pubertal development, has to be considered.83

Bone health and osteopenia

Pubertal delay

The bone mass reaches its peak in early adulthood, and permanently reduced bone mass in JIA may be due to several factors, such as inflammation, corticosteroids, decreased physical activity, delayed puberty, and suboptimal calcium and vitamin D intake.74 Several studies have shown reduced bone mineral density and increased frequencies of osteopenia and osteoporosis in

Timing of puberty in JIA is rarely studied, may be difficult to measure, and varies among countries and populations.83 Although some studies have shown delayed pubertal onset, decreased pubertal tempo, and delayed menarche, the studies have been small and performed in the prebiologic era.84 The consequences for final height, osteoporosis, and psychosocial issues for

FIG. 105.12  Valgus deformity in the left ankle caused by long-standing arthritis in a 5-year-old girl with juvenile idiopathic arthritis since age 21 months. (Courtesy Marite Rygg.)

Cervical spine Cervical spine arthritis may result in apophyseal joint space narrowing and bony ankylosis (especially of C2–C3) (Fig. 105.13). Similar findings are not seen in the lumbar spine, but compression fractures of the thoracic spine may occur, particularly in children with systemic JIA taking long-term corticosteroids.

Temporomandibular joint

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SECTION 8  Pediatric Rheumatology

*

a

b

c

FIG. 105.14  Temporomandibular joint involvement. Note failure of development of the lower jaw, short and slightly flexed neck (a), malocclusion on the radiograph (b), and widened fossa (asterisk) and flattened condyle with irregular areas suggestive of erosions (arrowhead), increased amounts of intraarticular fluid, and the synovial enhancement on magnetic resonance imaging (MRI) sagittal oblique T1 fat-suppressed MRI 5 minutes after intravenous gadolinium administration (c). (c, Courtesy Thomas Augdal.)

patients with JIA treated with modern therapy are therefore not yet ascertained78 (or simply “not known”).

OPHTHALMOLOGIC COMPLICATIONS AND DAMAGE Uveitis is the most common extraarticular disease manifestation in JIA, and ophthalmologic complications are the most common extraarticular organ damage. According to data from population-based JIA series, chronic uveitis occurs in 3% to 30% of patients.22,85,86,87 In the majority of cases, the uveitis is anterior and asymptomatic. Uveitis occurs more commonly in children with early-onset arthritis, and 50% to 80% test positive for ANAs by immunofluorescence. Interestingly, there are ethnic differences in incidence,88 and some geographic areas (e.g., Costa Rica, Japan, India, and South Africa) report very few or no patients with ANA-positive oligoarthritis associated with uveitis,89–91 which suggests true differences in JIA manifestations pertaining to immunogenetics or environmental factors or a combination of both. Uveitis is rare among children with systemic and polyarticular RF-positive arthritis. Symptomatic uveitis occurs more often in boys and is associated with HLAB27 and enthesitis-related arthritis.92 Most cases of symptomatic uveitis are acute and episodic, but the uveitis may take a chronic course. According to population-based data, the median age at onset of JIA associated with uveitis is 5 years (range, 1–16 years); that is, lower than the age at onset in the total cohort of JIA. In about 80% of patients, uveitis appears within the first 4 years after onset of arthritis, but late cases may occur more than 7 years after disease onset.88,93,94 The uveitis is bilateral in about threefourths of the cases. The course of uveitis is unrelated to the course of the arthritis and may persist after arthritis has remitted. Ongoing active uveitis might be seen into adulthood in 30% to 50%.95,96 Because the uveitis is mostly asymptomatic, a slit-lamp examination for early detection of uveitis is necessary in all children with JIA. A cloudy light path looking like a light shaft in a smoky room is seen when the anterior chamber contains inflammatory cells and fibrin debris. The iris may be irregular because of posterior synechiae (Fig. 105.16). To avoid sight-threatening complications, several recommendations for timing and frequency of eye examination in JIA have been proposed; for example, the recommendations from the American Academy of Pediatrics Sections on Rheumatology and Ophthalmology.97,98 In general, the highest frequency of eye screening, every 3 to 4 months, is recommended in children with young age at onset of arthritis and during the first years after diagnosis of JIA in all children except for the systemic and RF-positive polyarticular categories. Even with screening programs aimed for early detection of uveitis, complications will develop in about 20% to 40% of patients with uveitis; the numbers seem to be stable even with better screening and treatment options, although the visual outcomes have improved.94,99,87 Complications are associated with early-onset uveitis, ongoing active inflammation, and prolonged local corticosteroid treatment, and include synechiae, band keratopathy, cataracts, glaucoma, and macular edema, phthisis, and loss of vision.100,101,87 The outcome is worse when uveitis occurs before or at the diagnosis of JIA and when the uveitis is severe at onset and continually active.100 Early detection and intensive treatment of uveitis seem to have improved the prognosis for vision considerably.99,102 However, a few patients who do not respond even to the most intensive treatments available today still

develop severely impaired vision. In population-based studies in Finland and the United States, the prognosis regarding blindness and severe vision loss is good. In the Finnish study, one-third of patients still had active uveitis after a median of 7 years, but only 3% had severe visual loss.99 In the study in Olmsted County, Minnesota, only 3% developed uveitis, and none had visual impairment after 8 to 24 years.103 The importance of screening for uveitis and early local and systemic treatment of inflammation and its complications must be stressed.91

PHYSICAL DISABILITY The functional outcome of JIA seems to have improved considerably over the past decades. The decline in number of patients with severe functional disability is likely due to early and more active treatment strategies with disease-modifying antirheumatic drugs such as methotrexate and biologic agents, treatment with intraarticular corticosteroids, and implementation of team-based comprehensive care. Physical disability may be measured with the Childhood Health Assessment Questionnaire (C-HAQ) in children and adolescents (HAQ in young adults). In recent long-term follow-up studies of young adults and adolescents with JIA, the percentages of participants reporting an HAQ or C-HAQ score of more than 0 were consistently above 30% (see Table 105.4). Similar results were found for the physical summary score of the generic health questionnaire, Short Form 36 (SF-36), in which young adults with JIA scored significantly lower compared with healthy age-matched controls.47 However, severe disability seems to be rare and decreasing with time. Physical disability according to disease categories is fairly distinct when evaluated by the C-HAQ/HAQ.28,57 Overall, 80% of patients with persistent oligoarticular JIA report no difficulties at 30-year follow-up.47 However, of those with an oligoarticular extended or polyarticular arthritis, more than half develop some functional disability, with highest rates among RF-positive patients.28,48 Poor functional outcome can also be seen in patients with systemic JIA who develop polyarticular disease.

QUALITY OF LIFE Quality of life measurements include items such as pain, fatigue, and psychosocial health, all items with a major impact on a person’s self-perceived health.

Pain Pain is common in all children, and musculoskeletal pain, headache, and abdominal pain are the most frequent complaints.104 Girls and older children experience pain more often than boys and younger children, and pain is associated with subjective disability. Self-reported pain is influenced by previous experience, development, and beliefs, as well as lifestyle factors, anxiety and depression, and family function.105,106 Sällfors and coworkers found a strong influence of experienced pain in the daily lives of children with JIA.107 Pain leads to many social consequences, such as nonparticipation in physical and social activities. Also, the fact that pain cannot be seen makes obtaining understanding from peers difficult. Selfreported, disease-related pain among children with JIA is common in the early

CHAPTER 105  Clinical features of juvenile idiopathic arthritis

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GROWTH CHART OF A GIRL WITH SYSTEMIC JIA 170

160

150

140 cm 55

FLICKOR F - 8 AR

250 150

250 150 0

50

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HUVUDOMFANG

cm

130

90 80

120

-250

-350

-350

110

100

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cm 140

70 110

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100

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90 35

40

LANGD

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250 15030

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FIG. 105.15  Inhibition of growth by corticosteroid therapy in a girl with systemic juvenile idiopathic arthritis (JIA). The first arrow indicates the start of corticosteroid treatment. The second arrow indicates start time of autologous stem cell transplantation.

phases of the disease and may also be a warning signal predicting persistent pain and unfavorable disease outcomes after many years of disease.106,108 Although median pain scores were usually low in recent long-term follow-up studies on JIA cohorts, about half of the adolescents and young adults with JIA scored above 0 on a visual analog scale for pain.28,47

Fatigue and sleep disturbance Fatigue is acknowledged as an important manifestation of rheumatic disease in adults and has also received increasing attention in children. Clinical follow-up studies using different instruments showed that fatigue is prevalent among both children and young adults with JIA.109,110 The PedsQL

904

SECTION 8  Pediatric Rheumatology

TRANSITION OF CARE Many young people have ongoing active disease into adulthood, and this group needs continuity of care in the transition from child-centered to adult-oriented systems. Young people should be given the chance to express their views and should be seen without their parents at visits.122 Continuity in health personnel, individualized timing of information provision and transition, increasing self-advocacy over several years, and implementing ­evidence-based, youth-friendly, and interdisciplinary health care principles are important elements of a successful transition process.123,124 Implementation of a structured and evidence-based transitional care program has been shown to increase HRQOL in adolescents moving from pediatric to adult care.124

REFERENCES

FIG. 105.16  Chronic anterior uveitis with band keratopathy and keratic precipitates, flair in the anterior chamber, cataract, and irregular pupil caused by synechiae. Note that the eye of this 5-year-old boy is not red. (Courtesy Terje Christoffersen.)

Multidimensional Fatigue Scale is shown to be valid and reliable in pediatric patients with rheumatic diseases.111 Other patient-reported measures, such as pain, are highly associated with fatigue.112 Sleep is of primary importance for physical and intellectual growth, and sleep disturbances beginning in childhood may persist into adulthood. Studies show that sleep disturbances are common in children with JIA and that sleep patterns in these children are different in multiple sleep domains compared with patterns in healthy children.113 The cause is multifactorial, but it leads to a common endpoint of sleep fragmentation, deprivation, or both. The associations between sleep characteristics and functional limitations in children with JIA are partially mediated by pain intensity.114

Psychosocial health Psychosocial health in JIA is an important outcome measure that is not always easy to assess because of different or difficult-to-obtain instruments.115 Most studies find less reduction in psychosocial health compared with physical function in JIA. In a prospective 8-year follow-up study, Nordal and coworkers found that 32% of the adolescents scored more than 0 on the C-HAQ or HAQ and 19% scored less than 40 on the Child Health Questionnaire (CHQ) physical summary score but only 8% scored below 40 on the CHQ psychosocial summary score.28 Psychosocial health in long-term follow-up studies in young adults is mostly measured with the generic instrument mental summary score (MSS) of the SF-36. The MSS shows much more divergent results than physical disability. Whereas Foster and coworkers found reduced MSS in adults with JIA with median 21 years’ disease duration compared with healthy controls in the United Kingdom,55 the MSS scores were equal to those of control participants in studies from Finland54 and Norway,47 measured after mean 16 and 30 years, respectively. In a large cross-sectional questionnaire-based study from 2012 of more than 2500 German adults with JIA, health-related quality of life (HRQOL) was considerably lower than in the general population with the largest differences regarding pain, anxiety and depression.116 Lower HRQOL was associated with female sex, older age, lower level of education, ongoing antirheumatic treatment, and disability.

Participation School attendance and participation in social activities are improved during the recent years but are still influenced by the disease.117–119 Several studies have shown that education and academic competence seem to be similar or even better in young adults with JIA compared with controls.54,120 However, a recent paper from Germany enrolling more than 2500 former pediatric rheumatology patients demonstrated educational achievements significantly lower than in the general population.121 Unemployment rates differ from near equal in Finland, United States, and Germany to more than twofold higher in United Kingdom,54,120,121 but studies are few and comparisons difficult. Education and employment are important issues to deal with, especially in the vulnerable period of transition from pediatric to adult health care for young adults with pediatric rheumatic diseases.

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The mortality rate and causes of death among juvenile idiopathic arthritis patients in Finland. Clin Exp Rheumatol. 2019;37(3):508–511. 40. Horne A, Delcoigne B, Palmblad K, et al. Juvenile idiopathic arthritis and risk of cancer before and after the introduction of biological therapies. RMD Open. 2019;5(2):e001055. 41. Kok VC, Horng JT, Huang JL, et al. Population-based cohort study on the risk of malignancy in East Asian children with juvenile idiopathic arthritis. BMC Cancer. 2014;14:634. 42. Vlahos AP, Theocharis P, Bechlioulis A, et al. Changes in vascular function and structure in juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2011 43. Aulie HA, Estensen ME, Selvaag AM, et al. Arterial properties in adults with long-lasting active juvenile idiopathic arthritis compared to healthy controls. Pediatr Rheumatol Online J. 2018;16(1):85. 44. Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol. 2004;31(11):2290–2294. 45. Wallace CA, Giannini EH, Huang B, et al. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2011;63(7):929–936. 46. Tiller G, Buckle J, Allen R, et al. Juvenile idiopathic arthritis managed in the new millennium: one year outcomes of an inception cohort of Australian children. Pediatr Rheumatol Online J. 2018;16(1):69. 47. Tollisen A, Selvaag AM, Aulie HA, et al. Physical functioning, pain, and health-related quality of life in adults with juvenile idiopathic arthritis: a longitudinal 30-year followup study. Arthritis Care Res. 2018;70(5):741–749. 48. Tollisen A, Selvaag AM, Aasland A, et al. Longitudinal health status from early disease to adulthood and associated prognostic factors in juvenile idiopathic arthritis. J Rheumatol. 2019;46(10):1335–1344. 49. Zak M, Pedersen FK. Juvenile chronic arthritis into adulthood: a long-term follow-up study. Rheumatology (Oxford). 2000;39(2):198–204. 50. Oen K, Malleson PN, Cabral DA, et al. Disease course and outcome of juvenile rheumatoid arthritis in a multicenter cohort. J Rheumatol. 2002;29(9):1989–1999. 51. Minden K, Niewerth M, Listing J, et al. Long-term outcome in patients with juvenile idiopathic arthritis. Arthritis Rheum. 2002;46(9):2392–2401. 52. Packham JC, Hall MA. Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome. Rheumatology (Oxford). 2002;41(12):1428–1435. 53. Fantini F, Gerloni V, Gattinara M, et al. Remission in juvenile chronic arthritis: a cohort study of 683 consecutive cases with a mean 10 year followup. J Rheumatol. 2003;30(3):579–584. 54. Arkela-Kautiainen M, Haapasaari J, Kautiainen H, et al. Favourable social functioning and health related quality of life of patients with JIA in early adulthood. Ann Rheum Dis. 2005;64(6):875–880. 55. Foster HE, Marshall N, Myer A, et al. Outcome in adults with juvenile idiopathic arthritis: a quality of life study. Arthritis Rheum. 2003;48(3):767–775. 56. Dimopoulou D, Trachana M, Pratsidou-Gertsi P, et al. Predictors and long-term outcome in Greek adults with juvenile idiopathic arthritis: a 17-year continuous follow-up study. Rheumatology (Oxford). 2017;56(11):1928–1938. 57. Bertilsson L, Andersson-Gare B, Fasth A, et al. Disease course, outcome, and predictors of outcome in a population-based juvenile chronic arthritis cohort followed for 17 years. J Rheumatol. 2013;40(5):715–724. 58. Shoop-Worrall SJW, Kearsley-Fleet L, Thomson W, et al. How common is remission in juvenile idiopathic arthritis: a systematic review. Semin Arthritis Rheum. 2017;47(3):331–337.

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59. Flato B, Lien G, Smerdel-Ramoya A, et al. Juvenile psoriatic arthritis: longterm outcome and differentiation from other subtypes of juvenile idiopathic arthritis. J Rheumatol. 2009;36(3):642–650. 60. Selvaag AM, Aulie HA, Lilleby V, et al. Disease progression into adulthood and predictors of long-term active disease in juvenile idiopathic arthritis. Ann Rheum Dis. 2016;75(1):190–195. 61. Guzman J, Oen K, Loughin T. Predicting disease severity and remission in juvenile idiopathic arthritis: are we getting closer? Curr Opin Rheumatol. 2019;31(5):436–449. 62. van Dijkhuizen EH, Wulffraat NM. Early predictors of prognosis in juvenile idiopathic arthritis: a systematic literature review. Ann Rheum Dis. 2015;74(11):1996–2005. 63. Magnani A, Pistorio A, Magni-Manzoni S, et al. Achievement of a state of inactive disease at least once in the first 5 years predicts better outcome of patients with polyarticular juvenile idiopathic arthritis. J Rheumatol. 2009;36(3):628–634. 64. Minden K, Horneff G, Niewerth M, et al. Time of disease-modifying antirheumatic drug start in juvenile idiopathic arthritis and the likelihood of a drug-free remission in young adulthood. Arthritis Care Res. 2019;71(4):471–481. 65. Lovell DJ, Johnson AL, Huang B, et al. Risk, timing, and predictors of disease flare after discontinuation of anti–tumor necrosis factor therapy in children with polyarticular forms of juvenile idiopathic arthritis with clinically inactive disease. Arthritis Rheumatol (Hoboken). 2018;70(9):1508–1518. 66. Flato B, Lien G, Smerdel A, et al. Prognostic factors in juvenile rheumatoid arthritis: a case-control study revealing early predictors and outcome after 14.9 years. JRheumatol. 2003;30(2):386–393. 67. Oen K, Malleson PN, Cabral DA, et al. Early predictors of longterm outcome in patients with juvenile rheumatoid arthritis: subset-specific correlations. J Rheumatol. 2003;30(3):585–593. 68. Bertolani MF, Bergamini BM, Marotti F, et al. Cricoarytenoid arthritis as an early sign of juvenile chronic arthritis. Clin Exp Rheumatol. 1997;15(1):115–116. 69. Sherry DD, Stein LD, Reed AM, et al. Prevention of leg length discrepancy in young children with pauciarticular juvenile rheumatoid arthritis by treatment with intraarticular steroids. Arthritis Rheum. 1999;42(11):2330–2334. 70. Arvidsson LZ, Smith HJ, Flato B, et al. Temporomandibular joint findings in adults with long-standing juvenile idiopathic arthritis: CT and MR imaging assessment. Radiology. 2010;256(1):191–200. 71. Stoustrup P, Herlin T, Spiegel L, et al. Standardizing the clinical orofacial examination in Juvenile idiopathic arthritis: an interdisciplinary, consensus-based, short screening protocol. J Rheumatol. 2019 72. El Assar de la Fuente S, Angenete O, Jellestad S, et al. Juvenile idiopathic arthritis and the temporomandibular joint: a comprehensive review. J Craniomaxillofac Surg. 2016;44(5):597–607. 73. Stoustrup P, Pedersen TK, Norholt SE, et al. Interdisciplinary management of dento facial deformity in juvenile idiopathic arthritis. Oral Maxillofac Surg Clin North Am. 2020;32(1):117–134. 74. Huber AM, Giannini EH, Bowyer SL, et al. Protocols for the initial treatment of moderately severe juvenile dermatomyositis: results of a Children’s Arthritis and Rheumatology Research Alliance Consensus Conference. Arthritis Care Res. 2010;62(2):219–225. 75. Hamalainen H, Arkela-Kautiainen M, Kautiainen H, et al. Bone mineral content in young adults with active or inactive juvenile idiopathic arthritis and in controls. Scand J Rheumatol. 2010;39(3):219–222. 76. Stagi S, Cavalli L, Bertini F, et al. Comparison of bone mass and quality determinants in adolescents and young adults with juvenile systemic lupus erythematosus (JSLE) and juvenile idiopathic arthritis (JIA). Lupus. 2014;23(13):1392–1406. 77. Rousseau-Nepton I, Lang B, Rodd C. Long-term bone health in glucocorticoid-treated children with rheumatic diseases. Curr Rheumatol Rep. 2013;15(3):315. 78. Wong SC, Dobie R, Altowati MA, et al. Growth and the growth hormone-insulin like growth factor 1 axis in children with chronic inflammation: current evidence, gaps in knowledge, and future directions. Endocr Rev. 2016;37(1):62–110. 79. Allen DB, Julius JR, Breen TJ, et al. Treatment of glucocorticoid-induced growth suppression with growth hormone. National Cooperative Growth Study. J Clin Endocrinol Metab. 1998;83(8):2824–2829. 80. McErlane F, Carrasco R, Kearsley-Fleet L, et al. Growth patterns in early juvenile idiopathic arthritis: results from the Childhood Arthritis Prospective Study (CAPS). Semin Arthritis Rheum. 2018;48(1):53–60. 81. Guzman J, Kerr T, Ward LM, et al. Growth and weight gain in children with juvenile idiopathic arthritis: results from the ReACCh-Out cohort. Pediatr Rheumatol Online J. 2017;15(1):68. 82. Marino A, Stagi S, Simonini G, et al. Growth and body mass index in a cohort of patients with juvenile idiopathic arthritis: effects of second line treatments. Clin Exp Rheumatol. 2018;36(5):929–933. 83. Bechtold S, Beyerlein A, Ripperger P, et al. Total pubertal growth in patients with juvenile idiopathic arthritis treated with growth hormone: analysis of a single center. Growth Horm IGF Res. 2012;22(5):180–185. 84. Maher SE, Ali FI. Sexual maturation in Egyptian boys and girls with juvenile rheumatoid arthritis. Rheumatol Int. 2013;33(8):2123–2126. 85. Angeles-Han ST, Pelajo CF, Vogler LB, et al. Risk markers of juvenile idiopathic arthritis-associated uveitis in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. J Rheumatol. 2013;40(12):2088–2096. 86. Moradi A, Amin RM, Thorne JE. The role of gender in juvenile idiopathic arthritis–­ associated uveitis. J Ophthalmol. 2014;2014:461078. 87. Rypdal V, Glerup M, Songstad NT, et al. Nordic Study Group of Pediatric Rheumatology, Uveitis in juvenile idiopathic arthritis: 18-year outcome in the population-based Nordic Cohort Study. Ophthalmology. 2021;128(4):598–608. Epub 2020 Aug 29. 88. Saurenmann RK, Levin AV, Feldman BM, et al. Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long-term followup study. Arthritis Rheum. 2007;56(2):647–657.

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89. Arguedas O, Fasth A, Andersson-Gare B, et al. Juvenile chronic arthritis in urban San Jose, Costa Rica: a 2 year prospective study. J Rheumatol. 1998;25(9):1844–1850. 90. Keino H, Watanabe T, Taki W, et al. Clinical features of uveitis in children and adolescents at a tertiary referral centre in Tokyo. Br J Ophthalmol. 2016 91. Sen ES, Ramanan AV. Juvenile idiopathic arthritis–associated uveitis. Clin Immunol. 2020;211:108322. 92. Tappeiner C, Klotsche J, Schenck S, et al. Temporal change in prevalence and complications of uveitis associated with juvenile idiopathic arthritis:data from a cross-sectional analysis of a prospective nationwide study. Clin Exp Rheumatol. 2015;33(6):936–944. 93. Nordal EB, Songstad NT, Berntson L, et al. Biomarkers of chronic uveitis in juvenile idiopathic arthritis: predictive value of antihistone antibodies and antinuclear antibodies. J Rheumatol. 2009;36(8):1737–1743. 94. Zak M, Fledelius H, Pedersen FK. Ocular complications and visual outcome in juvenile chronic arthritis: a 25-year follow-up study. Acta Ophthalmol Scand. 2003;81(3):211–215. 95. Saurenmann RK, Rose JB, Tyrrell P, et al. Epidemiology of juvenile idiopathic arthritis in a multiethnic cohort: ethnicity as a risk factor. Arthritis Rheum. 2007;56(6):1974–1984. 96. Kotaniemi K, Arkela-Kautiainen M, Haapasaari J, et al. Uveitis in young adults with juvenile idiopathic arthritis: a clinical evaluation of 123 patients. Ann Rheum Dis. 2005;64(6):871–874. 97. Angeles-Han ST, Ringold S, Beukelman T, et al. 2019 American College of Rheumatology/ Arthritis Foundation guideline for the screening, monitoring, and treatment of juvenile idiopathic arthritis–associated uveitis. Arthritis Rheumatol (Hoboken). 2019;71(6):864–877. 98. Constantin T, Foeldvari I, Anton J, et al. Consensus-based recommendations for the management of uveitis associated with juvenile idiopathic arthritis: the SHARE initiative. Ann Rheum Dis. 2018;77(8):1107–1117. 99. Kotaniemi K, Sihto-Kauppi K, Salomaa P, et al. The frequency and outcome of uveitis in patients with newly diagnosed juvenile idiopathic arthritis in two 4-year cohorts from 19901993 and 2000-2003. Clin Exp Rheumatol. 2014;32(1):143–147. 100. Angeles-Han ST, Yeh S, Vogler LB. Updates on the risk markers and outcomes of severe juvenile idiopathic arthritis-associated uveitis. Int J Clin Rheumatol. 2013;8:1. 101. Heiligenhaus A, Niewerth M, Ganser G, et al. Prevalence and complications of uve itis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines. Rheumatology (Oxford). 2007;46(6):1015–1019. 102. Horton S, Jones AP, Guly CM, et al. Adalimumab in juvenile idiopathic arthritis–associated uveitis: 5-year follow-up of the Bristol participants of the SYCAMORE Trial. Am J Ophthalmol. 2019;207:170–174. 103. Carvounis PE, Herman DC, Cha SS, et al. Ocular manifestations of juvenile rheumatoid arthritis in Olmsted County, Minnesota: a population-based study. Graefes Arch Clin Exp Ophthalmol. 2005;243(3):217–221. 104. Hoftun GB, Romundstad PR, Zwart JA, et al. Chronic idiopathic pain in adolescence—high prevalence and disability: the young HUNT study 2008. Pain. 2011;152(10):2259–2266. 105. Hoftun GB, Romundstad PR, Rygg M. Factors associated with adolescent chronic non-­ specific pain, chronic multisite pain, and chronic pain with high disability: the youngHUNT Study 2008. J Pain. 2012;13(9):874–883. 106. Thastum M, Herlin T. Pain-specific beliefs and pain experience in children with juvenile idiopathic arthritis: a longitudinal study. J Rheumatol. 2011;38(1):155–160. 107. Sallfors C, Fasth A, Hallberg LR. Oscillating between hope and despair—a qualitative study. Child Care Health Dev. 2002;28(6):495–505.

108. Arnstad ED, Rypdal V, Peltoniemi S, et al. Early self-reported pain in juvenile idiopathic arthritis as related to long-term outcomes: results from the Nordic Juvenile Idiopathic Arthritis Cohort Study. Arthritis Care Res. 2019;71(7):961–969. 109. Armbrust W, Siers NE, Lelieveld OT, et al. Fatigue in patients with juvenile idiopathic arthritis: a systematic review of the literature. Semin Arthritis Rheum. 2016;45(5):587–595. 110. Arnstad ED, Glerup M, Rypdal V, et al. Nordic Study Group of Pediatric Rheumatology (NoSPeR), Fatigue in young adults with juvenile idiopathic arthritis 18 years after disease onset: data from the prospective Nordic JIA cohort. Pediatr Rheumatol Online J. 2021;19(1):33. 111. Varni JW, Burwinkle TM, Szer IS. The PedsQL Multidimensional Fatigue Scale in pediatric rheumatology: reliability and validity. J Rheumatol. 2004;31(12). 2494-500. 112. Ringold S, Ward TM, Wallace CA. Disease activity and fatigue in juvenile idiopathic arthritis. Arthritis Care Res. 2012 113. Stinson JN, Hayden JA, Ahola Kohut S, et al. Sleep problems and associated factors in children with juvenile idiopathic arthritis: a systematic review. Pediatr Rheumatol Online J. 2014;12:19. 114. Bromberg MH, Connelly M, Anthony KK, et al. Prospective mediation models of sleep, pain, and daily function in children with arthritis using ecological momentary assessment. Clin J Pain. 2016;32(6):471–477. 115. Adunuri NR, Feldman BM. Critical appraisal of studies measuring quality of life in juvenile idiopathic arthritis. Arthritis Care Res. 2015;67(6):880–884. 116. Barth S, Haas JP, Schlichtiger J, et al. Long-term health-related quality of life in German patients with juvenile idiopathic arthritis in comparison to German general population. PLoS One. 2016;11(4):e0153267. 117. Nordal E, Rypdal V, Arnstad ED, et al. Participation in school and physical education in juvenile idiopathic arthritis in a Nordic long-term cohort study. Pediatr Rheumatol Online J. 2019;17(1):44. 118. Milatz F, Klotsche J, Niewerth M, et al. Participation in school sports among children and adolescents with juvenile idiopathic arthritis in the German National Paediatric Rheumatologic Database, 2000–2015: results from a prospective observational cohort study. Pediatr Rheumatol Online J. 2019;17(1):6. 119. Risum K, Hansen BH, Selvaag AM, et al. Physical activity in patients with oligo- and polyarticular juvenile idiopathic arthritis diagnosed in the era of biologics: a controlled cross-­ sectional study. Pediatr Rheumatol Online J. 2018;16(1):64. 120. Packham JC, Hall MA. Long-term follow-up of 246 adults with juvenile idiopathic arthritis: education and employment. Rheumatology (Oxford). 2002;41(12):1436–1439. 121. Schlichtiger J, Haas JP, Barth S, et al. Education and employment in patients with juvenile idiopathic arthritis—a standardized comparison to the German general population. Pediatr Rheumatol Online J. 2017;15(1):45. 122. Cruikshank M, Foster HE, Stewart J, et al. Transitional care in clinical networks for young people with juvenile idiopathic arthritis: current situation and challenges. Clin Rheumatol. 2016;35(4):893–899. 123. Ambresin AE, Bennett K, Patton GC, et al. Assessment of youth-friendly health care: a systematic review of indicators drawn from young people’s perspectives. J Adolesc Health. 2013;52(6):670–681. 124. McDonagh JE, Farre A. Are we there yet? An update on transitional care in rheumatology. Arthritis Res Ther. 2018:20.

Etiology and pathogenesis of juvenile idiopathic arthritis Robert A. Colbert

Key Points n Juvenile idiopathic arthritis (JIA) refers to the majority of chronic childhood arthritis and is classified using the International League of Associations for Rheumatology criteria.

pathogenic mechanisms vary. This chapter focuses on common themes for JIA but also highlights differences between JIA subtypes when appropriate.

n Subtypes of JIA are defined largely by clinical and laboratory features.

GENETIC FACTORS

n The etiology of JIA is best explained by multiple common genetic variants interacting with environmental factors.

Human leukocyte antigen region

n Genetic risk variants identified in genome-wide association studies account for only a small proportion of susceptibility. n T helper 1, T helper 17, and regulatory T cells contribute to pathogenesis, but antigenic targets remain poorly defined. n Cytokines such as tumor necrosis factor, interleukin-6, and interleukin-1 are currently the most relevant therapeutic targets in various subtypes of JIA.

INTRODUCTION Juvenile idiopathic arthritis (JIA) encompasses several categories of chronic inflammatory arthritis that are distinguished by clinical features, laboratory tests, and family history. The term juvenile idiopathic arthritis was first adopted when juvenile arthritis was reclassified by the International League of Associations for Rheumatology (ILAR) more than 20 years ago.1 Despite limitations, JIA and the ILAR classification have gained widespread acceptance, replacing juvenile rheumatoid arthritis (JRA) and juvenile chronic arthritis (JCA) and their respective classification systems.2 This chapter focuses on the etiology and pathogenesis of JIA, but when studies based on previous classifications are cited, the corresponding name is used. To be diagnosed with JIA, arthritis must begin before 16 years of age and be present for at least 6 weeks with no recognized etiology.1 The ILAR classification scheme defines seven major categories of JIA (Table 106.1), whose clinical and epidemiologic features are described in detail elsewhere in this textbook (see Chapters 104 and 105). Systemic juvenile idiopathic arthritis (sJIA) accounts for 5% to 15% of cases of JIA. Oligoarthritis (oligo-JIA) accounts for approximately 40% of cases of JIA and involves four or fewer joints in the first 6 months. It is called persistent if no additional joints are affected or extended if more than four joints (cumulative total) are involved after 6 months. Polyarthritis (poly-JIA), which involves five or more joints in the first 6 months, represents approximately 20% of JIA. Poly-JIA is subdivided into rheumatoid factor–negative (RF-negative), which comprises the vast majority of poly-JIA (85%), and RF-positive poly-JIA, which is an earlyonset form of rheumatoid arthritis (RA). Children with enthesitis-related arthritis (ERA) (9%–19% of JIA) and psoriatic arthritis (psor-JIA) (7% of JIA) have features of spondyloarthritis (SpA), but axial skeletal involvement is less common at disease onset than in adults with SpA.3 ERA represents a form of undifferentiated SpA that can progress to ankylosing spondylitis, particularly when HLA-B27 is present. The seventh JIA category is undifferentiated arthritis (undiff-JIA), which is used for children with arthritis who do not fulfill criteria for any single category or have features that would place them in more than one category.

ETIOLOGY Although mendelian inheritance and large multiplex families with JIA are very uncommon, a few monozygotic twin studies have shown 25% to 40% concordance for arthritis, including similar onset and course in oligo- and poly-JIA.4 A small number of complex pedigrees have revealed that siblings of probands have up to an 11.6-fold increased risk of JIA compared with the general population. These and other studies5 have suggested that oligo- and poly-JIA are complex genetic diseases influenced by environmental factors,6 and these studies have provided the rationale for large-scale genome-wide association studies (GWASs). Although other forms of JIA have not been investigated to the same extent, complex genetic predisposition is likely. However, subtype phenotypic heterogeneity also implies that risk genes and

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Genes encoding human leukocyte antigen (HLA) class I and class II proteins located in the major histocompatibility complex (MHC) are involved in predisposition to JIA, as well as most other immune-mediated inflammatory diseases. Table 106.1 summarizes the most prominent HLA allele associations for the major JIA subtypes.4 For oligo-JIA, there is an increased frequency of the class I allele HLA-A*02, as well as class II alleles DRB1*01, DRB1*08, DRB1*11, and DPB1*02. DRB1*04 and DRB1*07 are associated with reduced risk of oligo-JIA (i.e., protective). In poly-JIA, HLA associations in RF-negative and RF-positive disease are different, with HLA-A*02 conferring risk for the former but protection for the latter. Differences are also seen with class II alleles, where DRB1*08 and DRB1*11 confer risk for RF-negative poly-JIA but DRB1*01 and DRB1*04 increase risk for RF-positive disease. In addition to RF, patients with RF-positive poly-JIA are typically positive for antibodies against citrullinated proteins (ACPAs) and have erosive symmetric polyarthritis. There is an increased frequency of the RA-associated HLA class II “shared epitope” alleles (including HLA-DRB1*01:01, DRB1*04:01, DRB1*04:04, DRB1*04:05, and DRB1*04:08), and having more than one SE allele is associated with a further increase in risk.7 When oligo-JIA and poly-JIA are grouped together, genetic differences between early and late ages of onset have emerged. For example, DRB1*01 is also associated with early-onset poly-JIA8 in addition to oligo-JIA, and DRB1*11 (subtypes 11:03 and 11:04) is associated with early-onset RF-negative poly-JIA but not late-onset disease. In contrast, DRB1*08:01 is associated with risk in both early- and late-onset patients with oligo-JIA and poly-JIA (RF negative). Additional HLA class II associations with JIA and their relationship with age at onset have been summarized recently4 and support the idea that the presence of multiple risk alleles simultaneously is associated with earlier disease onset.9 Accumulating evidence has suggested that age of onset may be a better feature for distinguishing oligo- and polyJIA subtypes than the number of joints involved in the first 6 months.10–12 HLA-B*27 is a well-known risk factor for spondyloarthritis in adults as well as children. HLA-B*27 is found in 60% to 90% of patients with ERA, depending on the study,3 but because of its use as an inclusion criterion for classification in subjects who have only arthritis or enthesitis, these frequencies do not necessarily reflect independent measures of association. Small studies have reported HLA class II associations with ERA, including DRB1*01 and DQA1*01 on a haplotype that includes DQB1*05.13 Negative associations between ERA and DRB1*07 and DPB1*02 were also seen. In one study, HLA-DRB1*08 was associated with failure to achieve remission in ERA, with DPB1*02 appearing to be protective.14 Juvenile psoriatic arthritis (non-ILAR classification) was associated with the class I alleles HLA-A*02 and B*17 in one study,15 but a second study revealed an increase in HLA-B*27.16 ILAR-classified psor-JIA excludes male patients older than age 6 years who are HLA-B*27-positive (Chapter 104), thus limiting assessment of the frequency of this allele in psor-JIA. Whereas HLA-DRB1*01 and DQA1*01 have been reported to confer risk for psorJIA, protective effects for DRB1*04 and DQA1*03 and DQB1*03 have been reported. These studies of HLA class II associations in psor-JIA and ERA (discussed earlier) were based on 37 and 34 participants, respectively, and thus require validation in larger populations.13 Human leukocyte antigen associations with sJIA have now been definitively established. Previously, small studies suggested that HLA-DR4 (DRB1*04) conferred risk for systemic-onset JCA in a U.K. population,17 HLA-DRB1*04:05 and DQB1*04:01 with systemic-onset JRA in a Japanese population,18 and HLA-DRB1*01 and DRB1*04 with sJIA in Mexican patients.19 These were frequently considered weak associations and of 907

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uncertain significance. However, a large-scale study of 982 children with sJIA and 8010 healthy control participants across populations in nine countries revealed genome-wide significance for HLA-DRB1*11 (P = 2.7 × 10−16, odds ratio [OR] = 2.3) and the DRB1*11-DQA1*05-DQB1*03 haplotype.20 These findings have important considerations for pathogenesis (see later).

Non–human leukocyte antigen genes The search for predisposing genetic factors outside the HLA region has historically focused on genes that were considered to be likely candidates in the etiology of inflammatory and autoimmune diseases. Many studies with small sample sizes examining a limited number of genetic variants revealed associations that were difficult to replicate. Larger studies relying on ­single-nucleotide polymorphisms (SNPs) identified from unbiased GWASs of other autoimmune diseases have begun to yield more robust results.21–26 For example, there are associations between JIA and PTPN22,21,25 IL2RA/ CD25,22 STAT4,24,25 and TRAF1/C5.24 In addition, associations with PTPN2, ADAD1-IL2-IL21, C12orf30, COG6, and ANGPT125 and a region on 3q13 within C3orf1 and near CD8027 have been demonstrated. In the largest study of common immune-related variants associated with susceptibility to JIA using the Immunochip, 14 loci were identified at genome-wide significance, with an additional 11 regions suggestive for association (Table 106.2).28 The Immunochip study focused on the two most common forms of JIA, oligo-JIA (persistent and extended) and poly-JIA (RF negative). Several previous studies included all JIA subtypes, yet when the data were analyzed by subtype, the predominant effect was in extended oligo- and poly-JIA (RF negative).21,22,24 Many of these studies have revealed significant sharing of risk alleles between JIA and RA, including PTPN22, STAT4, CCR5, COG6, ANGPT1, IL2RA, TNFAIP3, TRAF1/C5, and PRKCQ,

Table 106.1

Selected HLA Class I and Class II Associations in Juvenile Idiopathic Arthritisa HLA Allele A*02 B*27 DRB1*01 DRB1*04 DRB1*07 DRB1*08 DRB1*11 DPB1*02 DQA1*01

Systemic

↑ ↑

Oligo↑

↑ ↓ ↓ ↑ ↑ ↑

Poly- (RF−)

↑

Poly- (RF+) ERA ↓

↑ ↑

↑ ↑

↓

↑ ↑

↓ ↑

Psor ↑ ↓

↑

Up arrows indicate increased relative risk, and down arrows denote lower risk (protection) when the allele is present. Adapted from Hersh AO, Prahalad S. Immunogenetics of juvenile idiopathic arthritis: a comprehensive review. J Autoimmun 2015;64:113-24.

a

as well as overlaps with SLE (STAT4), type 1 diabetes (PTPN2, IL2RA, ADAD1-IL2-IL21, C12orf30), multiple sclerosis (IL2RA), and Kawasaki disease (ANGPT1), consistent with previous studies showing increased familial autoimmunity.5 Considerable sharing of non-HLA risk alleles between JIA and RA suggests common etiologic factors despite difference in HLA susceptibility alleles, perhaps contributing to the earlier age of onset. In a number of complex genetic diseases, common variants identified by GWASs account for only a small fraction of overall heritability. The top 27 loci in the JIA Immunochip study account for only about 18% of heritability for the oligo- and polyarticular subgroups.28 The problem of “missing heritability” is a matter of debate and could be a consequence of a variety of factors,29–31 including underestimates of the contribution of rare variants to true heritability.32 Thus, although current estimates of how much variance is explained may be low by a factor of 2 or more,32 other factors such as rare variants and gene–gene interactions may play a role. The use of genetic testing in common variant associated diseases such as JIA has yet to reach the clinic, with a few exceptions such as HLA-B*27. In the future, as genetic risk is better defined, it may be possible to use this information to predict outcome or response to therapy.

ENVIRONMENTAL FACTORS Microbes Infectious etiologies or triggers that would account for a large proportion of JIA have long been suspected, yet none has been established. Transient self-limited arthritis after infection with certain viruses, including Coxsackie B, Epstein–Barr virus, rubella, or parvovirus, has been reported,33,34 and such infections could be associated with the onset of JIA in a subset of cases. Studies of vaccine-associated JIA have also been negative.35,36 A lack of temporal or geographic case clustering also argues against the role of pathogens, at least those that would come to the attention of public health officials. In sJIA, in which systemic features are more reminiscent of infection, a relationship between seasonal peaks in sJIA onset37,38 and viral infection has been sought, with little supportive evidence emerging.39 Reactive arthritis after gastrointestinal and genitourinary infection is strongly associated with HLA-B*27 (see Chapter 116). Although a proportion of these individuals eventually develop ankylosing spondylitis, the vast majority of subjects with ankylosing spondylitis do not have a history of reactive arthritis or other infectious triggers. Although gastrointestinal or genitourinary infections could trigger juvenile spondyloarthritis40 and ERA, this would not account for the vast majority of cases. The use of high-throughput next-generation sequencing and bioinformatics tools to identify and classify microbial species via their 16 S ribosomal RNA genes has revolutionized our understanding of the microbes that inhabit the human body—our microbiome. The importance of microbial communities to the development and maintenance of our immune system is well documented and has also provided insights into their contribution to disease. As a consequence, there has been a shift in focus from pathogens to altered commensals

Table 106.2

Associations With Genome-Wide Significance in Oligoarticular and Rheumatoid Factor–Negative Polyarticular Juvenile Idiopathic Arthritis Gene or Locus

Chromosome

PTPN22 ATP8B2-IL6R STAT4 IL2-IL21 ANKRD55 ERAP2-LNPEP C5orf56-IRF1 HLA-DQB1-DQA2 IL2RA FAS SH2B3-ATXN2 ZFP36L1 PTPN2 TYK2 RUNX1 UBE2L3 IL2RB

1 1 2 4 5 5 5 6 10 10 12 14 18 19 21 22 22

P Value

3.2 × 10−25 2.8 × 10−8 1.3 × 10−13 6.2 × 10−11 4.4 × 10−11 7.5 × 10−9 1.0 × 10−8 3.1 × 10−174 8.0 × 10−10 2.9 × 10−8 2.6 × 10−9 1.6 × 10−8 1.4 × 10−12 1.0 × 10−10 1.1 × 10−9 6.2 × 10−9 1.6 × 10−8

MAF Control/Case

OR

0.10/0.14 0.10/0.12 0.23/0.28 0.29/0.24 0.25/0.20 0.44/0.47 0.44/0.39 0.02/0.12 0.11/0.08 0.44/0.48 0.49/0.54 0.47/0.43 0.17/0.20 0.05/0.03 0.37/0.33 0.19/0.22 0.44/0.39

1.59 1.33 1.29 0.79 0.78 1.32 0.84 6.01 0.72 1.18 1.20 0.77 1.31 0.56 0.78 1.24 0.84

SNP → Location

rs6679677 → intergenic rs11265608 → intergenic rs10174238 → intronic rs1479924 → intergenic rs71624119 → intronic rs27290 → intronic rs4705862 → intergenic rs7775055 → intergenic rs7909519 → intronic rs7069750 → intronic rs3184504 → coding rs12434551 → intergenic rs2847293 → intergenic rs34536443 → coding rs9979383 → intergenic rs2266959 → intronic rs2284033 → intronic

MAF, Minor allele frequency; OR, odds ratio; rs, reference single-nucleotide polymorphism; SNP, single-nucleotide polymorphism. Adapted from Hinks A, Cobb J, Marion MC, et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet 2013;45(6):664–9; and Hersh AO, Prahalad S. Immunogenetics of juvenile idiopathic arthritis: a review. J Autoimmun 2015;64:113–24.

CHAPTER 106  Etiology and pathogenesis of juvenile idiopathic arthritis (dysbiosis) as a potential disease trigger. Early studies in JIA suggest that fecal microbiota are altered in ERA41 and JIA in general.42 Although provocative, these studies are small, and it remains to be determined whether the differences are truly disease related or a consequence of other variables such as therapy. In a recent review where results from several studies were combined, clustering of fecal microbiota by subject nationality (e.g., geographic region/environment and/or genetic differences) was much stronger than by diagnosis (JIA vs healthy control),43 a phenomenon similar to what has been described in different strains of HLA-B27 transgenic rats that serve as a model for spondyloarthritis.44 These studies are consistent with an ecological model of dysbiosis where functional differences between altered communities may be as or even more important than differences in one or a small number of bacteria. Epidemiologic studies have suggested a link between antibiotic use and JIA. In a Finnish study, purchase of one or more courses of antibiotics between birth and diagnosis of JIA over a 10-year period was associated with an overall 1.6-fold increase in the risk of JIA, with risk increasing with the number of prescriptions filled.45 In a study from the United Kingdom, previous antibiotic

a

c

909

prescriptions were associated with a 2.1-fold increased JIA risk that was again dose dependent and was stronger for prescriptions given within 1 year of diagnosis.46 No relationship was seen for antiviral and antifungal drugs. These two studies establish a relationship between antibiotics and JIA, but interpretation remains problematic. Short courses of antibiotics alter the gut microbiome, so the possibility of dysbiosis and immune dysregulation secondary to antibiotics must be considered. However, it is also conceivable that genetic susceptibility to JIA could be associated with a greater need for antibiotics.

PATHOGENESIS PATHOLOGY The predominant clinical manifestation of nonsystemic juvenile arthritis is inflammation of synovial joints (Fig. 106.1, a). At the tissue level, arthritic joints exhibit, to varying degrees, synovial hyperplasia, soft tissue swelling, joint effusion, cartilage destruction, and bone erosion (Fig. 106.1, b to d).

b

d

FIG. 106.1  (a) Typical appearance of polyarthritis involving the left knee and ankle and bilateral wrists and small joints of the hands in a young child. (b) Schematic of joint with left side normal and right side depicting characteristic pathology of juvenile idiopathic arthritis (JIA). (c and d) Destructive inflammatory pannus typical of severe JIA. (c) Photograph of a frontal section taken through the femoral head showing extensive destruction of articular cartilage with erosion of subchondral bone. (d) Photomicrograph of a histologic section taken at the articular margin of the specimen demonstrated in c showing destructive inflammatory pannus extending onto the articular surface. (a, From Torok K, Rosen P. Rheumatology. In Zitelli BJ, McIntire SC, Nowalk AJ, editors. Zitelli and Davis’ atlas of pediatric physical diagnosis. 6th ed. Philadelphia: Elsevier; 2012. b, Modified from Chapel H, Haeney M, Misbah S, et al. Essentials of clinical immunology. Oxford: Blackwell Science; 1999. c and d with permission from Bullough PG. Orthopedic pathology. 3rd ed. London: Mosby-Wolfe; 1997.)

910

SECTION 8  Pediatric Rheumatology

Synovial fluid and tissue infiltrates include lymphocytes, neutrophils, plasma cells, macrophages, and dendritic cells (Fig. 106.1, b). Synovial fluid volume is increased but viscosity is decreased, and various proinflammatory cytokines are overexpressed in the fluid and in the tissue, including tumor necrosis factor (TNF) and interleukin-6 (IL-6).47,48 Synovial proliferation supported by angiogenic growth factors (e.g., vascular endothelial growth factor, angiopoietin 1) contributes to pannus formation49,50 and destruction of the normal architecture. Chronic cellular infiltrates include CD4+ and CD8+ CD3+ T cells, B cells, and CD68+ myeloid cells. Synovial biopsies of early untreated disease have suggested that children with polyarthritis and oligoarthritis who eventually developed polyarthritis had more CD4+ T cells and B cells and more vascularization than subjects with oligoarthritis who did not progress.51 However, these differences are not sufficiently distinctive to classify JIA subtypes by immunohistochemistry. Enthesitis is a common feature of ERA and psor-JIA, but this can also occur in nonspondyloarthritic forms of JIA. Similarly, dactylitis is common in psorJIA and, to a lesser extent, ERA but can also occur in JIA and a variety of other noninfectious or infectious conditions. Studies of the histopathology of enthesitis in ERA and psor-JIA are limited. In adults, CD68+ macrophages predominate in fibrous tissue of early entheseal lesions along with increased vascularity but a lack of CD3+ or CD8+ T cells.52 More lymphocytic infiltration has been reported in the underlying bone marrow in those with chronic disease,53 which may be consistent with increased bone marrow edema on magnetic resonance imaging. In one child with psor-JIA and features of juvenile dermatomyositis, an inflamed enthesis revealed perivascular lymphocytic infiltration with predominantly CD3+/CD4+ T cells but also CD20+ B cells and CD117+ mast cells but no plasma cells or neutrophils.54 In the fibrocartilage, there was increased necrosis with myxoid matrix but little inflammation.

PATHOGENESIS OF OLIGO- AND POLY-JUVENILE IDIOPATHIC ARTHRITIS Strong HLA associations, activated and clonally expanded CD4+ and CD8+ T-cell receptor (TCR) αβ T cells in synovial fluid and peripheral blood,55–60 and evidence that T-cell blocking therapies are beneficial61 strongly support the importance of adaptive immunity in the pathogenesis of oligo- and polyJIA. The majority of evidence suggests multiple T-cell clones rather than a highly targeted immune response, most consistent with multiple antigens being recognized. The nature of putative autoantigens and why they are targeted remains unknown. Because most of these studies are performed by necessity on cells and tissues from individuals with established disease, the initial triggers may no longer be present. The regulatory T cell (Treg) response has also been implicated in oligoand poly-JIA pathogenesis, with increased numbers of Tregs reported in peripheral blood and synovial fluid in association with remission.62–64 Greater numbers of Tregs have also been reported at sites of active inflammation but with impaired function, suggesting an inadequate regulatory capacity.65 Recent studies revealing reduced Treg TCR β chain (TRB) diversity in oligo-JIA synovial fluid and peripheral blood have also suggested reduced competency for suppressing divergent T-cell responses.66 Thus, the normal mechanisms that regulate tolerance may be impaired, resulting in the development of oligoclonal autoreactive T cell responses.67 T helper (Th) T-cell subsets Th1 and Th17 have been implicated in JIA pathogenesis. Th1 T cells develop from naïve CD4+ T cells under the influence of interleukin 12 (IL-12) and interferon-γ (IFN-γ) and make IFN-γ and TNF. IFN-γ is an important driver of macrophage activation, bactericidal activity, and antigen presentation. Th17 T cells are also derived from naïve CD4+ T cells but develop under the influence of IL-6, transforming growth factor-β (TGF-β), IL-1, IL-21, and IL-23. Th17 cells are important producers of IL-17 (A and F) and IL-22. Naïve CD4+ T cells also develop into Tregs under the influence of TGFβ and IL-2. Although often presented as distinct lineages, T helper T-cell subsets exhibit considerable plasticity. For example, CD4+ Th17 T cells expressing IFN-γ have been found in tissues from patients with chronic inflammatory diseases and may be driven in this direction by IL-12.68 In JRA, Th1 cells and Th1 cytokines are found in synovial tissue and fluid47,69,70 and have been associated with progression from oligo- to poly-JIA.71 There are fewer descriptions of Th17 T cells in JIA, which may reflect the more recent recognition of this lineage and its importance in immune-­ mediated inflammatory diseases. In one study, CD4+ Th17 cells were increased in synovial fluid compared with peripheral blood in JIA and were found in the synovial tissue.72 Subjects with oligo-JIA, poly-JIA, and sJIA were included in this study, and the CD4+ Th17 T cells were more frequent in extended compared with persistent oligo-JIA. In the joints, there was an inverse relationship between IL-17–expressing T cells and Tregs.

FIG. 106.2  Interleukin 23 (IL-23) promotes enthesitis by activating entheseal-resident T cells in mice. Pathways that may contribute to IL-23 overproduction include HLAB27-induced endoplasmic reticulum stress with activation of the unfolded protein response (UPR), gut microbial products, and biomechanical stress. IL-23 acts locally on IL-23R+/CD3+/CD4−/CD8−/ROR-γt+ T cells, stimulating them to produce IL-17 and IL-22. IL-17 can promote tumor necrosis factor (TNF) production, inflammation, and bone loss without synovitis, and IL-22 may contribute to osteoproliferation. (From Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells. Nat Med 2012;18[7]:1018–9. Original illustration by Katie Vacari.)

ENTHESITIS-RELATED ARTHRITIS The IL-23/IL-17 axis, including CD4+ Th17 T cells, CD4−/CD8− T cells, and innate lymphoid cells that produce IL-17 and related cytokines, plays an important role in the pathogenesis of SpA.73,74 HLA-B27 has been linked to activation of the IL-23/IL-17 pathway through noncanonical mechanisms involving misfolding and dimerization, but a role in presentation of arthritogenic peptides to CD8+ T cells remains unclear.74–76 Aberrant forms of HLA-B27 on the cell surface can be recognized by killer immunoglobulin receptors (KIR3DL2) expressed on CD4+ Th17 T cells,75 triggering them to produce IL-17, and misfolded forms of HLA-B27 that accumulate in the endoplasmic reticulum (ER) can generate ER stress, which promotes IL-23 production.76 In ERA, IL-17 is increased in synovial fluid,77 and Th17/Th1 cells accumulate compared with peripheral blood.78 Matrix metalloproteinase 3, which is induced by IL-17 as well as other proinflammatory cytokines, has been shown to correlate with disease activity in one study of ERA.79 Animal models have shown that enthesitis can be driven by IL-23mediated activation of a unique population of T cells that reside in the enthesis80 (Fig. 106.2). The cells are unusual in that they express CD3, identifying them as T cells, but are negative for CD4 and CD8. They express the IL-23 receptor and the retinoic acid receptor–related orphan receptor γt (ROR-γt) transcription factor, a characteristic feature of Th17 cells and other cells that produce IL-17 and related inflammatory mediators (including IL-6, IL-22, and CXCL1) when activated by IL-23. Overexpression of IL-23 alone in mice creates a striking spondyloarthritis phenotype, with peripheral and axial entheseal inflammation, aortic root and valvular inflammation, and osteoproliferation, which may be a precursor to new bone formation as seen in ankylosing spondylitis. The CD3+, CD4−, CD8−, ROR-γt+ cells found in rodents have not been reported in humans, whereas type 3 innate lymphoid cells (ILC3s) that exhibit a cytokine expression profile similar to Th17 cells have been described in the soft tissue adjacent to entheses.81 Thus, entheseal-resident T cells or ILC3s provide a plausible anatomic explanation for the spondyloarthritis phenotype that is unrelated to tissue-specific antigen presentation by HLA class I.

SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS Systemic juvenile idiopathic arthritis has distinct clinical and epidemiologic features from other JIA subtypes and distinct pathogenic mechanisms, including a strong association with macrophage activation syndrome (MAS).82 sJIA is itself variable, with three clinical subtypes identified—monocyclic,

CHAPTER 106  Etiology and pathogenesis of juvenile idiopathic arthritis polycyclic, and persistent—referring to the pattern of systemic inflammation. Systemic inflammation frequently precedes arthritis, occasionally by months. Active, destructive arthritis can occur and proceed even after severe systemic inflammation has subsided, suggesting distinct phases of disease with different pathogenic mechanisms. Overproduction of IL-6 and IL-1 clearly plays a role in systemic inflammation,83,84 and serum levels of other inflammatory cytokines, including IL-8, IL-18, macrophage migration inhibitory factor (MIF), and TNF, have been documented.85–90 Serum IL-6 correlates with fever, joint involvement, and certain laboratory features,83 and biologics that target IL-6 and IL-1 have demonstrated efficacy in sJIA,91–94 but TNF inhibitors are generally not useful. However, there is also evidence of heterogeneity in sJIA, with studies showing that although about 50% of unselected patients exhibit a dramatic response to IL-1 blockade with anakinra, a similar percentage have an incomplete or no response.95,96 There is increasing recognition that a small percentage of patients with sJIA develop severe life-threatening pulmonary complications, including, with varying frequency, pulmonary hypertension, interstitial lung disease, pulmonary alveolar proteinosis, and/or endogenous lipoid pneumonia.97 Recent case series extending these initial observations98,99 have highlighted an association with early onset sJIA (17 for high disease activity.

 Trincianti C, Van Dijkhuisen EHP, Alongi A, Pediatric Rheumatology International Trials Organization, Definition and validation of the American College of Rheumatology 2021 Juvenile Arthritis Disease Activity Score cutoffs for disease activity states in juvenile idiopathic Arthritis. Arthritis Rheumatol. 2021;73(11):1966–1975. c

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PGA, physician global assessment.

Table 107.2

Subtypes of Juvenile Idiopathic Arthritis Subtype

Proportion of Patients (%)

Systemic arthritis (starts with a spiking fever, rash) Oligoarthritis (≤4 joints in the first 6 mo) Persistent oligoarthritic course Extended polyarticular course Polyarthritis rheumatoid factor negative (≥4 joints in the first 6 mo) Polyarthritis rheumatoid factor positive Enthesitis-related arthritis (formerly called spondyloarthropathy) Psoriatic arthritis Other (fits none or >1 category)

5–10 40–50 25–35 15–20 20–25 5–10 10–20 5–15 10–20

Adapted from Petty RE, Laxer RM, Wedderburn LR. Juvenile idiopathic arthritis. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia: ElsevierSaunders; 2016 pp. 188–204.

TREATMENT RECOMMENDATIONS FOR JUVENILE IDIOPATHIC ARTHRITIS (TABLE 107.3) The current aim of treatment is to achieve a state of disease inactivity and ultimately medication-free long-term sustained remission. Treatment recommendations were published by the ACR in 2019 for nonsystemic polyarthritis, sacroiliitis, and enthesitis23 (update from 201116), in 2013 for systemic JIA,24 and 2011 for oligoarthritis16 using the best available evidence to propose treatment based on the disease activity and prognosis (see eTable 107.1, available online at www.expertconsult.com).23,25 The initial set of recommendations was based on clinical scenarios that included features of a poor prognosis and disease activity levels (low, moderate, and high) and were developed for each JIA treatment group, and treatment recommendations were developed accordingly. The updated guidelines from 2019 do not specifically address timing of treatment changes nor specifics of risk groups beyond the presence of one of the following: RF, ACPA, or joint damage. In this set of recommendations, the clinical JADAS (cJADAS) was used to define low versus high/moderate disease activity10,26,27 (Box 107.2). A specific emphasis is placed on the shared decision-making process, patient preferences, and comorbidities. Treatment recommendations by other national groups, including the Royal Australian College of General Practitioners, the German Society for Pediatric Rheumatology, and the British Society for Paediatric and Adolescent Rheumatology, did not differ substantially from the ACR recommendations. These recommendations have yet to apply “treat-to-target” strategies.28,29 The first treat-to-target recommendations for JIA were published in 2018 following a consensus-based Delphi-like procedure with participation from

CHAPTER 107  Management of juvenile idiopathic arthritis

915

Table 107.3

Major Medications and Indications for Treatment of Juvenile Idiopathic Arthritis Medication

Arthritis Subtype

Other Indication, Medication Class

NSAIDs

All types

Intraarticular corticosteroids Systemic corticosteroids Methotrexate

All types, mainly oligoarthritis Systemic, polyarthritis All types, uveitis; less effective for systemic and enthesitis-related axial disease Polyarthritis Oligoarthritis, polyarthritis, enthesitis-related peripheral disease Systemic Systemic Polyarthritis, enthesitis-related, less effective for systemic disease Polyarthritis Systemic Systemic, polyarthritis Enthesitis-related, psoriatic arthritis ​Polyarthritis Systemic

Symptomatic: pain, stiffness, serositis, antiinflammatory in mild cases Injection of few active joints Fever, serositis, bridging medication, MAS Synthetic disease modifier

Leflunomide Sulfasalazine Cyclosporine Thalidomide TNFi (etanercept infliximab, adalimumab, golimumab, certolizumab) Abatacept Anti–IL-1 (anakinra, canakinumab, rilonacept) Anti–IL-6 (tocilizumab) ​Anti IL-17 (secukinumab) ​JAK inhibitor (tofacitinib) IVIG

Synthetic disease modifier Synthetic disease modifier MAS, immunosuppressant Synthetic disease modifier Uveitis (infliximab, adalimumab), biologic modifier Uveitis,a biologic modifier MAS, biologic modifier Uveitis,a biologic modifier Biologic modifier Small molecule inhibitor Steroid sparing, MAS

IL-1, Interleukin-1; IVIG, intravenous immune globulin; JAK, Janus kinase; MAS, macrophage activation syndrome; NSAID, nonsteroidal antiinflammatory drug; TNF, tumor necrosis factor. a Can be considered in uveitis unresponsive to TNFi.

an international task force of 30 pediatric rheumatologists and a steering committee. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and time line of follow-up evaluations to ensure achievement and maintenance of the target depend on the category of JIA and level of disease activity. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research.29 An initial study from Germany indicates that use of this strategy may increase the rate of remission by JADAS criteria one year from the start of treatment.30 Comparative effectiveness research based on consensus treatment plans, developed by CARRA in North America, are currently underway for systemic and polyarthritis JIA. The one- and two -year results of the Start Time Optimization of Biologics in Polyarticular JIA (STOP-JIA) trial were recently published (see below Studies of Disease-Modifying Antirheumatic Drug Versus Biologic Combination Therapy for Juvenile Idiopathic Arthritis).31 These projects, facilitated by multicenter and international research organizations, will refine and improve current treatment recommendations in real life situations. The ACR has released guidelines for the management of pediatric rheumatology diseases, including JIA, during the coronavirus disease 2019 (COVID-19) pandemic.32 The overriding recommendation is to adequately and continuously treat JIA in order to suppress inflammation and prevent flares as detailed in this chapter, while minimizing corticosteroid use. Patients with JIA exposed to patients with COVID-19 and asymptomatic children infected with COVID-19 should continue therapy without change, whereas symptomatic children should temporarily delay or defer methotrexate, Janus kinase (JAK) inhibitors and most biologic modifiers (except interleukin [IL]-1 and perhaps IL-6 inhibitors) should be held until 7 to 14 days after resolution of fever and respiratory symptoms. Corticosteroids should be continued at the minimal necessary dose.

OLIGOARTHRITIS Patients with low disease activity (based on the number of active joints, ESR, CRP, and physician and patient or parent global assessments) and no features of a poor prognosis (arthritis of the hip, cervical spine, wrist, or ankle with marked elevation of ESR or CRP or radiographic damage) may respond to treatment with NSAIDs alone. In patients not responsive to NSAIDs after 2 months or in patients with local complications, including flexion contracture and/or leg-length discrepancy, intraarticular corticosteroid injections with triamcinolone hexacetonide are effective in many patients (Fig. 107.1). If the response lasts less than 4 months or extended oligoarthritis (polyarticular course) develops, treatment should proceed as for patients with polyarthritis. For patients with high disease activity and features of a poor prognosis, MTX should be initiated (can substitute with leflunomide if MTX is not tolerated). However, a controlled study showed that early initiation of

ALGORITHM FOR MEDICAL TREATMENT OF OLIGOARTICULAR-ONSET JUVENILE IDIOPATHIC ARTHRITIS (JIA) NSAID#, IATH* Improve&

Remission

No or shortlived improvement^ Repeat IATH

Flare

Inadequate response Remains oligoarticular

Extends to polyarticular

Intermittent IATH and/or methotrexate or, sulfasalazine$ or, leflunomide or anti-TNF

Manage as polyarticular JIA

* Prefer early IATH if knee monoarthritis and/or patient has local complications: contractures, leg length discrepancy, significant muscle atrophy # NSAID trial for 4 to 6 weeks ^ ≤ 4 months $ Consider sulfasalazine for older boys with enthesitis/peripheral arthritis & Aim for inactive disease/remission or at least a JADAS score 2.5) ** IATH for select joints *** PO steroids can be considered as bridging medicine or during significant flares for up to 3 months + Improved; Pediatric ACR70 response (or JADAS score 4 active joints 1–4 active joints

Type of JIA

Features of a Poor Prognosis or Risk Factors for Severe Disease

High Disease Activity

PGA of overall disease activity ≥5 of 10 irrespective of active joints PGA of overall disease activity 4 active joints PGA of overall disease activity palmitic acid,78 with JNK-1/c-Jun mediated hyperproduction of proinflammatory mediators (TNF-α, IL-6, and CCL-2).208

Clinical features and laboratory findings Majeed syndrome is characterized by neonatal-onset recurrent multifocal osteomyelitis, neutrophilic dermatosis, and congenital dyserythropoietic anemia.209 Disease flares occur 1 to 3 times per month and are sometimes associated with mild fever. The patients failed to thrive with height and weight below the 5th percentile and with delayed bone age. All patients reported had significant hepatosplenomegaly and required blood transfusions on several occasions.203 Pustular dermatitis is the most common skin manifestation, although psoriasis-like lesions have also been reported.209 The most frequent sites of osteomyelitis are clavicles, sternum, and long bones, whereas mandible and vertebral bodies are rarely affected.204,207 Bone biopsy studies usually show a neutrophilic infiltrate.204,206

Treatment Majeed syndrome is unresponsive to treatment with antibiotics and patients may respond to NSAIDs, corticosteroids, IFN-γ, bisphosphonates, and antiTNF drugs have been reported.206,207,209 The efficacy of IL-1 inhibition with either anakinra or canakinumab was shown in three patients with Majeed syndrome who were refractory to anti-TNF or corticosteroid therapy, thus suggesting a major role of IL-1 in the disease pathogenesis.210,211

PARTIALLY INTERLEUKIN-1–MEDIATED PYOGENIC DISORDERS PYOGENIC STERILE ARTHRITIS, PYODERMA GANGRENOSUM, AND ACNE SYNDROME Background In 1997, Lindor et al. described a kindred of 10 affected members presenting with pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne.212

1534

SECTION 15  Other Systemic Illnesses

a

b

c

FIG. 174.7  (a) Right elbow magnetic resonance imaging showing synovial thickening and enhancement with moderate fluid in a patient with PAPA syndrome. (b) Extensive pyoderma gangrenosum lesion in a patient with pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. (c) Diffuse erythematous and scaly skin rash in a patient with CARD14-mediated psoriasis. A second kindred of 11 affected patients was described by Wise et al. in 2000,213 and in 2002, using genome-wide linkage, CD2BP1/PSTPIP1 was identified, with two missense mutations, A230T and E250Q, as the disease-causing gene in both kindreds.214

Genetics and pathophysiology Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome (MIM#604416) is a pyogenic autoinflammatory disease caused by autosomal dominant LOF mutations in PSTPIP1 gene, also called CD2BP1.214 Twenty-five variants have been described in PSTPIP1, so far 15 of them being disease related.128 PAPA is exceedingly rare, with less than 20 families with the syndrome identified so far. PSTPIP1 encodes a cytoskeletal protein, proline-serine-threonine-phosphatase–interacting protein-1 (PSTPIP1). PSTPIP1 is an adaptor protein that interacts with the protein tyrosine phosphatases (PEST-PTPs), Wiskott-Aldrich syndrome protein (WASP), and pyrin, the protein encoded by MEFV, the gene mutated in FMF.215–217 Diseasecausing PSTPIP1 mutations diminish the interactions with PEST-type protein, which results in increased phosphorylation of mutated PSTPIP1 and increased interaction with pyrin.217 It is suggested that PSTPIP1 mutants increase activation of the pyrin (pyroptosome) associated IL-1b activation,27 but PSTPIP1 does not seem to be an essential regulator of the NLRP3, AIM2, or NLRC4 IL-1β–activating inflammasomes in a mouse model.218 Recent findings that PSTPIP1 regulates macrophage podosome organization and matrix degradation, and also has cytoskeletal regulatory functions, suggest that it may play a role in healing impairment in PAPA syndrome.219

Clinical features and laboratory findings Fever is rarely observed in PAPA patients, who present with early-onset flares of painful sterile and deforming arthritis (Fig. 174.7, a), cutaneous ulcers (pyoderma gangrenosum) (Fig. 174.7, b) and pathergy, cystic acne, or skin abscesses at the injections sites.214,220,221 Laboratory findings are nonspecific and include leukocytosis and increased ESR and CRP during flares.214,220 PAPA syndrome symptoms usually persist into adulthood and significant joint destruction with an impaired quality of life related to physical disability is observed.222 The classic clinical triad consists of severely scarring cystic acne, recurrent destructive pyogenic arthritis, and difficult-to-control pyoderma gangrenosum. Since the description of classic PAPA syndrome, the spectrum of PSTPIP1-associated diseases has expanded to include PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome.223,224 PAMI patients may present with pyoderma gangrenosum or skin lesions around the palpebral region of the eye, they are more likely to have failure to thrive, organomegaly, lymphadenopathy, and arthritis/ arthralgia. Many have pancytopenia with dyserythropoiesis, fibrosis, and lymphocytosis of bone marrow.224 More typically around puberty, cystic acne and hidradenitis suppurativa of the axilla and groin can develop.212,225 The pyogenic arthritis results in joint destruction, with ankylosis affecting joint mobility; and the pyoderma lesions heal with significant scarring of the skin. Laboratory findings are nonspecific and include leukocytosis and increased ESR and CRP during flares.214,220 Joint aspirates are sterile, and the predominant cells in the synovial fluid aspirate and in skin biopsies are mature neutrophils.

Treatment Treatment of PAPA syndrome is challenging, and corticosteroids, thalidomide, cyclosporine, dapsone, tacrolimus, and IVIG have been used with variable individual responses.222,226 Regarding biologics, two case reports showed that etanercept was efficacious in PAPA syndrome.226,227 Responses to infliximab were observed in one patient, to adalimumab in two patients,

and to anakinra in two cases.222,228 On the other hand, two patients did not respond to anakinra, one did not respond to infliximab, and another did not respond to etanercept therapy.222 In general, monoclonal anti-TNF antibodies (infliximab and adalimumab) were considered more effective in treating skin manifestations of PAPA syndrome.222 A recent study of 13 patients with active PAPA lesions found increased NLRP3-mediated IL-1β secretion and also reported long-term efficacy of IL-1 blockade.229

HA20: HAPLOINSUFFICIENCY OF A20 (MONOGENIC FORM OF BEHÇET’S DISEASE) Background Zhou et al. have recently described heterozygous mutations in TNFAIP3 (A20) in six families with an autosomal dominant form of Behçet’s disease. Because the truncating mutations detected in TNFAIP3 cause haploinsufficiency of A20, the disease has been termed haploinsufficiency of A20 (HA20).230

Genetics and pathophysiology HA20 or familial Behçet-like autoinflammatory syndrome (MIM#616744) is caused by autosomal dominant LOF mutations in TNFAIP3. Eight mutations have thus far been reported as causing HA20: four frameshift mutations,230 three nonsense,230,231 and one missense variant.232 A20 is a negative regulator of NF-κB signaling mainly via its deubiquitinase activity. Disease-causing TNFAIP3 mutations lead to an impaired regulatory function of A20 and to a consequent upregulation of the NF-κB signaling pathway.230 A20 also has an inhibitory role in NLRP3 inflammasome activity, and haploinsufficiency of A20 leads to constitutive activation of the NLRP3 inflammasome.233,234

Clinical features and laboratory findings Patients with HA20 have a disease onset in early childhood or in adolescence, and the main clinical features include nondeforming polyarthritis of small and large joints, uveitis, retinal vasculitis, gastrointestinal manifestations such as colitis, diffuse ulcers in oropharynx, colon, and the terminal ileum, erythema nodosum-like skin lesions, pseudofolliculitis, pathergy, and rarely CNS vasculitis. Autoantibodies to ANA, RNP, ds-DNA, and lupus anticoagulant can be found.230,232

Treatment Patients with HA20 have a variable response to colchicine; corticosteroids and TNF blockade with infliximab and adalimumab has been successful in some cases. Anti-IL-1 therapy was successfully used in a refractory case232 and in a case associated with lung autoinflammation.235 One patient with a missense TNFAIP3/A20 mutation236 and four patients with frameshift mutations237 were effectively and safely treated with the JAK1/2 inhibitor baricitinib.

PYOGENIC DISORDERS CAUSED BY NON– INTERLEUKIN-1 CYTOKINE DYSREGULATION DEFICIENCY OF INTERLEUKIN 36 RECEPTOR ANTAGONIST Background In 2011, Marrakchi et al. described 16 patients from nine Tunisian families with generalized pustular psoriasis and fever flares who were found to be homozygous for a mutation in IL36RN gene, L27P, indicating a founder mutation in Tunisia leading to this disease.238

CHAPTER 174  Monogenic autoinflammatory diseases Genetics and pathophysiology Deficiency of interleukin 36 receptor antagonist (DITRA) (MIM#614204) is caused by autosomal recessive LOF mutations in IL36RN, which encodes the antagonist of IL36 receptor. So far, 17 mutations have been associated with a DITRA phenotype INFEVERS (https://infevers.umai-montpellier.fr/ web/). IL36RN encodes for the IL-36-receptor antagonist (IL-36Ra), which binds to IL-36 receptor, thus blocking binding by IL-36α, -β, and -γ and inhibiting NF-κB and MAP kinase signaling.238 IL-36Ra is highly expressed in keratinocytes and plays an important role in downregulating exacerbated inflammatory responses. Therefore the absence of the IL-36 receptor antagonist in DITRA patients leads to constitutively enhanced IL-36 receptor signaling. The complete response of DITRA manifestations to IL-12/IL-23 blockade suggests an important role of Th17-mediated inflammatory pathways in the disease pathogenesis.239

Clinical features and laboratory findings Most of the patients with DITRA develop the disease during childhood.238 Patients present with recurrent and sudden onset of skin flares characterized by generalized erythematous and pustular skin rashes, associated with high fevers up to 40°C to 42°C, asthenia, high levels of acute phase reactants (i.e., CRP), and high white blood cell counts.238 Secondary skin infections and sepsis may also occur.238 In most patients, disease flares are thought to be triggered by viral or bacterial infections, but withdrawal of retinoid therapy, menstruation, and pregnancy were also triggers.238 Skin biopsies demonstrate spongiform pustules, acanthosis, and parakeratosis in the stratum corneum and infiltration of the skin by CD8+ and CD3+ T cells and macrophages.238

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anti-TNF agents, more recently including biologics targeting IL-17 and IL-23. Familial pityriasis rubra pilaris is considered refractory to the standard therapies, and a partial response has been described with retinoids, cyclosporine, and etanercept.244

AP1S3-MEDIATED PUSTULAR PSORIASIS Background In 2014, heterozygous mutations in AP1S3 gene, which encodes a subunit of the cytosolic transport complex AP1, were described in 15 unrelated patients with pustular psoriasis.248,249

Genetics and pathophysiology AP1S3-mediated pustular psoriasis (AMPS; MIM#616106) is caused by autosomal dominant LOF mutations in AP1S3, the gene encoding AP-1 complex subunit σ1C. Two disease-causing mutations have been reported in 20 patients.249,250 The adaptor protein (AP) complexes are cytosolic structures that assemble and traffic small transport vesicles.251 The variants detected in AMPS patients were predicted to destabilize the 3D structure of the AP-1 complex and silencing AP1S3 in immortalized keratinocyte cell lines disrupted the endosomal translocation of TLR3 leading to a marked inhibition of its downstream signaling.249 AP1S3 expression has been shown to be elevated in keratinocytes, and AP1S3 knockout disrupts keratinocyte autophagy with abnormal accumulation of p62, an adaptor protein that mediates NF-κB activation. Consequently, AP1S3-deficient cells upregulate IL-1 and IL-36 production, which can be reversed by IL-36 blockade.250

Clinical features and laboratory findings

Acitretin has been used as treatment with appropriate response.238,239 Other therapeutic regimens tried with variable individual responses were oral and topical steroids, methotrexate, cyclosporine, and TNF inhibitors (adalimumab, infliximab, and etanercept).238 The monoclonal antibody anti IL-12 and IL-23 (ustekinumab) has also been used in some cases with remarkable responses.239

Patients with AMPS present with pustular psoriasis that often manifest with concomitant plaque psoriasis. The pustular manifestations can range from a more severe form, generalized pustular psoriasis (GPP), to a chronic pustular involvement of palmar plantar psoriasis (PPP) or acrodermatitis continua of Hallopeau (ACH).249 In the patients thus far reported, disease onset was more frequent in adulthood (25 to 76 years old), and in one patient each, the clinical findings developed in the first year of life and at the age of 10 years old, respectively.249

CARD14-MEDIATED PSORIASIS

Treatment

Treatment

Background In 1994, Tomfohrde et al. identified a psoriasis susceptibility locus, PSORS2, in a single large family of European ancestry that mapped to human chromosomal region 17q25-qter.240 A five-generation psoriasis pedigree from Taiwan exhibited significant linkage to the same locus.241 Recently targeted and exome capture followed by NextGen sequencing of DNA from members of the family identified a splice site mutation in the caspase recruitment domain family member 14, CARD14 encoding a protein that carries a CARD domain that mediates the assembly of CARD-containing proteins into apoptosis and NF-κB signaling complexes.242,243

Genetics and pathophysiology CARD14-mediated psoriasis (CAMPS) is caused by autosomal dominant GOF mutations in CARD14 gene and can present as a monogenic form of pustular psoriasis (MIM#602723)243 or as pityriasis rubra pilaris (MIM#173200).244 Thirteen disease-causing mutations have so far been reported as causing CAMPS (https://infevers.umai-montpellier.fr/web/). Mutant CARD14 leads to increased NF-κB translocation and increased production of chemokines by keratinocytes. It is hypothesized that tissue macrophages produce and secrete IL-23 and recruit and induce Th17 cell differentiation and the release of IL-17A and IL-17F, cytokines that are also produced by CD4+ and CD8+ T cells, γδ T cells, neutrophils, and mast cells. This can induce a proinflammatory cytokine and chemokine milieu. Their targets include keratinocytes that become more activated245,246 and fuel an abnormal amplification loop that further augments keratinocyte activation and inflammatory cell recruitment.245,246

Similarly to treatment of other monogenic non-IL-1-mediated pustular diseases DITRA and CAMPS, IL-36, IL-12/IL-23, or IL-17 may be considered therapeutic targets in AMPS.249

EARLY-ONSET INFLAMMATORY BOWEL DISEASE Background In 2009 Glocker et al. mapped chromosome 11q and 21q as the regions of interest in two families with early-onset severe enterocolitis.252 Targeted sequencing showed a homozygous missense mutation in IL10RA and a homozygous nonsense mutation in IL10RB in each of the families evaluated. In 2010, the same group also found that autosomal recessive mutations in IL10 gene may cause refractory early-onset IBD. Very early onset IBD (VEO-IBD), in the neonatal period and early infancy, is phenotypically and genetically different from older child-onset IBD, and may include intractable ulcerating enterocolitis. IL-10RA mutations are associated with onset in infancy, perianal fistulae, poor response to therapy, and early surgical interventions.

Genetics and pathophysiology

Patients with CARD14 mutations can present with typical plaque psoriasis that can be more limited to some areas of the skin or generalized involving 100% of the body surface area (see Fig. 174.7, c).243,244 Fever and other systemic manifestations are generally not present but can occur with superinfections of the skin in patients with CAMPS.243,247

Infantile IBD is caused by autosomal recessive LOF mutations in IL-10R (MIM#613148) (MIM#612567) and IL-10 (MIM#612381) encoding genes.252,253 In total, six disease-causing mutations in each of the IL-10 receptor genes (IL10RA and IL10RB) and two mutations in the IL-10 gene have been described. Interleukin-10 is an antiinflammatory cytokine that is secreted by a wide variety of cells and has immunoregulatory effects on T cells, B cells, myeloid cells, and other cell types. IL-10 limits the secretion of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-12. IL-10 signals through the IL-10 receptor, which consists of two receptor subunits, IL10RA and IL10RB. Dysfunction of IL-10 receptor and impaired signaling of IL-10 leads to increased production of the proinflammatory cytokines including TNF-α; interleukin-1α, -1β, -2, and -6; and chemokines RANTES; MIP-1α and MIP-1β. Mice deficient in either IL-10 receptor A or IL-10 receptor B also present with severe enterocolitis.252,253

Treatment

Clinical features and laboratory findings

The therapeutic approach in CAMPS includes drugs used for the treatment of moderate-to-severe psoriasis, such as methotrexate, cyclosporine, and

Patients with EO-IBD present with severe enterocolitis, characterized by bloody diarrhea, colonic abscesses, perianal fistula, and oral ulcers.252,254

Clinical features and laboratory findings

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SECTION 15  Other Systemic Illnesses

Symptoms usually start in the first year of life, before 3 months of age.254 Additionally, they present with impaired weight and height development and recurrent fever.254 Musculoskeletal manifestations include acute recurrent arthritis of large joints, especially affecting knees.254 Remarkably, recurrent folliculitis has been observed in 75% of the patients.254 Recurrent infections, such as otitis media, bronchitis, pneumonia, septic arthritis, and renal abscesses, may indicate a defect in the immune responses in patients with EO-IBD.252,254

Treatment Because EO-IBD is a severe disease and frequently refractory to standard immunosuppressants, hematopoietic stem cell transplantation (HSCT) has been proposed as a curative treatment.255 HSCT was performed in 9 out of the 29 patients with IL-10 deficiency and complete clinical remission was achieved in all but one of the patients.254–256

VASCULOPATHY AND PANNICULITIS/ LIPOATROPHY SYNDROMES CHRONIC ATYPICAL NEUTROPHILIC DERMATOSIS WITH LIPODYSTROPHY AND ELEVATED TEMPERATURE SYNDROME OR PROTEASOME-ASSOCIATED AUTOINFLAMMATORY SYNDROMES Background In 1993, Tanaka et al. reported 13 Japanese patients and proposed that all patients previously published suffered from the same syndrome that included earlier descriptions dating back to 1939 of patients with lipodystrophy rashes and systemic inflammation.257 In 2010 Garg et al. reported two Mexican siblings and a Portuguese patient258 and noted the similarities with the Japanese patients. The disorder was termed JMP syndrome, for joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy. All patients had short stature, generalized lipodystrophy, severe joint contractures of the elbows, hands, fingers, feet, and toes. In childhood, all patients had erythematous nodular skin lesions and one patient had panniculitis on skin biopsy. Earlier the same year, Torrelo et al. proposed the acronym CANDLE for a disease described in four patients, including two sisters who had recurrent fevers,

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c

annular erythematous skin lesions, lipodystrophy, and high elevation of acute phase reactants with hypochromic anemia.259

Genetics and pathophysiology In 2011, several studies showed that autosomal recessive LOF mutations in proteasome subunit βeta type (PSMB8) gene cause JMP syndrome,260 Nakajo-Nishimura syndrome (NNS),261 Japanese autoinflammatory syndrome with lipodystrophy (JASL),262 and CANDLE263 (MIM#256040), thus indicating that these disorders are disease phenotypes along the same disease spectrum.259,263,264 Currently, eight pathogenic mutations have been described in PSMB8 (https://infevers.umai-montpellier.fr/web/). In addition to the PSMB8 mutations,260–263,265 LOF mutations in other proteasome subunits (PSMB9, PSMB4, PSMA3, PSMB10)266,267 and the proteasome assembly proteins, POMP268 and PSMG2,269 thus expanding the inheritance to compound heterozygous (mutations in PSMB4,266 PSMB8,270 and PSMG2269), digenic recessive (combinations of PSMA3, PSMB4, and/or PSMB9),266 and autosomal dominant (AD) (POMP).266,268 CANDLE is a rare disease with less than 100 cases described worldwide. Proteasomes are protein degradation systems that target intracellular polyubiquitinated proteins derived from self-structures or foreign structures for proteolytic destruction.271 Proteasomes are implicated in cellular processes including apoptosis, the removal of various misfolded and immature proteins, and the production of peptides for presentation by MHC class I molecules.272 Gene expression profiling using whole blood microarrays identified the IFN pathway as the most differentially regulated pathway in all six CANDLE patients tested,263 and inhibition of IFN signaling with the Janus kinase (JAK) inhibitors decreased IFN-γ induced IP-10 production of the patients’ cells,263 thus suggesting that IFN pathway may be a target for therapeutic intervention.

Clinical features and laboratory findings Common clinical features seen in the majority of the patients historically described as either NNS, JMP, or CANDLE include high fevers, clubbed fingers, skin rashes varying from small nodules to violaceous plaques (Fig. 174.8, a), also described as “pernio-like” lesions covering trunk and extremities, facial rashes leading to various degrees of edema, mimicking heliotrope rashes in some patients, arthritis with more variable joint contractures, and progressive lipodystrophy affecting initially the face and extremities but can be generalized (Fig. 174.8, b). “Clubbed fingers” seen are a result of the arthropathy and the lipoatrophy that develops early in the hands, but

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d

FIG. 174.8  (a) Erythematous, annular, and nodular rash in a patient with CANDLE. (b) Lipodystrophy (black arrows) and acanthosis nigricans (red arrow) in a patient with

CANDLE. (c) Brain magnetic resonance imaging (MRI) showing basal ganglia calcifications in a patient with CANDLE. (d) Bilateral thigh MRI showing signs of myositis (white patches) in a patient with CANDLE.

CHAPTER 174  Monogenic autoinflammatory diseases elevation of the nail bed seen in hypertrophic osteoarthropathy is not typically seen in these patients. Myositis (Fig. 174.8, d), hepatosplenomegaly, basal ganglia calcification (Fig. 174.8, c), microcytic anemia, and increased acute phase reactants (ESR and CRP) are present. More variable symptoms include muscle atrophy, dyspnea, seizures, lymphadenopathy, low weight and height, hepatosplenomegaly, and metabolic abnormalities including truncal obesity and hyperlipidemias, insulin resistance, and acanthosis nigricans.258,263,273 Less frequent clinical and laboratory findings observed were perioral swelling, parotitis, conjunctivitis or episcleritis, hypertrichosis, ear and nose chondritis, lymphocytic aseptic meningitis recurrent otitis or sinusitis, epididymitis, thrombocytosis, hypergammaglobulinemia, neutropenia, and thrombocytopenia.261,263 In childhood, severe inflammatory attacks that cannot be controlled by any antiinflammatory medications including high-dose steroids can result in sudden death likely from a triggered systemic inflammatory syndrome resulting in organ failure. In older patients, some insights into the development of organ damage from untreated disease are provided by earlier reports on adult patients,258,273 suggesting the development of muscle atrophy and joint contracture, the development of cardiac arrhythmias, and heart failure. Autopsy results from a patient who died of heart failure have provided further insights into the disease pathology. Extensive endothelial cell damage and calcification of multiple vessels including cardiac and basal ganglia vessels was observed, and it was proposed that ischemia may cause the severe skeletal muscle atrophy and myofibrillary necrosis. Other muscles affected included tongue, extraocular muscles, and heart.274

Treatment Most clinical symptoms partially respond to high doses of steroids (1–2 mg/ kg/day).263 NSAIDs, colchicine, dapsone, methotrexate, tacrolimus, and azathioprine were not effective in most of the patients.263 A variable response was temporarily observed to anti-TNF, anti–IL-1, and anti-IL-6 agents, but complete disease remission was not achieved with any of the therapies described.263 The increase in STAT-1 phosphorylation and the strong interferon response prompted treatment with JAK1/2 inhibitor baricitinib. At optimal doses, 5 out of 10 CANDLE patients achieved long-lasting remission off steroids. All patients benefited with significant reductions in daily disease symptoms, corticosteroid requirement, and reduction in IFN scores. The patients’ quality of life and height and bone mineral density Z-scores significantly improved. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.275 Drug exposure at optimal doses were 1.8-fold higher than the exposure in RA patients receiving 4 mg/day with dose-level dependent reduction in STAT-1 signaling.276 JAK inhibition with ruxolitinib269 or baricitinib277 were also reported to be beneficial in two additional CANDLE patients.

OTULIN-RELATED AUTOINFLAMMATORY SYNDROME Background Recently, an autoinflammatory disease clinically characterized by early-onset panniculitis, recurrent fevers, arthritis, and diarrhea was linked to homozygous mutations affecting the deubiquitinase OTULIN: the OTULIN-related autoinflammatory syndrome (ORAS)278,279 (AIPDS, MIM#617099).278,279

Genetics and pathophysiology Damgaard et al. reported three patients from a consanguineous family with the homozygous hypomorphic LOF mutations (p.L272P) in OTULIN/FAM105B,278 and Zhou et al. described four patients from three families with mutations (p.L272P, p.Y244C, and p.G174Dfs2) causing the disease.279 Methionine-1 (M1)-linked ubiquitin chains regulate the

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activity of NF-κB, immune homeostasis, and responses to infection. The M1-specific deubiquitinase OTULIN is essential for preventing TNFassociated systemic inflammation in humans and mice. Four independent OTULIN mouse models revealed that OTULIN deficiency in immune cells results in cell type–specific effects, ranging from overproduction of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells.278

Clinical features and laboratory findings The disease presents similar to CANDLE with early onset recurrent fevers, relapsing neutrophilic nodular panniculitis, diarrhea, and arthritis. Lymphadenopathy and hepatosplenomegaly may occur. Laboratory manifestations include neutrophilia, elevated CRP and hypergammaglobulinemia, and low titer autoantibodies in the first family. All patients had growth retardation, which in one patient was corrected with anti-TNF treatment.278,279

Treatment Remarkably, treatment with anti-TNF antibodies ameliorated inflammation in ORAS patients and rescued mouse phenotypes.278

NEMO DELETED EXON 5-AUTOINFLAMMATORY SYNDROME (NEMO-NDAS) AND SAMD9L-ASSOCIATED AUTOINFLAMMATORY DISEASE (SAMD9L-SAAD) Two novel diseases that present with prominent panniculitis and lipodystrophy and mimic CANDLE were characterized. Four patients, two other males and one female, had de novo splice-site variants that led to deletion of exon 5 of IKBKG, the gamma subunit of the IκB kinase complex that regulates NF-κB activation.186 Due to the presence of a homologous pseudogene, the mutations were not found by WES/WGS and detection required targeted Sanger sequencing and ultimately protein confirmation of the presence of a spliced protein lacking exon 5.280 Patients present with lymphohistiocytic panniculitis, variable ectodermal dysplasia of teeth similar to patients with NEMO immunodeficiency syndrome (Fig.174.9, a). Other findings include progressive B-cell lymphopenia and hypogammaglobulinemia. In contrast to NEMO immunodeficiency syndrome, NF-κB signaling is normal or increased in NEMO-NDAS patients. Six patients with CANDLE-like disease had de novo frameshift mutations in SAMD9L; their clinical manifestations resembled CANDLE with prominent neutrophilic panniculitis that was clinically and histologically indistinguishable from CANDLE (Fig.174.9, b). However, four patients also had early-onset, severe interstitial lung disease, a clinical feature that is not seen in CANDLE; SAAD patients had lower IRG-S in the context of high CRPs and developed progressive isolated B-cell and natural killer cell cytopenias that were accelerated in the context of infections.186 The presence of increased NF-κB and IFN signaling in both diseases suggests broader cytokine dysregulation.

VASCULOPATHY AND/OR VASCULITIS WITH LIVEDO RETICULARIS SYNDROMES WITHOUT SIGNIFICANT CENTRAL NERVOUS SYSTEM DISEASE Sting-associated vasculopathy with onset in infancy Background Dominant GOF mutations in STING1 (also TMEM173) encoding stimulator of interferon genes (STING) cause the autoinflammatory syndrome

b

FIG. 174.9  (a) Conical teeth in a patient with NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS). (b) Erythematous nodular rash in a patient with SAMD9Lassociated autoinflammatory disease (SAMD9L-SAAD).

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SECTION 15  Other Systemic Illnesses

STING-associated vasculopathy with onset in infancy (SAVI) with disease-causing mutations thus far limited to exon 5 in STING residues V147, N154, V155.7,281–284 A report of a family with four mutation-positive (V155M) members in three generations with variable clinical phenotype and onset (ranging from onset at 1 year of age with febrile attack and rash with lung disease and failure to thrive in one individual to adult-onset arthralgia and systemic inflammation), all with overexpression of interferon-regulated genes281 suggests modifiers that influence the severity of SAVI.

Genetics and pathophysiology SAVI (MIM#615934) is an ultra-rare autoinflammatory disease caused by de novo GOF mutations in STING1, which encodes the stimulator of IFN genes (STING),285 an adaptor protein in the cytosolic DNA-sensing pathway.7 Disease-causing missense mutations affect three amino acids, V155, N154, V147,7,281,282,286 in the recently characterized connector loop area of STING (class I mutations); another mutation cluster was found in the oligomerization domain of STING (class III mutations) R281 and R284.287 STING is a dimeric, endoplasmic reticulum (ER) transmembrane adaptor molecule that coordinates viral immunity.288,289 Upon activation it recruits and activates TANK-binding kinase 1 (TBK1) and causes IRF3 phosphorylation/activation and IFNB1 transcription.289 The disease-causing STING mutations lead to constitutive transcription of IFNB17,281 and to the presence of a strong IFN response-gene-signature in whole-blood RNA of SAVI patients,7 thus suggesting a critical role of chronic IFN stimulation in the disease pathogenesis. The STING/IFN-β pathway can be directly activated in endothelial cells indicating that the development of vasculitis may be triggered directly by dermal endothelial cell activation.7,281 Because STING coordinates signals from multiple upstream dsDNA sensors, it may be a target for therapeutic interventions not only in SAVI but also in a wider variety of IFN-mediated diseases.7,281,282

Clinical features and laboratory findings Rash with systemic inflammation (fever, elevated acute phase reactants) are typically seen in the first months of life.7,2831–284 Vasculopathic lesions are most prominent in cold-sensitive acral areas and present as violaceous plaques, nodules on face, nose, ears, and distal ulcerations (Fig. 174.10, a and b and e). Features of vascular and/or tissue damage include nail dystrophy, gangrene/ infarcts of fingers/toes with tissues loss, and nasal septal perforation.7,281–283

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d

In lesional skin biopsy endothelial cells, there is upregulation of endothelial inflammation (inducible nitric oxide synthase), coagulation (tissue factor), and endothelial cell adhesion and activation (E-selectin). Although immune complexes were seen in partially destroyed vessels, many vessels did not have immune complex deposition and affected cutaneous small-vessels were surrounded by neutrophils and leukocytoclasia (Fig. 174.10, c).7 Paratracheal adenopathy, abnormal pulmonary function tests, and variable interstitial lung disease on computed tomography (CT) (Fig. 174.10, d) are seen with or without symptoms; the extent of lung fibrosis varies between patients.7,281–284 SAVI patients present with increased alveolar macrophages, activation of type 2 pneumocytes, follicular hyperplasia, and prominent fibrosis7; however, no vasculitis is observed in the lung of SAVI patients. Myositis, arthritis, and arthralgia are variably seen.7,281,284 Early mortality due to severe lung disease often in the context of infections is seen.7,281,282

Treatment Immunosuppressive agents including high-dose steroids, azathioprine, colchicine, methotrexate, mycophenolate mofetil, cyclophosphamide, tumor necrosis factor antagonist, IL-1 blockade, IL-6 blockade, and anti-CD 20 therapy have not resulted in sustained responses.7,281–284 The use of JAK inhibitors in SAVI patients provides partial responses with stabilization of the lung disease but variable responses on skin manifestations.275,290–292 Therapeutic strategies targeting STING are not yet available.

WITH SEVERE CENTRAL NERVOUS SYSTEM DISEASE Deficiency of adenosine deaminase 2 Background In 2014, autosomal recessive mutations in ADA2 (previously CECR1), the gene encoding the enzyme adenosine deaminase 2 (ADA2), were reported as the cause of an early-onset vasculopathy resembling polyarteritis nodosa (PAN).293,294

Genetics and pathophysiology Deficiency of adenosine deaminase 2 (DADA2, MIM#615688) is an autosomal recessive disorder caused by homozygous or compound heterozygous LOF mutations in ADA2. Endothelialization of the hepatic sinusoids

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c

e

FIG. 174.10  (a) Typical facial distribution of vasculitic lesions on the nose and cheeks of a patient with STING-associated vasculopathy with onset in infancy (SAVI). (b)

Violaceous vasculitic plaques and self-amputations on the hand of a patient with SAVI. (c) Dense inflammatory infiltrate with fibrinoid necrosis of vessel wall and nuclear debris in dermis and subcutis. (d) High-resolution chest computed tomography depicting interstitial lung disease in a patient with SAVI. (e) Ear lobe changes due to vasculitis.

CHAPTER 174  Monogenic autoinflammatory diseases in liver biopsy has been reported.293 In vitro reduced adenosine deaminase 2 (ADA2) activity causes endothelial damage and impaired M2 macrophage differentiation that are hypothesized to lead to vasculopathy and inflammation. An upregulation of interferon-stimulated gene signature in peripheral blood with marked overexpression of neutrophil-derived gene was seen in patients with DADA2.295 The lack of ADA2 activity in patients with DADA2 causes accumulation of extracellular adenosine that engages the A1 adenosine receptor (A1AR) and/or A3AR in neutrophils leading to neutrophil extracellular traps (NET) formation. NETs are thought to activate macrophages to increase proinflammatory cytokines such as TNF-α and IL-6 in an NF-κB dependent manner. TNF-α☐ can prime neutrophils to undergo further NETosis, leading to a vicious cycle.296

Clinical features and laboratory findings Patients present with polyarteritis nodosa like lesions, early-onset strokes, peripheral neuropathy, livedo reticularis, and Raynaud symptoms; other features include hypertension, renal infarct, hepatosplenomegaly, portal hypertension, cervical lymphadenopathy, and systemic manifestations of chronic inflammation including anemia. Variable low serum immunoglobulin levels are found, with or without autoantibodies.293,295,298 Disease severity can vary even within families with the same mutations, ranging from limited skin eruptions to severe fatal systemic vasculitis. MRI of the brain abnormalities include acute or chronic subcortical lacunar infarct in deep-brain nuclei and the brain stem, indicating small-vessel occlusions.293 Hemorrhagic strokes, in the context of anticoagulation, have been seen. Some angiographic studies show aneurysms and stenosis of abdominal arteries (mesentery, celiac, hepatic, and renal); renal cortical infarcts or intracranial calcification on brain CT are sometimes seen.294 Histologic findings of skin biopsies include a predominantly interstitial inflammatory infiltrate composed of myeloperoxidase, (MPO+) neutrophils and CD68+ macrophages with perivascular CD3+ T lymphocytes,293 intravascular thrombosis, and necrotizing arterial vasculitis.294 In lesional skin and brain biopsies, endothelial damage on staining by anti-CD31 antibodies and endothelial-cell activation by E-selectin is seen.

Treatment Many patients respond to TNF inhibitors but only partially to high doses of glucocorticoids; the benefit of TNF inhibition in preventing recurrence of stroke development has recently been reported.299 Fresh frozen plasma and hematopoietic stem cell transplantation have been shown to be effective in some patients with deficiency of ADA2. Anticoagulation with aspirin and heparin is not effective; to avoid bleeding complications, anticoagulation is not recommended.

Aicardi-Goutières syndromes Genetics and pathophysiology Aicardi-Goutières syndrome (AGS) phenotype is caused by mutations in seven genes: AGS1 (TREX1) (MIM#225750), AGS2 (RNASEH2B) (MIM#610181), AGS3 (RNASEH2C) (MIM#610329), AGS4 (RNASEH2A) (MIM#610333), AGS5 (SAMHD1) (MIM#612952), AGS6 (ADAR1) (MIM#615010), AGS7 (IFIH1) (MIM#615846).300 AGS is mostly inherited as a recessive disorder caused by LOF mutations in genes that encode nucleic acid repair enzymes. They include mutations in TREX1, a DNA 3′ repair exonuclease 1; RNASEH2A, -B and -C, all subunits of ribonuclease H2 enzyme complex; and SAMHD1, cellular enzyme SAM domain and HD domain containing protein 1. Autosomal dominant and sporadic forms are caused by heterozygous LOF mutations in ADAR1, an RNA repair/editing enzyme resulting in haploinsufficiency. More variable disease phenotypes are seen with autosomal dominant GOF mutations in two cytosolic dsRNA sensors, IFIH1 encoding MDA5301,302 and in DDX58 encoding RIG-I.300

Clinical features and laboratory findings Aicardi-Goutières syndrome is characterized by early-onset inflammatory encephalopathy associated with chronic CSF lymphocytosis and high IFNα levels in the CSF, although less severe CNS disease is found in a number of later onset patients with milder disease or patients with more skin and autoimmune diseases that can mimic CANDLE.303 Brain MRI and CT findings include intracranial calcifications in the white matter, basal ganglia, and thalami; ischemic or hemorrhagic strokes; and white matter loss resulting in cerebral atrophy and microcephaly.304 Patients with AGS may present with spasticity, dystonia, large vessel disease (including moya-moya), stenosis or aneurysms, psychomotor retardation, and death in childhood.305,306 Patients may have low titer of autoantibodies. Some patients may develop features of autoimmune disorders later in life. Vascular mineral deposits and cortical microinfarctions were occasionally found in postmortem brains. Some heterozygous mutations in TREX1 and STING1 may cause autosomal dominant

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forms of sporadic or familial “Chilblain Lupus.”307 Cutaneous manifestations include digital vasculitis and or necrosis, chilblains, skin mottling, sometimes with panniculitis, necrotic cheek eruptions, and lipoatrophy.

Treatment Therapy with type-I IFN-inhibiting agents is being explored and a few case reports have shown mild to moderate clinical response to JAK inhibitors (baricitinib and ruxolitinib) in patients with AGS (reviewed in Tonduti et al.308 and Crow et al.309). Reverse transcriptase inhibitors have also been tried in eight AGS patients with better response in patients with mutations in the RNASEH2 complex.310

Spondyloenchondrodysplasia with immune dysregulation Genetics and pathophysiology Spondyloenchondrodysplasia with immune dysregulation (SPENCDI, MIM#607944) is caused by recessive LOF mutations in the ACP5 gene encoding tartrate-resistant phosphatase (TRAP).311 Lack of TRAP activity leads to hyperphosphorylation and constitutive GOF of osteopontin (OPN), a multifunctional protein that plays a role in bone remodeling through osteoclasts and immune regulation through Toll-like receptor 9 (TLR-9).312

Clinical features and laboratory findings Characteristics of this syndrome include short stature, bone dysplasia, neurologic dysfunction including spastic paraparesis, seizures, cerebral atrophy, and intracranial calcifications. Many patients developed three or more autoimmune diseases during childhood, most commonly SLE with thrombocytopenia, and antiphospholipid syndrome, hemolytic anemia, hypothyroidism, Sjogren’s syndrome, and inflammatory myositis. Increased levels of serum IFN-α and an upregulation of an interferon signature were noted in patients with SPENCDI. Other features suggesting autoimmune dysregulation include lupus nephritis, arthritis, increased bone mineral density, recurrent respiratory infections, rarely interstitial lung disease, positive antinuclear and anti-dsDNA antibodies, and hypocomplementemia. Cutaneous manifestations includes palpable purpura, petechiae on the lower limbs, severe eczema, hyperpigmented macules, vitiligo, Raynaud phenomenon with dilated loops of capillaries, livedo reticularis, sclerodermatous or acrocyanotic changes of hands and feet with edema, and digital vasculitis, which leads to necrosis and amputation. Affected skin biopsies show a perivascular polymorphonuclear infiltrate without evidence of deposition of complement or immunoglobulin, consistent with a nonspecific leukocytoclastic vasculitis.

Treatment Skin lesions are responsive to oral steroid therapy, chloroquine and cyclophosphamide. Treatment with other immunosuppressive agents, such as azathioprine, mycophenolate mofetil, and rituximab, showed good response.311,313 JAK inhibitors are being explored.

AUTOINFLAMMATORY DISORDERS WITH GRANULOMATOUS SKIN DISEASES WITHOUT SIGNIFICANT IMMUNODEFICIENCY Blau syndrome/early onset sarcoidosis (pediatric granulomatous arthritis) Background In 1985, Blau and Jabs et al. described an autosomal dominant inherited disorder characterized by a clinical triad of chronic arthritis, granulomatous dermatitis, and recurrent uveitis starting before the age of 4 years, which was called Blau syndrome.314,315 In 1996, Tromp et al. mapped the genetic cause of the disease to chromosome 16 (16q 12.1–13),316 and in 2001 Miceli-Richard et al. discovered that missense mutations in NOD2/CARD15 gene caused this clinical phenotype.317 In 2005, mutations in the same gene were found to cause a sporadic disease, early onset sarcoidosis, with clinical resemblance.318,319 To reflect the fact that the familial and the sporadic forms are the same disease, the disease spectrum is referred to as pediatric granulomatous arthritis (PGA).320

Genetics and pathophysiology PGA (MIM#186580) is caused by autosomal dominant gain-of-function mutations in the NACHT domain (exon 4) of NOD2/CARD15.128,321 PGA can be inherited in an autosomal dominant pattern, and familial cases have traditionally been called Blau syndrome. However, mutations can occur sporadically, and in these instances, the disease has been referred to as early-onset sarcoidosis.322 So far, 33 disease-causing mutations in NOD2 gene have been reported to cause PGA.128

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Like NLRP3, NOD2 (nucleotide oligomerization domain 2) is a member of the NOD-like receptor family (NLR), playing an important role in innate immune defenses through detection and clearance of intracellular invasive bacterial and viral infections323 (see Fig.174.1, c).

Clinical features and laboratory findings PGA symptoms typically occur before the age of 4 years due to a granulomatous inflammation of eyes, joints, and skin, leading to an early-onset classic triad of disease manifestations comprising chronic uveitis, arthritis, and dermatitis.320 All patients present with chronic arthritis, which almost always presents as polyarthritis (96%).320 A symmetric hypertrophic tenosynovitis is observed in approximately 40% of the patients.320 Typical PGA exanthema is described as ichthyosis-like and occurs in over 85% of the patients (Fig. 174.11, a).322,323 Ocular involvement is very frequent (84%) and is usually chronic and persistent (Fig. 174.11, b).320,324 Uveitis presents more commonly as panuveitis (50%), but 25% of the subjects may present with anterior uveitis.320,324 Most of the subjects have bilateral eye involvement, and cataract and glaucoma occur in 50% and 30% of them, respectively.320,323 Up to 40% of the untreated patients with PGA uveitis develop irreversible blindness.324 Less commonly observed findings include fever, camptodactyly, and central neuropathy.322 Laboratory investigations Laboratory exams demonstrate persistent leukocytosis, thrombocytosis, and increased ESR and CRP.320 Synovial, skin, and liver biopsies may show noncaseating granulomata, but a definitive diagnosis is only achieved with DNA sequencing showing NOD2/CARD15 mutations.128,324

Complications of untreated disease The most significant morbidity is eye involvement, and frequently cataract, glaucoma, and retinal detachment are complications and may lead to visual impairment and permanent vision loss.320,325 Untreated patients may also

develop complication of chronic arthritis, such as joint deformities, ankylosis and contractures of small joints, and decreased motion of large joints.326,327

Treatment Optimal therapy for PGA has not been well defined; NSAIDs can be used for mild clinical manifestations, whereas severe symptoms are treated with systemic corticosteroids.328 Immunosuppressants (methotrexate and cyclosporine) and biologics targeting TNF and IL-1 (etanercept, infliximab, and anakinra) have been reported to result in clinical benefit, especially in patients with refractory uveitis.323,324,329

WITH VARIABLE FEATURES OF IMMUNODEFICIENCY PLCG2-associated antibody deficiency and immune dysregulation Genetics and pathophysiology Autosomal dominant mutations in PLCG2 cause two different syndromes, called PLAID (MIM# #614468) and APLAID (MIM# #614878), respectively.

Clinical features and laboratory findings While PLAID leads to cold-induced urticaria, autoimmune manifestations, and susceptibility to infections, APLAID leads to early-onset recurrent erythematous plaques and vesicopustular skin lesions associated with arthralgia, corneal erosions, and interstitial pneumonia.330 The two patients identified thus far with APLAID developed recurrent sinopulmonary infections presumed due to a lack of class-switched memory B cells.330

Treatment Both patients with APLAID described were partially responsive to anakinra and high-dose corticosteroids.330

OTHER AUTOINFLAMMATORY SYNDROMES LACC1-MEDIATED MONOGENIC STILL DISEASE Background LACC1-mediated monogenic Still disease (MIM# 613409) is an autosomal-recessive form of systemic JIA, associated with homozygous missense mutation of LACC1, which encodes laccase.

Genetics and pathophysiology LACC1 is a multicopper oxidoreductase that catalyzes the oxidation of a variety of phenolic and nonphenolic compounds.

Clinical features and laboratory findings

a

Patients present with quotidian fever, associated with erythematous maculopapular rash, symmetric polyarthritis affecting small and large joints, and sometimes with tenosynovitis, serositis, organomegaly, and lymphadenopathy. Laboratory findings include leukocytosis, thrombocytosis, and elevated acute phase reactants. Some patients may have positive ANA and low-titer rheumatoid factor. Erosive arthritic changes with joint destruction can be seen on imaging studies.

Treatment The disease is refractory to different immunosuppressive agents: NSAIDs, systemic corticosteroids, methotrexate, and biologic agents including etanercept, adalimumab, tocilizumab, and rituximab.331

FAMILIAL COLD-INDUCED AUTOINFLAMMATORY SYNDROME 2 (FCAS2) Background In 2008, two unrelated families from Guadeloupe presenting with episodes of fever, arthralgia, and myalgia after generalized exposure to cold were found to have autosomal dominant mutations in NLRP12.332 The disease is referred to NLRP12-associated diseases (NLRP12AD) and is also known as FCAS2 since it clinically resembles FCAS, a NLRP3-associated cryopyrinopathy. Several more cases and families have been described.332–334 The effects of the disease-causing mutations on NLRP12 function are currently being investigated. b

FIG. 174.11  (a) Diffuse ichthyosis-like skin rash in a patient with Blau syndrome. (b) Cataract and anterior synechiae as a sequela of chronic anterior uveitis in a patient with Blau syndrome.

Genetics and pathophysiology FCAS2 (MIM# 611762) is caused by autosomal dominant mutations in NLRP12, also known as NALP12 or MONARCH-1.332 NLRP12 is a member of the NLR family of intracellular proteins, but the disease pathogenesis remains unclear. Some data suggest that NLRP12 acts as a proinflammatory protein on caspase-1 signaling and speck formation with the adaptor

CHAPTER 174  Monogenic autoinflammatory diseases protein ASC.335 Monocytes from patients with mutated NLRP12 present with increased concentrations of ROS and upregulation of antioxidant systems in the absence of PAMP stimulation334 and accelerated kinetics of IL-1β secretion.336 The early secretion of IL-1β, even in the absence of an overall increased secretion of the cytokine, may be sufficient to account for the mild inflammatory symptoms seen with that syndrome.

Clinical features and laboratory findings In the nine patients with FCAS2 described so far, the age of onset of the clinical manifestations varied from the first days of life until 20 years of age.332–334 Patients with FCAS2 present with cold-induced episodes of high-grade fever and urticarial rash associated with myalgia, arthralgia, abdominal pain, and headache.332–334 Other manifestations observed are vomiting, oral ulcers, and lymphadenopathy.332–334 Two monozygotic twins presented with sensorineural bilateral hearing loss.332 Among the nine patients, the length of episodes varied from several hours to 15 days.332–334 During flares, FCAS2 patients can present with increased acute phase reactants (ESR and CRP).332–334 However, three out of the nine patients described did not present evidence of increased inflammatory serum markers.332–334

Treatment Preventing cold exposure can avoid or ameliorate FCAS2 symptoms.332–334 Symptoms can be partially controlled with NSAIDs and variable courses of oral steroids.332–334 Prophylactic administration of low-dose steroids and antihistamines during the winter prevented the disease manifestation in one patient.334 Colchicine was not effective in the three patients reported to have received it.332,333 In the two patients who received anakinra, although an initial partial clinical response was observed, the drug was discontinued after 14 months due to a progressive clinical relapse.335

SYNDROMES PRESENTING WITH A WIDER CLINICAL PHENOTYPE SIDEROBLASTIC ANEMIA, B-CELL IMMUNODEFICIENCY, PERIODIC FEVERS, AND DEVELOPMENTAL DELAY SYNDROME Background In 2013, the syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay syndrome (SIFD) was described,337 and in 2014 SIFD was shown to be caused by mutations in TRNT1 gene.338

Genetics and pathophysiology SIFD (MIM#616084) is a mitochondrial disease caused by autosomal recessive loss-of-function mutations in TRNT1.338 TRNT1 encodes an enzyme that adds two cytosine- and one adenosine-(CCA) residues to the 3′ end mitochondrial and cytosolic tRNA molecules, which is necessary for tRNA aminoacylation.339 The disease-causing mutations lead to a reduction in CCA enzyme activity, defective mitochondrial translation, and the inability to detect tRNAs with backbone damage.340 This defect is thought to result in a “loss of quality-control-mechanisms” that recognize and prevent damaged tRNA from CCA maturation and from entering the ribosome machinery of protein synthesis, thus suggesting a role of CCA addition in intracellular stress responses.341

Clinical features and laboratory findings

The initial description of TRNT1 deficiency patients (n = 17)338 was followed by reports of six additional patients, expanding SIFD clinical phenotype.342–344 Most patients described to date presented in infancy with transfusion-dependent sideroblastic anemia and developed recurrent noninfectious fever episodes, B-cell lymphopenia with hypogammaglobulinemia with recurrent sinopulmonary bacterial infections and progressive developmental delay, occult multiorgan failure, and/or cardiomyopathy were seen in around 60% of the patients. Other manifestations include childhood cataract and inner retinal dysfunction. Early allogenic bone marrow transplant can be curative in SIFD.337,342–344

RIPK1 DEFICIENCY (CLEAVAGE-RESISTANT RIPK1-INDUCED AUTOINFLAMMATORY SYNDROME) Heterozygous missense mutations p.D324N, p.D324H, p. D324V, and p.D324Y in RIPK1 result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy.345,346 The described mutations impair cleavage of RIPK1 at position D324 by caspase-8, which sensitized patients’ peripheral blood mononuclear cells to RIPK1 activation, apoptosis, and

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necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signaling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confer increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis but also to induction of proinflammatory cytokines such as IL-6 and TNF. In contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human noncleavable RIPK1 variants promote activation of RIPK1 and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory responses in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.346

CHERUBISM Cherubism is caused by autosomal dominant mutations in SH3BP2, and approximately 50% of the cases occur de novo. SH3BP2 is a cytoplasmic adaptor protein that interacts with TNFAIP3/A20 and with protein tyrosine kinases such as ABL1 and SYK that regulate transcriptional activity in immune cells. Patients develop symmetrical multilocular and radiolucent lesions in the mandible and the maxilla that expand and first appear in childhood in the presence of submandibular and cervical lymphadenopathy. Patients can present with significant dental problems. The majority of cherubism cases regress spontaneously after puberty.347,348

AUTOINFLAMMATION AND IMMUNODEFICIENCY A number of conditions caused by mutations in linear ubiquitylation present with autoinflammatory phenotypes but also with features of immunodeficiencies. The “mixed phenotype” is determined by the impact the mutation can have in different immune cells. These conditions include autosomal recessive mutations in HOIL, a component of the linear ubiquitination chain assembly complex (LUBAC).349 These mutations result in impairment of LUBAC stability, leading to reduced NF-κB activation in response to IL-1β in fibroblasts but hyperresponsiveness to IL-1 in mononuclear leukocytes, particularly monocytes.349 Of the patients with HOIL deficiency who have been described, two of them were siblings born to nonconsanguineous parents.349 All three patients presented with early-onset recurrent fevers, hepatosplenomegaly, and increased acute phase reactants.349 Two patients presented with chronic bloody diarrhea, and two had eczema and diffuse erythroderma. These patients showed severe recurrent pyogenic, fungal, and viral infections, and all three patients had a fatal outcome.349 Additionally, all three patients had cardiomyopathy, and two patients had amylopectinosis in cardiomyocytes.349 The autoinflammatory manifestations in two of the three patients were partially responsive to corticosteroids but refractory to colchicine, anti-TNF, and anti-IL-1 agents. The third patient had an allogeneic HSCT performed at the age of 13 months but was deceased 3 years after the transplantation.349

ACKNOWLEDGMENT This research was supported in part by the Intramural Research Program of the NIH, NIAID (AAJ, RGM), and NHGRI (DLK).

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Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra. Br J Dermatol. 2009;161:1199–1201. 229. Omenetti A, Carta S, Caorsi R, et al. Disease activity accounts for long-term efficacy of IL-1 blockers in pyogenic sterile arthritis pyoderma gangrenosum and severe acne syndrome. Rheumatology (Oxford). 2016;55:1325–1335. 230. Zhou Q, Wang H, Schwartz DM, et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016;48:67–73. 231. Ohnishi H, Kawamoto N, Seishima M, et al. A Japanese family case with juvenile onset Behcet’s disease caused by TNFAIP3 mutation. Allergol Int. 2016 232. Shigemura T, Kaneko N, Kobayashi N, et al. Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Behcet’s disease. RMD Open. 2016;2:e000223. 233. Duong BH, Onizawa M, Oses-Prieto JA, et al. A20 restricts ubiquitination of pro-interleukin-1beta protein complexes and suppresses NLRP3 inflammasome activity. Immunity. 2015;42:55–67. 234. Vande Walle L, Van Opdenbosch N, Jacques P, et al. Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. Nature. 2014;512:69–73. 235. Hautala T, Vahasalo P, Kuismin O, et al. A Family With A20 Haploinsufficiency Presenting With Novel Clinical Manifestations and Challenges for Treatment. J Clin Rheumatol. 2020 236. Mulhern CM, Hong Y, Omoyinmi E, et al. Janus kinase 1/2 inhibition for the treatment of autoinflammation associated with heterozygous TNFAIP3 mutation. J Allergy Clin Immunol. 2019;144:863–866. e865. 237. Schwartz DM, Blackstone SA, Sampaio-Moura N, et al. Type I interferon signature predicts response to JAK inhibition in haploinsufficiency of A20. Ann Rheum Dis. 2020;79:429–431. 238. Marrakchi S, Guigue P, Renshaw BR, et al. 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248. Feliubadalo L, Font M, Purroy J, et al. Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT. Nat Genet. 1999;23:52–57. 249. Setta-Kaffetzi N, Simpson MA, Navarini AA, et al. AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking. Am J Hum Genet. 2014;94:790–797. 250. Eleftheriou D, Batu ED, Ozen S, Brogan PA. Vasculitis in children. Nephrol Dial Transplant. 2015;30(Suppl 1):i94–103. 251. Jesus AA, Goldbach-Mansky R. IL-1 blockade in autoinflammatory syndromes. Annu Rev Med. 2014;65:223–244. 252. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361:2033–2045. 253. Glocker EO, Frede N, Perro M, et al. Infant colitis—it’s in the genes. Lancet. 2010;376:1272. 254. Kotlarz D, Beier R, Murugan D, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. 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An autopsy case of a syndrome with muscular atrophy, decreased subcutaneous fat, skin eruption and hyper gamma-globulinemia: peculiar vascular changes and muscle fiber degeneration. Acta Neuropathol. 1987;73:313–319. 275. Sanchez GAM, Reinhardt A, Ramsey S, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018 276. Kim H, Brooks KM, Tang CC, et al. Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibitor Baricitinib in Pediatric and Young Adult CANDLE and SAVI Patients. Clin Pharmacol Ther. 2018;104:364–373. 277. Boyadzhiev M, Marinov L, Boyadzhiev V, et al. Disease course and treatment effects of a JAK inhibitor in a patient with CANDLE syndrome. Pediatr Rheumatol Online J. 2019;17:19. 278. Damgaard RB, Walker JA, Marco-Casanova P, et al. The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity. Cell. 2016 279. Zhou Q, Yu X, Demirkaya E, et al. 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SECTION 15  Other Systemic Illnesses

281. Jeremiah N, Neven B, Gentili M, et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest. 2014;124:5516–5520. 282. Omoyinmi E, Melo Gomes S, Nanthapisal S, et al. Stimulator of interferon genes-associated vasculitis of infancy. Arthritis Rheumatol. 2015;67:808. 283. Munoz J, Rodiere M, Jeremiah N, et al. Stimulator of interferon genes-associated vasculopathy with onset in infancy: a mimic of childhood granulomatosis with polyangiitis. JAMA Dermatol. 2015;151:872–877. 284. Chia J, Eroglu FK, Ozen S, et al. Failure to thrive, interstitial lung disease, and progressive digital necrosis with onset in infancy. J Am Acad Dermatol. 2016;74:186–189. 285. Stingl K, Bartz-Schmidt KU, Besch D, et al. [What can blind patients see in daily life with the subretinal Alpha IMS implant? Current overview from the clinical trial in Tubingen]. Ophthalmologe. 2012;109:136–141. 286. Munoz J, Rodiere M, Jeremiah N, et al. 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Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. 2017;76:468–472. 292. Volpi S, Insalaco A, Caorsi R, et al. Efficacy and adverse events during janus kinase inhibitor treatment of SAVI syndrome. J Clin Immunol. 2019;39:476–485. 293. Zhou Q, Yang D, Ombrello AK, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370:911–920. 294. Navon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370:921–931. 295. Belot A, Wassmer E, Twilt M, et al. Mutations in CECR1 associated with a neutrophil signature in peripheral blood. Pediatr Rheumatol Online J. 2014;12:44. 296. Carmona-Rivera C, Khaznadar SS, Shwin KW, et al. Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. Blood. 2019;134:395–406. 297. Kastner DL, Zhou Q, Aksentijevich I. Mutant ADA2 in vasculopathies. 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Neuroradiologic patterns and novel imaging findings in Aicardi-Goutieres syndrome. Neurology. 2016;86:28–35. 305. Adang L, Gavazzi F, De Simone M, et al. Developmental outcomes of aicardi goutieres syndrome. J Child Neurol. 2020;35:7–16. 306. Livingston JH, Crow YJ. Neurologic Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutieres Syndrome and Beyond. Neuropediatrics. 2016;47:355–360. 307. Konig N, Fiehn C, Wolf C, et al. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. 2016 308. Tonduti D, Fazzi E, Badolato R, Orcesi S. Novel and emerging treatments for AicardiGoutieres syndrome. Expert Rev Clin Immunol. 2020;16:189–198. 309. Crow YJ, Shetty J, Livingston JH. Treatments in Aicardi-Goutieres syndrome. Dev Med Child Neurol. 2020;62:42–47. 310. Rice GI, Meyzer C, Bouazza N, et al. Reverse-transcriptase inhibitors in the aicardi-goutieres syndrome. N Engl J Med. 2018;379:2275–2277. 311. Briggs TA, Rice GI, Daly S, et al. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet. 2011;43:127–131. 312. Shinohara ML, Lu L, Bu J, et al. Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Nat Immunol. 2006;7:498–506. 313. Lausch E, Janecke A, Bros M, et al. Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat Genet. 2011;43:132–137. 314. Blau EB, Familial granulomatous arthritis, iritis, and rash. J Pediat. 1985;107:689–693. 315. Jabs DA, Houk JL, Bias WB, and Arnett FC .Familial granulomatous synovitis, uveitis, and cranial neuropathies. Am J Med. 1985;78:801–804. 316. Tromp G, Kuivaniemi H, Raphael S, et al. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16. Am J Hum Genet. 1996;59:1097–1107.

317. Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet. 2001;29:19–20. 318. Kanazawa N, Okafuji I, Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. Blood. 2005;105:1195–1197. 319. Rose CD, Doyle TM, McIlvain-Simpson G, et al. Blau syndrome mutation of CARD15/ NOD2 in sporadic early onset granulomatous arthritis. J Rheumatol. 2005;32:373–375. 320. Rose CD, Wouters CH, Meiorin S, et al. Pediatric granulomatous arthritis: an international registry. Arthritis Rheum. 2006;54:3337–3344. 321. Alonso D, Elgart GW, Schachner LA. Blau syndrome: a new kindred. J Am Acad Dermatol. 2003;49:299–302. 322. Rose CD, Arostegui JI, Martin TM, et al. NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: study of an international registry and a national cohort in Spain. Arthritis Rheum. 2009;60:1797–1803. 323. 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Sarcoidosis Jeffrey A. Sparks • Elizabeth V. Arkema

Key Points n Sarcoidosis is a systemic inflammatory disorder characterized by noncaseating, granulomatous inflammation that can affect any organ. n Nonmusculoskeletal features are common and include hilar lymphadenopathy, pulmonary infiltrates, uveitis, cardiac and neurologic involvement, and cutaneous involvement such as erythema nodosum and lupus pernio. n Sarcoidosis can manifest as inflammatory arthritis with both acute (Löfgren syndrome) or chronic forms that can affect any joint but often have a predilection for ankle involvement. n Osseous involvement of sarcoidosis is uncommon but may affect the digits or axial skeleton. n Muscle involvement of sarcoidosis is usually asymptomatic but may cause acute or chronic myopathies or nodular masses.

HISTORY Sarcoidosis derives from the Greek sarco, meaning “flesh,” eidos, meaning “like,” and sis, meaning “condition.”1 In 1877, Jonathan Hutchinson published the first case seen at King’s College Hospital in London. Later, Caesar Boeck advanced the description of sarcoidosis by emphasizing the granulomatous inflammation characteristic of this disease. He was the first to use the term sarkoid (sarcoid) because he thought the lesions resembled sarcoma but were benign. In 1953, Sven Löfgren reported the acute sarcoidosis syndrome of bilateral hilar adenopathy and erythema nodosum, frequently associated with arthritis, fever, and uveitis. Over the past century, sarcoidosis has become recognized as a multisystem granulomatous disorder with protean manifestations that may affect any organ.

EPIDEMIOLOGY PREVALENCE AND INCIDENCE The prevalence of sarcoidosis varies greatly across the world, from 2 to 4 per 100,000 in East Asia to 160 per 100,000 in Sweden.2 In the United States (U.S.), the prevalence of sarcoidosis is estimated to be 60 per 100,000, and it differs by race, with the highest estimates in African Americans (141 per 100,000) compared to Whites (50 per 100,000), Hispanics (22 per 100,000), and Asians (19 per 100,000).3 Sarcoidosis incidence is 7 to 15 per 100,000 people per year in Northern European countries, 1 to 5 per 100,000 people per year in Southern European, and 1 to 3 per 100,000 people per year in East Asian countries. The incidence in the U.S. and Canada are similar to Northern European countries, ranging between 8 and 10 per 100,000.3–5 Sarcoidosis equally affects males and females, although some studies report a slightly higher prevalence in females while others report a higher prevalence in males. The average age of diagnosis is between 40 and 55, and onset is typically at a younger age in males (30–50 years old) compared to females (50–60 years old).6

RISK FACTORS Having a family history of sarcoidosis is one of the strongest risk factors for the disease. Family-based studies from the U.S. and Sweden show that having a first-degree relative with sarcoidosis increases the risk of getting the disease four- to fivefold.7, 8 Heritability, the percent of phenotypic variance due to genetic variation, was estimated to be 39% in a large, case control family study in Sweden.7 The disease coaggregates with other autoimmune diseases within individuals and within families.9 Sarcoidosis is most strongly associated with alleles in the human leukocyte antigen (HLA) region on chromosome 6 (especially HLA-DRB1 alleles)10; however, associations with other non-HLA genes have also been identified.11 Löfgren and non-Löfgren syndrome are associated with different loci, further indicating that the two phenotypes are distinct with only a small amount of genetic overlap.12

175

Sarcoidosis is hypothesized to be related to a combination of both genes and environment, but a gene–environment interaction has yet to be reported in the literature. Since only 39% of the susceptibility of sarcoidosis is estimated to be due to genetic variation, this indicates that environmental (nongenetic) factors play an important role in sarcoidosis pathogenesis. An environmental factor could explain the regional clustering of sarcoidosis cases in some countries. Areas with lower population density were associated with higher rates of sarcoidosis in some studies, and agricultural exposures such as insecticides, pesticides, and agricultural occupation carry a higher risk.13,14 Occupational exposures from other industries have also been implicated in sarcoidosis risk, especially jobs that involve inhalation of dust, debris, and mold. Silica exposure among miners,15 work with industrial organic dusts,16 and occupational exposure to mold/musty environments or high humidity13 carry an increased risk of sarcoidosis. Firefighters have an increased risk of “sarcoid-like” granulomatous pulmonary disease.17 There is a higher rate of sarcoidosis than expected in first responders who worked on the debris pile at the World Trade Center on September 11, 2001.18 Increased rates have been observed in other unrelated occupations as well (educators and healthcare workers).14 Several studies have shown an inverse association between smoking and sarcoidosis.13,19,20 It is theorized that nicotine has an immune-modulating effect; however, there is no association with moist snuff,19 suggesting that a component of cigarette smoke other than nicotine may have a protective effect. Obesity is associated with an increased risk of sarcoidosis in a similar magnitude seen in other chronic inflammatory diseases. In a study of Black women (a group with the highest incidence and prevalence of the disease in the U.S.), obesity was associated with a 40% increased risk of sarcoidosis.21 Findings were similar in a study of female nurses (the majority of whom were White).22 Sarcoidosis is thought to vary seasonally, although reports are not consistent, and it may be that only the Löfgren phenotype is more commonly diagnosed in the spring. Sarcoidosis is hypothesized to be triggered by an infection, possibly through molecular mimicry.23

IMMUNOPATHOGENESIS The noncaseating epithelioid granuloma is the histologic hallmark of sarcoidosis and is formed by a stepwise series of events (Fig. 175.1).24–26 Granuloma formation is a protective response to isolate poorly degraded antigens to prevent both dissemination and further local tissue damage. Candidate antigens in sarcoidosis include environmental substances, microbial remnants, vimentin, and misfolded serum amyloid A.

STEP 1: LYMPHOCYTIC ALVEOLITIS The initial event in sarcoidosis is thought to be the uptake of a triggering antigen through Toll-like receptors and processing by antigen-presenting cells (type II alveolar epithelial cells, alveolar macrophages, and dendritic cells) bearing major histocompatibility complex class II molecules in the lower respiratory tract. This antigen uptake activates alveolar macrophages by stimulating secretion of chemoattractant cytokines (interleukin [IL]-15, IL-16) and chemokines (MCP1/CCL2, MIP-1/CCL3-4, RANTES/CCL5, IL-8/CXCL8, IP-10/CXCL10) coupled with the cytokine-mediated (tumor necrosis factor [TNF]-α, IL-1, IL-15) upregulation of endothelial cell adhesion molecules (ICAMs). This is central to the marked accumulation of inflammatory cells and recruitment of lymphocytes (CD4+ T cells) from the peripheral blood into the lung alveoli. Studies indicate that an inflammatory alveolitis precedes granuloma formation and is primarily associated with the infiltration of CD4+ T lymphocytes and mononuclear phagocytes. Th17 cells may also contribute to the alveolitis. However, the recognition of antigen presented by antigen-presenting cells to CD4+ T cells is considered to be a critical event in the disease. In patients with established sarcoidosis, there is a selective oligoclonal expansion of αβ T cells in the lung, which exhibits a restricted T-cell receptor repertoire (Vβ2, Vβ8, Vβ12, Vα2.3). This strongly suggests an antigen-specific immune response. 1547

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SECTION 15  Other Systemic Illnesses GRANULOMA FORMATION IN SARCOIDOSIS

BV lumen

Candidate antigens T L R

CD4+ T cell

APC RBCs

IL-1 IL-15 MIP-1 MCP-1 TNFα

Monocyte

Alveolar macrophage

IL-12 Th0 CD4+

BV lumen

IL-4 IL-10 Th1 IL-2

IFNγ

Th2 IL-4

RBCs IL-13

CCL-18 PDGF TGF-β

Fibrocyte Macrophage

Fibrosis Granuloma

FIG. 175.1  Proposed mechanisms of granuloma formation in sarcoidosis. APC, Antigen-presenting cell; BV, blood vessel; IFN-γ, interferon γ; IL, interleukin; MCP, monocyte chemoattractant protein; MIP, monocyte inflammatory protein; PDGF, platelet-derived growth factor; RBC, red blood cell; TGF-β, transforming growth factor β; Th, T-helper cell; TLR, Toll-like receptor; TNF-α, tumor necrosis factor α.

STEP 2: GRANULOMA FORMATION

STEP 3: GRANULOMA RESOLUTION

The accumulation and activation of antigen-specific Th1 lymphocytes and the reciprocal suppression of the Th2 subset and inadequate regulatory T-cell (Treg) function are the initial events in the development of granulomatous inflammation. Alveolar macrophage/dendritic cell–derived IL-12 with the help of IL-18 and IL-27 are critical to the differentiation of naive CD4+ T lymphocytes into Th1 cells. The polarized Th1 cells secrete the Th1 cytokines IL-2 and interferon (IFN)-γ. IL-2 acts synergistically with IL-15 and TNF-α from macrophages to stimulate further T-lymphocyte proliferation and differentiation. Other T-lymphocyte cytokines stimulate macrophage recruitment, activation, and proliferation (granulocyte-macrophage colony-stimulating factor, MCP-1/CCL2, MIP-1/CCL3-4). The macrophage-derived cytokines, IL-12 and IL-18, coupled with IL-2, are potent stimulators of further IFN-γ production; this amplifies the immune response through its effects on multiple target cells, including macrophages, which differentiate into secretory epithelioid cells at the center of the granuloma. Whereas both IL-1β and IFN-γ as well as several chemokines are important in the early recruitment stage of granuloma formation, TNF-α may be particularly important in the later maintenance of granuloma formation and perpetuation of inflammation. The sarcoidal granuloma is well circumscribed, round or oval, noncaseating, and made up of compact, radially arranged epithelioid cells with pale nuclei (Fig. 175.2). Some of the epithelioid cells fuse to form giant cells, typically of the Langhans type, in which the nuclei are arranged in an arc or circular pattern around a central granular zone. Stellate asteroids (entrapped collagen) and blue Schaumann inclusion bodies (altered lysosomes in giant cells) are occasionally observed. The center of the granuloma is composed of macrophage-derived epithelioid cells and CD4+ Th1 lymphocytes, and the outer zone contains many CD4+ and CD8+ T lymphocytes, fibroblasts, and interdigitating antigen-presenting cells entwined in bands of collagen. Notably, sarcoid granulomas have a predilection for forming in the perilymphatic areas and bronchovascular bundles within the lungs.

The immunologic factors that determine the ultimate fate of sarcoid granulomas are poorly understood. Most granulomas resolve spontaneously or with therapy, but others are converted into a fibrotic scar. In the minority of patients who develop progressive fibrosis there appears to be a shift from a Th1 to a Th2 cytokine (IL-4, IL-10, IL-13) predominance at the local tissue level. Alveolar macrophages, mast cells, and neutrophils contribute to this fibrotic process by releasing superoxide radicals and proteases that cause local tissue injury. This is reflected clinically by the association of progressive lung fibrosis and a worse prognosis with neutrophilia and cytotoxic T/natural killer (NK) cells in BAL fluid. Alveolar macrophages also secrete transforming growth factor-β (TGF-β) and CC motif ligand 18 (CCL18) among others. TGF-β induces local epithelial cells to transform into collagen matrix–producing fibroblasts. CCL18 attracts bone marrow–derived fibrocytes and Treg cells from the peripheral blood. The fibrocytes differentiate and contribute to the fibroblast pool. Treg cells produce IL-10 in conjunction with other cells producing IL-13. These Th2 cytokines contribute to the transformation of alveolar macrophages into macrophages of the M2 phenotype, which secrete fibroproliferative cytokines (platelet-derived growth factor). This adds to the fibrogenic cytokines (fibroblast growth factor 2, insulin-like growth factor 1, fibronectin) produced by fibroblasts, causing more proliferation and collagen matrix production. The collagen matrix produced stimulates alveolar macrophages to make more CCL18, which results in a positive feedback loop.

DIAGNOSTIC INVESTIGATIONS The diagnosis of sarcoidosis is made by a combination of clinical, laboratory, and imaging findings and confirmed by characteristic histologic findings.27 Patients with a classic presentation such as Löfgren syndrome may not need to undergo tissue biopsy. However, in all doubtful cases and in cases in which immunosuppressive treatment is likely to be needed, histologic confirmation of disease in one organ is essential, particularly since atypical

CHAPTER 175 Sarcoidosis

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without considering other clinical data, particularly biopsy. Of note, ACE inhibitors lower the serum ACE level, so patients should be tested when off these medications. ACE levels sometimes correlate with active pulmonary disease and normalize with successful therapy but in only a minority of patients. Elevated ACE levels are not specific for sarcoidosis and may be caused by many other entities, such as hyperthyroidism, Gaucher disease, diabetes mellitus, leprosy, α1-antitrypsin deficiency, Kaposi sarcoma in HIV-infected patients, primary biliary cirrhosis, silicosis, hypersensitivity pneumonitis, cirrhosis, histoplasmosis, coccidioidomycosis, tuberculosis, beryllium disease, and asbestosis. Serum lysozyme levels may also be elevated in active sarcoidosis. Lysozyme is produced by monocytes and may be elevated when serum ACE levels are normal. Therefore an elevated ACE or lysozyme level may be supportive but is not diagnostic of sarcoidosis.

IMAGING a

The chest radiographic staging system is described later (see section “Respiratory tract involvement”). The high-resolution computed tomography (HRCT) scan is more sensitive and correlates with histologic and pulmonary function test abnormalities more closely than the plain chest x-ray.31 Plain bone x-rays and technetium-99m diphosphonate scanning can sometimes detect osseous lesions. Magnetic resonance imaging (with gadolinium) can be used to detect brain, myocardial, muscle, and osseous involvement.32 Positron emission tomography is a sensitive test for detecting sarcoidal involvement of multiple tissues and showing organs that are candidates for diagnostic biopsy and is increasingly available for diagnosis and monitoring.33

BIOPSY

b

FIG. 175.2  Sarcoidal granulomas. (a) Histologic section of lymph node showing noncaseating epithelioid and giant cell granulomas. (b) Histologic section from a patient with acute sarcoidosis showing noncaseating granulomas with central eosinophilic necrosis of collagen. There was subsequent natural resolution without treatment in this case.

presentations of malignancy or serious infections can mimic sarcoidosis. Clinical criteria for organ involvement without a biopsy have been established.28 After the diagnosis is established, the American Thoracic Society recommends the comprehensive baseline evaluation presented in Box 175.1.

Biopsy of affected tissue is the gold standard for confirming a clinical and radiographic diagnosis of sarcoidosis. Tissue biopsy should be performed in most patients, particularly those with atypical presentation or for whom therapy is being considered to exclude infection or malignancy. Transbronchial, lymph node, and skin biopsies are the most common, but a specimen can be obtained from any clinically involved organ.34 The diagnostic yield is shown in Table 175.1. The characteristic histologic finding is that of well-circumscribed, compact, noncaseating granulomas of the epithelioid type rimmed by hyaline collagen. However, the presence of noncaseating granulomas is not diagnostic of sarcoidosis until other granulomatous diseases are excluded. Notably, a few patients with sarcoidosis (20%) may have granulomas with some minor necrosis on biopsy. Use of the Kveim-Siltzbach skin test is no longer recommended.

ADDITIONAL TESTS Two additional tests that should be performed as a baseline assessment in all patients with sarcoidosis are an electrocardiogram (ECG) and an ophthalmologic examination with a slit lamp to rule out asymptomatic

LABORATORY TESTS Laboratory evaluation of patients with sarcoidosis may reveal many abnormalities.29 Most patients have anemia of chronic inflammation and lymphopenia; some (≤15%) may have eosinophilia. Leukocyte and platelet counts are usually normal unless there is significant bone marrow involvement (90 40–60 >90 >90 79 36 93 67 10–55 0–10 80 >90 50–80 50–80 50–80 20

CXR, Chest x-ray; EBUS-FNA, endobronchial ultrasound-guided transbronchial fine needle aspiration.

abnormalities. Fluorescein angiography is helpful to document posterior uveitis. Pulmonary function testing, bronchoalveolar lavage fluid cell analysis, Holter monitoring, and echocardiography are described in the sections discussing respiratory tract and cardiac involvement, respectively.

DIFFERENTIAL DIAGNOSIS Several diseases can result in clinical presentations and granulomas on biopsy specimens that resemble those of sarcoidosis. Acute histoplasmosis can mimic Löfgren syndrome and must be excluded by serologic studies and cultures. Acute arthritis with erythema nodosum, but without hilar adenopathy, can occur in inflammatory bowel disease, coccidioidomycosis, histoplasmosis, psittacosis, and reactions to various medications. The pattern of arthritis in these patients is also similar to that seen in sarcoidosis. In patients with more insidious presentations other diseases need to be considered, depending on the organ involved. In patients with pulmonary disease, chronic berylliosis should be excluded by lack of a clinical history of exposure and a negative beryllium lymphocyte proliferation test. Hypersensitivity pneumonitis is ruled out by lack of a history of occupational and environmental exposure and results of serologic tests for precipitins. Reactions to drugs (e.g., etanercept) and other inorganic agents, such as metals (titanium, aluminum, zirconium), silica, and talc, are excluded by thorough history. Fungal serologic studies or stains or cultures for organisms rule out fungal and mycobacterial disease. Granulomatosis with polyangiitis may be excluded by the absence of a positive result on the ANCA test and the absence of vasculitis on biopsy. Patients with eosinophilic granulomatosis with polyangiitis have a history of asthma and prominent eosinophilia. Tissue biopsy results exclude lymphoma and eosinophilic granuloma. In patients with cutaneous granulomatous lesions, treponemal infections, leprosy, tularemia, and leishmaniasis should be excluded by serologic studies, cultures, or both. Granuloma annulare and granulomatous rosacea are ruled out clinically by lack of systemic involvement. Lupus vulgaris caused by mycobacterial infection may mimic cutaneous plaques of sarcoidosis. Primary biliary cirrhosis can cause liver granulomas but is associated with antimitochondrial antibodies. Fungal or mycobacterial infections and brucellosis should be considered in patients with monoarticular, axial, or peripheral arthritis. Fungal and mycobacterial infections, leprosy, brucellosis, syphilis, granulomatosis with polyangiitis, eosinophilic granuloma, multiple myeloma, and lymphoma can also present with osseous lesions similar to those caused by sarcoidosis. Toxoplasmosis can mimic acute and chronic sarcoid myopathy, and various neoplasms and infections need to be excluded in patients with a muscle mass. Finally, granulomas in a single organ (e.g.,

idiopathic granulomatous hepatitis, giant cell myocarditis, or panuveitis) without evidence of other organ involvement should not necessarily be labeled as sarcoidosis.

CLINICAL FEATURES Sarcoidosis is a systemic inflammatory disorder. The clinical manifestations are diverse, ranging from an abnormal chest x-ray found incidentally in an otherwise asymptomatic individual (5% of cases) to severe multiorgan involvement.29 Although sarcoidosis most commonly involves the lung, up to 30% of patients present with extrapulmonary sarcoid as their initial manifestation. Because there is no specific test for sarcoidosis, the diagnosis is established when well-recognized clinical and radiographic findings are supported by histologic evidence of widespread noncaseating epithelioid granulomas in more than one organ system. Other granulomatous diseases must be excluded. The presenting manifestations and cumulative organ involvement in patients with sarcoidosis are shown in Table 175.2. The ACCESS (A Case Control Etiologic Study of Sarcoidosis) study evaluated 736 patients with sarcoidosis confirmed that during the course of their follow-up, 95% of patients had thoracic involvement, 50% had extrathoracic involvement, and only 2% had isolated extrathoracic sarcoidosis.35 Notably, there were significant differences in clinical presentation and prognosis among according to race, sex, and age.

RESPIRATORY INVOLVEMENT Respiratory tract involvement is the most common organ manifestation (90%–95% of cases), and any part from the upper respiratory tract to lungs can be involved.36 The clinical spectrum ranges from asymptomatic (usually bilateral) hilar adenopathy (20%–50%) to parenchymal lung disease with granulomatous infiltration or fibrosis. Pleural effusions are uncommon (40%  lgG4 cells >hpf > 10

Yes C4

No

None

C5

Probable

C6 Denial

Organ-specific criteria for  lgG4-related AIP  lgG4-related Mikulicz disease  lgG4-related kidney disease  lgG4-related sclerosing cholangitis  lgG4-related ophthalmic disease

FIG. 178.5  Diagnostic algorithm performance for comprehensive diagnostic criteria for IgG4-RD. This figure shows a diagnostic algorithm for IgG4-RD, using comprehensive diagnostic criteria combined with organ-specific criteria. A diagnosis of IgG4-RD is definitive in patients with (1) organ enlargement, mass or nodular lesions, or organ dysfunction; (2) a serum IgG4 concentration >135 mg/dL; and (3) histopathologic findings of >10 IgG4 cells/HPF and an IgG4/IgG cell ratio >40% (C1). A diagnosis of IgG4-RD is possible in patients who fulfill criteria (1) and (2) but with negative results on histopathology or without histopathologic examination (C2 and C3), whereas a diagnosis of IgG4-RD is probable in patients with (1) organ involvement and (3) fulfilled histopathologic criteria but without increased serum IgG4 concentration (C4). Patients with organ symptoms without satisfying the serologic or histopathologic criteria are considered unlikely to have IgG4-RD (C5 and C6). For patients in C2 to C6, organ-specific criteria for IgG4-related AIP, IgG4-related Mikulicz disease, IgG4-related kidney disease, IgG4-related sclerosing cholangitis, and IgG4-related ophthalmic disease should be applied. Patients who fulfill the organ-specific criteria have a definite diagnosis of IgG4-RD (C7). (From Umehara H, Nakajima A, Nakamura T, et al. IgG4-related disease [IgG4-RD] and its pathogenesis-crosstalk between innate and acquired immunity. Int Immunol. 2014;26[11]:585–95.)

.

CHAPTER 178  IgG4-related disease possible (category 4) for IgG4-RD, depending on how many of these diagnostic items are present. Patients with organ symptoms without satisfying the serologic or histopathologic criteria are considered unlikely to have IgG4-RD (category 5 and 6). IgG4-RD can be definitively diagnosed in patients with (1) organ enlargement or dysfunction, (2) a serum IgG4 concentration ≥135 mg/dL, and (3) histopathologic findings of >10 IgG4 cells/HPF and an IgG4-positive/IgG-positive cell ratio ≥40%.20 Patients who could not be diagnosed by these CD criteria could be rediagnosed with organ-specific criteria by specialists in each field.

THE 2019 AMERICAN COLLEGE OF RHEUMATOLOGY (ACR)/ EUROPEAN LEAGUE AGAINST RHEUMATISM (EULAR) CLASSIFICATION CRITERIA FOR IgG4-RD64,65 A steering committee composed of international multidisciplinary experts has established classification criteria, which has been approved by ACR and EULAR (Tables 178.2 and 178.3).64,65 This employs a three-step classification process: (1) presence of at least one of 11 inclusion criteria; (2) none of exclusion criteria consisting of 32 clinical, serologic, radiologic, and pathologic criteria; (3) total points of weighted 8 inclusion criteria more than 20. This method reveals a specificity of 99.2% and sensitivity of 85.5 in validation cohort of 1879 subjects.64,65 To study a true cause of this unique disease and a clinical trial to develop innovative therapeutics, a criteria with a high specificity should be important.

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However, classification criteria alone will not suffice for diagnosis. A patient’s not fulfilling classification criteria should not preclude a diagnosis of IgG4-RD.

DIFFERENTIAL DIAGNOSIS Although accurate pathological characterization is essential to the diagnosis of IgG4-RD, it is often difficult to differentiate IgG4-RD from immune-mediated conditions and malignant tumors. Pancreatic cancer and other malignancies are sometimes associated with a reactive IgG4-positive plasma cell infiltration and fibrosis in the peritumoral tissues.28 Therefore it is important to exclude malignant cells by careful histopathologic evaluation. Nonmalignant conditions can also bear strong resemblance to IgG4-RD. These include Table 178.3

Immunostaining IgG4+ Cells/High-Power Field IgG4/IgG Ratio

0–9

Indeterminate

10–50

0 to 40% Indeterminate 41 to 70% >70%

0 0 7 7

7 7 7 7

7 7 14 14

>50 7 7 14 16

Table 178.2

The 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification Criteria for IgG4-RD64,65. Histopathology

Uninformative biopsy Dense lymphocytic infiltrate Dense lymphocytic infiltrate and obliterative phlebitis Dense lymphocytic infiltrate and striaform fibrosis with or without obliterative phlebitis

0 +4 +6 +13

Dense lymphocytic infiltrate

0–16

>Normal or not checked Normal but >5× upper limit of normal

0 +4 +6 +11

Immunostaining

See Table 178.3 Serum IgG4 concentration

Bilateral lacrimal, parotid, sublingual and submandibular glands

No set of glands involved One set of glands involved Two or more sets of glands involved

0 +6 +14

Not checked or neither of the items listed is present Peribronchovascular and septal thickening Paravertebral band-like soft tissue in the thorax

0 +4 +10

Not checked or neither of the items listed is present Diffuse pancreas enlargement (loss of lobulations) Diffuse pancreas enlargement and capsule-like rim with decreased enhancement Pancreas (either of above) and biliary tree involvement

0 +8 +11 +19

Not checked or none of the items listed is present Hypocomplementemia Renal pelvis thickening tissue Bilateral renal cortex low-density areas

0 +6 +8 +10

Not checked or neither of the items listed is present Diffuse thickening of the abdominal aortic wall Circumferential or anterolateral soft tissue around the infrarenal aorta or iliac arteries

0 +4 +8

Chest

Pancreas and biliary tree

Kidney

Retroperitoneum

Total points: A case meets the classification criteria for IgG4-RD if the entry criteria are met, no exclusion criteria are present, and the total points is >20. Adapted from Wallace ZS, Naden RP, Chari S, et al. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol. 2020; 72(1):7−19.

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SECTION 15  Other Systemic Illnesses

Sjögren syndrome, primary sclerosing cholangitis, multicentric Castleman’s disease, idiopathic retroperitoneal fibrosis, granulomatosis with polyangiitis (formerly Wegener’s disease), sarcoidosis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome).43 The response to glucocorticoids can sometime be a useful indicator of IgG4-RD in patients from whom it is difficult to obtain diagnostic tissue, e.g., pancreas, retroperitoneum, and pituitary gland. However, lymphoma and paraneoplastic lesions can also improve following glucocorticoid therapy, and so empiric steroid trials must not be undertaken lightly.41

MANAGEMENT In asymptomatic patients or those with limited disease, “watch-and-wait” approach can be applied with careful observation assessing organ function or clinical symptoms.2,66 All patients with symptomatic and active IgG4-RD need treatment. The International Consensus guidance statement on the management and treatment of IgG4-RD recommend urgent therapy for some conditions such as IgG4-related aortitis, retroperitoneal fibrosis, proximal biliary strictures, tubulointerstitial nephritis, pachymeningitis, pancreatic enlargement, and pericarditis.34 In symptomatic cases, systemic glucocorticoids are the first-line and standard therapy for most patients. A Japanese approach suggests an initial dose of 0.6 mg/kg/day for 2 to 4 weeks and then tapering by 10% of the previous prescription every 1 to 2 weeks to low maintenance dose of prednisone 2.5 to 5 mg, which is continued more than 6 months.67 Another approach by the Mayo Clinic is an initial treatment with prednisone 40 mg/day for 4 weeks and then tapering 5 mg/week during a 7-week period until the patient is off prednisone by the end of 11 weeks.68 Although systemic glucocorticoids usually show a good response in most cases, 25% to 50% of patients relapse on low maintenance dose or after discontinuation of glucocorticoids.69 Immunomodulators such as azathioprine, mycophenolate mofetil, and methotrexate have been used for additional immunosuppression or steroid-sparing purposes in the maintenance of remission or in relapsing disease. B-cell depletion with rituximab induces a prompt clinical response to generalized or glucocorticoid-resistant patients with IgG4-RD. It is thought that the good efficacy of rituximab in the treatment of IgG4-RD is achieved by apoptosis of short-lived plasma cells, producing IgG4.34

REFERENCES 1. Umehara H, Okazaki K, Masaki Y, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol. 2012;22(1):1–14. 2. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366(6):539–551. 3. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732–738. 4. Hamano H, Kawa S, Ochi Y, et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet. 2002;359(9315):1403–1404. 5. Yamamoto M, Ohara M, Suzuki C, et al. Elevated IgG4 concentrations in serum of patients with Mikulicz’s disease. Scand J Rhumatol. 2004;33:432–433. 6. Kamisawa T. IgG4-positive plasma cells specifically infiltrate various organs in autoimmune pancreatitis. Pancreas. 2004;29(2):167–168. 7. Masaki Y, Dong L, Kurose N, et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis. 2009;68(8):1310–1315. 8. Stone JH, Khosroshahi A, Deshpande V, et al. IgG4-Related disease: recommendations for the nomenclature of this condition and its individual organ system manifestations. Arthritis Rheum. 2012;64:3061–3067. 9. Kanno A, Masamune A, Okazaki K, et al. Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2011. Pancreas. 2015;44(4):535–539. 10. Sugumar A, Kloppel G, Chari ST. Autoimmune pancreatitis: pathologic subtypes and their implications for its diagnosis. Am J Gastroenterol. 2009;104(9):2308–2310. quiz 2311. 11. Kawa S, Okazaki K, Kamisawa T, et al. Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 II. Extrapancreatic lesions, differential diagnosis. J Gastroenterol. 2014;49(5):765–784. 12. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40(3):352–358. 13. Maruyama M, Watanabe T, Kanai K, et al. Autoimmune pancreatitis can develop into chronic pancreatitis. Orphanet J Rare Dis. 2014;9:77. 14. Kanai K, Maruyama M, Kameko F, et al. Autoimmune pancreatitis can transform into chronic features similar to advanced chronic pancreatitis with functional insufficiency following severe calcification. Pancreas. 2016;45(8):1189–1195. 15. Ohara H, Okazaki K, Tsubouchi H, et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J Hepatobiliary Pancreat Sci. 2012 16. Naitoh I, Nakazawa T, Ohara H, et al. Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing cholangitis. Journal of gastroenterology. 2009;44(11):1147–1155. 17. Goto H, Takahira M, Azumi A. Japanese Study Group for IgG4-related Ophthalmic Disease. Diagnostic criteria for IgG4-related ophthalmic disease. Jpn J Ophthalmol. 2015;59:1–7.

18. Sogabe Y, Ohshima K, Azumi A, et al. Location and frequency of lesions in patients with IgG4-related ophthalmic diseases. Graefes Arch Clin Exp Ophthalmol. 2014;252(3):531–538. 19. Japanese study group of Ig Grod A prevalence study of IgG4-related ophthalmic disease in Japan. Jpn J Ophthalmol. 2013;57(6):573–579. 20. Kawano M, Saeki T, Nakashima H, et al. Proposal for diagnostic criteria for IgG4-related kidney disease. Clin Exp Nephrol. 2011;15(5):615–626. 21. Saeki T, Nishi S, Imai N, et al. Clinicopathological characteristics of patients with IgG4related tubulointerstitial nephritis. Kidney Int. 2010;78(10):1016–1023. 22. Raissian Y, Nasr SH, Larsen CP, et al. Diagnosis of IgG4-related tubulointerstitial nephritis. J Am Soc Nephrol. 2011;22(7):1343–1352. 23. Takahashi N, Kawashima A, Fletcher JG, et al. Renal involvement in patients with autoimmune pancreatitis: CT and MR imaging findings. Radiology. 2007;242(3):791–801. 24. Yoshita K, Kawano M, Mizushima I, et al. Light-microscopic characteristics of IgG4-related tubulointerstitial nephritis: distinction from non-IgG4-related tubulointerstitial nephritis. Nephrol Dial Transplant. 2012;27(7):2755–2761. 25. Mizushima I, Yamamoto M, Inoue D, et al. Factors related to renal cortical atrophy development after glucocorticoid therapy in IgG4-related kidney disease: a retrospective multicenter study. Arthritis Res Ther. 2016;18(1):273. 26. Kawano M, Saeki T, Nakashima H. IgG4-related kidney disease and retroperitoneal fibrosis: an update. Mod Rheumatol. 2019;29(2):231–239. 27. Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology. 2009;251(1):260–270. 28. Shiokawa M, Kodama Y, Yoshimura K, et al. Risk of cancer in patients with autoimmune pancreatitis. Am J Gastroenterol. 2013;108(4):610–617. 29. Matsui S, Yamamoto H, Minamoto S, et al. Proposed diagnostic criteria for IgG4-related respiratory disease. Respir Investig. 2016;54(2):130–132. 30. Zen Y, Inoue D, Kitao A, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol. 2009;33(12):1886–1893. 31. Ikeda S, Sekine A, Baba T, et al. Abundant immunoglobulin (Ig)G4-positive plasma cells in interstitial pneumonia without extrathoracic lesions of IgG4-related disease: is this finding specific to IgG4-related lung disease? Histopathology. 2017;70(2):242–252. 32. Kasashima S, Zen Y. IgG4-related inflammatory abdominal aortic aneurysm. Curr Opin Rheumatol. 2011;23(1):18–23. 33. Stone JH, Khosroshahi A, Hilgenberg A, et al. IgG4-related systemic disease and lymphoplasmacytic aortitis. Arthritis Rheum. 2009;60(10):3139–3145. 34. Khosroshahi A, Wallace ZS, Crowe JL, et al. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis Rheumatol. 2015;67(7):1688–1699. 35. Mizushima I, Inoue D, Yamamoto M, et al. Clinical course after corticosteroid therapy in IgG4-related aortitis/periaortitis and periarteritis: a retrospective multicenter study. Arthritis Res Ther. 2014;16(4):R156. 36. Stone JH, Khosroshahi A, Deshpande V, et al. IgG4-related systemic disease accounts for a significant proportion of thoracic lymphoplasmacytic aortitis cases. Arthritis Care Res (Hoboken). 2010;62(3):316–322. 37. Kasashima S, Zen Y, Kawashima A, et al. A clinicopathologic study of immunoglobulin G4-related sclerosing disease of the thoracic aorta. J Vasc Surg. 2010;52(6):1587–1595. 38. Inoue D, Zen Y, Matsui O, et al. Periarterial Lesions. Tokyo: Springer; 2013. 39. Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related periaortitis and periarteritis: CT findings in 17 patients. Radiology. 2011;261(2):625–633. 40. Masaki Y, Kurose N, Yamamoto M, et al. Cutoff values of serum IgG4 and histopathological IgG4+ plasma cells for diagnosis of patients with IgG4-related disease. Int J Rheumatol. 2012;2012:580814. 41. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21–30. 42. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25(9):1181–1192. 43. Strehl JD, Hartmann A, Agaimy A. Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders. J Clin Pathol. 2011;64(3):237–243. 44. Nakajima K, Inaki A, Mochizuki T, et al. Positron Emission Tomography with F-18 Fluorodeoxyglucose. Tokyo: Springer; 2013. 45. Umehara H, Okazaki K, Kawano M, et al. The front line of research into immunoglobin (Ig) G4-related disease-Do autoantibodies cause IgG4-RD? Modern Rheumatology. 2019 46. van der Neut Kolfschoten M, Schuurman J, Losen M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317(5844):1554–1557. 47. Du H, Shi L, Chen P, et al. Prohibitin is involved in patients with IgG4 related disease. PLoS One. 2015;10(5):e0125331. 48. Hubers LM, Vos H, Schuurman AR, et al. Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease. Gut. 2018;67(4):728–735. 49. Shiokawa M, Kodama Y, Sekiguchi K, et al. Laminin 511 is a target antigen in autoimmune pancreatitis. Sci Transl Med. 2018;10(453). 50. Perugino CA, AlSalem SB, Mattoo H, et al. Identification of galectin-3 as an autoantigen in patients with IgG4-related disease. J Allergy Clin Immunol. 2018. 51. Liu H, Perugino CA, Ghebremichael M, et al. Disease severity is linked to an increase in autoantibody diversity in IgG4-related disease. Arthritis Rheumatol. 2019. 52. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35. 53. Egawa M, Mukai K, Yoshikawa S, et al. Inflammatory monocytes recruited to allergic skin acquire an anti-inflammatory M2 phenotype via basophil-derived interleukin-4. Immunity. 2013;38(3):570–580. 54. Yanagawa M, Uchida K, Ando Y, et al. Basophils activated via TLR signaling may contribute to pathophysiology of type 1 autoimmune pancreatitis. J Gastroenterol. 2018;53(3):449–460. 55. Umehara H, Nakajima A, Nakamura T, et al. IgG4-related disease and its pathogenesis-cross-talk between innate and acquired immunity. Int Immunol. 2014;26(11):585–595. 56. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29:621–663.

CHAPTER 178  IgG4-related disease 57. Akiyama M, Suzuki K, Yamaoka K, et al. Number of circulating follicular helper 2 T cells correlates with IgG4 and interleukin-4 levels and plasmablast numbers in IgG4-related disease. Arthritis Rheumatol. 2015;67(9):2476–2481. 58. Kubo S, Nakayamada S, Zhao J, et al. Correlation of T follicular helper cells and plasmablasts with the development of organ involvement in patients with IgG4-related disease. Rheumatology (Oxford). 2018;57(3):514–524. 59. Mattoo H, Mahajan VS, Maehara T, et al. Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease. J Allergy Clin Immunol. 2016;138(3):825–838. 60. McHeyzer-Williams LJ, McHeyzer-Williams MG. Antigen-specific memory B cell development. Annu Rev Immunol. 2005;23:487–513. 61. Umehara H, Okazaki K, Kawa S, et al. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. Mod Rheumatol. 2021;31(3):529–533. 62. Okazaki K, Kawa S, Kamisawa T, et al. Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal. J Gastroenterol. 2006;41(7):626–631. 63. Mizushima I, Kasashima S, Fujinaga Y, et al. IgG4-related periaortitis/periarteritis: An under-recognized condition that is potentially life-threatening. Mod Rheumatol. 2019;29(2):240–250.

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64. Wallace ZS, Naden RP, Chari S, et al. The 2019 American college of rheumatology/european league against rheumatism classification criteria for IgG4-related disease. Arthritis Rheumatol. 2020;72(1):7–19. 65. Wallace ZS, Naden RP, Chari S, et al. The 2019 American College of Rheumatology/ European League Against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 2020;79(1):77–87. 66. Kamisawa T, Zen Y, Pillai S, et al. IgG4-related disease. Lancet. 2015;385(9976):1460–1471. 67. Okazaki K, Kawa S, Kamisawa T, et al. Japanese clinical guideline for autoimmune pancreatitis. Pancreas. 2009;38:849–866. 68. Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134(3):706–715. 69. Kamisawa T, Shimosegawa T, Okazaki K, et al. Standard steroid treatment for autoimmune pancreatitis. Gut. 2009;58(11):1504–1507.

179

Immune-mediated complications of checkpoint inhibitors Alexa Simon Meara • Cassandra Calabrese

Key Points n Immune checkpoint inhibitors (CPI) are revolutionary new cancer treatments that work by dysregulating the body’s immune regulation, thereby allowing the opportunity for autoimmune disease to develop, known as immune-related adverse events (irAEs). n irAEs can affect any organ at any time post CPI therapy. n irAEs mimic known rheumatic diseases without the development of the prototypic serum antibodies. n A multidisciplinary approach is key to managing irAEs. n This is a new emerging field that holds promise for future developments and greater understanding of the immune system in disease.

INTRODUCTION Immune checkpoint inhibitors (CPIs) are revolutionary cancer treatments that improve survival for multiple types of cancers including lung, melanoma, and urothelial cell cancers.1 The number of patients eligible to receive CPI has risen from 1% to 43% in the last 7 years (Fig. 179.1).2,3 CPI therapy boosts an individual’s natural ability to fight cancer by blocking intrinsic regulatory immune checkpoints. The currently approved CPIs target two immunologic checkpoint pathways: cytotoxic T-lymphocyte antigen 4 (CTLA-4) and the program cell death 1 (PD-1)/ligand-1 (PD-L1) pathway.4 There are currently seven U.S. Food and Drug Administration approved CPIs on the market (Table 179.1). The immune system defends the human body from foreign bodies like viruses and bacteria.5 When the immune system’s regulatory mechanisms are disrupted, an opportunity to attack the cancer as well as to develop autoimmune disease emerges. These therapies are a double-edged sword; patients are living longer but may develop one of many autoimmune conditions as an adverse effect of CPI. As shown in Fig. 179.2, CTLA-4 was the first target for immunotherapy. CTLA-4, primarily an intracellular antigen, is expressed on the T-cell surface to attenuate early activation of naïve memory T cells.6 PD-1/PD-L1 is expressed on multiple different cells including regulatory cells, B cells, T cells, natural killer cells, dendritic cells, and monocytes. The PD-1/PD-L1 pathway acts in the periphery to inhibit T cells at the effector stage.7 When these checkpoints are impaired, there is an enhanced immune response to the cancer, but T-cell activation can run unchecked, and an abundance of elaborated cytokines through the T-helper 1 and T-helper 17 pathways can develop.8 The TH1 and Th17 pathways can turn on preexisting autoimmune disease (AID) and autoantibodies.9 A consequence of the CPI therapy is the disruption of immune system normal checks and balances allowing for the development of autoimmune disease or immune-related adverse events (irAEs).10 This effect is detailed in Fig. 179.2. IrAEs are underappreciated as a major adverse event that impacts patients over the long term. CPIs are generally better tolerated compared to traditional cancer treatment such as cytotoxic chemotherapy; however, unlike traditional chemotherapy side effects, irAEs may be associated with the potential for long-term multisystem chronic medical diseases requiring medical management and physician subspecialist care.11 IrAEs can affect any organ and can be life threatening when producing conditions such as myocarditis or pneumonitis, or may be more treatable in situations such as colitis, interstitial nephritis, inflammatory arthritis, Sheehan’s syndrome, polymyalgia rheumatica, vasculitis, as well as various skin changes.12,13 CPIs gain new indications monthly and are being combined with each other as well as traditional chemotherapy. Understanding their side effects is imperative for the development of a personalized cancer care plan.

MECHANISM OF ACTION/REVIEW OF T-CELL ACTIVATION NORMAL T-CELL ACTIVATION BACKGROUND DATA Naïve T cells leave the thymus and circulate around the body through the bloodstream.5 T cells will migrate to lymph nodes and interact with antigen-presenting cells (APC) and other lymphocytes. If T cells are not activated, 1582

they will leave the lymph nodes and circulate again until activation occurs. T-cell activation occurs when the T-cell receptor (TCR) binds to an antigen on the MHC receptor of the APC. However, once the T cell is activated there is a consequent profound inflammatory response. The T cell has a CD-28 molecule that must bind to the B7 receptor on the APC. This dual signal stimulation is required for T cells to proliferate, differentiate, and release various proinflammatory molecules. These dual signals are required immune checkpoints where the immune system can block the cosignals to be able to dampen and control the immune response and turn off the activation of the T cells. This happens through the CTLA-4 pathway and the PD-1 pathway.14

CTLA-4 ANTAGONIST Activation of naive T cells requires two signals: one is through the connection with the unique antigen on APC and the other is the costimulating signal on the APC, CD28. CD28 must interact with CD80/CD86 to be active.15 These two signals together allow the naïve T cells to become effector T cells that will proliferate and release inflammatory cytokines. CTLA-4 naturally tempers the upregulated T-cell responses. Specifically, CTLA-4 blocks the required costimulating signal of CD28 that is required to effectively activate the T cell. Specifically, CTLA-4 binds to CD80/CD86 (see Fig. 179.1).4 When the CTLA-4 blocks the CD28 cosignal, it signals the T cells to turn off and become apoptotic. Blocking CTLA-4 allows the T cell to be upregulated without control, thus a controlled checkpoint in the immune system is now dysregulated. This allows the T cell to continue to release cytokines and active costimulatory requirement for T cells allowing the body to attack the cancer.

PD-1 INHIBITION PD-1 is expressed on T cells that circulate in the peripheral tissues. PD-1 binds to PD-L1. PD-L1 is expressed on various different types of tissues, and PD-L2 is expressed solely on APCs. The CPI blockade of PD-1 pathways happens at both the PD-1 and PD-L1 sites.16 By activating the PD-1 pathway a cascade of chemical effects ensue that ultimately leads to death of the T cell. The blockage of PD-1 leads to enhanced T-cell cytotoxicity, increased cytokine production, and ultimately tumor cell lysis.17

IMMUNE-RELATED ADVERSE EVENTS The unique properties of these CPIs that dysregulate the body’s own regulatory systems allows the potential for autoimmune disease to take place. When autoimmune diseases occur as a result of CPI use, this is called irAEs. irAEs can affect any organ and can occur at any time after exposure to CPI.18 irAEs are also associated with a better prognosis in cancer survival; thus these irAEs are double-edged swords. IrAEs are broken down by which organ is affected; the most difficult to define are the rheumatic irAEs, such as arthralgias, arthritis, myalgia, polymyalgia rheumatic, and myositis.19 The most common irAEs are rashes, pruritis, gastrointestinal symptoms, and thyroid disorders. The majority of irAEs occur within the first few doses of CPI therapy. However, there are irAEs that develop late or even after CPI therapy is completed. The most common early irAEs are hepatitis and hypophysitis.14 The most common serious irAEs are myocarditis, pneumonitis, colitis, and neurotoxicities. Pneumonitis account for 28% of the deaths in clinical trials.20 IrAEs may require additional medications and subspecialty involvement, as well as, in severe cases, discontinuation of the CPI therapy.

OVERVIEW OF IrAE TOXICITY GRADES The severity of the irAEs is quantified by grades using the Common Terminology Criteria for Adverse Events v4.03. CTCEA is a classification for standardization for reporting cancer treatments in clinical trials. Low-grade irAEs (grade 1–2) are mild to moderate, do not require hospitalization, and are often treated in an outpatient setting. Higher-grade irAEs (grade 3–4) are severe to life threatening and often require inpatient hospital care. Grade 5 refers to death related to the adverse event.21

CHAPTER 179  Immune-mediated complications of checkpoint inhibitors Endocrine Endocrine irAEs are among the most regularly reported toxicities.22 The most common are hypophysitis mostly associated with CTLA-4 blockade and thyroid dysfunction. However, there has been reports of adrenal insufficiency, hypoparathyroidism, and immunotherapy-related type 1 diabetes mellitus with associated diabetic ketoacidosis and diabetes insipidus.

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Hypophysitis has an incidence of 10% to 17% with use of anti-CTLA-4 (depending on dose), whereas a combination of ipilimumab and nivolumab induced hypophysitis in 13% of patients.23 Hypophysitis often occurs within the first 2 months of treatment with CPI therapy. Hypothyroidism is seen in about 10% of patients on an anti-PD-1/PD-L1. Hyperthyroidism and subsequent thyrotoxicosis is less common in CTLA-4 exposed patients and more often seen with PD-1/PD-L1 inhibition.14

NUMBER OF INDICATIONS BY EACH IMMUNE CHECKPOINT INHIBITOR BY YEAR

70 60 50 40

FIG. 179.1  Number of indications for each immune checkpoint inhibitors

30

by year.

20 10 0 2011

2012

2013

2014

2015

2016

2017

2018

Atezolizumab

Avelumab

Cemiplimab-rwic

Durvalumab

Ipilimumab

Nivolumab

Pembrolizumab

cumulative

2019

Table 179.1

U.S. Food and Drug Administration–Approved Checkpoint Inhibitors on the Market Therapeutic Agent

Molecular Target

Atezolizumab

PD-L1

Avelumab

PD-L1

Cemiplimab

PD-1

Durvalumab

PD-L1

Ipilimumab

CTLA-4

Nivolumab

PD-1

Indications Urothelial cell carcinoma NSCLC Metastatic NSCLC+ traditional chemotherapy Unresectable or metastatic triple negative breast cancer ES-ECLC + traditional chemotherapy Metastatic NSCLC + traditional chemotherapy Unresectable or metastatic hepatocellular carcinoma Unresectable or metastatic melanoma Metastatic bladder cancer Merkel-cell carcinoma Urothelial cell carcinoma Advance renal cell carcinoma Head and neck cancer Cutaneous squamous cell carcinoma/locally advance squamous cell Advanced basal cell Non–small cell lung cancer Urothelial cell carcinoma Unresectable Stage III NSCLC Advance RCC + axitinib Extensive small cell lung cancer Melanoma Melanoma in combination with nivolumab Microsatellite instability high with nivolumab Mismatch repair deficient metastatic colorectal cancer with nivolumab Advance renal cell carcinoma with nivolumab Hepatocellular carcinoma Metastatic or recurrent non–small cell lung cancer Advanced esophageal squamous cell carcinoma Untreated unresectable malignant pleural mesothelioma Small cell lung cancer Advanced or metastatic gastric cancer High risk urothelial carcinoma Unresectable advanced or metastatic esophageal cancer Nonresectable small cell cancer Melanoma NSCLC Renal cell carcinoma Hodgkin lymphoma Head and neck cancer Urothelial carcinoma Hepatocellular carcinoma Metastatic colon cancer Melanoma with lymph node involvement Mismatch repeat deficient metastatic colon cancer Microsatellite instability high metastatic colorectal cancer Metastatic small cell lung cancer Hepatocellular carcinoma Non–small cell cancer Advanced esophageal carcinoma Untreated unresectable malignant pleural mesothelioma

Year Approved 2016 2016 2018 2019 2019 2019 2020 2020 2021 2017 2017 2019 2018 2018 2021 2021 2017 2018 2019 2020 2011 2014 2018 2018 2018 2020 2020 2020 2020 2020 2021 2021 2022 2022 2013 2014 2015 2016 2016 2017 2017 2017 2017 2017 2017 2018 2020 2020 2020 2020

(continued)

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SECTION 15  Other Systemic Illnesses

Table 179.1 (continued)

U.S. Food and Drug Administration–Approved Checkpoint Inhibitors on the Market Therapeutic Agent

Molecular Target

Pembrolizumab

PD-1

Indications

Year Approved

Melanoma NSCLC Hodgkin’s lymphoma Urothelial carcinoma Head and neck cancer PDL1 gastric and GE adenocarcinoma Microsatellite instability high or mismatch repair deficient solid tumors Hepatocellular carcinoma Metastatic squamous NSCLC + carboplatin Nonsquamous NSCLC+ Pemetrexed Refractory primary mediastinal large B-cell lymphoma PDL1 expression in recurrent/metastatic cervical cancer Hepatocellular carcinoma Advanced Merkel cell carcinoma Melanoma with lymph node involvement after complete resection State III NSCLC—not surgical candidate Advanced RCC + axitinib Metastatic or unresectable HNSCC Metastatic SCLC Esophageal squamous cell cancer Advance endometrial carcinoma Invasive bladder cancer Biomarker-based indication regardless of tumor type Cutaneous squamous cell carcinoma Colorectal cancer Refractory Hodgkin’s lymphoma Triple negative breast cancer Advanced gastric cancer Advanced renal cell carcinoma Recurrent or metastatic cervical cancer

2014 2015 2017 2017 2017 2017 2017 2018 2018 2018 2018 2018 2019 2019 2019 2019 2019 2019 2019 2019 2020 2020 2020 2020 2020 2020 2021 2021 2021

CTLA-4, Cytotoxic T lymphocyte antigen 4; NSCLC, non–small cell lung cancer; PD-1, protein cell death protein 1; PDL-1, program cell death ligand 1; RCC, renal cell carcinoma; SCLC, small cell lung cancer.

IMMUNE CHECKPOINTS CONTROL IMMUNE DEACTIVATION AND REGULATION

a

b

FIG. 179.2  Immune checkpoints control immune deactivation and regulation. (a) Cytotoxic T lymphocyte antigen 4 (CTLA 4) is a member of the B7 family and is present on the surface of CD4+ and CD8+ T cells. It is a negative regulator of T-cell activation. CTLA-4 expression is induced upon activation of T cells, and it competitively binds CD80/86, attenuating early activation of naïve memory T cells. (b) PD1/PDL1 acts in the periphery to inhibit T cells at the effector stage, and its expression is associated with T-cell exhaustion.

Gastrointestinal

Hepatic

Diarrhea and colitis are some of the most common gastrointestinal-related irAEs and are seen in almost 30% to 40% of patients treated with ipilimumab.24 The onset of symptoms occur within the first 2 weeks of CPI therapy. The differential diagnosis is broad when these patients present with diarrhea and includes infectious diarrhea (e.g., Clostridium difficile), diverticulitis, intestinal perforation, enteritis, or inflammatory bowel disease.25 The diagnosis is made by clinical assessment; a computed tomography (CT) scan or colonoscopy may be useful as well. The most severe complications are colon perforation.26

Autoimmune hepatitis is seen in up to a third of patients treated with CPI, particularly CTL-4 blockade.12 Elevation in liver function tests develop within the first 3 months of treatment. Severe hepatitis is rare but seen with combination CPI therapy. Most often the hepatitis is asymptomatic; however, if elevated liver functions tests persist, treatment with corticosteroids typically resolves the findings within a few months. Discontinuation of CPI therapy is often not necessary.13

CHAPTER 179  Immune-mediated complications of checkpoint inhibitors CLINICAL SPECTRUM OF IMMUNE-RELATED ADVERSE EVENTS

Neurologic/Ocular

Keratoconjuncvis sicca

Polymyalgia rheumaca Sarcoidosis

Vasculis

Systemic

Neuropathy Demye Guillan-Barré Syndrome

Endocrine

Hypophys s Hypothyroidism Hyperthyroidism Insulin-dependent diabetes

Pulmonary GI/hepa s Pancre

Psoriasis

Inflammatory arthris

Renal s Acute intyers

s

Dermatologic Scleroderma Myosis

o Psoriasis Sweets’ Syndrome

FIG. 179.3  Clinical spectrum of immune-related adverse events GI, Gastrointestinal.

Pulmonary Pneumonitis is a rare but severe life-threatening irAE that is seen with all CPIs; however, it is commonly associated with PD-1 therapy.27 Patients with non–small cell lung cancer (NSCLC) appear to have the most severe pneumonitis that may lead to death. A metaanalysis of studies with PD-1/PD-L1 inhibitors reported that time to onset of pneumonitis may be 7 to 24 months after initiation of therapy. Pneumonitis is a rare but potentially life-threatening complication (10 mg/ day.17 Rheumatic disease factors associated with a higher odds of death included moderate or high disease activity, as compared to low disease activity or remission. Compared to methotrexate use, the use of rituximab, sulfasalazine, and other immunosuppressants (including methotrexate, leflunomide, azathioprine, mycophenolate mofetil, and cyclophosphamide), and the use of no DMARDs at baseline were also associated with higher odds of death. In these observational data, the potential for residual or unmeasured confounding, which could explain some of these associations, remains a limitation. In summary, analyses to date of this large physician-entered registry suggests that risks of poor outcomes in COVID-19 for people with rheumatic disease include the same demographic or comorbid conditions as the general population plus a number of disease- and drug-specific factors. Future analyses as the registry grows and data from other sources will supply further insights. Other data have also provided insights about outcomes after COVID-19 in people with rheumatic disease. A high-quality comparative cohort study has used a U.S. national network with real-time access of electronic health records to evaluate COVID-19-related outcomes of people with systemic autoimmune disease compared to people with COVID-19 and no rheumatic disease.18 Analysis 2 months after infection showed people with rheumatic disease had higher risk of hospitalization (increased risk estimated 24%), mechanical ventilation (77%), intensive care admission (75%), and acute kidney injury (83%) than matched controls without rheumatic disease. However, analysis at 6 months after pandemic onset, with additional adjustment for presence of comorbidities, showed that the association with increased risk of poor outcomes only remained for acute kidney injury (33%) and venous thromboembolism (60%). The data to date suggest that risk factors for increased likelihood of poor outcomes of COVID-19 in people with rheumatic diseases are similar to those seen in the general population. In addition, based on observational studies, the GRA has also found that glucocorticoid use, particularly in higher doses, before COVID-19 diagnosis and higher levels of disease activity are associated with poor outcomes in people with rheumatic disease. These data have provided the reassurance for clinical care and for rheumatic disease patients, so needed in 2020.

USE OF ANTIRHEUMATIC MEDICATIONS FOR THE MANAGEMENT OF COVID-19 Early in the pandemic, medication repurposing for treatment of patients critically ill with COVID-19 occurred, often based on some biologic plausibility arguments and low-quality data. Well-designed randomized controlled studies followed, some with conflicting results, which might be in part explained by timing of medication in the COVID-19 disease process. The data, organized by drug groups, will be briefly discussed.

ANTIMALARIALS Early in vitro studies provided evidence that antimalarial drugs such as hydroxychloroquine (HCQ) or chloroquine (CQ) could be efficacious for use against SARS-CoV-2 via inhibition of viral entry.19,20 Widespread, off-label use of antimalarials for the treatment of COVID-19 followed, in parallel with initiation of multiple clinical trials. Based on high-quality evidence from randomized controlled trials21–24 and well-designed, large, observational studies,25,26 HCQ was not found to be efficacious for the treatment of mild, moderate, or severe COVID-19. These findings were supported by several systematic reviews and metaanalyses.27–29 Furthermore, randomized clinical trials did not demonstrate that HCQ was efficacious as pre- or postexposure prophylaxis for COVID-19.23,30,31 There is no current evidence that chronic therapy with HCQ for rheumatic disease such as systemic lupus erythematosus or rheumatoid arthritis is protective against COVID-19. In data from the COVID-19 GRA registry, the use of antimalarials was not associated with lower odds of hospitalization

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following COVID-19 diagnosis.12 A retrospective study in the Veterans Health Administration network of individuals with rheumatic disease comparing those on long-term HCQ to those not taking HCQ did not show a statistically significant difference in risk of SARS-CoV-2 infection.32 In the U.K. population-based study OpenSAFELY, there was no significant difference in COVID-19 mortality comparing HCQ users to nonusers.33 The risk of developing new cardiac arrhythmias on antimalarials, particularly when used in conjunction with azithromycin, may be heightened in those with COVID-19.34 Evidence for cardiac adverse events among those with rheumatic disease on maintenance therapy with hydroxychloroquine who do not have COVID-19 has been mixed. An analysis of veterans prescribed HCQ from 2000 to 2020, mainly for the indication of systemic lupus erythematosus, found that HCQ use was associated with longer QTc intervals but not increased mortality.35 In contrast, using international claims data from multiple sources, Lane and colleagues studied the risk of cardiovascular outcomes in individuals with RA, comparing HCQ users to active comparators (sulfasalazine), as well as combination HCQ and azithromycin users to active comparators (sulfasalazine and amoxicillin).36 Although their study did not find a difference in short-term outcomes with 30-day follow-up, they did detect a concerning safety signal. HCQ combined with azithromycin was associated with increased risk of three separate outcomes: cardiovascular death, chest pain/angina, and heart failure.

GLUCOCORTICOIDS The current data regarding glucocorticoids in treatment of COVID-19 are conflicting. While most of the studies examining glucocorticoids in COVID19 included severe and critically ill patients, these had varying proportions of subjects requiring invasive mechanical ventilation.37–42 In one study, none of the patients required invasive mechanical ventilation at enrollment.42 This, along with the variability of other inclusion criteria, may have contributed to the heterogeneity of results. The benefit of glucocorticoids in COVID-19 is likely to be restricted to those requiring supplemental oxygen or noninvasive or mechanical ventilation. The evidence is strongest for dexamethasone. The study from the RECOVERY Collaborative Group enrolled 6425 patients with severe COVID-19, of which 2104 were assigned to receive dexamethasone in addition to standard of care and 4321 to receive standard of care only.37 The two groups were comparable with regard to need of oxygen therapy/noninvasive or invasive mechanical ventilation at randomization. The addition of dexamethasone to standard of care significantly reduced mortality but only in patients requiring respiratory support. In a randomized controlled trial (RCT) involving 299 adults with moderate or severe acute respiratory distress syndrome due to COVID-19, dexamethasone plus standard of care compared with standard of care alone significantly increased the number of days alive and free of mechanical ventilation during the first 28 days.39 In another RCT, the addition of methylprednisolone to standard of care reduced mortality only in patients aged 60 years or over.38 Hydrocortisone failed to show benefit in reducing mortality in two studies.40,41 Importantly, the RECOVERY trial also reported that in patients not receiving oxygen therapy, dexamethasone may have a possible (even if not statistically significant) deleterious effect on mortality.37

INTERLEUKIN-6 INHIBITORS Interleukin-6 inhibitors (IL-6) block either the IL-6 receptor (tocilizumab and sarilumab) or the IL-6 cytokine (siltuximab). High IL-6 levels at the time of hospitalization with COVID-19 have been identified as a strong and independent predictor of mortality.43 In view of the high IL-6 levels observed and the previous success in hyperinflammatory states such as the cytokine release syndrome in CAR-T cell therapy,44 agents targeting IL-6 were widely used in a compassionate capacity for the treatment of COVID19. Multiple observational trials in hospitalized patients showed positive results.45 Subsequently, four RCTs of tocilizumab in COVID-19 have shown negative or null results.46–49 In the BACC Bay trial (n = 243) the hazard ratio for the primary outcome of time to intubation or death was 0.83 (95% CI, 0.38–1.81).46 In the COVACTA study (n = 452), there was no difference in clinical status at day 28 or death for tocilizumab (19.7%) vs placebo (19.4%), respectively.47 Other trials of IL-6-inhibitors have been completed and although initial reports suggest some have met their endpoints, these trials remain unpublished at the time of writing.

INTERLEUKIN-1 INHIBITORS Endogenous interleukin-1α (IL-1α) is elevated in patients with COVID19. SARS-CoV-2 causes epithelial damage that leads to the release of

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IL-1β, which recruits inflammatory cells and induces the release of IL-1β in monocytes. This in turn leads to release of more IL-1 to recruit and activate additional innate immune cells. This so-called autoinflammatory loop can be interrupted with drugs that block the IL-1 receptor, such as anakinra, or drugs that block IL-1 signaling, such as canakinumab. These agents are being investigated to reduce hyperinflammation associated with COVID-19. Prior evidence suggests that anakinra may have a role in treating sepsis. In a large sepsis trial,50 the drug did not reduce mortality, but the subgroup of patients with features of macrophage activation syndrome characterized by high ferritin levels, coagulopathy, and elevated liver enzymes seemed to have a survival benefit.51 In COVID-19, one small retrospective cohort study including 29 patients compared the addition of anakinra to standard of care therapy in consecutive hospitalized patients with moderate-to-severe infection and C-reactive protein levels ≥100 mg/L, ferritin ≥900 ng/mL, or both.52 At 21 days, the study found improved survival with anakinra vs standard treatment (90% vs 56%, p = 0.009). In another small, retrospective study of 22 hospitalized patients with COVID-19 and hypoxemic pneumonia or acute respiratory distress syndrome, anakinra-treated patients had clinical improvement and more decreases in oxygen requirements compared to those receiving standard of care.53 Conclusions from these small, retrospective studies are limited. Large RCTs of both anakinra and canakinumab are ongoing.

TUMOR NECROSIS FACTOR INHIBITORS The observation that patients on TNFi in the SECURE-IBD registry14 had better survival led to significant interest in these agents being used to treat COVID-19.54,55 Tumor necrosis factor is elevated in COVID-19 and high levels are associated with poor outcomes.56 Animal data from SARS-CoV-1 demonstrates dramatically improved survival when TNFi are administered.57 At the time of this writing, clinical trials of TNFi in COVID-19 management are underway, including both infliximab for patients admitted to hospital (ACTIV-1, NCT04593940 and CATALYST, ISRCTN40580903) and adalimumab in outpatients to prevent disease deterioration and hospital admission (AVID-CC, ISRCTN33260034). The only published data to date have been small case reports and case series that have shown encouraging results.54

COLCHICINE Colchicine is a widely used drug used to treat autoinflammatory conditions such as gout and familial Mediterranean fever. COVID-19 is characterized by both innate and adaptive immune activation, and several cohorts have reported elevated innate system cytokines such as IL-1β.58 Colchicine inhibits the inflammasome and consequently reduces production of IL-1, IL-6, TNF, and inflammatory cell recruitment. Observational data on the outcomes in COVID-19 with colchicine use were encouraging. In the GRECCO-19 prospective, randomized, open-label study, 105 participants were randomized to a loading dose of colchicine then 0.5 mg twice daily or standard of care.59 The primary clinical outcome was time to deterioration by two points on a seven-grade clinical status scale. This outcome was reached by 14% in the control group and 2% of the colchicine group (OR, 0.11; 95% CI, 0.01–0.96). Another small randomized, double-blind, placebo-controlled study published as a preprint also has shown encouraging results.60 Larger studies are required to clarify evidence of efficacy and safety in COVID-19.

AUTOIMMUNE/INFLAMMATORY MANIFESTATIONS OF COVID-19 MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN AND ADULTS While children had largely been spared from severe disease related to COVID19, there were multiple early reports of a Kawasaki disease-like hyperinflammatory illness affecting children with evidence of current or prior SARS-CoV-2 infection.67 While the syndrome shared many features with that of Kawasaki disease including fever, conjunctivitis, rash, mucocutaneous involvement, and cardiac complications, it affected older children, did not have a predilection for those of Asian descent, and appeared to be temporally related to COVID-19. The World Health Organization, Centers for Disease Control, and other health organizations quickly recognized this was a specific entity and called it multisystem inflammatory syndrome in children (MIS-C), previously known as pediatric inflammatory multisystem syndrome.68,69 A similar syndrome was also described to rarely occur in adults, called MIS-A.70 A large review of published studies showed the mean age of children with MIS-C to be nine years of age, with 52.3% of children male.71 Peaks of MIS-C hospitalization followed peaks of local COVID-19 cases by 4 to 6 weeks.72 The fact that virtually all patients had positive SARS-CoV-2 serologies, as opposed to positive PCR tests, suggests that this hyperinflammatory syndrome is a postinfectious process. It is hypothesized that SARS-CoV-2 triggers the development of autoantibodies, which cause formation of immune complexes or the development of self-reactive cells that attack host tissues.73 Common clinical manifestations included fever, gastrointestinal (abdominal pain, diarrhea, vomiting), cardiovascular, and mucocutaneous (conjunctivitis, rash) manifestations. Along with neutrophilia and lymphopenia, patients typically had elevated inflammatory markers, including C-reactive protein, ferritin, procalcitonin, and IL-6 levels. They often had elevated markers of coagulation including elevated D-dimer and fibrinogen and cardiac markers including troponin and brain natriuretic peptide.71 Echocardiography showed depressed left ventricular ejection fraction (45.1%) and coronary artery aneurysms in 8.1%.71 Most patients (71%) required intensive care unit admission, and 60.1% needed vasoactive support and/or fluid resuscitation, with 22% requiring mechanical ventilation and a minority (4.4%) extracorporeal membrane oxygenation. As with COVID-19 among adults, Black and Hispanic children in the United States and Black and Asian children in the United Kingdom appeared to be overrepresented among those with MIS-C, suggesting that social determinants of health may influence the development of MIS-C.72 Most children responded quickly to treatment, which included IVIG, glucocorticoids, and/ or cytokine blockade with IL-6 or IL-1 inhibition. Of 662 children in a large report, there were only 11 deaths (1.7%).71

THROMBOTIC EVENTS A large number of studies described an increased prevalence of thrombosis and thromboembolic disease in patients with SARS-CoV-2 infection. Controversy still exists as to whether hypercoagulability in SARS-CoV-2 infection may be immune driven, immunothrombotic in nature, or may be linked to direct viral endotheliitis. Platelet aggregation and activation, as expected in the context of endothelial injury and immune activation, were observed and were more pronounced in severe COVID-19.74–76

JANUS KINASE (JAK) INHIBITORS

NEW ONSET ARTHRITIS IN COVID-19

Baricitinib was the initial Janus kinase (JAK) inhibitor studied for COVID19 treatment, due to its antiviral properties in vitro: it inhibits viral endocytosis that occurs through interaction with the ACE-2 receptor and reduces the production of proinflammatory cytokines that are elevated in severe COVID-19.61,62 However, initial concerns were raised about using JAK inhibitors for treating COVID-19 due to two class effects seen in RCTs in rheumatoid arthritis and other rheumatic disease. First, JAK inhibitors inhibit the interferon response that is important in the context of viral infections and is thought to be responsible for increased risk of herpes zoster infections.63 Second, JAK inhibitors lead to an elevated risk of venous thromboembolism,64 which is concerning in the context of hypercoagulopathy in severe cases of COVID-19.65 In the ACTT-2 trial, 1033 patients hospitalized for COVID-19 were randomized to remdesivir plus baricitinib or remdesivir plus placebo.66 This trial met its primary endpoint with a median one-day shorter time to recovery in the baricitinib arm, with larger effects seen in those requiring high-flow oxygen but not invasive mechanical ventilation. No new safety signals were detected in the baricitinib arm.

Nonspecific musculoskeletal symptoms, such as arthralgia or myalgia, have been commonly reported in COVID-19.77,78 There have also been increasing case reports of new onset inflammatory arthritis with negative serologies for other causes among people diagnosed with COVID-19.79 Some of these reported cases have presented with reactive arthritis features, such as enthesitis, tenosynovitis, and psoriatic skin lesions. It remains unclear whether there is a causal relationship between COVID-19 and new onset inflammatory arthritis. Arthritis associated with both acute and chronic viral infections have been seen with other viruses, such as parvovirus, chikungunya, HIV, or hepatitis B and C. An unmasking of previously undiagnosed inflammatory arthritis is another possible explanation that will require further study.

POST-COVID SYNDROME After COVID-19 infection many people recover completely. An as yet incompletely quantified proportion of people will not fully recover due

CHAPTER 180  The epidemiology of coronavirus disease 2019 (COVID-19) and rheumatic disease to individual or multiple organ damage,80 postintensive care syndrome (PICS),81 or due to the emerging phenomenon of a postviral infectious syndrome known as “Long-COVID” or post-COVID syndrome.80,82 Commonly reported ongoing symptoms after COVID-19 include fatigue, arthralgia, dyspnea, cough, and chest pain, with other reported symptoms including cognitive impairment, depression, myalgia, headache, fever, and palpitations.83 Long-COVID does not yet have a widely accepted definition; however, this has been operationalized for research purposes as people who were symptom-free before infection, have laboratory confirmed SARS-CoV-2 infection, and continue to report symptoms attributed to COVID-19 for more than 28 days.84 It remains unknown, in the first year of pandemic, what proportion of people with Long-COVID have persistent symptoms due to organ damage and which have symptoms in the absence of demonstrable organ dysfunction. Certainly, data from previous pandemic and endemic viral infections would suggest that as many as two in three people will experience significant fatigue for up to 6 months post viral infections.85 A large U.K. study of over 4000 people prospectively reporting symptoms during and after COVID-19 via a mobile app has shown that symptoms persist for at least 4 weeks in 13.3% and at least 8 weeks in 4.5% of people.84 Most common symptoms recorded as lasting 28 days included fatigue, headaches, dyspnea, and anosmia. Increasing age, higher body mass index, and female sex were risk factors for Long-COVID. Having five or more symptoms in the first week of COVID-19 was associated with a higher odds of Long-COVID (OR, 3.5; 95% CI, 2.75–4.50). Studies are underway to prospectively evaluate organ damage and new illness complexes post COVID-19.86–88

IMPACT OF THE COVID-19 PANDEMIC ON PEOPLE WITH RHEUMATIC DISEASE During the early stages of the pandemic, few data were available to inform discussions about the risk or consequences of SARS-CoV-2 infection in people with rheumatic diseases. However, subsequent studies evaluating the impacts of the COVID-19 pandemic on the lives of people living with rheumatic disease have provided necessary data to inform the provision of care and understanding healthcare accessibility. Reassuringly, patients with rheumatic disease reported being able to practice risk-mitigating behaviors. Those with rheumatic disease were more likely to isolate compared to matched friend/family controls in a Dutch study.89 A U.K. study found that patients on biologic medications were more likely to practice shielding.90 The repurposing of medications such as antimalarials before robust efficacy data were available led to potentially harmful shortages for people with rheumatic diseases.91 Accessibility to other care during the early stages of the pandemic was limited, with patients reporting difficulty contacting their rheumatologists or with attending medical appointments or obtaining regular infusions and procedures.92 Additionally, higher levels of stress or anxiety during the pandemic were associated with worse patient-reported outcomes in both axial spondyloarthritis and lupus cohorts.93,94 Other studies have suggested worsening levels of patient-reported mental and physical health that were associated with being in quarantine and having difficulty communicating with healthcare providers.95,96 However, the uptake of telemedicine has had the potential to mitigate barriers to healthcare accessibility.

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11.​ Liew JW, Bhana S, Costello W, et al. The COVID-19 Global Rheumatology Alliance: evaluating the rapid design and implementation of an international registry against best practice.​ Rheumatology Published online August 13, 2020.​ 12.​ Gianfrancesco​M, Hyrich​KL, Al-Adely​S, et al. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry​. Ann Rheum Dis. 2020;79​:859​–866​. 13.​ Price-Haywood​EG, Burton​J, Fort​D, et al. Hospitalization and Mortality among Black Patients and White Patients with Covid-19​. N Engl J Med. 2020;382​:2534​–2543​. 14.​ Brenner EJ, Ungaro RC, Gearry RB, et al. Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an international registry. ​Gastroenterology Published online May 18, 2020.​ 15.​ Gianfrancesco MA, Leykina LA, Izadi Z, et al. 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C ​ lin Microbiol Infect Published online August 26, 2020.​ 28.​ Putman M, Chock YPE, Tam H, et al. Antirheumatic disease therapies for the treatment of COVID-19: A systematic review and meta-analysis. A ​ rthritis Rheumatol Published online August 2, 2020.​ 29.​ Axfors C, Schmitt AM, Janiaud P, et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials. ​MedRxiv Published online 2020. ​https://www.medrxiv.org/content/10.1101/2020.09.16. 20194571v2.full-text​.​ 30.​ Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and safety of hydroxychloroquine vs placebo for pre-exposure SARS-CoV-2 prophylaxis among health care workers: A randomized clinical trial. J​ AMA Intern Med Published online September 30, 2020.​ 31.​ Boulware​DR, Pullen​MF, Bangdiwala​AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19​. N Engl J Med. 2020;383​:517​–525​. 32.​ Gentry​CA, Humphrey​MB, Thind​SK, et al. Long-term hydroxychloroquine use in patients with rheumatic conditions and development of SARS-CoV-2 infection: a retrospective cohort study​. Lancet Rheumatol. 2020;2​:e689​–e697​. 33.​ Rentsch CT, DeVito NJ, MacKenna B, et al. Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform. ​Lancet ​ttps://www.sciencedirect.com/science/article/pii/ Rheumatol Published online 2020. h S2665991320303787​.​ 34.​ Wang​Y, Wang​Z, Tse​G, et al. Cardiac arrhythmias in patients with COVID-19​. J Arrhythm. 2020;36​:827​–836​. 35.​ Hooks​M, Bart​B, Vardeny​O, et al. Effects of hydroxychloroquine treatment on QT interval​ . Heart Rhythm. 2020;17​:1930​. 36.​ Lane​JCE, Weaver​J, Kostka​K, et al. Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study​. Lancet Rheumatol. 2020;2​:e698​–e711​. 37.​ Recovery Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19—preliminary report. N ​ Engl J Med Published online July 17, 2020.​ 38.​ Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as adjunctive therapy for patients hospitalized With COVID-19 (Metcovid): A randomised, double-blind, phase IIb, placebo-controlled trial. C ​ lin Infect Dis Published online August 12, 2020.​ 39.​ Tomazini​BM, Maia​IS, Cavalcanti​AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: The CoDEX randomized clinical trial​. JAMA. 2020;324​:1307​–1316​. 40.​ Angus​DC, Derde​L, Al-Beidh​F, et al. 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41.​ Dequin​P-F, Heming​N, Meziani​F, et al. Effect of hydrocortisone on 21-Day mortality or respiratory support among critically Ill patients with COVID-19: A randomized clinical trial​ . JAMA. 2020;324​:1298​–1306​. 42.​ Edalatifard M, Akhtari M, Salehi M, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. E ​ ur Respir J Published online September 17, 2020.​ 43.​ Del Valle​DM, Kim-Schulze​S, Huang​H-H, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival​. Nat Med. 2020;26​:1636​–1643​. 44.​ Amigues I, Pearlman AH, Patel A, et al. Coronavirus disease 2019: investigational therapies in the prevention and treatment of hyperinflammation. E ​ xpert Rev Clin Immunol Published online 2020.​ 45.​ Malgie J, Schoones JW, Pijls BG. Decreased mortality in COVID-19 patients treated with Tocilizumab: a rapid systematic review and meta-analysis of observational studies. C ​ lin Infect Dis Published online September 23, 2020.​ 46.​ Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with Covid-19. N ​ Engl J Med Published online October 21, 2020.​ 47.​ Rosas I, Bräu N, Waters M, et al. Tocilizumab in hospitalized patients with COVID-19 pneumonia. ​medRxiv Published online 2020. ​https://www.medrxiv.org/content/10.1101/2020.08. 27.20183442v2.full.pdf​+​html​.​ 48.​ Hermine O, Mariette X, Tharaux P-L, et al. Effect of Tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: A randomized clinical trial. J​ AMA Intern Med Published online October 20, 2020.​ 49.​ Salvarani C, Dolci G, Massari M, et al. Effect of Tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: A randomized clinical trial.​ JAMA Intern Med Published online October 20, 2020.​ 50.​ Opal​SM, Fisher​Jr CJ, Dhainaut​JF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group​. Crit Care Med. 1997;25​:1115​–1124​. 51.​ Shakoory​B, Carcillo​JA, Chatham​WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: Reanalysis of a prior phase III trial​. Crit Care Med. 2016;44​:275​–281​. 52.​ Cavalli​G, De Luca​G, Campochiaro​C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study​. Lancet Rheumatol. 2020;2​:e325​–e331​. 53.​ Cauchois​R, Koubi​M, Delarbre​D, et al. Early IL-1 receptor blockade in severe inflammatory respiratory failure complicating COVID-19​. Proc Natl Acad Sci. 2020;117​:18951​–18953​. 54.​ Robinson PC, Richards D, Tanner HL, et al. Accumulating evidence suggests anti TNF therapy needs to be given trial priority in COVID-19 treatment. ​Lancet Rheumatol Published online 2020. ​ https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913​ (20)30309-X/fulltext.​ 55.​ Robinson PC, Liew DFL, Liew JW, et al. The potential for repurposing anti-TNF as a therapy for the treatment of COVID-19. M ​ ed Published online 2020. h ​ ttps://www.sciencedirect.com/ science/article/pii/S2666634020300283​.​ 56.​ Kaneko​N, Kuo​H-H, Boucau​J, et al. Loss of Bcl-6-Expressing T follicular helper cells and germinal centers in COVID-19​. Cell. 2020;183​:143​–157​. e13​. 57.​ Channappanavar​R, Fehr​AR, Vijay​R, et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice​. Cell Host Microbe. 2016;19​:181​–193​. 58.​ McKechnie​JL, Blish​CA. The innate immune system: Fighting on the front lines or fanning the flames of COVID-19?​Cell Host Microbe. 2020;27​:863​–869​. 59.​ Deftereos​SG, Giannopoulos​G, Vrachatis​DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial​. JAMA Network Open. 2020;3​ e2013136-e2013136​. 60.​ Lopes MIF, Bonjorno LP, Giannini MC, et al. Beneficial effects of colchicine for moderate to severe COVID-19: an interim analysis of a randomized, double-blinded, placebo controlled clinical trial. ​MedRxiv Published online 2020. ​https://www.medrxiv.org/content/10.1101/20 20.08.06.20169573v2.full.pdf​+​html​.​ 61.​ Richardson​P, Griffin​I, Tucker​C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease​. Lancet. 2020;395​:e30​–e31​. 62.​ Stebbing​J, Krishnan​V, de Bono​S, et al. Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients​. EMBO Mol Med.. 2020;12​(8​):e12697​. 63.​ Bechman​K, Subesinghe​S, Norton​S, et al. A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis​. Rheumatology. 2019;58​ :1755​–1766​. 64.​ Yates M, Mootoo A, Adas M, et al. Venous thromboembolism risk with JAK inhibitors: A Meta-analysis. A ​ rthritis Rheumatol Published online November 10, 2020.​ 65.​ Bikdeli​B, Madhavan​MV, Jimenez​D, et al. COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up: JACC State-ofthe-Art review​. J Am Coll Cardiol. 2020:75​. 66.​ Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N ​ Engl J Med Published online December 11, 2020.​ 67.​ Verdoni​L, Mazza​A, Gervasoni​A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study​. Lancet. 2020;395​:1771​–1778​.

68.​ Multisystem Inflammatory Syndrome in Children and Adolescents Temporally Related to COVID-19. World Health Organisation. Accessed December 30, 2020. ​https://www.who.int/ news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19​.​ 69.​ Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19). Centers for Disease Control and Prevention. Accessed December 30, 2020. h ​ ttps://emergency.cdc.gov/han/2020/han00432.asp​.​ 70.​ Morris​SB, Schwartz​NG, Patel​P, et al. Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection—United Kingdom and United States, March– August 2020​. MMWR Morbidity and Mortality Weekly Report. 2020;69​:1450​–1456​. 71.​ Ahmed​M, Advani​S, Moreira​A, et al. Multisystem inflammatory syndrome in children: A systematic review​. EClinicalMedicine. 2020;26​:100527​. 72.​ Abrams JY, Godfred-Cato SE, Oster ME, et al. Multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2: A systematic review.​ J Pediatr Published online August 5, 2020.​ 73.​ Gruber​CN, Patel​RS, Trachtman​R, et al. Mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (MIS-C)​. Cell. 2020;183​:982​ –995​. e14​. 74.​ Di Minno​A, Ambrosino​P, Calcaterra​I, et al. COVID-19 and venous thromboembolism: A meta-analysis of literature studies​. Semin Thromb Hemost. 2020;46​:763​–771​. 75.​ Manne​BK, Denorme​F, Middleton​EA, et al. Platelet gene expression and function in patients with COVID-19​. Blood. 2020;136​:1317​–1329​. 76.​ Hottz​ED, Azevedo-Quintanilha​IG, Palhinha​L, et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19​. Blood. 2020;136​:1330​–1341​. 77.​ Cipollaro​L, Giordano​L, Padulo​J, et al. Musculoskeletal symptoms in SARS-CoV-2 (COVID-19) patients​. J Orthop Surg Res. 2020;15​:178​. 78.​ Ciaffi​J, Meliconi​R, Ruscitti​P, et al. Rheumatic manifestations of COVID-19: a systematic review and meta-analysis​. BMC Rheumatol. 2020;4​:65​. 79.​ Conway​R, Konig​MF, Graef​E, et al. Inflammatory arthritis in patients with COVID-19​. Best Pract Res Clin Rheumatol. 2020 In press​. 80.​ Greenhalgh​T, Knight​M, A’Court​C, et al. Management of post-acute covid-19 in primary care​. BMJ. 2020;370​:m3026​. 81.​ Stam​H, Stucki​G, Bickenbach​J. Covid-19 and post intensive care syndrome: A call for action​. J Rehabil Med. 2020;52​(4​):jrm00044​. 82.​ Mahase E. Covid-19: What do we know about “long covid”? B ​ MJ. Published online 2020:m2815.​ 83.​ CDC. Late Sequelae of COVID-19. Published November 13, 2020. Accessed December 2, 2020. h ​ ttps://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/late-sequelae.html​.​ 84.​ Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App.​ 85.​ Islam​MF, Cotler​J, Jason​LA. Post-viral fatigue and COVID-19: lessons from past epidemics​ . Fatigue: Biomed, Health Behav. 2020;8​(2​):61​–69​. 86.​ A Longitudinal Study of COVID-19 Sequelae and Immunity. Accessed December 2, 2020.​ https://clinicaltrials.gov/ct2/show/NCT04411147​.​ 87.​ Long-term Impact of Infection With Novel Coronavirus (COVID-19)—Tabular View— ClinicalTrials.gov. Accessed December 2, 2020. h ​ ttps://clinicaltrials.gov/ct2/show/record/ NCT04362150​.​ 88.​ Long-term follow up of adults hospitalised with COVID-19.​ 89.​ Hooijberg​F, Boekel​L, Vogelzang​EH, et al. Patients with rheumatic diseases adhere to COVID-19 isolation measures more strictly than the general population​. Lancet Rheumatol. 2020;2​:e583​–e585​. 90.​ Yates​M, Mahil​S, Langan​S, et al. Risk mitigating behavior in people with rheumatic diseases or psoriasis during the COVID-19 pandemic differ by immunosuppressant treatment type: A patient survey study​. Arthritis Rheumatol. 2020 ABSTRACT NUMBER: L02​. 91.​ Kim​AHJ, Sparks​JA, Liew​JW, et al. A rush to judgment? Rapid reporting and dissemination of results and its consequences regarding the use of hydroxychloroquine for COVID-19​. Ann Intern Med. 2020;172​:819​–821​. 92.​ Sirotich​S, Kennedy​K, Surangiwala​S, et al. Antimalarial drug shortages during the COVID19 pandemic: Results from the global rheumatology alliance patient experience survey​. Arthritis Rheumatol. 2020 ABSTRACT NUMBER: 0007​. 93.​ Liew​JW, Castillo​M, Zaccagnino​E, et al. Patient-reported disease activity in an axial spondyloarthritis cohort during the COVID-19 pandemic​. ACR Open Rheumatol. 2020;2​(9​):533​ –539​. 94.​ Patterson​S, Trupin​L, DeQuattro​K, et al. Perceived stress during the COVID-19 pandemic independently associates with worse patient-reported outcomes in systemic lupus erythematosus (SLE)​. Arthritis Rheumatol. 2020 ABSTRACT NUMBER: 1267​. 95.​ Cleaton N, Raizada S, Barkham N, et al. COVID-19 prevalence and the impact on quality of life from stringent social distancing in a single large UK rheumatology centre. ​Ann Rheum Dis Published online July 21, 2020.​ 96.​ Kennedy​K, Sirotich​E, Surangiwala​S, et al. Modeling the effects of Covid-19 protective behaviors and healthcare delivery on the health of patients with rheumatic disease​. Arthritis Rheumatol. 2020 ABSTRACT NUMBER: 0613​.

Section

16

OSTEOARTHRITIS

Epidemiology and classification of osteoarthritis Amanda E. Nelson

Key Points n Osteoarthritis (OA), the most common form of arthritis, is strongly associated with aging and typically affects the knee, hip, spine, great toe, and hands. n OA frequency varies by sex as well as race/ethnicity. n OA can be defined by x-rays, clinical examination, or symptoms, with frequency dependent on both definition and population. n The mortality rate may be increased in individuals with OA, particularly painful OA, compared with the general population. n As more sensitive measures of OA such as magnetic resonance imaging and biomarkers are developed and validated, definitions of OA will continue to evolve.

INTRODUCTION Osteoarthritis (OA) is the most common form of arthritis, affecting an estimated 53 million adults in the United States in 2010 to 2012, according to data from the National Health Interview Survey,1 although even this is likely to be an underestimate.2,3 According to the Healthcare Cost and Utilization Project website (https://www.hcup-us.ahrq.gov/), OA was the most common principal diagnosis for inpatient hospital stays in adults 65 to 74 years of age in 2015 (1472 per 100,000 stays), an increase from 1231 per 100,000 in 2005 and overtaking “coronary atherosclerosis and other heart disease.”4 Because of its effect on ambulation and mobility, OA of the knee and hip has significant functional impact and is associated with considerable medical costs, accounting for the vast majority of the 752,921 total inpatient stays for knee replacements and 522,820 total inpatient stays for hip replacements in the United States in 2014, dramatic increases from the 534,209 knee and 371,606 hip replacement inpatient stays in 2005.4 Because of the aging of our society and the obesity epidemic, the burden of OA will continue to increase over the next 20 years.1,5–7 The joint degradation in OA affects all structures in the joint and should be considered a failure of the total joint. The pathology of OA is characterized by thinning and fibrillation of articular cartilage with loss of joint space, osteophyte formation, subchondral bony sclerosis, subchondral cysts, and joint deformity. The pathophysiology of OA involves not only cartilage degradation but also changes in the subchondral bone, synovium, ligaments, tendons, meniscus, muscle, and nerve tissues. Clinically, this can be accompanied by pain on use of the joint; stiffness, particularly after inactivity; bony enlargement and tenderness; synovial hypertrophy and effusion; limited range of motion; and decreased joint function. End-stage OA likely represents a final common pathway of a variety of conditions (e.g., inflammation, trauma, metabolic disorders) that, despite differences in etiology, lead to the same pathologic and clinical result. Osteoarthritis typically affects the knees, hips, hands, spine, and feet. Classifications can differentiate between OA that is localized and OA that affects multiple joint groups. OA can also be classified as hypertrophic or atrophic, based on radiographic features of osteophytosis or joint space narrowing, and as primary or secondary to other conditions, such as metabolic disorders (e.g., ochronosis or hemochromatosis), anatomic abnormalities

181

(e.g., slipped capital femoral epiphysis or chondrodysplasias), trauma or joint surgery, or previous inflammatory arthritis. This type of classification can be useful in clinical care and in development of inclusion and exclusion criteria for epidemiologic studies and clinical trials, but the distinctions can be artificial and ignore the more common situation of overlapping causes. The American College of Rheumatology (ACR) classification of subsets of OA is shown in Box 181.1.8

DEFINITIONS OF OSTEOARTHRITIS Osteoarthritis can be defined pathologically, radiographically, or clinically, and the choice of definition can substantially affect prevalence estimates.9 The ACR criteria for the classification and reporting (for research purposes) of OA of the hand, hip, and knee are shown in Table 181.1.8,10,11 The European League Against Rheumatism (EULAR) has published recommendations for the clinical diagnosis of OA at the hand12 and knee (Tables 181.2 and 181.3; Fig. 181.1).13 A study of over 13,000 knee OA patients treated in primary care settings in Denmark compared the ACR, EULAR, and National Institute for Health and Care Excellence (NICE) clinical classification criteria and found that 39% fulfilled all three criteria, with 52%, 48%, and 89% of patients meeting the ACR, EULAR, or NICE criteria, respectively.14 Given the imperfect congruence between different clinical definitions,15 radiographic and clinical definitions,16 the variation in frequencies of and risk factors for OA in different joint sites, and new and more sensitive metrics, such as magnetic resonance imaging (MRI) and biochemical markers, to identify pathologic features, OA definitions for epidemiologic investigation are evolving. Generally speaking, the presence of radiographic OA usually requires identification of a definite osteophyte with or without joint space narrowing on plain radiographs. Clinical OA is usually defined by abnormalities on physical examination consistent with OA, such as Heberden or Bouchard nodes in the hand, or limited and painful range of motion on internal rotation of the hip. Symptomatic OA is usually defined as the presence of joint symptoms such as pain, aching, or stiffness, in a joint with radiographic OA. Definitions can vary according to joint site, frequency or intensity of pain, and time span over which symptoms are assessed. Definitions of incident OA and progression of OA may also vary according to joint site, individual radiographic features assessed, and the original metric used to define OA.

RADIOGRAPHIC OSTEOARTHRITIS: DEFINITIONS Radiographic determination of OA has long been considered the gold standard, and multiple ways to define radiographic disease have been devised. The Kellgren-Lawrence (KL) radiographic grading scale and atlas have been in use for more than 6 decades. This overall joint scoring system grades OA in five levels from 0 to 4, defining OA by the presence of a definite osteophyte and more severe grades by the presumed successive appearance of joint space narrowing, sclerosis, cysts, and deformity (Table 181.4 and Fig. 181.2).16 The KL scoring system has been used extensively but has been criticized because of its reliance on the presence of a definite osteophyte to define a case, inconsistencies in interpretation across studies, and 1595

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SECTION 16 Osteoarthritis

BOX 181.1 AMERICAN COLLEGE OF RHEUMATOLOGY CRITERIA FOR

CLASSIFICATION OF OSTEOARTHRITIS SUBSETS

I. Idiopathic A. Localized 1. Hands (e.g., Heberdenand Bouchard nodes [nodal], erosive interphalangealarthritis [non-nodal]): scaphometacarpal, scaphotrapezial 2. Feet (e.g., hallux valgus, hallux rigidus, contracted toes [hammer/ cock-up toes]): talonavicular 3. Knee a. Medial compartment b. Lateral compartment c. Patellofemoral compartment (e.g., chondromalacia) 4. Hip a. Eccentric (superior) b. Concentric (axial, medial) c. Diffuse (coxae senilis) 5. Spine (particularly cervical and lumbar) a. Apophyseal b. Intervertebral (disk) c. Spondylosis(osteophytes) d. Ligamentous (hyperostosis [Forestier disease or DISH]) 6. Other single sites (e.g., shoulder, temporomandibular, sacroiliac, ankle, wrist, acromioclavicular) B. Generalized: includes three or more areas listed above (Kellgren-Moore) 1. Small (peripheral) and spine 2. Large (central) and spine 3. Mixed (peripheral and central) and spine II. Secondary A. Posttraumatic B. Congenital or developmental diseases 1. Localized a. Hip diseases (e.g., Legg-Calvé-Perthes, congenital hip dislocation, slipped capital femoral epiphysis, shallow acetabulum) b. Mechanical and local factors (e.g., obesity [?], unequal lower extremity length, extreme valgus/varus deformity, hypermobility syndromes, scoliosis) 2. Generalized a. Bone dysplasias (e.g., epiphyseal dysplasia, spondyloapophyseal dysplasia) b. Metabolic diseases (e.g., hemochromatosis, ochronosis, Gaucherdisease, hemoglobinopathy, Ehlers-Danlos syndrome) C. Calcium deposition disease 1. Calcium pyrophosphate deposition disease 2. Apatite arthropathy 3. Destructive arthropathy (shoulder, knee) D. Other bone and joint disorders (e.g., avascular necrosis, rheumatoid arthritis, gouty arthritis, septic arthritis, Paget disease, osteopetrosis, osteochondritis) E. Other diseases 1. Endocrine diseases (e.g., diabetes mellitus, acromegaly, hypothyroidism, hyperparathyroidism) 2. Neuropathic arthropathy (Charcot joints) 3. Miscellaneous (e.g., frostbite, Kashin-Beck disease, caisson disease) DISH, Diffuse idiopathic skeletal hyperostosis. From Altman R, Asch E, Bloch D, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986;29:1039–49.

lack of sensitivity to change.17 Additionally, although individuals categorized as having KL grade 1 are often classified as unaffected, these individuals likely have early OA, based on their more likely progression to higher radiographic grades over time compared with those categorized as KL grade 0.18,19 Semiquantitative evaluation of individual radiographic features such as osteophytes, joint space narrowing, sclerosis, and cysts at individual joint sites can also be used.20 Direct measurement of the interbone distance as an indicator of the joint space width in the knees and hips is a more powerful tool to define OA and to investigate progression in epidemiologic studies and clinical trials of disease-modifying therapies.21–24 Standardized protocols for radiographic image acquisition and methods for scoring have been devised that show good reliability and use of digitized images and computer scoring reduces error. An OA definition based on MRI has been proposed,23 as have screening tools for MRI-based eligibility for clinical trials.24 These

Table 181.1

American College of Rheumatology Criteria for Classification and Reporting of Osteoarthritis of the Hand, Hip, and Knee Items Required for Presence of Osteoarthritis Hand

Clinical

1. Hand pain, aching, or stiffness for most days of prior month 2. Hard tissue enlargement of ≥2 of 10 selected hand jointsa 3. MCP swelling in ≤2 joints 4. Hard tissue enlargement of ≥2 DIP joints 5. Deformity of ≥1 of 10 selected hand jointsa

1, 2, 3, 4 or 1, 2, 3, 5

Hip

Clinical and radiographic

1. Hip pain for most days of the prior month 2. ESR ≤20 mm/hr (laboratory) 3. Radiographic femoral and/or acetabular osteophytes 4. Radiographic hip joint space narrowing

1, 2, 3 or 1, 2, 4 or 1, 3, 4

Knee

Clinical



1. Knee pain for most days of prior month 2. Crepitus on active joint motion 3. Morning stiffness ≤30 min in duration 4. Age ≥38 yr 5. Bony enlargement of the knee on examination

1, 2, 3, 4 or 1, 2, 5 or 1, 4, 5

Clinical and radiographic



1. Knee pain for most days of prior month 2. Osteophytes at joint margins (x-ray) 3. Synovial fluid typical of OA (laboratory) 4. Age ≥40 yr 5. Morning stiffness ≤30 min in duration 6. Crepitus on active joint motion

1, 2 or 1, 3, 5, 6 or 1, 4, 5, 6

Ten selected hand joints include bilateral second and third proximal interphalangeal joints, second and third distal interphalangeal (DIP) joints, and first carpometacarpal joints. ESR, Erythrocyte sedimentation rate; MCP, metacarpophalangeal; OA, osteoarthritis. From Altman R, Asch E, Bloch D, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum 1986;29:1039–49; Altman R, Alarcon G, Appelrouth D, et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip. Arthritis Rheum. 1991;34:505–14; and Altman R, Alarcon G, Appelrouth D, et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hand. Arthritis Rheum. 1990;33:1601–10.

a

issues, as well as other imaging modalities in OA, are discussed further in Chapter 187. The presence of radiographic OA has an imperfect correlation with symptoms,15 although this relationship is partially dependent on study design. Neogi and colleagues,25 after controlling for confounding by examining knee pain and radiographic OA features within individuals with knees discordant for pain, found strong correlations between radiographic measures (KL grade, osteophytes, or joint space narrowing) and pain. Composite definitions accounting for both osteophytes and joint space narrowing, vs those features alone, are most strongly associated with hip pain and later total hip replacement.26 A 2011 study of hand OA found independent associations between osteophytes and joint space narrowing and hand joint pain.27

Prevalence of radiographic osteoarthritis Although OA affects individuals worldwide, some geographic variation in disease does exist and can inform investigations into etiology and pathogenesis. The following discussion includes data on radiographic OA of the hip, knee, and hand, with a mention of other sites that have been less well characterized.

Prevalence of radiographic hip osteoarthritis The overall prevalence of radiographic hip OA varies widely, from less than 1% to 27%, depending on the population being studied.28 Radiographic hip OA was present in about 20% of participants in the Framingham Study Community cohort (2002–2005).29 Although early studies reported low

CHAPTER 181  Epidemiology and classification of osteoarthritis

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Table 181.2

European League Against Rheumatism Propositions for Hand Osteoarthritis Diagnosis With Strength of Recommendationa Proposition

1 2

3

4 5 6 7

8 9

10

Risk factors: female sex, age >40 yr, menopausal status, family history, obesity, higher bone density, greater forearm muscle strength, joint laxity, prior hand injury and occupation or recreation-related usage Typical symptoms: pain on usage and only mild morning or inactivity stiffness affecting one to a few joints at any one time; symptoms are often intermittent and target characteristic sites (DIP joints, PIP joints, thumb base, index and middle MCP joints). With such typical features, a confident clinical diagnosis can be made in adults aged >40 yr. Clinical hallmarks: Heberden and Bouchard nodes and/or bony enlargement with or without deformity (e.g., lateral deviation of IP joints, subluxation and adduction of thumb base) affecting characteristic target joints (DIP joints, PIP joints, thumb base and index and middle MCP joints) Functional impairment: may be as severe as in RA. Function should be carefully assessed and monitored using validated outcome measures. Patients with polyarticular HOA are at increased risk of knee OA, hip OA, and OA at other common target sites and should be assessed and examined accordingly. Recognized subsets with different risk factors, associations and outcomes (requiring different assessment and management) include IP joint OA (with or without nodes), thumb base OA, and erosive OA. Erosive hand OA targets IP joints and shows radiographic subchondral erosion, which may progress to marked bone and cartilage attrition, instability, and bony ankylosis. Typically, it has an abrupt onset, marked pain and functional impairment, inflammatory symptoms and signs (stiffness, soft tissue swelling, erythema, paresthesia), mildly elevated CRP levels, and a worse outcome than nonerosive IP joint OA. Differential diagnosis includes PsA (which may target DIP joints or affect just one ray), RA (mainly targeting MCP joints, PIP joints, wrists), gout (which may superimpose on preexisting HOA), and hemochromatosis (mainly targeting MCPJs, wrists). Plain radiographs provide the gold standard for morphologic assessment of HOA. A posteroanterior radiograph of both hands on a single film or field of view is adequate for diagnosis. Classical features are joint space narrowing, osteophyte, subchondral bone sclerosis and subchondral cyst, and subchondral erosion occurs in erosive hand OA. Further imaging modalities are seldom indicated for diagnosis. Blood tests are not required for diagnosis of HOA but may be required to exclude coexistent disease or to screen for additional inflammatory arthritides.

Level of Evidence

Strength of Recommendation

Ib–IIb

69 (54–84)

IIb

85 (77–92)

Ib–IV

80 (69–90)

IIb

57 (42–73)

IIa–IIb

77 (62–92)

IIa–IIb

68 (56–79)

IIa–IIb

87 (81–93)

Ib–IIb

81 (73–89)

Ib–IIb

87 (81–93)

Ib–IIb

78 (63–92)

95% confidence interval. CRP, C-reactive protein; DIP, distal interphalangeal; HOA, hand osteoarthritis; MCP, metacarpophalangeal; OA, osteoarthritis; PIP, proximal interphalangeal; PsA, psoriatic arthritis; RA, rheumatoid arthritis. Adapted from Zhang W, Doherty M, Leeb BF, et al. EULAR Evidence-based recommendations for the diagnosis of hand osteoarthritis: report of a Task Force of ESCISIT. Ann Rheum Dis. 2009;68:8–17.

a

rates of hip OA in Black individuals of African and Caribbean descent,30,31 evidence from population-based studies shows that Blacks (32%) and Whites (27%) in the United States have a similar prevalence of hip OA.32 Hip OA was 80% to 90% less frequent in Chinese individuals, around 1%, compared with Whites in a 2002 study using standardized methods and the same readers for all x-rays.33 A similarly low prevalence of 2% was seen in a random sample of South Korean adults older than 65 years of age.34 In contrast, 16% of adults in a recent Japanese cohort study had radiographic hip OA.35

Prevalence of radiographic knee osteoarthritis A subset of individuals aged 60 years and older participating in the National Health and Nutrition Examination Survey (NHANES) III (1991–1994) had an overall prevalence of radiographic knee OA of 37%, higher than estimates from NHANES I, and higher in Blacks (52%) than in Mexican Americans (40%) or non-Hispanic Whites (36%).36 Radiographic knee OA was present in 33% of men and 42% of women in the original cohort of the Framingham Osteoarthritis Study (1983–1985), without substantial change at follow-up (1992–1995).37 At baseline, 28% of participants in the Johnston County Osteoarthritis Project aged 45 years and older had radiographic knee OA, with slightly more Blacks affected than Whites.38 At follow-up nearly 30 years later, this had increased to 61%, again with Blacks more affected than Whites.39 A population-based study in South Korea found a 33% prevalence of radiographic knee OA overall, higher in women (44%) compared with men (21%).40 In the Beijing Osteoarthritis Study, radiographic knee OA was more common in Chinese women than in White women from Framingham despite a lower body mass index (BMI) among the Chinese women.41 The Copenhagen Osteoarthritis Study (1992–1994) found a relatively low prevalence of radiographic knee OA of 12% for men and 14% for women, which was partially explained by a low BMI (mean, 26 kg/m2) in that group.42 Many studies of radiographic knee OA are limited to the tibiofemoral joint and therefore underestimate the prevalence of radiographic knee OA and symptomatic knee OA by omitting the patellofemoral joint. Much of patellofemoral joint OA coexists with tibiofemoral OA,43 but it can exist as an isolated phenomenon in 7% to 13% of individuals.43,44

(PIP) joints, metacarpophalangeal (MCP) joints, and carpometacarpal (CMC) joints or thumb base. Criteria for case definitions may include the presence of radiographic hand OA in any hand joint or in a selected subset of hand joint sites, usually including the DIPs, PIPs, and CMCs.10 Radiographic hand OA is extraordinarily common, particularly in older age groups. The Rotterdam study reported that 67% of women and 55% of men aged 55 years and older had radiographic hand OA in at least one joint and 28% had radiographic hand OA in at least two of three hand joint sites (DIP, PIP, CMC).45 The Framingham Osteoarthritis Study reported an age-standardized prevalence of radiographic hand OA (at least one joint with KL grade 2 or more) of 44% in women and 38% in men, most commonly involving the DIP and thumb base, and frequently involving multiple joints (Fig. 181.3).46 Radiographic hand OA involving any hand joint was present in 25.5% of Black women and 19.2% of White women in the Southeast Michigan cohort of perimenopausal women.47 In contrast, The Johnston County Osteoarthritis Project reported a much lower frequency of hand OA among Black compared with White older adults.48 Radiographic hand OA was relatively uncommon in Chinese and Japanese adults in early reports49,50 but more recently was identified in 60% of a South Korean cohort34 and more than 90% of participants in a Japanese cohort.51 Erosive changes in the hands have been reported in up to 4% of men and 10% of women in the Framingham cohort.46

Prevalence of radiographic osteoarthritis in other sites Osteoarthritis in other common sites such as the spine and first metatarsophalangeal joints is less well studied. A recent study of phenotypes of lumbar spine OA demonstrated that, in a community-based cohort, 23% had facet OA, 13% had spine OA (defined as at least mild osteophytosis and disc space narrowing at the same level), and nearly half had both facet and spine OA; all of these groups were also more likely to have concomitant knee OA.52 Spine OA (KL grade of 2 or more at least at one level) was found in two-thirds of a random sample of older adults in South Korea.34 OA of the joints of the feet is also common but understudied; prevalence of radiographic OA at the first metatarsophalangeal joint has been reported in the range of 20% to 40%.53,54

Prevalence of radiographic hand osteoarthritis

Incidence and progression of radiographic osteoarthritis

Radiographic hand OA is usually defined as a KL grade of 2 or higher in specific joints, namely, the distal interphalangeal (DIP) joints, proximal interphalangeal

Incidence (new onset) and progression (worsening) of radiographic OA are defined separately for individual joint groups and, increasingly, for the

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SECTION 16 Osteoarthritis

Table 181.3

European League Against Rheumatism Propositions for Knee Osteoarthritis Diagnosis With Strength of Recommendationa Proposition 1

2

3

4

5

6

7

8

9

10

Knee OA is characterized clinically by usage-related pain and/or functional limitation. It is a common complex joint disorder showing focal cartilage loss, new bone formation, and involvement of all joint tissues. Structural tissue changes are mirrored in classical radiographic features. Risk factors that are strongly associated with the incidence of knee OA can help to identify patients in whom knee OA is the most likely diagnosis. These include increasing age >50 yr, female gender, higher BMI, previous knee injury or malalignment, joint laxity, occupational or recreational usage, family history, and the presence of Heberden nodes. Subsets with different risk factors and outcomes can be defined according to varying compartmental involvement (patellofemoral, medial or lateral tibiofemoral), bone response (atrophic, hypertrophic), global pattern of OA (generalized, localized), crystal presence (pyrophosphate, basic calcium phosphates), and the degree of inflammation. However, the ability to discriminate subsets and the relevance for routine practice are unclear. Typical symptoms of knee OA are usage-related pain, often worse toward the end of the day, relieved by rest; the feeling of “giving way”; only mild morning or inactivity stiffness, and impaired function. More persistent rest and night pain may occur in advanced OA. OA symptoms are often episodic or variable in severity and slow to change. In adults aged >40 yr with usage-related knee pain, only short-lived morning stiffness, functional limitation, and one or more typical examination findings (crepitus, restricted movement, bony enlargement), a confident diagnosis of knee OA can be made without a radiographic examination. This applies even if radiographs appear normal. All patients with knee pain should be examined. Findings indicative of knee OA include crepitus, painful or restricted movement, bony enlargement, and absent or modest effusion. Additional features that may be present include deformity (fixed flexion and/or varus—less commonly valgus), instability, periarticular or joint-line tenderness, and pain on patellofemoral compression. Red flags (e.g., severe local inflammation, erythema, progressive pain unrelated to usage) suggest sepsis, crystals, or serious bone pathology. Involvement of other joints may suggest a wide range of alternative diagnoses. Other important considerations are referred pain, ligamentous and meniscal lesions, and bursitis. Plain radiography (both knees, weight-bearing, semiflexed PA view, plus a lateral and skyline view) is the current “gold standard” for morphologic assessment of knee OA. Classical features are focal joint space narrowing, osteophyte, subchondral bone sclerosis, and subchondral cysts. Further imaging modalities (MRI, sonography, scintigraphy) are seldom indicated for diagnosis of OA. Laboratory tests on blood, urine, or synovial fluid are not required for the diagnosis of knee OA but may be used to confirm or exclude coexistent inflammatory disease (e.g., pyrophosphate crystal deposition, gout, rheumatoid arthritis) in patients with suggestive symptoms or signs. If a palpable effusion is present, synovial fluid should be aspirated and analyzed to exclude inflammatory disease and to identify urate and calcium pyrophosphate crystals. OA synovial fluid is typically noninflammatory with knee > hip),37 it is probable that rates of progression from preclinical OA to preradiographic and radiographic OA

SECTION 16 Osteoarthritis

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OA PROGRESSION FROM PRECLINICAL TO CLINICALLY RECOGNIZABLE STAGES

? 7%–8% per year ? 2%–5% per year

? 2%–19% per year Radiographic OA

Preradiographic OA

Preclinical OA

FIG. 189.4  At present, the rates of evolution from preclinical to preradiographic to radiographic osteoarthritis (OA) are not precisely known. After a severe acute knee injury, the annual rate of progression in the preclinical phase of OA is at least 2% to 5% annually to account for the overall average risk of developing radiographic OA of 50% by 10 to 20 years later9; under less extreme circumstances, the rate is likely lower. Knowledge of rates of progression to radiographic OA from preradiographic OA are limited but may be estimated at 7% to 8% annually given the current information available.28 The rate of progression of radiographic OA to more severe radiographic stages is estimated to be 2% to 19% annually based on calculations using the data from the placebo arms of a number of studies (summarized by Manno et al.35 and Emrani et al.36). These should be treated as rough estimates in need of refinement through future longitudinal studies with more comprehensive patient phenotyping of different joints and patient subtypes with sensitive imaging and biochemical markers.

Table 189.1

Summary of Studies Providing Estimates of Radiographic Osteoarthritis (OA) Progressiona

Study (n in Placebo Arm)

Study Duration (wk/yr)

Participants With Radiographic Progression Among Those With Baseline Symptoms Progressors (n)/Total (n) (% Progression and % Per Year)

Participants With Radiographic Progression Among All Participants With OA Progressors (n)/Total (n) (% Progression and % Per Year)

Hip studies

ECHODIAH (136) 156/3 ERADIAS (127) 156/3

30/52 (58%; 19%) 24/46 (52%; 17%)

30/136 (22%; 7%) 24/127 (19%; 6%)

3/14 (21%; 7%) 12/26 (46%; 15%) 16/37 (43%; 19%) 4/30 (13%; 7%) 55/316 (17%; 9%) 19/68 (28%; 14%)

3/54 (6%; 2%) 12/69 (17%; 6%) 16/120 (13%; 6%) 4/50 (8%; 4%) 55/625 (9%; 4%) 19/163 (12%; 6%)

Knee studies

PAVELKA (54) REGINSTER (69) DOXY (120) GAIT (50) KOSTAR (625) STOPP (163)

156/3 156/3 120/2.31 104/2 104/2 104/2

Progression defined as change JSW >0.5 mm by study end. DOXY, Doxycycline trial; ECHODIAH, Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip; ERADIAS, Evaluation of the structure-modifying effect of Avocado-Soybean Unsaponifiables (ASU) in Hip OA; GAIT, Glucosamine/Chondroitin Arthritis Intervention Trial (of glucosamine and/or chondroitin sulfate); KOSTAR, Knee OA Structural ARthritis study (of Resedronate); PAVELKA, first author of cited publication; REGINSTER, first author of cited publication; STOPP, The Study on Osteoarthritis Progression Prevention (chondroitins 4 and 6 sulfate). Data derived from Manno RL, Bingham CO 3rd, Paternotte S, et al. OARSI-OMERACT initiative: defining thresholds for symptomatic severity and structural changes in disease modifying osteoarthritis drug (DMOAD) clinical trials. Osteoarthritis Cartilage. 2012;20:93–101. a

also vary by joint type as suggested for rates of progression35 and rates of joint replacement38 for different joint sites. Polymorphisms of several genes encoding growth factors, TGFβ1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), and GDF5 (growth differentiation factor 5) increase susceptibility to osteoarthritis,39,40 underscoring the importance

of endogenous cartilage maintenance and repair of synovial joints in OA development. Further longitudinal studies are needed to provide more precise estimates of progression for each stage of disease and to understand how these rates may differ by patient subsets, joint type, and risk factors. A better understanding of these differences could enhance our ability to identify at-risk joints early in the disease development stage and avoid the risk of overtreatment in future. The paradigm of joint injury in humans would seem to be the best place to start to gain such information.

TRIGGERING MECHANISMS As proposed for other diseases,41 the action of additional potentiating “triggering” mechanisms in the presence of preclinical disease also impacts progression to events, namely progression to preradiographic and radiographic OA. Given the waxing and waning of symptoms, there is every reason to believe that disease progression undergoes nonlinear or phasic progression; this has been supported by the observation that metabolic disturbances in cartilage turnover, reflected by serum COMP concentrations, are phasic and elevated during periods of knee radiographic OA progression.42 Molecular differences between the cartilage at different joint sites37,43 and the generation of specific neoepitopes from joint tissue with metabolic disturbances suggest that biomarkers might be developed in the future that reflect disease activity of specific joint types or even of OA specifically. Taken together, biomarkers indicative of joint tissue metabolism could constitute a means of detecting the preclinical molecular stages of OA in advance of preradiographic OA and assess the impact of specific triggering events. With the recent recognition of a definite and central role for innate immunity in OA, it is now possible to develop a holistic understanding of the pathogenesis of the disease process. From its inception, OA is an active biologic disease process, not just a process of mechanical attrition, involving mechanical insults that activate mechanosensors to induce cellular responses to altered mechanical load, including the induction and activation of specific matrix-degrading enzymes44; this propagates inflammation through the generation of molecular fragments that act as DAMPs to activate the innate immune response (Fig. 189.3)—a major biologic transducer of disease progression. Fig. 189.3 shows the interaction of inciting mechanical insults and environmental factors, the potentiation by risk factors and genetics, and the resulting activation of an innate immune response and impaired wound healing45 in the context of varying innate anabolic capacity of cartilage,10 leading to three possible outcomes, full reversal of OA pathogenesis to a no OA state, arrested OA pathogenesis, or a chronic disease process culminating in preclinical OA progressing to preradiographic and/ or radiographic OA. Given this newly emerging understanding of OA disease pathogenesis, it is intriguing to speculate that a robust innate immune response would be protective for infectious disease, particularly in a preantibiotic era, but deleterious for potentiating age-related chronic diseases in our current postantibiotic era characterized by increasing longevity. There are in fact hints that the latter is true based on studies showing that low innate production of cytokines upon ex vivo stimulation of blood with lipopolysaccharide is associated with a lower risk of OA and the absence of OA in old age.46,47 Conversely, a robust repair response would be expected to protect from OA and prevent OA progression along the stages of disease (see Fig. 189.3).

TREATMENT PARADIGMS Osteoarthritis is a slow, insidious, and debilitating process that, similar to other prominent chronic diseases, is likely more amenable to remission early in the disease process. Maintenance of cartilage homeostasis would be expected to halt progression of disease. A tipping of the homeostatic balance in favor of anabolism over catabolism would be expected to reverse disease. As noted by Luyten et al.,48 inactivation of inflammation and joint destruction would be sufficient in some patients at a very early disease stage; however, additional therapies targeting tissue restoration through cell proliferation and differentiation might be needed to achieve the ultimate goal of complete recovery of structural joint integrity. The pattern of biomarker alterations observed after joint injury matches the pattern of cartilage components released from cartilage stimulated in vitro with proinflammatory cytokines.49,50 Many treatments exist for in vitro cartilage injury, suggesting potential benefit. These biomarker observations provide great hope that disease-modifying therapies are within reach for early preclinical OA when it can be diagnosed reliably because there are already many pharmacologic agents with chondroprotective effects in vitro and in vivo joint injury in animal models and emerging in humans.51–55

CHAPTER 189  Preclinical and early osteoarthritis

POTENTIAL BENEFITS TO AN EARLY DIAGNOSIS OF OSTEOARTHRITIS Annual medical expenditures in the United States attributable to OA are estimated to be as high as $185.5 billion, or 19% of the aggregate medical expenditures for the U.S. adult population.56,57 It is generally agreed that the prospect for early diagnosis and intervention in OA would improve the likelihood of disease modification and thereby reduce medical costs, morbidity, and disability. In this regard, OA fits the description provided by Machiavelli more than 500 years ago: “In the beginning of the malady it is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”58 A precedent for improved outcomes with early identification and early treatment now exists for rheumatoid arthritis.59,60 This paradigm should inform the approach to the diagnosis and treatment of patients with OA.

SUMMARY There is general agreement that early stages of OA would be more amenable to modification, including halting or slowing the disease process to prevent recalcitrant, disabling, and more costly late stages of the disease. Consensus, however, is needed around a new paradigm of OA that conceives of a pathologic continuum beginning with a preclinical stage; such a conception is the norm for other chronic diseases.61 This would require a reclassification of the disease from a purely radiographic entity to a disease process with preclinical (characterized by serologic abnormalities such as cartilage extracellular matrix component elevations in body fluids), preradiographic, and radiographic stages. Just as not all radiographic OA progresses, it is likely that not all preclinical or preradiographic OA progresses to later stages. To gain this information, more studies are needed to discern and monitor the disease process from its incipient to its end stages. The scenario of acute joint injury, with a known date of onset, provides a potential gateway to understanding the preclinical stages of OA and offers the most promising context in which to elucidate the continuum of pathologic stages of this joint disorder. Ultimately, it will be important to establish the temporal relationship between changes in imaging markers and symptom onset and the molecular events that predate these manifestations of disease to achieve the goal of ultimately preventing and curing OA.

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The complement system is activated in synovial fluid from subjects with knee injury and from patients with osteoarthritis. Arthritis research & therapy. 2016;18(1):223. 18. Orlowsky EW, Kraus VB. The role of innate immunity in osteoarthritis: when our first line of defense goes on the offensive. J Rheumatol. 2015;42(3):363–371. 19. Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. 2018;18(4):e27. 20. Atukorala I, Kwoh CK, Guermazi A, et al. Synovitis in knee osteoarthritis: a precursor of disease? Ann Rheum Dis. 2016;75(2):390–395. 21. Blumenfeld O, Williams FM, Hart DJ, Spector TD, Arden N, Livshits G. Association between cartilage and bone biomarkers and incidence of radiographic knee osteoarthritis (RKOA) in UK females: a prospective study. Osteoarthritis and cartilage. 2013;21(7):923–929. 22. Golightly Y, Marshall1 S, Kraus V, et al. Serum cartilage oligomeric matrix protein, hyalutonan, high-sensitivity C-reactive protein and keratan sulfate as predictors of incident radiographic knee osteoarthritis: differences by chronic knee symptoms. Osteoarthritis & Cartilage. 2010;18(Supplement 2):S62–S63. 23. Kelman A, Lui L, Yao W, Krumme A, Nevitt M, Lane NE. Association of higher levels of serum cartilage oligomeric matrix protein and N-telopeptide crosslinks with the development of radiographic hip osteoarthritis in elderly women. Arthritis and rheumatism. 2006;54(1):236–243. 24. Chaganti RK, Kelman A, Lui L, et al. Change in serum measurements of cartilage oligomeric matrix protein and association with the development and worsening of radiographic hip osteoarthritis. Osteoarthritis and cartilage. 2008;16(5):566–571. 25. Dragomir A, Jordan J, Arab L, et al. Serum cartilage oligomeric matrix protein (COMP) levels and current hormone replacement therapy (HRT) in postmenopausal African-American and Caucasian women. Arthritis Rheumatism. 2002;46(Suppl 9). 26. Ling SM, Patel DD, Garnero P, et al. Serum protein signatures detect early radiographic osteoarthritis. Osteoarthritis and cartilage. 2009;17(1):43–48. 27. van Valburg AA, Wenting MJ, Beekman B, Te Koppele JM, Lafeber FP, Bijlsma JW. Degenerated human articular cartilage at autopsy represents preclinical osteoarthritic cartilage: comparison with clinically defined osteoarthritic cartilage. J Rheumatol. 1997;24(2):358–364. 28. Thorstensson CA, Andersson ML, Jonsson H, Saxne T, Petersson IF. Natural course of knee osteoarthritis in middle-aged subjects with knee pain: 12-year follow-up using clinical and radiographic criteria. Ann Rheum Dis. 2009;68(12):1890–1893. 29. Peat G, Thomas E, Duncan R, Wood L. Is a “false-positive” clinical diagnosis of knee osteoarthritis just the early diagnosis of pre-radiographic disease? Arthritis care & research. 2010;62(10):1502–1506. 30. Zengini E, Finan C, Wilkinson JM. The genetic epidemiological landscape of hip and knee osteoarthritis: where are we now and where are we going? J Rheumatol. 2016;43(2):260–266. 31. Garriga C, Sanchez-Santos MT, Judge A, et al. Predicting incident radiographic knee osteoarthritis in middle-aged women within four years: the importance of knee-level prognostic factors. Arthritis care & research. 2020;72(1):88–97. 32. Harkey MS, Davis JE, Lu B, et al. Early pre-radiographic structural pathology precedes the onset of accelerated knee osteoarthritis. BMC Musculoskelet Disord. 2019;20(1):241. 33. Mobasheri A, van Spil WE, Budd E, et al. Molecular taxonomy of osteoarthritis for patient stratification, disease management and drug development: biochemical markers associated with emerging clinical phenotypes and molecular endotypes. Curr Opin Rheumatol. 2019;31(1):80–89. 34. Lories RJ, Luyten FP. The bone-cartilage unit in osteoarthritis. Nat Rev Rheumatol. 2011;7(1):43–49. 35. Manno RL, Bingham 3rd CO, Paternotte S, et al. OARSI-OMERACT initiative: defining thresholds for symptomatic severity and structural changes in disease modifying osteoarthritis drug (DMOAD) clinical trials. Osteoarthritis Cartilage. 2012;20(2):93–101. 36. Emrani PS, Katz JN, Kessler CL, et al. Joint space narrowing and Kellgren-Lawrence progression in knee osteoarthritis: an analytic literature synthesis. Osteoarthritis Cartilage. 2008;16(8):873–882. 37. Hsueh MF, Onnerfjord P, Bolognesi MP, Easley ME, Kraus VB. Analysis of “old” proteins unmasks dynamic gradient of cartilage turnover in human limbs. Sci Adv. 2019;5(10):eaax3203. 38. Bager CL, Karsdal M, Bihlet A, Thudium C, Byrjalsen I, Bay-Jensen AC. Incidence of total hip and total knee replacements from the prospective epidemiologic risk factor study: considerations for event driven clinical trial design. BMC Musculoskelet Disord. 2019;20(1):303. 39. Zhang R, Yao J, Xu P, et al. A comprehensive meta-analysis of association between genetic variants of GDF5 and osteoarthritis of the knee, hip and hand. Inflamm Res. 2015;64(6):405–414. 40. Tachmazidou I, Hatzikotoulas K, Southam L, et al. Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019;51(2):230–236. 41. Devereux RB, Alderman MH. Role of preclinical cardiovascular disease in the evolution from risk factor exposure to development of morbid events. Circulation. 1993;88(4 Pt 1):1444–1455.

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42. Sharif M, Kirwan JR, Elson CJ, Granell R, Clarke S. Suggestion of nonlinear or phasic progression of knee osteoarthritis based on measurements of serum cartilage oligomeric matrix protein levels over five years. Arthritis and rheumatism. 2004;50(8):2479–2488. 43. Onnerfjord P, Khabut A, Reinholt FP, Svensson O, Heinegard D. Quantitative proteomic analysis of eight cartilaginous tissues reveals characteristic differences as well as similarities between subgroups. The Journal of biological chemistry. 2012;287(23):18913–18924. 44. Vincent TL. Targeting mechanotransduction pathways in osteoarthritis: a focus on the pericellular matrix. Curr Opin Pharmacol. 2013;13(3):449–454. 45. Scanzello CR, Plaas A, Crow MK. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Curr Opin Rheumatol. 2008;20(5):565–572. 46. Riyazi N, Slagboom E, de Craen AJ, et al. Association of the risk of osteoarthritis with high innate production of interleukin-1beta and low innate production of interleukin-10 ex vivo, upon lipopolysaccharide stimulation. Arthritis and rheumatism. 2005;52(5):1443–1450. 47. Goekoop RJ, Kloppenburg M, Kroon HM, et al. Low innate production of interleukin-1beta and interleukin-6 is associated with the absence of osteoarthritis in old age. Osteoarthritis and cartilage. 2010;18(7):942–947. 48. Luyten FP, Lories RJ, Verschueren P, de Vlam K, Westhovens R. Contemporary concepts of inflammation, damage and repair in rheumatic diseases. Best Pract Res Clin Rheumatol. 2006;20(5):829–848. 49. Catterall JB, Stabler TV, Flannery CR, Kraus VB. Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254). Arthritis Res Ther. 2010;12(6):R229. 50. Kraus V, Hsueh M-F. Biomarkers and Osteoarthritis. In: Ginsburg G, Willard H, Tsalik E, Woods C, eds. Genomic and Precision Medicine. Vol Infectious and Inflammatory Diseases. 3rd ed. : Elsevier; 2020:429–444. 51. Lotz MK, Kraus VB. New developments in osteoarthritis. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Res Ther. 2010;12(3):211.

52. Kraus VB, Birmingham J, Stabler TV, et al. Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: a randomized controlled pilot trial (NCT00332254). Osteoarthritis Cartilage. 2012;20(4):271–278. 53. Olson SA, Furman BD, Kraus VB, Huebner JL, Guilak F. Therapeutic opportunities to prevent post-traumatic arthritis: lessons from the natural history of arthritis after articular fracture. J Orthop Res. 2015;33(9):1266–1277. 54. Lattermann C, Jacobs CA, Proffitt Bunnell M, et al. A multicenter study of early anti-inflammatory treatment in patients with acute anterior cruciate ligament tear. Am J Sports Med. 2017;45(2):325–333. 55. Zhang W, Robertson WB, Zhao J, Chen W, Xu J. Emerging trend in the pharmacotherapy of osteoarthritis. Frontiers in endocrinology. 2019;10:431. 56. Kotlarz H, Gunnarsson CL, Fang H, Rizzo JA. Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data. Arthritis Rheum. 2009;60(12):3546–3553. 57. Murphy LB, Helmick CG, Cisternas MG, Yelin EH. Estimating medical costs attributable to osteoarthritis in the US population: comment on the article by Kotlarz et al. Arthritis Rheum. 2010;62(8):2566–2567. author reply 2567-2568. 58. Machiavelli N. The prince: concerning mixed principalities. 2010:1505. Constitution Society. http://www.constitution.org/mac/prince00.htm. 59. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580–1588. 60. Dale J, Porter D. Pharmacotherapy: concepts of pathogenesis and emerging treatments. Optimising the strategy of care in early rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2010;24(4):443–455. 61. Kraus V. Waiting for action on the osteoarthritis front. Current Drug Targets. 2010;11(4):1–2.

Management of osteoarthritis Sharon L. Kolasinski • Margreet Kloppenburg

Key Points n Osteoarthritis (OA) is the most common form of arthritis, and pain is its most common symptom. n The aims of treatment are to reduce pain, improve health-related quality of life, maximize activity, and optimize participation. n Management of OA should be tailored to the individual based on shared decision making between the patient and their health care provider(s), considering patient preferences and values, the disease phenotype, and comorbid medical conditions. n Management of OA requires a combination of multiple modalities that can include psychosocial, physical, occupational, and pharmacologic therapies, as well as surgical interventions. n Patient education and exercise are the cornerstones of successful management of all patients with OA. n Oral and topical pharmacologic therapies can be effective in relieving pain due to OA. n Intraarticular glucocorticoids are useful in the symptomatic treatment of OA in some joints. n Intraarticular hyaluronate products remain controversial in the symptomatic treatment of OA. n Surgical interventions are an option for some patients whose disease fails to respond to nonsurgical interventions.

INTRODUCTION Osteoarthritis (OA) is a condition that affects all components of the joint, including articular cartilage, subchondral bone, synovium, tendons, and muscles (Chapter 185) and has numerous presentations (Chapter 183). The diagnosis of OA should be made by history and physical examination and confirmed by conventional radiographic imaging if necessary. Alternative diagnoses should be excluded with appropriate laboratory tests and imaging. Monoarticular, oligoarticular, and polyarticular involvement may or may not be evident on physical and/or radiographic examination (Chapter 187) at the time of symptom onset (Chapter 188). Nonetheless, a treatment plan can be formulated to address symptoms even early in the course of osteoarthritis. The progression of disease varies among individuals regarding pace, severity, and the number of joints involved. Treatment, too, will vary based on these phenotypic features, as well as patient preferences and values. In addition, each patient should be assessed for the presence of medical comorbidities, such as hypertension and cardiovascular disease including heart failure, gastrointestinal (GI) bleeding risk, and chronic kidney disease that might have an impact on the ability to participate in exercise, and on the risk for side effects from certain pharmacologic agents. Consideration should be given to a history of injuries or surgical procedures, as well as access to and availability of treatment options, for instance, within a reasonable geographic area. The treatment approach summarized in this chapter is informed by recommendations for management published by the American College of Rheumatology (ACR) in 2020,1 the Osteoarthritis Research Society International (OARSI) in 2019,2 and the European League Against Rheumatism (EULAR) in 2018.3 Additional guidelines were issued by the National Institute for Clinical Excellence (NICE) in 20144 and the American Academy of Orthopaedic Surgeons (AAOS) in 2013.5

CORE PRINCIPLES IN OSTEOARTHRITIS MANAGEMENT EDUCATION There is universal agreement among national and international guidelines across subspecialties that, once the diagnosis of OA has been made, clinicians should provide all patients with education about the disease, its nature and course, as well as on self-management and treatment options.1–5 A range of practitioners, including those in family medicine, internal medicine,

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rheumatology, orthopedic and plastic surgery, rehabilitation medicine, and physical and occupational therapy, may be involved in these educational efforts at various points in the course of the disease.6,7 The educational process should include a discussion of the goals of therapy, namely, the control of symptoms, particularly pain, and optimization and maintenance of physical function so that patients can maximize quality of life, activity, and participation. Management aims not merely for a patient-acceptable state, but one that also includes training in ergonomic principles and pacing of activities. Education is an ongoing process and requires reinforcement and expansion at various points in treatment as the patient’s needs evolve. In addition to one-on-one discussions with providers, evidence supports the delivery of educational content in self-efficacy and self-management programs for lower extremity OA, but not for hand OA. These programs use multidisciplinary group–based formats combining sessions on skill-building (goal setting, problem-solving, positive thinking), education about the disease and about medication effects and side effects, joint protection measures, and fitness and exercise goals and approaches.8 Health educators, fitness instructors, nurses, physical therapists, occupational therapists, physicians, and patient peers may lead in person or online sessions.

EXERCISE An ever-increasing literature supports the use of exercise in the management of OA in virtually all affected patients, regardless of the location of involved joints.9,10 An exercise program can reduce pain, increase or maintain range of joint motion, increase or maintain muscular strength, improve mobility and participation in activities, and reduce functional limitations. The introduction to exercise as an appropriate therapeutic intervention for OA will often come as a result of a prescription for physical and/or occupational therapy. There have been numerous randomized controlled trials and systematic reviews of trials of different exercise programs in patients with hip and knee OA. These studies conclude that programs of exercise therapy are able to decrease pain and improve functional capacity in patients with OA. The broad menu of exercise options includes range of motion exercises,11 stretching exercises, aerobic activities (walking, stationary or outdoor biking),12 strength training (exercise bands, free weights, weight machines),13 balance training,14 neuromuscular exercise,7 aquatic exercise,15 yoga,16 and tai chi.17 The quantity of studies for each exercise type varies depending on the location of OA and the type of exercise evaluated, and the quality of studies ranges from low to high. For any specific disease phenotype, there is generally not enough high-quality comparative literature to rank one type of exercise as superior to any other. Nonetheless, structured exercise programs can often provide the foundation of treatment for most OA patients and may include one or more forms of exercise at a given time. Exercises should be adapted according to the presence or absence of a painful episode of OA. During painful episodes, isometric exercises such as quadriceps contraction or exercises in a nonloading position (cycling, rowing with adapted tools) or in a partial nonloading position (aquatic exercises) might be proposed. During painless or less painful periods, the exercise program could include stretching and muscle performance exercises. Whatever the type of exercise prescribed, regular practice is likely to result in better outcomes, and although not well studied, many authors suggest that exercise be performed at least three times per week. Strategies to ensure long-term adherence to the exercise program should be sought in order to enhance ongoing participation.

INDIVIDUALIZED TREATMENT The variety of symptoms OA patients report is extensive, including pain, physical disability, fatigue and sleep disturbances, reduced activities and participation in society, reduced strength, embarrassment due to aesthetic damage, joint cracking and clicking, limping, and swelling. Symptoms vary between patients over time in location and severity. Moreover, patients have personal beliefs and perceptions about their disease, resulting in different 1679

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coping strategies, which influence their attitude toward different treatment options. In addition, preferences and educational and cultural backgrounds have an important impact on treatment choices. The presence of medical comorbidities and psychosocial constraints may vary as well. Thus the overall treatment program for a given patient should be arrived at by shared decision making between the health professional and the patient and individualized to the needs of the patient at that time.18 Similarly, long-term follow-up should be adapted to the patient’s individual needs.

supported the use of acupuncture for analgesia in OA and safety has not been an issue, reported benefits may arise largely from contextual effects.31 The local application of heat or cold may provide temporary reduction in symptoms,32,33 but interventions such as transcutaneous electrical nerve stimulation (TENS), iontophoresis, and pulsed vibration therapy are not recommended.

MULTIDISCIPLINARY APPROACH

TOPICAL AGENTS

As is evident from the variety of opportunities for education, exercise, and occupational interventions, a broad team of practitioners may be engaged to aid in the management of OA symptoms. Furthermore, in most patients, a single therapeutic modality may not provide an adequate clinical response. Despite the lack of adequate clinical trials establishing efficacy, multidisciplinary supervision of multimodal therapy that combines educational, behavioral, psychosocial, and physical interventions, as well as topical, oral, and intraarticular medications is commonly used for treatment of individual patients.19

Topical agents can be considered first-line therapy due to their favorable safety profile, particularly in older adults or those who have medical comorbidities that put them at increased risk of adverse effects from oral NSAIDs.34 The most widely used topical agents are preparations containing nonsteroidal antiinflammatory drugs (NSAIDs) or capsaicin, both available as over-the-counter products. Topical NSAID use is associated with small improvements in pain and function over 8 to 12 weeks in double-blind placebo-controlled trials of knee and hand OA.35 For some patients, topical NSAIDs can be as efficacious as orally administered NSAIDs and present less of a risk of GI side effects.36 Studies have also shown that patients with elevated risk of NSAID-related adverse events, particularly older patients and those with comorbidities, experienced similarly low rates of adverse events as patients at low risk of these complications, even when using topical NSAIDs for longer periods of time (up to 12 months).37,38 Capsaicin contains a substance that gives the “hot” taste to chili peppers, causes desensitization of skin nerve fibers, and may have analgesic effects through modulation of a number of neurotransmitter pathways.39 Preparations have shown small effects on pain in controlled double-blind studies of OA of the hand and knee.40,41 Patients may discontinue treatment because of local burning and stinging sensations though serious adverse events have not been reported.

BEHAVIORAL, PSYCHOSOCIAL, AND PHYSICAL INTERVENTIONS WEIGHT LOSS Weight loss is recommended for all patients with symptomatic lower limb OA who are overweight.1,2 There is evidence that weight loss of at least 5% of body weight is associated with a small but significant improvement in both pain and physical function and that long-term weight loss of 10% to 20% of body weight has substantially more clinical and mechanistic benefits than less weight loss.20 Many patients with OA who are overweight have comorbid cardiovascular and metabolic conditions such as hypertension, diabetes mellitus, and coronary artery disease.21,22 Reducing weight in overweight patients may have beneficial effects on the outcomes of these conditions, in addition to OA. It is important that individualized weight loss programs are available and that they include education and follow-up, including monitoring (health professional or self).

ORTHOSES, BRACES, AND ASSISTIVE DEVICES Orthoses and braces may improve symptoms and functioning by reducing overuse and abnormal biomechanical forces operating across the joint. The type of orthotic used is joint specific. A variety of products is available for use with symptomatic carpometacarpal joints, wrists (particularly in secondary OA in those with inflammatory arthritis), knees, ankles, and joints of the feet, but little comparative data exist on which to choose one type over another. In the knees, limited data support the use of tibiofemoral or patellofemoral bracing in some patients.23 However, high-quality evidence is lacking, and not all patients are able to tolerate the inconvenience and burden of using braces. While orthoses and braces maintain the joint in a fixed position, the use of tape across the joint is intended to permit motion while redirecting abnormal biomechanical forces. The application of tape across the knee may reduce symptoms, but since studies evaluating the use of this modality cannot be blinded, the evidence is of low quality.24 In patients with weight-bearing joint pain, appropriate use of a cane, crutch, or walker can be a helpful therapeutic intervention. A cane or single crutch should be held on the side contralateral to the affected hip or knee and be advanced with the affected limb when walking to effectively reduce load on the affected joint; the tip should be changed regularly. A useful length of a cane is the distance from the floor to the patient’s greater trochanter; this brings the elbow into 15 to 20 degrees of flexion when using the cane. Ideally, the patient should be fitted for a cane and instructed in its use by a physical therapist. The same principles of appropriate sizing and instruction in use apply to a walker.

OTHER BEHAVIORAL, PSYCHOSOCIAL, AND PHYSICAL INTERVENTIONS Cognitive behavioral therapy (CBT), particularly in conjunction with an exercise program, or mind–body interventions that include a component of exercise, such as tai chi and yoga, may be appropriate for many patients with OA. Although studies involving patients with OA are limited,25,26 a body of literature on pain due to other conditions27,28 supports the use of CBT and mind–body interventions in OA. Acupuncture has been extensively studied, but many trials have lacked adequate controls.29,30 While some work has

PHARMACOLOGIC TREATMENTS

ORAL AGENTS Nonsteroidal antiinflammatory drugs Nonsteroidal antiinflammatory drugs, including cyclooxygenase 2-selective inhibitors, are used widely for pain relief and improvement of function in OA. A detailed description of their mechanism of action and the potential GI, renal, and cardiovascular toxicity observed in clinical trials and observational studies can be found in Chapter 61. Several systematic reviews of randomized placebo-controlled clinical trials that evaluated the use of NSAIDs for OA, primarily in the knee and hip, demonstrate moderate short-term efficacy compared with placebo.1 It is recognized that NSAID use is associated with some risk of GI and cardiovascular toxicities and that a number of medical comorbidities increase the risk, including a prior history of GI bleeding, myocardial infarction, heart failure, or chronic kidney disease.42,43 In those with a history of GI symptoms, a proton pump inhibitor (PPI) may be co-prescribed.44 Due to safety concerns arising from long-term NSAID use, most authorities recommend using the lowest possible dose of NSAIDs for the shortest possible time with the recognition that, in the absence of agents that can effectively prevent or halt the progression of OA, many patients use NSAIDs over an extended period. Given the availability of numerous over-the-counter (OTC) NSAID preparations, it is important for clinicians to educate patients about restrictions on OTC products when prescription strength NSAIDs are recommended.

OTHER ORAL AGENTS Acetaminophen Acetaminophen (also known as paracetamol, N-acetyl-para-aminophenol, or APAP) has historically been recommended as the first-line pharmacologic treatment for patients with OA in mild to moderate pain and continues to be recommended by many health professionals. Acetaminophen has generally been considered a safe treatment option, but in recent years its risk–benefit profile has been debated. The most up-to-date systematic evaluations, especially in knee and hip OA, have suggested that the effect size of acetaminophen for pain relief in OA is small and may be below the level of clinical significance.45 The efficacy of acetaminophen in hand OA is still uncertain and likely small as well. Furthermore, patients’ experience with acetaminophen is known to be variable, and the majority of patients find NSAIDs to be more efficacious.46 The safety profile of acetaminophen, like NSAIDs, continues to be examined. Acetaminophen has been shown to be associated with an increased risk of liver test abnormalities, although the clinical relevance of this finding is unknown.47 That acetaminophen use could lead to serious adverse effects is supported by the observation that it is a leading cause of drug-induced liver failure and overdose-related liver

CHAPTER 190  Management of osteoarthritis transplantation in the United States.48 Acetaminophen exposure may also contribute to the risk of hypertension, cardiovascular, GI, and renal toxicity, particularly when used in conjunction with NSAIDs,49 though these conclusions from observational studies have a risk of bias due to confounding by indication.50 Acetaminophen is a common ingredient in OTC products and total daily intake can unwittingly exceed current recommendations of no more than 3000 mg/day. Since the efficacy of acetaminophen is small in many patients and acetaminophen is not free of adverse effects, it should be considered only in selected patients, such as those with contraindications to other treatments, preferably for a short duration. After decades of clinical use, it is clear that no single algorithm for use of either NSAIDs or acetaminophen fits all patients. Clinicians need to continue to educate patients on potential risks and benefits, create individualized treatment plans that may change over time, and recognize that oral medications are only one aspect of the multimodal approach often needed by those with OA.

Duloxetine Duloxetine, a dual serotonin and norepinephrine reuptake inhibitor, has been shown to be effective in relieving chronic pain in patients with knee OA.51 It can be used either alone or in combination with NSAIDs in patients with persistent pain.52

Glucosamine sulfate and chondroitin sulfate Glucosamine is an amino sugar derived from chitin, often extracted from the exoskeleton of shrimp, lobster, and crab. Chondroitin sulfate is a glycosaminoglycan that is a major constituent of cartilage. For decades, glucosamine sulfate and chondroitin sulfate, often used in combination, have been the most popular OTC products used for the treatment of OA worldwide. Pharmaceutical grade preparations of these dietary supplements have also been available in some countries. Despite their popularity, however, clinical trials have led to conflicting results regarding efficacy. Some randomized controlled trials have suggested that statistically significant but small improvements in pain may occur with use of these products, similar in magnitude to that demonstrated by NSAIDs. Others have concluded that no benefit occurs. The heterogeneity of results may arise from publication bias, industry sponsorship, quality of trial design, preparations used, and large contextual effects.1,2,53

Opioids While there has long been concern about the use of opioid analgesics for the management of noncancer chronic pain, it has become increasingly clear that the potential for devastating adverse effects far exceeds the likely benefit in most patients with knee and hip OA.54,55 Many opioid side effects may be particularly problematic in older adults who are overrepresented among those with OA. These include the risk of chemical dependency (which may occur at lower doses than in younger individuals), altered mental status (somnolence, drowsiness, cognitive impairment), balance dysregulation and increased fall risk, constipation, and respiratory depression (particularly in the setting of age-related reductions in the ventilatory response to hypercapnia and hypoxemia). The effect size of opioids in the treatment of pain due to knee and hip OA is also limited and is not superior to NSAIDs.56 Tramadol has been evaluated as a possible treatment in OA, but metaanalysis suggests little benefit and a high rate of discontinuation.57 Opioids are not an appropriate treatment for the routine management of OA. Use should be limited to those patients with persistent pain for whom the use of ongoing multimodal nondrug treatments and nonopioid analgesic and adjunctive pain medications have failed to provide adequate relief who are at low risk for substance abuse and in whom potential benefits outweigh risks.58

INTRAARTICULAR THERAPY GLUCOCORTICOIDS Intraarticular glucocorticoids are recommended in several guidelines for the management of patients with OA. The most robust evidence pertains to use in knee OA,45 but some data support the use of intraarticular glucocorticoids in the hip.59 The onset of symptomatic improvement is relatively rapid, with maximal efficacy reached in less than 1 week with reported effect sizes up to 0.63.60 As with other therapies, response to intraarticular steroid injection is variable. The presence of effusion, withdrawal of fluid from the knee, severity of disease, absence of synovitis, injection delivery under US guidance, and greater symptoms at baseline may all improve the likelihood of response though further research will be required to fully characterize predictors of response.61 The duration of response is variable but may exceed 3 months.62 Radiographic guidance (ultrasound, fluoroscopy) is recommended when injecting glucocorticoids into hip joints.63 Adverse

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events after intraarticular glucocorticoid injection are uncommon.45 A placebo-controlled trial of repeated intraarticular steroid injections given every 3 months for 2 years demonstrated no detectable side effect nor change in joint space width compared with intraarticular saline.64 A more recent trial in which patients with knee OA similarly received repeated steroid or saline injections over a 2-year period showed that the steroid injections reduced cartilage volume seen on magnetic resonance imaging but were not associated with a worsening in pain, functioning, or other radiographic features.65

HYALURONATE PREPARATIONS Viscosupplementation refers to the intraarticular injection of preparations of hyaluronic acid, a high-molecular-weight polysaccharide that is a major component of normal synovial fluid and cartilage. Many hyaluronate preparations are currently available; there are differences in molecular weight, viscosity, origin (avian or bacterial), presence or absence of cross-linkage, and number of injections in each series. While some studies have suggested a modest benefit from the use of intraarticular hyaluronate preparations, the best available evidence from high-quality trials indicates no benefit compared with saline injections.1 Adverse events include uncommon local injection site reactions and rare pseudoseptic reactions.45

SURGICAL INTERVENTIONS Surgical interventions employed in the management of knee and hip OA have included arthroscopy, osteotomy, and total joint arthroplasty. However, no clear benefit from arthroscopy has been established, and the procedure is not recommended for routine management of OA.66 Osteotomy is reserved for a subset of often younger patients with anatomic malalignment that may have resulted from developmental or posttraumatic conditions.67 In contrast, OA is the most common indication for total knee arthroplasty and total hip arthroplasty.68,69 However, only a fraction of patients with OA are eventually treated surgically. For instance, of the close to 55 million individuals with OA in the US,70 about 2.5 million have had hip replacements and 4.7 million have had knee replacements.71 Total joint arthroplasty is performed in patients with irreversible structural disease, including the destruction of joint cartilage. It is indicated for the management of severe pain and functional limitations that have been unresponsive to the range of nonoperative treatments and should not be based solely or primarily on the presence of moderate to severe radiographic findings. In daily practice, the decision to proceed with surgery should include consideration of the patient’s comorbid medical conditions and willingness to undergo the procedure and should occur only after prescription and use of nonsurgical treatment modalities, such as education, exercise, weight loss, and optimal use of analgesics. Although joint replacement has often been considered the “gold standard” treatment for OA due to its effectiveness in reducing pain and improving function, recent studies have demonstrated that up to a quarter of patients may be dissatisfied with their postoperative status.72,73 Factors associated with postoperative dissatisfaction include preoperative patient expectations, depression, pain in locations other than the joint undergoing replacement, and the presence of postoperative pain in the replaced joint.74

ISSUES SPECIFIC TO THE MANAGEMENT OF HAND OSTEOARTHRITIS Hand OA is a heterogeneous disorder in which multiple hand joints are often simultaneously involved, such as multiple interphalangeal (IP) or both first carpometacarpal (CMC) joints. The location of the affected joint (especially in the finger or thumb base) and severity of involvement (such as a high number of affected hand joints, one or two severely affected joints, or acute joint inflammation due to OA) are important considerations when deciding on a treatment approach. Optimal management requires a multidisciplinary approach.

CORE PRINCIPLES OF HAND OSTEOARTHRITIS MANAGEMENT All patients should be offered education and training in ergonomic principles and pacing of activities and on use of assistive devices, such as built-up handles, ergonomic pens, and equipment to facilitate opening bottles, cans, or jars, which can improve patient’s self-management. All patients should be considered for exercise. Hand exercises have small but beneficial effects on self-reported pain and function, joint stiffness, and grip strength.75 Exercise regimens for hand OA vary greatly among intervention trials and depend on the joint affected but usually involve both range of motion and strengthening exercises. They can usually be done at

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home. An occupational or physical therapist can provide patients with useful information on the best way to perform such exercises. The beneficial effects of exercises are not sustained when patients stop exercising. If the patient had thumb base OA, the use of orthoses or splints can be considered. Orthoses can reduce pain and, to a lesser extent, improve function when consistently used for a prolonged period of time (at least 3 months).76 A variety of orthoses are on the market and different products may be used only whenever symptoms occur, during all activities of daily living, or only during the day or at night. The type of orthosis to prescribe and the instructions for use can be a shared decision with the patient because there is no evidence available to guide these choices. It is important to pay attention to prescribing a well-fitted orthosis to improve compliance and increase its long-term use. These treatment modalities are sometimes combined in structured multidisciplinary programs or care pathways, but studies have not shown a consistent beneficial effect of these programs over simpler strategies in hand OA.

PHARMACOLOGIC TREATMENTS As for knee OA, topical NSAIDs are the first-line pharmacologic treatment for pain relief in hand OA. However, when many joints are affected, systemic treatment with oral NSAIDs might be preferred. Clinical trials in patients with hand OA showed pain relief after 2–4 weeks, with an effect size of 0.40.77 Again, like recommendations for treatment of OA in other locations, in hand OA oral NSAIDs should be prescribed at the lowest effective dose, for a limited duration. Intraarticular glucocorticoid injections are commonly used in patients with thumb base OA but can be applied to any of the hand joints. Generally, intraarticular injections are known to be associated with a large placebo effect,78 and there is no evidence from trials that glucocorticoid injections in the thumb base are more beneficial than placebo in relieving pain or improving function.76 However, some evidence exists that, in IP joints with symptomatic OA, an intraarticular glucocorticoid injection can be beneficial.76 EULAR recommends that intraarticular injections of glucocorticoids be given in specific cases where, for example, clear joint inflammation is present.3 Adverse effects are usually limited to local effects, including pain, bruising, mild skin atrophy, and hypopigmentation at the injection site. The efficacy of several immunosuppressive drugs, including conventional and biologic disease-modifying antirheumatic drugs (DMARDs), such as hydroxychloroquine,79 methotrexate,80 different tumor necrosis factor inhibitors,81,82 and anti–interleukin-1,83 has been investigated in clinical trials in patients with hand OA. However, trials have been negative, both regarding effects on symptoms and on radiographic progression. Therefore these treatment modalities are not recommended, even for severe cases of inflammatory, often erosive, hand OA. Recent data from a randomized placebo-controlled trial have shown that a short course of a low dose of oral glucocorticoids can be useful in temporarily relieving symptoms for patients with hand OA who experience a flare-up of the disease.84 Prolonged prescription of glucocorticoids, however, is discouraged due to their unfavorable safety profile.

SURGICAL INTERVENTIONS Surgery is reserved for symptomatic patients with structural abnormalities, in whom pain is not effectively managed with other treatment modalities. It is important to discuss with patients that surgery usually does not improve hand function. The surgical technique that is chosen depends mainly on the type of joint causing complaints, patient characteristics including functional demands and personal preference, and preferences of the operating surgeon. Trials with a placebo- or sham-controlled group have not been performed. The site most frequently operated on for hand OA is the first CMC joint, and trapeziectomy is generally the surgical technique of choice.85 Complications that may occur include pain, joint instability, nerve dysfunction, superficial wound infections, tendon-pulling sensation, and chronic regional pain syndrome. Arthroplasty (typically with silicone implants) is preferred for the proximal interphalangeal (PIP) joints, except the second PIP, whereas arthrodesis is preferred for the distal interphalangeal (DIP) joints and second PIP. In general, arthroplasty has the advantage of retaining some joint motion, whereas with arthrodesis, range of motion is completely lost. The disadvantages of arthroplasty, however, are that it is associated with more complications and instability compared with arthrodesis.

ACKNOWLEDGMENT The authors would like to acknowledge the contributions of Drs. Nigel K. Arden and Marc C. Hochberg, who were the authors of this chapter in the previous edition, and Dr. F.P. Kroon for assistance with the hand OA part.

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Comparative pain reduction of oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis: systematic analytic review. Osteoarthritis Cartilage. 2016;24(6):962–972. 57. Toupin April K, Bisaillon J, Welch V, et al. Tramadol for osteoarthritis. Cochrane Database Syst Rev. 2019;5(5):CD005522. 58. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain— United states, 2016. JAMA. 2016;315(15):1624–1645.

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59. McCabe PS, Maricar N, Parkes MJ, Felson DT, O’Neill TW. The efficacy of intra-ar ticular steroids in hip osteoarthritis: a systematic review. Osteoarthritis Cartilage. 2016;24(9):1509–1517. 60. Bannuru Saltychev M, Mattie R, McCormick Z, Laimi K. The magnitude and duration of the effect of intra-articular corticosteroid injections on pain severity in knee osteoarthritis: a systematic review and meta-analysis. Am J Phys Med Rehabil. 2020;99(7):617–625. 61. Maricar N, Callaghan MJ, Felson DT, O’Neill TW. Predictors of response to intra-articular steroid injections in knee osteoarthritis—a systematic review. Rheumatology (Oxford). 2013;52(6):1022–1032. 62. Saltychev M, Mattie R, McCormick Z, Laimi K. The magnitude and duration of the effect of intra-articular corticosteroid injections on pain severity in knee osteoarthritis: a systematic review and meta-analysis. Am J Phys Med Rehabil. 2020;99(7):617–625. 63. Micu MC, Bogdan GD, Fodor D. Steroid injection for hip osteoarthritis: efficacy under ultrasound guidance. Rheumatology (Oxford). 2010;49(8):1490–1494. 64. Raynauld JP, Buckland-Wright C, Ward R, et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-­ controlled trial [published correction appears in Arthritis Rheum. 2003 Nov;48(11):3300]. Arthritis Rheum. 2003;48(2):370–377. 65. McAlindon TE, LaValley MP, Harvey WF, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA. 2017;317(19):1967–1975. 66. Katz JN, Brownlee SA, Jones MH. The role of arthroscopy in the management of knee osteoarthritis. Best Pract Res Clin Rheumatol. 2014;28(1):143–156. 67. Cantin O, Magnussen RA, Corbi F, Servien E, Neyret P, Lustig S. The role of high tibial osteotomy in the treatment of knee laxity: a comprehensive review. Knee Surg Sports Traumatol Arthrosc. 2015;23(10):3026–3037. 68. Mahomed NN, Barrett J, Katz JN, Baron JA, Wright J, Losina E. Epidemiology of total knee replacement in the United States medicare population. J Bone Joint Surg Am. 2005;87(6):1222–1228. 69. Van Manen MD, Nace J, Mont MA. Management of primary knee osteoarthritis and indications for total knee arthroplasty for general practitioners. J Am Osteopath Assoc. 2012;112(11):709–715. 70. https://www.cdc.gov/arthritis/data_statistics/national-statistics.html. 71. Maradit Kremers H, Larson DR, Crowson CS, et al. Prevalence of total hip and knee replacement in the United States. J Bone Joint Surg Am. 2015;97(17):1386–1397. 72. Beswick AD, Wylde V, Gooberman-Hill R, Blom A, Dieppe P. What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open. 2012;2(1):e000435. 73. Gibon E, Goodman MJ, Goodman SB. Patient satisfaction after total knee arthroplasty: a realistic or imaginary goal? Orthop Clin North Am. 2017;48(4):421–431. 74. Scott CE, Howie CR, MacDonald D, Biant LC. Predicting dissatisfaction following total knee replacement: a prospective study of 1217 patients. J Bone Joint Surg Br. 2010;92(9):1253–1258. 75. Østerås N, Kjeken I, Smedslund G, et al. Exercise for hand osteoarthritis. Cochrane Database Syst Rev. 2017;1(1):CD010388. 76. Kroon FPB, Carmona L, Schoones JW, Kloppenburg M. Efficacy and safety of non-pharmacological, pharmacological and surgical treatment for hand osteoarthritis: a systematic literature review informing the 2018 update of the EULAR recommendations for the management of hand osteoarthritis. RMD Open. 2018;4(2):e000734. 77. Zhang W, Doherty M, Leeb BF, et al. EULAR evidence based recommendations for the management of hand osteoarthritis: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2007;66(3):377–388. 78. Bannuru RR, McAlindon TE, Sullivan MC, Wong JB, Kent DM, Schmid CH. Effectiveness and implications of alternative placebo treatments: a systematic review and network meta-analysis of osteoarthritis trials. Ann Intern Med. 2015;163(5):365–372. 79. Lee W, Ruijgrok L, Boxma-de Klerk B, et al. Efficacy of hydroxychloroquine in hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res (Hoboken). 2018;70(9):1320–1325. 80. Ferrero S, Wittoek R, Allado E, et al. Methotrexate in patients with hand erosive osteoarthritis refractory to usual treatments: a randomized, double-blind, placebo-controlled trial [abstract]. Arthritis Rheumatol. 2019;71(suppl 10). 81. Kloppenburg M, Ramonda R, Bobacz K, et al. Etanercept in patients with inflammatory hand osteoarthritis (EHOA): a multicentre, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2018;77(12):1757–1764. 82. Aitken D, Laslett LL, Pan F, et al. A randomised double-blind placebo-controlled crossover trial of HUMira (adalimumab) for erosive hand OsteoaRthritis—the HUMOR trial. Osteoarthritis Cartilage. 2018;26(7):880–887. 83. Kloppenburg M, Peterfy C, Haugen IK, et al. Phase IIa, placebo-controlled, randomised study of lutikizumab, an anti-interleukin-1α and anti-interleukin-1β dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis. Ann Rheum Dis. 2019;78(3):413–420. 84. Kroon FPB, Kortekaas MC, Boonen A, et al. Results of a 6-week treatment with 10 mg prednisolone in patients with hand osteoarthritis (HOPE): a double-blind, randomised, placebo-controlled trial. Lancet. 2019;394(10213):1993–2001. 85. Wajon A, Vinycomb T, Carr E, Edmunds I, Ada L. Surgery for thumb (trapeziometacarpal joint) osteoarthritis. Cochrane Database Syst Rev. 2015;2015(2):CD004631.

191

Emerging treatments for osteoarthritis Francis Berenbaum

Key Points n Therapeutic innovation in the field of osteoarthritis includes both symptomatic (aimed at relieving pain and improving joint function) and structure-modifying treatments (aimed at slowing down joint deterioration). n An analysis of the therapies currently under development shows that the intraarticular route is generally favored, even if the systemic route is still being studied with a few compounds. n Cell therapy, in particular with the use of stem cells, is attracting great interest in view of the number of clinical studies under way and their already wide use in practice. However, they should still be considered today as exploratory avenues as long as there is no evidence of their superiority over placebo.

Osteoarthritis (OA) is the most common disabling disease in adults over 50 years of age.1 The burden of this disease has increased considerably in recent years and is now in 10th place, up from 13th place 5 years ago.1,2 Moreover, patients with knee/hip OA have a 55% excess all-cause mortality compared with the general population mainly due to cardiovascular disease caused by OA-related reduced physical activity.3 The lack of curative treatment and the low effectiveness of symptomatic treatments largely explain these figures, which will dramatically increase due to the aging population and the global epidemic of obesity if effective therapeutic solutions are not found quickly. Fortunately, a number of academic laboratories and pharmaceutical companies are now taking up the challenge to search for new molecules that target pathways considered to be involved in the pathologic process of this disease. The purpose of this chapter is to take stock of these avenues being explored. Some of them are already sufficiently advanced to be studied in humans, and we will be particularly interested in those that are the most advanced in their development and therefore the most promising. We will distinguish between symptomatic emerging treatments and disease-modifying OA drugs (DMOADs). Nevertheless, it should be noted that this boundary is not always obvious. For example, if we consider that inflammation, a classic pathway involved in pain, is part of the structural pathologic process, then an antiinflammatory treatment could in theory act rapidly on pain and also slow the progression of OA. Thus it could be considered both symptomatic and structure-targeted treatments. This would be the case, for example, for drugs targeting cytokines or their signaling pathways. Similarly, it is not impossible that a disease-modifying treatment could have a symptomatic effect in the medium or long term due to a delay in joint degradation. Although there is no strict correlation between structural progression and symptom severity, it is hoped that an effective DMOAD will delay total joint replacement because of eventually reducing pain and improving function. In this chapter, the term symptomatic emergent treatment will therefore refer to molecules whose main, or even sole, objective is to act on symptoms without signals that might suggest that they would also have a DMOAD effect. This is the case for molecules specifically targeting pain pathways. The term DMOAD will include any treatment in which some (or even all) of their properties suggest that they could delay disease progression. This is of course the case of all molecules that target enzymes that degrade the cartilage matrix or that increase the anabolism of this matrix. But molecules regulating the metabolism of subchondral bone, molecules targeting pathways involved in inflammation and innate immunity within the synovial tissue, as well as cellular therapies with regenerative potential and/or immunomodulatory secretory potential can be included in this category too. For didactic reasons, we will thus separate the subchapters. Nevertheless, the separation is sometimes not so clear in practice, as molecules can in theory have effects on both cartilage and bone, or even effects on both matrices and inflammatory pathways.

EMERGING SYMPTOMATIC TREATMENTS (FIG. 191.1) DRUGS TARGETING THE NERVE GROWTH FACTOR PATHWAY Nerve growth factor (NGF) is a neurotrophic mediator discovered in 1950 that can promote the growth and survival of peripheral sensory and sympathetic nerve cells in mammals.4 This neuropeptide can also amplify nociceptive pain 1684

by increasing the synthesis and sensitization of neurons to several neurotransmitters involved in pain such as substance P or calcitonin gene-regulated peptide. Once activated, peripheral tissues produce and release NGF, which will exert its effects either directly on sensitive neurons via receptors (TrkA and p75NTR) present on their surface, activating a number of signaling pathways, or indirectly by activating mast cells. A distinction is made between anti-NGF antibodies and pharmacologic inhibitors of TrkA receptor.

Anti-NGF antibodies The first human studies of the use of a systemically injected antibody to NGF for the treatment of OA pain date back to 2005 with tanezumab, a human immunoglobulin G2 (IgG2) antibody raised against NGF. A proof-of-concept phase 2, randomized, placebo-controlled nonsteroidal antiinflammatory drug (NSAID) study whose primary endpoint was WOMAC pain at 16 weeks, in 450 patients with knee OA, found a dramatic effect of tanezumab (administered at baseline and week 8 at a dose of 10, 25, 50, 100, or 200 μg per kilogram of body weight intravenously) compared to the NSAID control.5 Several companies then embarked on the adventure of developing an anti-NGF for knee and hip OA including Regeneron, Amgen, AstraZeneca, Abbott, Johnson & Johnson, and Janssen. But in 2010 the development programs of anti-NGFs were interrupted by the FDA because of the discovery of more frequent serious joint adverse events in the groups treated with an anti-NGF than in the control groups. These events proved to be mostly rapid progressive OA or, more rarely, osteonecrosis.6 A mitigation plan was then applied, allowing the authorization to resume clinical trials 2 years later. This plan included the prohibition to co-prescribing NSAID on a chronic manner, to reduce dosages, to exclude patients who have already had osteonecrosis. However, in 2012, the development program was again halted by U.S. Food and Drug Administration (FDA) due to adverse changes in the sympathetic nervous system of mature animals, with the FDA requesting additional information. Finally, FDA agreed in 2015 to lift the partial clinical hold on the tanezumab development program after a review of a robust body of nonclinical data characterizing the sympathetic nervous system response to tanezumab. As of today, there are only two anti-NGF antibodies in development, tanezumab (Pfizer and Eli Lilly) and fasinumab (Regeneron and Teva).

Tanezumab Pfizer and Eli Lilly took advantage of these interruption periods to develop a subcutaneous form of their antibody. Thus whereas prior to 2010 published trials concerned only intravenous treatments, from 2015 onwards, the subcutaneous route will be preferred. An initial US pivotal study evaluated the efficacy and safety of subcutaneous administration of tanezumab 2.5 mg on day 1 and at week 8 (n = 231), tanezumab 2.5 mg on day 1 and 5 mg at week 8 (n = 233), and placebo.7 From the start of the study to the end of the 16-week period, mean WOMAC pain scores decreased from 7.1 to 3.6 in the group receiving 2.5 mg tanezumab, from 7.3 to 3.6 in the group receiving 2.5/5 mg tanezumab, and from 7.3 to 4.4 in the placebo group (differences: −0.60 [−1.07 to −0.13; P = 0.01] for tanezumab 2.5 mg, and −0.73 [−1.20 to −0.26; P = 0.002] for tanezumab 2.5/5 mg). Mean scores for WOMAC physical function and PGA-OA were also statistically significantly decreased. Rapidly progressive OA occurred only in patients treated with tanezumab (2.5 mg: n = 5.2%; 2.5/5 mg: n = 1.4%). The incidence of total joint replacements was 8 (3.5%), 16 (6.9%), and 4 (1.7%) in the tanezumab (2.5 mg), tanezumab (2.5/5 mg), and placebo groups, respectively. A European and Japanese pivotal study compared two doses of tanezumab (2.5 and 5 mg subcutaneously every 8 weeks) to placebo for 24 weeks followed by a 24-week safety monitoring period.8 The primary endpoint was a composite endpoint containing WOMAC pain, WOMAC function, and PGA at 24 weeks. Eight hundred and forty-nine patients were randomized and evaluated (placebo n = 282, tanezumab 2.5 mg n = 283, tanezumab 5 mg n = 284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (0.62 ± 0.18, p = 0.0006), WOMAC Physical Function (−0.71 ± 0.17,

CHAPTER 191  Emerging treatments for osteoarthritis

1685

INNOVATIVE PHARMACOLOGIC THERAPIES IN 2022

FIG. 191.1  Landscape of innovative pharmacologic therapies in 2020. Crossed circle or crossed triangle: drug development stopped. Circle or triangle with question mark: not enough information.

p < 0.0001) and PGA-OA (−0.19 ± 0.07, p = 0.0051). For tanezumab 2.5 mg, there was a statistically significant improvement in WOMAC Pain and Physical Function but not PGA-OA. With regard to tolerability, rapidly progressive OA was observed in 1.4% (4/283) and 2.8% (8/284) of patients in the tanezumab 2.5 mg and tanezumab 5 mg groups, respectively, and none receiving placebo. Total joint replacements (TJRs) were similarly distributed across all three treatment groups (6.7%–7.8%). Tanezumab-treated patients experienced more paraesthesia (5 mg) and hypoesthesia (both doses) than placebo. A randomized controlled study evaluated the long-term efficacy and safety (80 weeks total observation) of using tanezumab 2.5 and 5 mg subcutaneously every 8 weeks versus an NSAID in moderate to severe OA of the hip or knee.9 The tanezumab 5 mg treatment group achieved two of the three primary efficacy endpoints of pain and physical function at 16 weeks. With respect to safety, the rate of joint safety events in the tanezumab arms was higher than that of the NSAIDs at 80 weeks. The incidence of rapidly progressing OA, osteonecrosis and bone failure was 7.1% in the tanezumab 5 mg arm, 3.8% in the tanezumab 2.5 mg arm, and 1.5% in the NSAID group. The incidence of total prosthesis was 8.0% in the 5 mg tanezumab arm, 5.3% in the 2.5 mg tanezumab arm, and 2.6% in the NSAID arm.

Fasinumab Fasinumab is a human IgG4 antibody raised against NGF developed by Regeneron and co-developed with Teva. A randomized, double-blind, placebo-controlled phase 2 study was conducted in 421 patients with symptomatic knee OA not relieved by standard treatments.10 Fasinumab was tested at four doses (1, 3, 6, 9 mg) subcutaneously every 4 weeks for 16 weeks with follow-up for an additional 20 weeks. A statistically significant effect on both WOMAC pain and WOMAC function was observed in a non– dose-dependent manner. In contrast, 7% of fasinumab-treated patients and 1% of placebo-treated patients experienced dose-dependent development of arthropathies, with 2 occurring in patients receiving the lowest dose of fasinumab and 10 in patients receiving the highest dose; the majority (16 out of 25) occurred without any symptoms. Fasinumab is currently being studied

in another phase 3 placebo- and naproxen-controlled trial in patients with hip or knee osteoarthritis (NCT03161093). Recently, the FDA and the EMA decided not to grant marketing authorization for tanezumab, considering the unfavorable benefit-risk balance. The difficulty in identifying patients at risk of RPOA, partly due to a lack of understanding of the pathophysiology of RPOA, was a major factor in the decision. Although we have no information regarding the continuation of the fasinumab development program, it seems unlikely that it will continue.

TrkA inhibitors GZ389988A (Sanofi) is a TrkA inhibitor for intraarticular administration.11 In a randomized, double-blind, placebo-controlled trial, 104 subjects with knee OA were injected with GZ389988A or placebo. At 4 weeks, a difference in pain between groups of 7.49 (VAS 0–100) (P 71% among gout patients aged 40 years and older60 and rises progressively with increasing serum urate levels (Fig. 192.2), up to 90% among women with serum urate level >10 mg/ dL.61 Furthermore, higher adiposity (or weight gain) is strongly associated with an increased risk of both hyperuricemia and incident gout39,42,62–64; weight reduction is associated with reduced serum urate levels and the risk of gout.63,65 Finally, in the Swedish Bariatric Surgery Outcome study, gastric surgery–induced weight reduction was associated with substantially lower odds of hyperuricemia.66 Given their close pathogenetic link, patients with gout and hyperuricemia also suffer comorbidities and sequalae of the metabolic syndrome and obesity.67–71 For example, gout patients also have a high burden of CV-renalmetabolic comorbidities, including hypertension (74%), chronic kidney disease stage ≤2 (71%), obesity (53%), diabetes (26%), nephrolithiasis (24%), myocardial infarction (14%), and heart failure (11%).71 These comorbidities of gout and independent risks of cardiovascular outcomes and premature mortality72 provide a strong rationale for serious consideration of these issues when determining appropriate lifestyle approaches for gout (see Fig. 192.1).

Dietary factors Various dietary risk factors have been independently associated with the risk of incident gout. Higher meat intake (particularly red meat) and seafood intake (including fish and shellfish) are associated with an increased risk of hyperuricemia and gout30,73 (Table 192.3), probably because their high purine content raises urate levels, as demonstrated by short-term metabolic

GOUT RISK AND A HEALTHY EATING PLATE Symbols for gout risk (and hyperuricemia) Risk increase

FIG. 192.1  Impact of lifestyle factors on the risk of gout and their implications within a healthy eating plate. Directional arrows and blue font information are specific to gout and are not found in the original healthy eating plate. Upward red arrows denote an increased risk of gout, and downward green arrows denote a decreased risk. Horizontal green arrows denote no influence on the risk of gout. Dotted green arrows denote a potential effect but without prospective evidence for the outcome of gout. The references on the relation between diet and the risk of gout are listed in Table 192.3. (Adapted from http://www.hsph.harvard.edu/ nutritionsource/healthy-eating-plate/.)

Risk decrease

Drink water , tea , or coffee (with little or no sugar). Dairy/milk (1–2 servings/day). Low-fat dairy products and juice (1 small glass/day). Cherry juice Avoid sugary drinks .

Use healthy oils (e.g., olive and canola oil) for cooking, on salads, and at the table. Limit butter. Avoid trans fat.

Risk neutral

Alcohol (particularly beer and liquor) C

Vitamin C

The more veggies – and the greater the variety, the better. Potatoes and French fries don’t count.

S

FRUITS Eat plenty of fruits (sweet fruits ) of all colors.

Eat whole grains, (e.g., brown rice, whole-wheat bread, and whole-grain pasta). Limit refined grains (e.g., white rice and white bread).

VEGETABLES WHOLE GRAINS HEALTHY PROTEIN N

Choose fish , poultry, beans , nuts ; limit red meat ; avoid bacon , cold cuts , and other processed meats .

STAY ACTIVE AND WEIGHT CONTROL

SECTION 17  Crystal-Related Arthropathies

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PREVALENCE OF METABOLIC SYNDROME AMONG PATIENTS WITH GOUT AND HYPERURICEMIA

Prevalence of Metabolic Syndrome Among Paents with and without Gout in NHANES III 80

72

71

70

Prevalence (%)

60 49

50 40 30

Gout

31

27

No gout

20

Alcoholic beverages

12

10 0

20-39

40-59

≥60

Age (years)

a

Prevalence of Metabolic Syndrome According to Serum Urate Level in NHANES III 80.0

71

70.0 60

Prevalence (%)

60.0 50.0 36

40.0

62

41

19

10.0 0.0

b

10 mm Hg difference in any limb Audible murmurs or palpable thrills over large arteries Systolic or diastolic BP >95th percentile for height ESR >20 mm per first hour or CRP any value above normal (according to the local laboratory) Angiographic abnormalities of the aorta or its main branches and pulmonary arteries showing aneurysm or dilation (mandatory criterion) plus one of the five following criteria: Pulse deficit or claudication Four-limb BP discrepancy Bruits Hypertension Acute phase reactant

1. Pulse deficit or claudication

2. BP discrepancy 3. Bruits 4. Hypertension 5. Acute phase reactant

c-TA EULAR/PRINTO/PRES Ankara 2008 classification definition

CRP, C-reactive protein; CT, computed tomography; c-TA, c-Takayasu arteritis; ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; MRI, magnetic resonance imaging; PRES, Paediatric Rheumatology European Society; PRINTO, Paediatric Rheumatology International Trials Organisation. Modified from Ozen S, Pistorio A, Iusan SM, et al; Paediatric Rheumatology International Trials Organisation (PRINTO). EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis. 2010;69(5):798–806.

Appendix: Classification and Diagnostic Criteria

1907.e63

PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM Diagnostic Criteria for Primary Angiitis of the Central Nervous System (PACNS) 1. The presence of an acquired otherwise unexplained neurological or psychiatric deficit. 2. The presence of either classic angiographic or histopathological features of angiitis within the CNS. 3. No evidence of systemic vasculitis or any disorder that could cause or mimic the angiographic or pathological features of the disease. From Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore). 1988;67(1):20–39. Hajj-Ali RA, Calabrese LH. Diagnosis and classification of central nervous system vasculitis. J Autoimmun. 2014;48-49:149–52.

PERIODIC FEVER SYNDROMES Eurofever/PRINTO Classification Criteria for Hereditary Recurrent Fevers CAPS

FMF

TRAPS

MKD

Presence of a confirmatory NLRP3 genotypea and at least one among the following: Urticarial rash Red eye (conjunctivitis, episcleritis, uveitis) Neurosensorial hearing loss

Presence of confirmatory MEFV genotypea and at least one among the following: Duration of episodes 1–3 days Arthritis Chest pain Abdominal pain

Presence of confirmatory TNFRSF1A genotypea and at least one among the following: Duration of episodes ≥7 days Myalgia Migratory rash Periorbital edema Relatives affected

Presence of a confirmatory MVK genotypea and at least one among the following: Gastrointestinal symptoms Cervical lymphadenitis Aphthous stomatitis

OR Presence of not confirmatory NLRP3 genotypeb and at least two among the following: Urticarial rash Red eye (conjunctivitis, episcleritis, uveitis) Neurosensorial hearing loss

OR Presence of not confirmatory MEFV genotypec and at least two among the following: Duration of episodes 1–3 days Arthritis Chest pain Abdominal pain

OR Presence of a not confirmatory TNFRSF1A genotypeb and at least two among the following: Duration of episodes ≥7 days Myalgia Migratory rash Periorbital edema Relatives affected

A patient with (1) evidence of elevation of acute phase reactants (ESR or CRP or SAA) in correspondence to the clinical flares and (2) careful consideration of possible confounding diseases (neoplasms, infections, autoimmune conditions, other inborn errors of immunity) and a reasonable period of recurrent disease activity (at least 6 months) is classified as having hereditary recurrent fever if the criteria are met. a Pathogenic or likely pathogenic variants (heterozygous in AD diseases, homozygous or in trans [or biallelic] compound heterozygous in AR diseases). b Variant of uncertain significance (VUS). Benign and likely benign variants should be excluded. c In trans compound heterozygous for one pathogenic MEFV variants and one VUS, or biallelic VUS, or heterozygous for one pathogenic MEFV variant. See online supplementary Table 7 of original publication for glossary. AD, Autosomal dominant; AR, autosomal recessive; CAPS, cryopyrin-associated periodic syndromes; CRP, C-reactive protein; ESR, erythrocytes sedimentation rate; FMF, familial Mediterranean fever; MKD, mevalonate kinase deficiency; MVK, mevalonate kinase; PRINTO, pediatric rheumatology international trial organization; SAA, serum amyloid A; TRAPS, tumour necrosis factor receptor-associated periodic fever syndrome. Modified from Gattorno M, Hofer M, Federici S, et al. Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019.

1907.e64

Appendix: Classification and Diagnostic Criteria

Eurofever/PRINTO Clinical Classification Criteria for PFAPA and Hereditary Recurrent Fevers PFAPA

CAPS

FMF

At least seven out of eight: Presence Pharyngotonsillitis

At least two of fivea: Presence Urticarial rash

Duration of episodes, 3–6 days Cervical lymphadenitis

Cold/stress-triggered episodes Sensorineural hearing loss

At least six out of nine: Presence Eastern Mediterranean ethnicity Duration of episodes, 1–3 days Chest pain

Periodicity

Chronic aseptic meningitis

Abdominal pain

Skeletal abnormalities (epiphysial overgrowth/ frontal bossing)

Arthritis

Absence Diarrhea

Absence Aphthous stomatitis

Chest pain

Urticarial rash

Skin rash Arthritis

Maculopapular rash Painful lymph nodes

TRAPs

Score ≥5 points: Presence Fever ≥7 days (2 points) Fever 5–6 days (1 point) Migratory rash (1 point) Periorbital edema (1 point) Myalgia (1 point) Positive family history (1 point) Absence Aphthous stomatitis (1 point) Pharyngotonsillitis (1 point)

MKD At least three of six: Presence Age at onset