Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects [2 ed.] 012814551X, 9780128145517

Table of contents :
Chapter 1 - History of systemic lupus erythematosus with an emphasis on certain recent major issues
History of clinical observations
The age of dermatology
Transition of lupus erythematosus to systemic lupus erythematosus
History of laboratory investigations
Development of clinical tests
History of genetics of SLE
History of therapy in SLE with an emphasis on the use of steroids
History of classification criteria for SLE
References
Chapter 2 - The patient
Improve the interactions with your patients
Do not make your patient wait
Smile as you enter the patient’s room
Make a visible show of hand washing
Shake hands
Acknowledge and greet others in the room
Ask open-ended questions
Provide a mechanism for your patient to set the agenda
Speak in nonmedical terms
Be honest
Learn to be empathetic
Always examine your patient
End the visit with, “Do you have any other concerns or questions?”
Consulting in the hospital
Improving adherence
Disability
Patient education
The lupus secrets
References
Chapter 3 - A plea of a young patient to the lupus experts
Reference
Chapter 4 - Epidemiology
Introduction
Incidence and prevalence
Distribution according to gender
Distribution according to age
Distribution according to ethnic/racial group
Distribution around the world
Factors that affect the course of SLE
Impact of race/ethnicity
Impact of gender
Mortality and survival in SLE
References
Chapter 5 - Measuring disease activity
References
Chapter 6 - Disease development and outcome
Historical perspective
Clinical manifestations
Assessment of disease activity
Disease damage
Patient reported outcomes
Mortality
Causes of death
Treatment guidelines and quality indicators
Conclusions
References
Chapter 7 - Socioeconomic aspects of SLE
Introduction
Sociodemographic determinants of health in SLE
Gender as a construct in risk and morbidity
Race/ethnicity as a multidimensional determinant of outcomes
Age and aging
Income, poverty, and educational attainment
Healthcare access and utilization
Health literacy
Health insurance
The economic burden of SLE
Work and disability
Individual and societal costs
Conclusion
References
Chapter 8 - Biomarkers in systemic lupus erythematosus
Introduction
Biomarker definition and validation
Biomarkers for diagnosis of SLE
Cell-bound complement activation products
Interferon-α and interferon-α-inducible genes
T-cell gene expression assays
DNA methylation
Plasma thermograms
Biomarkers for measuring SLE disease activity
Cell-bound complement activation proteins
Interferon-α and interferon-α-inducible genes
B-lymphocyte stimulating factor/B-cell activating factor
MicroRNAs
Tumor necrosis factor α
CD27high plasma cells
CD44+ T cells
Biomarkers to detect specific organ involvement
Lupus nephritis biomarkers
Antibodies to complement C1q
Monocyte chemoattractant protein-1
Neutrophil gelatinase-associated lipocalin
Urinary TWEAK
MicroRNAs
Hepcidin
Urinary biomarker panels
Central nervous system biomarkers
Anti-NMDA receptor antibody
Antiribosomal P antibody
Antiphospholipid antibodies
Platelet-bound C4d
Other
Cardiovascular system biomarkers
Respiratory system biomarkers
Lupus arthritis biomarkers
Genetic susceptibility and theranostics
Conclusions
References
Chapter 9 - Overview of the pathogenesis of systemic lupus erythematosus
Genetics
Epigenetics
Gender
Environment
Immune dysregulation
Tissue damage
Conclusions
References
Chapter 10 - System lupus erythematosus and the environment
Introduction
Infectious agents, dysbiosis the microbiome, and SLE
Cigarette smoking, alcohol and SLE
Cosmetics, chemicals, and risk of SLE
Ultraviolet radiation, vitamin D, and SLE
Drugs, vaccines, and SLE
Geography, socioeconomics, and SLE
Conclusion
References
Chapter 11 - Genes and genetics in human SLE
Introduction
Transcription factors
Clearance of apoptotic cells and immune complexes
Autophagy
Type I IFN pathway
NFkB pathway
Neutrophils and NETosis
T cell signaling
B cell signaling
Genes and phenotypes
SLE risk genes as therapeutic targets
Drug repositioning and predicting clinical outcomes
Conclusions
References
Chapter 12 - Monogenic lupus
Introduction
Complement deficiency
Deficiencies in DNA damage repair and clearance
DNase1L3
DNase II
DNase III/TREX1
Abnormalities of DNA sensing
Stimulator of interferon genes (STING)
IFIH1
Other interferonopathies
Apoptosis
Fas/FasL
Cell signaling
PKCδ
Ras
STAT1
Implications for SLE as a whole
Conclusion
References
Chapter 13 - Hormones
Sex hormones
Estrogen-estrogen receptor signaling
Estrogen and the immune response
Innate immune response
Adaptive immune response
B cells
T cells
Estrogen and SLE
Other hormones
Hormone therapy
Conclusions
References
Chapter 14 - Clinical aspects of the complement system in systemic lupus erythematosus
Introduction
General comments
Historical notes
Complement testing and its interpretation
Serum levels and hemolytic activities for C4 and C3
Interpretation of C4 and C3 complement tests in SLE
Consumption versus biosynthesis
Chronically low C4 and C3: How to interpret?
When C4 and C3 are discrepant
Cryoglobulins
Cold activation
Copy-number variation (CNV)
Alternative pathway activation
New developments
Assessing a therapeutic response
Interpretation
Renal biopsy
New connections for lupus and complement
Local synthesis
Activation by local proteases
Intracellular complement activation
Exogenous coating with opsonic fragments leads to endogenous consequences
Conclusions
Lupus develops among complement deficient subjects
To treat or not to treat SLE with a complement inhibitor
Cons
Pros
Future considerations
References
Chapter 15 - T cells
Mechanisms through which T Cells promote SLE
B cell help
Proinflammatory activities
Defective regulation
Signaling and gene expression in SLE T cells
Apoptosis defects
References
Chapter 16 - B cells in SLE
Introduction
B lineage cell abnormalities in SLE indicating disturbances of B cell differentiation
Functional abnormalities of SLE B lineage cells
B cell signaling in “post-activated B cells” in SLE
Conclusions
References
Chapter 17 - Neutrophils in systemic lupus erythematosus
Introduction
Neutrophil dysfunction in SLE
NETosis in the pathogenesis of SLE
Low-density granulocytes (LDGs) in SLE
DNA methylation changes in SLE neutrophils and LDGs
Conclusion
References
Chapter 18 - The role of dendritic cells in systemic lupus erythematosus
Dendritic cell origins, subsets, and functions
Origins
Subsets/functions
Conventional/myeloid DCs
Plasmacytoid DCs
Monocyte-derived DCs (Mo-DCs)
DCs and tolerance
DCs in central tolerance
DCs in peripheral tolerance
DCs and SLE
Myeloid DCs
Number/activation status
Implication for T-cell activation
Implication for B-cells activation
pDCs
Number/activation status
Implication for T-cell activation
Implication for B-cells activation
Amplifying mechanisms promoting IFN-α secretion in SLE and activation of DCs
NK cell help
Platelet help
Neutrophil help
Overall picture of DC implication in SLE pathogenesis
References
Chapter 19 - Cytokines
Cytokines in SLE
IL-2
IL-17
IL-6
TNF
IFN-α
BAFF and APRIL
Conclusions
References
Chapter 20 - RNA/DNA sensing in SLE—Toll-like receptors and beyond
Introduction
Toll-like receptor family (TLRs)
Toll-like receptor 7 (TLR7)
TLR7 expression in SLE
TLR7 in murine lupus
TLR7 polymorphisms in SLE
Toll-like receptor 8 (TLR8)
TLR8 in murine lupus
TLR8 polymorphisms in SLE
Toll-like receptor 9 (TLR9)
TLR9 expression in SLE
TLR9 in murine lupus
TLR9 polymorphisms and copy number in SLE
Cytosolic RNA and DNA sensors
Activation of cytosolic RNA/DNA sensors
cGAS and RLRs in SLE
Conclusions
References
Chapter 21 - The role of interferons in systemic lupus erythematosus
Introduction
The interferon families
Regulation of interferon production
Interferons and the immune system
Interferons in systemic lupus erythematosus
Impact of interferons in pathogenesis and disease heterogeneity
Genetic factors
Measuring IFNs in blood
Targeting the interferon system in lupus
Conclusion
References
Chapter 22 - Fcγ receptors in autoimmunity and end-organ damage
Introduction
FcγRs structure
IgG and FcγR interactions
FcγRs and complement
Activating and inhibitory FcγR signaling
Regulation of FcγR affinity for ligand
Roles of FcγR in SLE
Maintenance of peripheral tolerance
Immune complex clearance
FcγR-mediated leukocyte recruitment
Activation of immune cell effector functions
Roles of FcγRs in lupus nephritis pathogenesis
FcγR polymorphisms and copy number variation in lupus
Future directions
References
Chapter 23 - Apoptosis, autophagy, and necrosis
Definition
Apoptosis
Pathways: intrinsic versus extrinsic
Apoptosis and SLE
NETosis, a special case of cell death
Autophagy
Autophagy and SLE
Necrosis
References
Chapter 24 - Infections in early systemic lupus erythematosus pathogenesis
Introduction
Pathogens associated with lupus autoimmunity and clinical disease
Epstein–Barr virus as a model infection in the etiology of SLE
Molecular mimicry and epitope spreading
Functional mimicry
Disruption of gene regulatory networks
Pathogen exposures that may protect against lupus autoimmunity
Conclusion
Acknowledgements
References
Chapter 25 - Microbiota influences on systemic lupus erythematosus and Sjögren’s syndrome
Introduction
Microbiota effects on the host immune system
Host effects on the microbiota
Microbiota in mouse models of SLE and pSS
Evidence for a role of the microbiota in SLE models
Antibiotic studies in TLR-sensitive models—focus on TLR4 and TLR7
Evidence for a role of the microbiota in models for Sjögren’s syndrome
Human host-microbiome studies in SLE and pSS
Mechanistic host-microbiota studies in SLE
Translocation of pathobionts
Microbial ortholog cross-reactivity in SLE
Associative microbiome studies in Sjögren’s syndrome
Conclusions/Outlook
References
Chapter 26 - Origin of autoantibodies
B cell tolerance in SLE
Altered BCR signaling in lupus
Properties of lupus autoantibodies
GC versus extrafollicular origin of autoantibodies
Role of GC
Role of extrafollicular responses
GC versus extrafollicular origin of human autoantibodies
Role of TLR signaling
TLRs in serological memory
Importance of the antigens
Intracellular accumulation nucleic acids promotes autoantibody production
How does IFN-I promote autoantibody production?
Association of autoantibodies with abnormal clearance of apoptotic cells
Phosphatidylserine (PtdSer) receptors
Role of complement proteins
References
Chapter 27 - Anti-DNA antibodies
Introduction
Cellular source of anti-DNA antibodies
Contribution of antigen selection
Triggers: chromatin and environmental exposures
Mechanisms of injury in the kidney and brain
Immune complexes and myeloid cell activation
Summary
References
Chapter 28 - Antihistone and antispliceosome antibodies
Histones are key protein components of chromatin
Anti-histone antibodies
Assays for anti-histone antibodies
Solid phase assays for anti-histone antibodies
Problems and discrepancies in measuring anti-histone antibodies
Prevalence and disease association of anti-histone and anti-nucleosome antibodies
Anti-histone in SLE
Anti-histone in drug-induced lupus
Anti-snRNP antibodies
Cellular localization and function of snRNP
Components of snRNPs
Reactivity of anti-snRNPs autoantibodies
History of detection of autoantibodies to snRNPs and potential problems
Detection of antibodies to snRNPs in clinical practice
Clinical significance of antibodies to snRNPs
Distribution and coexistence of anti-U1RNP and anti-Sm antibodies
Clinical association of anti-Sm and -U1RNP antibodies
Other anti-snRNPs antibodies
Mechanism of production
References
Chapter 29 - Immune complexes in systemic lupus erythematosus
Introduction
Basic immunochemistry of ICs
Generation of autoantibodies and ICs in SLE
IFN-α production from pDCs induced by ICs through TLRs
Vicious cycle between NETs and ICs
FcγRs and clearance of ICs
Role of FcγRs and ICs in each hematopoietic cell in SLE
Complement activation by ICs
Clearance of ICs by complement
Depositions of ICs in lupus nephritis
Detection of ICs in the tissue and serum
Treatment for SLE based on ICs
Summary
References
Chapter 30 - MicroRNA in systemic lupus erythematosus
Introduction
The biology of miRNAs
Role of miRNAs in SLE
Genetic risk factors associated with miRNAs in SLE
MiRNAs in innate immunity of SLE
MiRNAs in adaptive immunity of SLE
MiRNAs in target tissues of SLE
MiRNAs as biomarkers for SLE
MiRNAs as therapeutic targets for SLE
Conclusion
References
Chapter 31 - Metabolic control of lupus pathogenesis: central role for activation of the mechanistic target of rapamycin
Introduction
Accumulation of dysfunctional mitochondria is the source of oxidative stress in T cells
Extramitochondrial generation of oxidative stress
Oxidative stress emanates from the liver in SLE
Oxidative stress due to diminished reducing power
Biomarkers of oxidative stress reflect disease activity in SLE
Oxidative stress is a target for treatment in SLE
NAC-responsive accumulation of kynurenine is a trigger of mTOR pathway activation in SLE
Acknowledgments
References
Chapter 32 - Epigenetics
Introduction
DNA methylation in T Cells from SLE patients
Receptors and coreceptors
Cytokine and cytolysine genes
DNA hydroxymethylation
Histone modifications
Receptors and coreceptors
Cytokine genes
MicroRNAs in SLE
Molecular mechanisms of pathological epigenetic pemodeling in SLE
Transcription factors mediate epigenetic changes in SLE T cells
The extracellular signal-regulated kinase pathway and reduced DNA methylation in SLE T cells
GADD45α, AID, and MBD4 mediate reduced DNA methylation in SLE
DNA hydroxymethylation in SLE T cells
Epigenetic modification as promising targets for future treatment
Epigenetics as targets of already existing treatments
Epigenetic alterations as targets for potential future strategies in SLE therapy
Conclusions
References
Chapter 33 - What do mouse models teach us about human SLE?
Commonly used murine lupus models
Conditional knockout system of lupus models helps delineate the cell-intrinsic mechanisms of autoimmunity and lupus development
Murine lupus strains constitute excellent models for defining the genetic architecture of SLE
Mouse models help validate GWAS-identified lupus risk alleles
The contribution of antiDNA autoantibodies
The pathogenic role of leukocytes in lupus
B cells: more than just a source of autoantibodies
T cells: manifold contributions to lupus
Macrophage: the complex roles of macrophage subtypes in SLE
DCs: tipping the balance from immune tolerance towards autoimmunity
Multiple cytokines and chemokines also contribute to lupus pathogenesis
Lessons from therapeutic studies in murine lupus models
Concluding thoughts
References
Chapter 34 - Genes and genetics of murine systemic lupus erythematosus
Introduction
Mouse models of lupus used in genetic studies
Predisposing loci and genes in natural-occurring lupus models
Lupus predisposing variants that promote lupus in nonautoimmune mice
Genes affecting susceptibility to end-organ pathology
Susceptibility genes affect several key stages in lupus pathogenesis
Comparison with human SLE genes
Conclusion
Acknowledgment
References
Chapter 35 - Mechanisms of renal damage in systemic lupus erythematosus
Introduction
Autoimmunity and end-organ damage
Lessons learned from the mouse model NZM2328
Silent LN
Human genetics on lupus susceptibility genes
Origin of SLE-related auto-Abs
A useful model for the pathogenesis of SLE with protean initial clinical presentations and relapses
dsDNA is not the only auto-Ag in LN
Anti-dsDNA Abs may not be the Abs that initiate LN
Multiple cells and cytokines are involved in the pathogenesis of LN
Kidney disease in lupus is not always “lupus nephritis”
Regeneration and fibrosis are keys to recovery from LN.
Concluding remarks
Acknowledgements
References
Chapter 36 - Mechanisms of vascular damage in systemic lupus erythematosus
Epidemiology of vascular damage in systemic lupus erythematosus
Risk of vascular damage: traditional versus nontraditional factors
Role of cytokines in vascular damage in SLE
Type I interferons
Role of other cytokines
Autoantibodies and immune complexes
Cellular mediators
Adaptive immune responses
Innate immune responses
Oxidized lipoproteins
Modulation of CV risk in SLE
References
Chapter 37 - The mechanism of skin damage
Introduction
Clinical aspects
Pathogenesis of skin damage
Ultraviolet radiation and skin damage
Photosensitivity and photoprovocation
UV-triggered apoptotic cells
Immune cells, cytokines, and chemokines
Dendritic cells and T-cell subtypes
Type 1 interferon and tumor necrosis factor
Other cytokines and chemokines
The genetic and epigenetic mechanisms for skin damage in CLE
References
Chapter 38 - Pathogenesis of tissue injury in the brain in patients with systemic lupus erythematosus
The challenge of neurolupus
Models of neurolupus
Genetics of brain disease
The pathological substrates of lupus brain disease
Mechanisms of accelerated cerebrovascular disease
Antibody-mediated brain disease in lupus: antineuronal antibodies
Antibody-mediated brain disease in lupus: anti glial antibodies
Cytokine pathways: Type I interferon
Other cytokines pathways
Inflammatory cells
Future Challenges
References
Chapter 39 - Constitutional symptoms and fatigue in systemic lupus erythematosus
Introduction
Fatigue
Management of fatigue in SLE
Fever
Lymphadenopathy
Splenomegaly
Weight loss
Conclusion
References
Chapter 40 - The musculoskeletal system in SLE
Arthritis
Nonerosive arthritis
Erosive arthritis (rhupus)
Jaccoud’s arthropathy
Tendons and entheses
Treatment
Myalgia/myopathy/myositis
Fibromyalgia
Medication-related myopathy
Myositis
Histologic features
Treatment
Osteonecrosis
Clinical impact
Epidemiology
Pathogenesis
Risk factors
Diagnosis
Treatment
Osteoporosis
Epidemiology of osteopenia and osteoporosis
Risk factors and pathophysiology of bone loss
Glucocorticoids
Other factors
Treatment
References
Chapter 41 - Cutaneous lupus erythematosus
Epidemiology
Classification criteria for SLE
Photosensitivity
Cutaneous manifestations
Scores in cutaneous lupus erythematosus
Subtypes of cutaneous lupus erythematosus
Acute cutaneous lupus erythematosus
Subacute cutaneous lupus erythematosus (SCLE)
Chronic cutaneous lupus erythematosus (CCLE)
Discoid lupus erythematosus (DLE)
Lupus erythematosus profundus/panniculitis (LEP)
Chilblain lupus erythematosus (CHLE)
Intermittent cutaneous lupus erythematosus (ICLE)
Lupus erythematosus tumidus (LET)
Conclusion
Acknowledgment
References
Chapter 42 - The clinical evaluation of kidney disease in systemic lupus erythematosus
Introduction
The scope of lupus nephritis
The diagnosis of lupus nephritis
Evaluation of kidney function
Evaluation of the urine
Evaluation of proteinuria
The kidney biopsy
Antiphospholipid syndrome and the kidney
Pregnancy and lupus nephritis
Childhood lupus nephritis
Conclusion
References
Chapter 43 - The pathology of lupus nephritis
Introduction
Introduction to nephropathology
Introduction to the nephropathology of SLE
Renal biopsy and SLE
The lesions of lupus nephritis
Glomeruli
Tubulointerstitium
Vessels
Classification of lupus nephritis
Class I (Minimal mesangial LN)
Class II (mesangial proliferative LN)
Class III (Focal LN)
Class IV (Diffuse LN)
Class V (Membranous LN)
Class VI (Advanced sclerosing LN)
Selected topics in classification
Distinction between classes IV-S and IV-G
Fibrinoid necrosis and karyorrhexis
Glomerulosclerosis
Reproducibility of classification
Treatment and transformation
Activity, chronicity, plasticity, and prognosis
Selected clinco-pathologic topics
“Silent” LN
ANCA, crescentic GN and LN
Lupus podocytopathies
Other renal diseases and SLE
Transplantation
References
Chapter 44 - Cardiovascular disease in systemic lupus erythematosus: an update
Burden of cardiovascular disease in lupus
Traditional risk factors for cardiovascular disease in SLE
SLE-specific risk factors for cardiovascular disease
Atherogenesis
Biomarkers for atherosclerosis
Imaging strategies for early detection of cardiovascular disease
Treatment of cardiovascular disease in SLE
Summary
References
Chapter 45 - The lung in systemic lupus erythematosus
Introduction
Role of inflammation in SLE lung
IFN-driven autoimmune lung inflammation
Immune complex involvement
Neutrophils and NETosis
Clinical presentations of lung involvement in SLE
Pulmonary infection
Nonpulmonary involvement as a cause of respiratory symptoms
Pleural disease
Parenchymal disease
Acute lupus pneumonitis
Pulmonary hemorrhage/diffuse alveolar hemorrhage
Chronic interstitial lung disease
Shrinking lung syndrome
Pulmonary vascular disease
Pulmonary hypertension
Pulmonary Thromboembolism
Acute reversible hypoxia syndrome
Airway disease
Overlap syndromes
COPA syndrome and SAVI: Interferonopathies with lung involvement
COPA syndrome
SAVI syndrome
A case for screening for Lung Disease In SLE
Summary
Acknowledgment
References
Chapter 46 - Gastrointestinal, hepatic, and pancreatic disorders in systemic lupus erythematosus
Introduction
The gastrointestinal tract in SLE
Buccal cavity
Esophagus
Stomach
Small intestine
Mesenteric/Intestinal vasculitis/lupus enteritis
Mesenteric insufficiency
Intestinal pseudo-obstruction
Malabsorption and celiac disease
Protein-losing gastroenteropathy
Infective and eosinophilic enteritis
Ascites and peritonitis
Large intestine
Lupus colitis and inflammatory bowel disease
Infective and collagenous colitis
The liver in SLE
Subclinical liver disease
Autoimmune hepatitis
Viral and drug-induced hepatitis
Nodular regenerative hyperplasia
Other liver diseases
Biliary tract disease in SLE
The pancreas in SLE
Acute abdominal pain in SLE
Intestinal microbiome in SLE
Conclusions
References
Chapter 47 - Systemic lupus erythematosus and infections
Introduction
Epidemiology of SLE infections
Immunologic pathogenesis of infections in systemic lupus erythematosus
Treatment-associated immunosuppression and infection risk
Types of infections
Clinical considerations
Preventative strategies
References
Chapter 48 - Malignancies in systemic lupus erythematosus
Introduction
Hematologic cancers
Lung cancers
Cervical cancer
Increased risk of other cancers in SLE
Breast, ovarian, and endometrial cancers
Prostate cancers
Conclusions
References
Chapter 49 - The nervous system in systemic lupus erythematosus
Introduction
Classification of neurolupus
Mechanisms of neurolupus
Clinical approach
Investigations
Routine laboratory tests
Brain-reactive antibodies
Conventional neuroimaging
CSF examination
Neurophysiology
Neuropathology
Central nervous system disease in people with lupus
Neurovascular disease—large vessel
Neurovascular disease—small vessel
CNS vasculitis
Seizures
Movement disorder
Cognitive dysfunction
PRES
Psychiatric disease
Spinal cord disease
Meningeal disease
Progressive multifocal leukoencephalopathy
Functional neurological disorder
Peripheral nervous system disease in people with lupus
Peripheral neuropathy
Optic neuropathy
Questionable clinical syndromes
Lupus headache
Demyelinating syndrome
Acute confusional state
Treatment of neurolupus
Conclusion
References
Chapter 50 - Overlap syndromes
Introduction
Clinical and laboratory manifestations of overlap syndromes
Immunology of overlap syndromes
Genetics
Animal models
Treatment
References
Chapter 51 - Systemic lupus erythematosus and the eye
Introduction
The role of ophthalmic features in the criteria for classification and disease activity
Clinical presentation
Anterior segment
Keratoconjunctivitis sicca
Other corneal disease
Episcleritis
Scleritis
Other anterior segment complications
Orbits and lids
Lid disease
Orbital disease
Posterior segment
Classic lupus retinopathy
Severe vaso-occlusive retinopathy (“retinal vasculitis”)
Arteriole and venule occlusions
Other retinal manifestations
Lupus choroidopathy
Neuro-ophthalmic complications
Optic nerve disease
Ocular motility abnormalities
Retrochiasmal
Investigations
General
Ophthalmic
Anterior segment
Posterior segment
Treatment
General
Ophthalmic
Anterior segment
Posterior segment
Neuro-ophthalmic
Ophthalmic complications of systemic therapy
Conclusion
References
Chapter 52 - Fertility and pregnancy in systemic lupus erythematosus
Systemic lupus erythematosus—A manual
Fertility and SLE
Etiology of infertility in subsets of SLE patients
Preservation of fertility
Assisted reproductive techniques
Pregnancy in SLE patients
Pregnancy impact on SLE disease activity
Preeclampsia and SLE flare
SLE impact on pregnancy outcome
Pregnancy loss
Preterm birth and intrauterine growth restriction
Management of SLE during pregnancy
Medication management
Biological agents
Other medications
Medication summary
Conclusions
References
Chapter 53 - Neonatal lupus: Clinical spectrum, biomarkers, pathogenesis, and approach to treatment
Introduction
Risk of cardiac NL and population prevalence
Transient clinical manifestations of NL: cutaneous, hepatic, hematologic, and neurologic
Immutable manifestations of NL: cardiac
Factors contributing to mortality
Seeking biomarkers: the candidate autoantibodies
Linking antibody to tissue damage and fibrosis: accounting for antigen target accessibility
Guidelines for monitoring antiSSA/Ro-exposed pregnancies and approach to cardiac NL
Translating pathogenesis to prevention
References
Chapter 54 - Incomplete lupus syndromes
Definition
Significance
Epidemiology
Clinical manifestations
Transition to SLE
Treatment
References
Chapter 55 - Lupus in children
Epidemiology
Clinical m‑anifestations
Familial SLE
Morbidity and mortality
Therapeutic considerations in children
Medication toxicity
Fertility
Vaccinations
Malignancy risk
Psychosocial issues
References
Chapter 56 - Drug-induced lupus
Introduction and historical perspective
Diagnosis of drug-induced lupus
Lupus-inducing drugs with specific clinical features
Distinguishing DIL from idiopathic SLE
Treatment and management of DIL
Lupus-inducing drugs
The expanding breadth of lupus-inducing drugs
Epidemiology of DIL
Genetic factors in DIL
Human leukocyte antigens
Complement
Acetylator phenotype
Drug metabolism in the etiology of DIL
Pathogenesis of DIL
Proposed mechanisms underlying DIL
Drug-altered self-molecules induce autoimmunity
Cell death caused by reactive drug metabolites initiates autoimmunity
Drugs cause nonspecific lymphocyte activation
Drug metabolites disrupt central T cell tolerance
Mechanism underlying DIL related to immune-modulating biologics
Conclusions
References
Chapter 57 - Vasculitis in lupus
Prevalence and associated features of vasculitis in lupus
Cutaneous vasculitis
Lupus mesenteric vasculitis
Large vessel vasculitis
Other forms of vasculitis
References
Chapter 58 - Pathogenesis of antiphospholipid syndrome
Introduction
Pathogenic mechanisms of aPL
aPL and the coagulation system
aPL and the fibrinolytic system
Interaction of aPL with cells
Cell receptors for aPL interaction
Signaling pathways of aPL-mediated cell activation
aPL and atherothrombosis
aPL and oxidative stress
aPL and complement activation
Conclusion
Acknowledgment
References
Chapter 59 - Antibodies and diagnostic tests in antiphosholipid syndrome
Antiphospholipid syndrome as an autoantibody–mediated disease
Classification laboratory assays
Lupus anticoagulant
Anticardiolipin antibodies
Anti-β2 glycoprotein I antibodies
Nonclassification laboratory assays
Antiβ2 glycoprotein I domain I antibodies
Anti-cardiolipin and antiβ2 glycoprotein I antibody IgA
Antiprothrombin antibodies
Antibodies against phosphatidylethanolamine
Antibodies against anionic phospholipids other than cardiolipin
Annexin A5 resistance assay
Other autoantibodies in antiphospholipid syndrome
Antibodies possibly involved in thrombosis
Antibodies against proteins involved in hemostasis
Antibodies against protein C and S
Antibodies against coagulation factors
Antibodies against tissue type plasminogen activator
Antibodies against annexin A2
Antiplatelet antibodies
3-Anti-endothelial cell antibodies
Autoantibodies not involved in thrombosis
Antimitochondrial antibodies
Antinuclear antibodies
Antired blood cell antibodies
Antithyroid antibodies
Antibodies against plasma lipoproteins
Complement activation
References
Chapter 60 - Clinical manifestations
Introduction
Vascular thrombosis
Pregnancy morbidity
Catastrophic APS
Features associated with aPL
Cardiac manifestations
Hematological manifestations
Renal manifestations
Neurological manifestations
Skin manifestations
Pulmonary manifestations
References
Chapter 61 - Nonsteroidal antiinflammatory drugs in systemic lupus erythematosus
Introduction
Inhibitory role of NSAIDs
Effects on the kidneys
Gastrointestinal side effects
Increased cardiovascular risk: What is the Verdict?
Central nervous system (aseptic meningitis) side effects
Effects on reproduction
Conclusion
References
Chapter 62 - Value of antimalarial drugs in the treatment of lupus
Introduction
Pharmacokinetics and pharmacodynamics of antimalarials
Mechanisms of action
Modification of the lysosome pH
Blockade of Toll-like receptors
Nonimmunological effects of antimalarials
The beneficial effects of antimalarials in SLE
Practical aspects related to the use of antimalarials
Screening for glucose-6-phosphate dehydrogenase deficiency
Nonophthalmologic adverse effects of antimalarial agents
Ophthalmologic adverse effects of antimalarial agents
Use of antimalarials in pregnancy and lactation
References
Chapter 63 - Systemic glucocorticoids
Introduction
Nomenclature
Rationale and mechanism of action of glucocorticoids in SLE
Mechanism of action of glucocorticoids
Antiinflammatory and immunosuppressive effects of glucocorticoids
Forms and mode of administration of systemic corticosteroids
Forms of synthetic steroids
Mode of administration of systemic corticosteroids
Topical, intraarticular and intralesional glucocorticoids
Oral glucocorticoids
Intravenous glucocorticoids
Intramuscular therapy
Approach for the use of glucocorticoids based on organ system involvement
Mucocutaneous
Musculoskeletal
Cardiopulmonary
Renal
Hematologic
Neuropsychiatric
Tapering and withdrawal of glucocorticoids
Side effects of glucocorticoids
Future direction
References
Chapter 64 - Cytotoxic drug treatment
Introduction
Alkylating agents
Cyclophosphamide
Mechanism of action and pharmacokinetics
Use in renal disease
Use in extra-renal disease
Adverse effects
Nucleotide synthesis inhibitors
Azathioprine
Mechanism of action and pharmacokinetics
Use in renal disease
Use in extra-renal disease
Adverse effects
Mycophenolate mofetil/mycophenolate acid (MMF/MPA)
Mechanism of action and pharmacokinetics
Use in renal disease
Use in extra-renal disease
Adverse effects
Calcineurin inhibitors
Cyclosporine A
Mechanism of action and pharmacokinetics
Use in renal disease
Use in extra-renal disease
Adverse effects
Tacrolimus
Mechanism of action and pharmacokinetics
Use in renal disease
Use in extra-renal disease
Adverse effects
Voclosporin
Mechanism of action
Use in renal disease
General issues in lupus patients on cytotoxic- immunosuppressive drug treatment
Infections
Immunizations
Malignancy
Pregnancy
References
Chapter 65 - Treatment of antiphospholipid syndrome
Introduction
Primary thromboprophylaxis
Prevention of recurrent thrombosis
Alternative therapies for refractory and difficult cases
Other therapies
Pregnancy
Recurrent early miscarriage
Fetal death
Management of pregnancy in patients with APS and previous thrombosis
Management of refractory obstetric APS
Postpartum period
References
Chapter 66 - New treatments of systemic lupus erythematosus
Cytokines
B lymphocyte-activating factor (BAFF)
Interferon-α
Interferon-γ
Interleukin-23/Interleukin-17
Interleukin-2 (IL-2)
Complement
Costimulatory pathways
CD154-CD40
CD28-CD80/86
ICOS-B7RP
Cell surface molecules
CD20
CD22
CD19
Intracellular molecules
Bruton’s tyrosine kinase (Btk)
Cereblon
Calcineurin
Mammalian target of rapamycin (mTOR)
JAK/STAT
Proteasome
Conclusion
References
Chapter 67 - Repositioning drugs for systemic lupus erythematosus
Why try to repurpose/reposition drugs for SLE patients?
Strategies for drug repurposing/repositioning in SLE
Current and future repurposing/repositioning efforts
Summary
References

Citation preview

Systemic Lupus Erythematosus

Basic, Applied and Clinical Aspects Second Edition

Edited by George C. Tsokos Professor of Medicine, Harvard Medical School, and Chief, Rheumatology Division, Beth Israel Deaconess Medical Center, Boston, MA, United States

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2020 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-814551-7 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre Gerhard Wolff Acquisitions Editor: Linda Versteeg-buschman Editorial Project Manager: Leticia M. Lima Production Project Manager: Swapna Srinivasan Designer: Victoria Pearson Typeset by Thomson Digital

To patients, physicians, and researchers who fight lupus from dawn to dusk.

Contributors Nancy Agmon-Levin, Clinical Immunology, Angioedema and Allergy Unit, The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Tel Aviv; The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel

George Bertsias, Rheumatology, Clinical Immunology and Allergy, Medical School, University of Crete, Heraklion, Greece Tanmayee Bichile, Department of Medicine, Medicine and Autoimmunity Institute, Allegheny Health Network, Pittsburgh, PA, United States

Graciela S. Alarcón, Department of Medicine, Division of Clinical Immunology and Rheumatology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States; Department of Medicina, School of Medicine, Cayetano Heredia Peruvian University, Lima, Peru Olga Amengual, Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan Stacy P. Ardoin, Ohio State University, Columbus, OH, United States Swati Arora, Division of Nephrology, Allegheny Health Network, Pittsburgh, PA, United States Yemil Atisha-Fregoso, Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States John P. Atkinson, Washington University School of Medicine, Department of Medicine, Division of Rheumatology, St. Louis, MO, United States Tatsuya Atsumi, Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan Isabelle Ayoub, Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, OH, United States Maria-Louise Barilla-LaBarca, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States Bonnie L. Bermas, UTSouthwestern Medical Center, Dallas, TX, United States Sasha Bernatsky, Divisions of Rheumatology and Clinical Epidemiology, Department of Medicine, McGill University, Montreal, QC, Canada

Patrick Blanco, Laboratoire d’Immunologie et Immunogénétique, FHU ACRONIM, Hôpital Pellegrin, Centre Hospitalier Universitaire, CNRS-UMR 5164, ImmunoConcEpt, Université de Bordeaux, Bordeaux, France Miyuki Bohgaki, NTT Sapporo Medical Center, Sapporo Hokkaido; Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo Hokkaido, Japan Gisela Bonsmann, Department of Dermatology, University of Muenster, Muenster, Germany Maria Orietta Borghi, Immunology Research Laboratory, IRCCS Istituto Auxologico Italiano, Milan; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy Dimitrios T. Boumpas, Rheumatology and Clinical Immunology, 4th Department of Medicine, Medical School, University of Athens and Biomedical Research Foundation of the Academy of Athens, Athens, Greece Rebecka Bourn, Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States Jill P. Buyon, Division of Rheumatology, New York University School of Medicine, New York City, NY, United States Roberto Caricchio, Department of Medicine, Section of Rheumatology; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States Edward K.L. Chan, Department of Oral Biology, University of Florida, Gainesville, FL, United States Christopher Chang, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, United States xxi

xxii Contributors

Manon Charrier, Service de néphrologie, Hôpital Pellegrin, Centre Hospitalier Universitaire, Université de Bordeaux, Bordeaux, France Cecilia Beatrice Chighizola, Immunology Research Laboratory, IRCCS Istituto Auxologico Italiano, Milan, Italy Ann E. Clarke, Division of Rheumatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada José C. Crispín, Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico Bettina Cuneo, Department of Pediatrics and Obstetrics, University of Colorado School of Medicine, Aurora, CO, United States

Research Foundation of the Academy of Athens, Athens, Greece Marvin J. Fritzler, Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Shu Man Fu, Division of Rheumatology, Department of Medicine, University of Virginia, Charlottesville VA; Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, Charlottesville, VA; Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United States Richard Furie, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States

Thomas Dörner, Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany; German Rheumatism Research Center Berlin, Leibniz Institute, Berlin, Germany Erika M. Damato, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom Alastair K.O. Denniston, Academic Unit of Ophthalmology, University of Birmingham, Birmingham; Department of Ophthalmology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom Amy Devlin, Tufts Medical Center & Beth Israel Deaconess Medical Center, Division of Rheumatology, Boston, MA, United States Betty Diamond, Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States T. Ernandez, Service of Nephrology, University Hospital of Geneva, Switzerland Titilola Falasinnu, Department of Epidemiology and Population Health, Stanford Medicine, Stanford, CA, United States Ruth Fernandez-Ruiz, Colton Center for Autoimmunity and Division of Rheumatology, NYU School of Medicine, New York, NY, United States Brianna Fitzpatrick, Lupus Research Alliance Young Leaders Board Lindsy Forbess, Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, United States Eleni A. Frangou, Department of Nephrology, Limassol General Hospital, Limassol Cyprus; Medical School, University of Cyprus, Nicosia, Cyprus; Biomedical

Felicia Gaskin, Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, United States Dafna Gladman, University of Toronto, Toronto, ON, Canada Caroline Gordon, Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom Amrie C. Grammer, AMPEL BioSolutions and RILITE Research Institute, Charlottesville, VA, United States Eric L. Greidinger, Division of Rheumatology, Miami VAMC, University of Miami Miller School of Medicine, Miami, FL, United States Teri M. Greiling, Oregon Health & Science University, Portland, OR, United States Shuhong Han, Division of Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL, United States James E. Hansen, Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, United States Sarfaraz A. Hasni, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States Fadi Hassan, Department of Internal Medicine E, Galilee Medical Center, Nahariya, Israel Christian M. Hedrich, Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool; Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust Hospital, Liverpool; Institute in the Park, Alder Hey Children’s NHS Foundation Trust Hospital, Liverpool, United Kingdom

Contributors

Keiju Hiromura, Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan Diane Horowitz, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States Xin Huang, Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China David Hunt, Anne Rowling Neuroinflammation Clinic, University of Edinburgh, Edinburgh, United Kingdom Peter M. Izmirly, Division of Rheumatology, New York University School of Medicine, New York City, NY, United States Judith A. James, Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK; Departments of Medicine and Pathology, Oklahoma Clinical and Translational Science Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States Wael N. Jarjour, Ohio State University, Columbus, OH, United States Caroline A. Jefferies, Division of Rheumatology, Department of Medicine, Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, United States Caroline Jefferies, Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, United States Xiaoyue Jiang, Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Mariana J. Kaplan, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States Takayuki Katsuyama, Division of Rheumatology and Clinical Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States Munther Khamashta, Consultant Physician, London Lupus Centre, London Bridge Hospital, London, United Kingdom Kathryn M. Kingsmore, AMPEL BioSolutions and RILITE Research Institute, Charlottesville, VA, United States

xxiii

Takao Koike, Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo Hokkaido; Hokkaido Medical Center for Rheumatic Diseases, Sapporo Hokkaido, Japan Dwight H. Kono, Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States Martin A. Kriegel, Yale School of Medicine, New Haven, CT, United States Annegret Kuhn, Interdisciplinary Center for Clinical Trials (IZKS), University Medical Center Mainz, Mainz; Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany Vasileios C Kyttaris, Beth Israel Deaconess Medical Center, Division of Rheumatology, Harvard Medical School, Boston, MA, United States Antonio La Cava, Department of Medicine, University of California Los Angeles, Los Angeles, CA, United States Alexandra Ladouceur, Centre hospitalier de l’Université de Montréal (CHUM), Montréal, QC, Canada Robert G. Lahita, New York Medical College, University Hospital, Paterson, NJ, United States Aysche Landmann, Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany Estibaliz Lazaro, Service de Médecine interne, FHU ACRONIM, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire, CNRS-UMR 5164, ImmunoConcEpt, Université de Bordeaux, Bordeaux, France Mara L. Lennard Richard, Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, United States Andreia C. Lino, Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany; German Rheumatism Research Center Berlin, Leibniz Institute, Berlin, Germany Peter E. Lipsky, AMPEL BioSolutions and RILITE Research Institute, Charlottesville, VA, United States M. Kathryn Liszewski, Washington University School of Medicine, Department of Medicine, Division of Rheumatology, St. Louis, MO, United States Mindy S. Lo, Instructor, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States Qianjin Lu, Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China

xxiv Contributors

Mary Mahieu, Northwestern University Feinberg School of Medicine, Chicago, IL, United States Susan Malkiel, Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States Susan Manzi, Department of Medicine, Medicine and Autoimmunity Institute, Allegheny Health Network, Pittsburgh, PA, United States Galina Marder, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States T.N. Mayadas, Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States Pier Luigi Meroni, Immunology Research Laboratory, IRCCS Istituto Auxologico Italiano, Milan, Italy Joan T. Merrill, Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, University of Oklahoma, Norman, OK, United States Chandra Mohan, Department of Biomedical Engineering, University of Houston, Houston, TX, United States Chi Chiu Mok, Department of Medicine, Tuen Mun Hospital, New Territories, Hong Kong Vaishali R. Moulton, Division of Rheumatology and Clinical Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States Philip I. Murray, Academic Unit of Ophthalmology, University of Birmingham, Birmingham, United Kingdom Mohammad E. Naffaa, Division of Rheumatology, Galilee Medical Center, Nahariya, Israel Masaomi Nangaku, Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan Timothy Niewold, Colton Center for Autoimmunity and Division of Rheumatology, NYU School of Medicine, New York, NY, United States K. Okubo, Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States Nancy J. Olsen, Penn State MS Hershey Medical Center, Hershey, PA, United States Trina Pal, New York Medical College, University Hospital, Paterson, NJ, United States Ziv Paz, Division of Rheumatology, Galilee Medical Center, Nahariya, Israel Andras Perl, Division of Rheumatology, Departments of Medicine and Microbiology and Immunology, State University of New York, Upstate Medical University, College of Medicine, Syracuse, NY, United States

Guillermo J. Pons-Estel, Department of Medicine, Regional Center for Rheumatic and Autoimmune Diseases (GOCREAR), Rosario; Rheumatology Service, Rosario Provincial Hospital, Rosario, Argentina Bo Qu, Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Anisur Rahman, Division of Medicine, University College London, London, UK Ziaur S.M. Raman, Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, United States Rosalind Ramsey-Goldman, Northwestern University Feinberg School of Medicine, Chicago, IL, United States; Department of Medicine/Division of Rheumatology Northwestern University Feinberg School of Medicine, Chicago, IL, United States Westley H. Reeves, Division of Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL, United States Christophe Richez, Service de Rhumatologie, FHU ACRONIM, Hôpital Pellegrin, Centre Hospitalier Universitaire, CNRS-UMR 5164, ImmunoConcEpt, Université de Bordeaux, Bordeaux, France Florencia Rosetti, Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico Brad H. Rovin, Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, OH, United States Robert L. Rubin, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 1 University of New Mexico, Albuquerque, NM, United States Stephanie Saeli, Department of Medicine, Medicine and Autoimmunity Institute, Allegheny Health Network, Pittsburgh, PA, United States G. Saggu, Cue Biopharma, Boston, MA. United States Lisa R. Sammaritano, Hospital for Special Surgery, New York, NY, United States Minoru Satoh, Department of Clinical Nursing, University of Occupational and Environmental Health Japan, Kitakyushu, Fukuoka, Japan Amr H. Sawalha, Division of Rheumatology, Department Pediatrics; Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States

Contributors

Amit Saxena, Division of Rheumatology, New York University School of Medicine, New York City, NY, United States Savino Sciascia, Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases (CMID), Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Hospital and University of Turin, Turin, Italy Syahrul Sazliyana Shaharir, Rheumatology Unit, Department of Internal Medicine, National University of Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia Amir Sharabi, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv; Rheumatology Institute, Rabin Medical Center, Petach-Tikva, Israel Nan Shen, Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States Robert H. Shmerling, Tufts Medical Center & Beth Israel Deaconess Medical Center, Division of Rheumatology, Boston, MA, United States Julia F. Simard, Department of Epidemiology and Population Health, Stanford Medicine, Stanford, CA; Division of Immunology and Rheumatology, Department of Medicine, Stanford Medicine, Stanford, CA, United States Vanja Sisirak, CNRS-UMR 5164, ImmunoConcEpt, Université de Bordeaux, Bordeaux, France Samantha Slight-Webb, Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States Isaac Ely Stillman, Director, Renal Pathology Service – Beth Israel Deaconess Medical Center, Associate Professor of Pathology – Harvard Medical School, Boston, MA, United States Sun-Sang J. Sung, Division of Rheumatology, Department of Medicine, University of Virginia, Charlottesville, VA; Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, United States Payal Thakkar, Allegheny Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, United States Argyrios N. Theofilopoulos, Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States

xxv

Donald E. Thomas, Jr, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD; Arthritis and Pain Associates of Prince Georges County, Greenbelt, MD, United States Hiromi Tissera, McGill University Health Centre, Montreal, QC, Canada Zahi Touma, University of Toronto Lupus Clinic, Toronto Western Hospital, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto, ON; University of Toronto, Toronto Western Research Institute, University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, ON, Canada Betty P. Tsao, Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, United States Manuel F. Ugarte-Gil, Rheumatology Service, Guillermo Almenara Irigoyen National Hospital, Lima; Southern Scientific University, Lima, Peru Murray B. Urowitz, University of Toronto, Toronto Western Research Institute, University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, ON, Canada Silvio Manfredo Vieira, Yale School of Medicine, New Haven, CT, United States Benjamin Wainwright, Division of Rheumatology, New York University School of Medicine, New York City, NY, United States Daniel J. Wallace, Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, United States Hongyang Wang, Division of Rheumatology, Department of Medicine, University of Virginia, Charlottesville, VA; Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United States Haijing Wu, Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China Soad Haj Yahia, Clinical Immunology, Angioedema and Allergy Unit, The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Tel Aviv; The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel C. Yung Yu, Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children’s

xxvi Contributors

Hospital and Department of Pediatrics, The Ohio State University, Columbus, OH, United States Zhenhuan Zhao, Division of Rheumatology, Department of Medicine, University of Virginia, Charlottesville, VA; Department of Microbiology, Immunology and Cancer

Biology, University of Virginia, Charlottesville, VA, United States Haoyang Zhuang, Division of Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL, United States

Introduction As long as we consider systemic lupus erythematosus one disease and we see one clinical trial after another fail, we can offer the people who suffer only qualified hope and encouragement. There is no doubt that we understand the disease better now than we did 50 years ago but we still use the same immunosuppressive and cytotoxic drugs albeit more wisely. We have enlisted to the processes that lead to the expression of the disease additional players as we have followed new advances in the fields of immunology, inflammation, cell and molecular biology, and genomics. Yet we have not made much-needed advances in delineating the relative contribution of each mechanism to the expression of disease in each individual. It has become increasingly clear that cellular and molecular pathways may contribute to immunopathology at different degrees in each patient. There is no doubt that the biologics that have been tested in each trial do exactly what they were designed to do (deplete a cell, neutralize a cytokine or block a receptor, and so on) but if given indiscriminately to every lupus patient, the statistically recorded benefit may not rise to significant levels. There is no doubt that lupus cries out for individualized medicine and that herding everybody under the eleven American College of Rheumatology criteria misses the fact that each person with lupus “employs” individual pathways to express the same set of clinical manifestations. We have also been slow in identifying the molecular and cellular mechanisms, which are involved in the expression of injury in each affected organ. Even if the autoimmune response is responsible for instigating tissue injury it is now better understood that autoimmunity and organ damage do not go hand-in-hand. Attempts to reverse injurious processes in organs should prove of clinical value. We understand that molecules (cell surface receptors, kinases, phosphatases and others) that are found to be abnormally expressed in lupus and claimed to contribute to disease pathology, are usually expressed by additional cells in the body and if inhibited across the board will invariably bring about unwanted side effects. This argument mandates the consideration of targeted delivery of drugs and biologics to maximize clinical efficacy and minimize side effects. This book has taken a different approach in presenting the readers with state-of-the-art authoritative infor-

mation on current topics of lupus. In order to minimize the load to the contributors we have presented a rather large (66) number of chapters after parsing out topics. Each contributor was asked to present available information in a critical, authoritative manner in shorter text and a limited (around 50) number of references selected critically. There is no doubt that readers will recognize shortcomings. I invite all possible feedback to improve the next edition. While planning the book, we had in mind the increasing number of scientists, care givers, disease activists, clinical trial planners and industry officers who enter the battle against lupus. I believe that organization of the book will facilitate information retrieval and useful synthesis. The 66 chapters are organized in six sections. The first introduces the history, epidemiology, diagnosis, and the efforts to develop biomarkers for the disease. In the second section (pathogenesis) 24 players are presented including various cells, antibodies, inflammation mediators, and processes. In the third section (mechanisms of tissue injury) elements and processes involved in the development of organ injury are presented synthetically. In the fourth section the clinical manifestations of the disease are presented in 19 chapters. Special space was allotted to the 41st chapter, which presents the pathology of lupus nephritis. My friend Isaac (Dr. Stillman) understands the pathology of lupus nephritis in a way that very few do and I believe we should have a clear understanding of the pathology before we commit our patients to intense treatment with cytotoxic drugs. The fifth section is dedicated to the antiphospholipid syndrome and the sixth to the treatment of the disease. Besides the required chapters on the used drugs, a chapter on the lessons we have learned from clinical trials is included along with a chapter on the efforts to repurpose existing drugs to treat lupus. This book exists because of the encouragement and excitement of Linda Versteeg-Buschman of Elsevier whom I thank warmly through these lines. Halima Williams has provided unwavering support of the highest quality through the chapter solicitation, collection and editing phases of the chapters. She made my job easy and joyful. George C. Tsokos

xxvii

Introduction to the second edition The success of the first edition has encouraged me to prepare the second edition of this book. In addition, many advances have been reported during the last five years, which had to be presented. Although we lament the slow pace of appearance of drugs for lupus there is “light at the end of the tunnel.” Benlysta has claimed official success whereas a few more biologics hold high promise and they may soon make to the clinic. While planning the second edition of the book, I had in mind the increasing number of scientists, care givers, disease activists, clinical trial planners, and industry officers who enter the battle against lupus. I believe that organization of the book will facilitate information retrieval and useful synthesis. While the majority of the chapters have been updated by the same contributors, several are new to reflect recent advances. I have included a chapter by Brianna Fitzpatrick a young lady with lupus who presents in a most convincing manner what she expects from all of us. The second edition is again organized in six sections. The first introduces the history, epidemiology, diagnosis, and the efforts to develop biomarkers for the disease. In the

second section (pathogenesis) all players and contributors of the expression of the disease are presented including v cells, antibodies, inflammation mediators, and processes. In the third section (mechanisms of tissue injury) elements and processes involved in the development of organ injury are presented synthetically. In the fourth the clinical manifestations of the disease are presented. The fifth section is dedicated to the anti-phospholipid syndrome and the sixth to the treatment of the disease. This book exists because of the encouragement and excitement of Linda Versteeg-Buschman of Elsevier whom I thank warmly through these lines. Leticia Lima has provided unwavering support of the highest quality though the chapter solicitation, collection, and editing phases of the chapters. She made my job easy and joyful. Lastly, I want to thank in the most cordial way all my friends who updated their chapters or contributed new ones. My real contribution to the outstanding quality of the second edition is minimal, if any. George C. Tsokos

xxix

Chapter 1

History of systemic lupus erythematosus with an emphasis on certain recent major issues Shu Man Fua,b,c and Felicia Gaskind a

Division of Rheumatology, Department of Medicine, University of Virginia, Charlottesville VA, United States; bCenter for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, Charlottesville, VA, United States; cDepartment of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United States; dDepartment of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, United States

History of clinical observations The clinical history of systemic lupus erythematosus (SLE) is interesting and torturous. It took more than 150 years for clinicians to describe the characteristics of all involved organs. The detailed histories of SLE from Hippocrates to Osler and from 600 AD to the mid-1970s have been described by Smith and Cyr1 and by Benedek, respectfully.2 Here only the highlights of clinical history will be presented without specific references. Most of the hallmarks in the Age of Dermatology are from Smith and Cyr.1

The age of dermatology The Latin word lupus, meaning wolf, was in the medical literature prior to the 1200s to describe skin lesions that devour flesh. Because of the inability to distinguish herpes, leprosy, and cancer as the cause of the skin lesions devouring the flesh, the term lupus was then applied to skin lesions nonspecifically. Rogerius (1230) has been credited to dissociate the skin lesions of lupus from that of herpes. The term was applied mostly to lesions on the lower extremities and on the face. Robert Willan, a British physician published his Manual on Skin Diseases with color illustrations based on his astute clinical observations. He was able to identify distinct clinical presentations of lupus skin diseases. Most of the early description of lupus skin diseases were lupus vulgaris. Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00001-5 Copyright © 2020 Elsevier Inc. All rights reserved.

Lupus erythematosus was first described as Erythema centrifugum by Laurent T Biett (1781–1840), a prominent French dermatologist. This was reported in 1833 by his pupil Cazenave (1802–77) “….a remarkable variety of this disease under the name of Erythema centrifugum. It is often of very rare occurrence, and appears most frequently in young people, especially in females, whose health is otherwise excellent….” Cazenave in his article published in 1851 renamed Erythema centrifugum as lupus erthemteux (LE). Prior to this, Ferdinand von Hebra (1816–80), a Viennese physician used the term of butterfly rash in 1848 to describe one of the two types of lupus erythematosus. Regarding the etiology of lupus skin disease, it was remarkable that Jonathan Hutchinson (1828–1913), a British surgeon with multiple talents described photosensitivity in 1879 may be a cause of lupus by stating “ … Erythematous lupus is very rarely seen in those parts of the surface which is constantly protected by clothes. It is always made worse by exposure to the wind and cold… Sunburn of the nose is a common exciting cause.” In 1880, he described the lesion of lupus marginatus that resembles subacute lupus erythematosus described by Sontheimer et al.3 in 1979. During the 19th century there was much debate about the pathogenesis of lupus skin diseases. It was assumed to be due to infections because most lupus patients came from poor neighborhoods with crowded living arrangements. With the discovery of tubercle bacillus by Robert Koch in 1882, several reports of growing tubercle bacillus from 3

4 PART | I  Epidemiology and diagnosis

lupus lesions were published leading to popularity of the theory.4 Despite the finding by Walther Pick in 1901 that only 15 out of 29 patients with LE were positive for a tuberculin skin test with positive TB history, the tuberculous etiology of LE remained a favorite theory of LE pathogenesis. Most investigators argued for or against this theory based on clinical statistics,2 a practice still used by contemporary investigators in lupus research. The tuberculous etiology of LE led to the use of gold and other heavy metals such as bismuth as therapeutic agents for decades.

Transition of lupus erythematosus to systemic lupus erythematosus Moriz Kaposi (1837–1920) was credited as the first physician in 1872 to describe internal organ involvement in LE and coined the term of SLE in distinction to LE, a limited skin disease.1 He classified LE with internal organ involvement as Lupus erythematosus disseminates et aggregatus (SLE). He described these patients with fever, weight loss, anemia, amenorrhea, dysmenorrhea, adenitis, arthralgia/ arthritis, increased mental disturbance, and coma, realizing many major clinical features of SLE. Sir William Osler (1849–1919) is credited for the implication of lupus nephritis as the cause of early demise in SLE due to his 1895 description of two cases of fatal nephritis that developed shortly after the appearance of the skin disease. Prior to the description of fatal nephritis, the causes of death in LE were assumed to be due to infections. Regarding his contribution to the study of SLE, it has been over-emphasized. In his description of 29 cases of SLE from 1895 to 1904, only two were clearly SLE with the majority of the cases being Henoch-Schonlein purpura.5 In 1902, JH Sequeira and H Balean both being British dermatologists published their series of 71 lupus patients (60 being discoid lupus and 11 being SLE). They described acroasphyxia (Raynaud’s phenomenon) as a common feature. They gave detailed clinical features and autopsy findings of an 18 year old female with malaise, malar rash, headache, abdominal pain, and peripheral edema with hematuria and casts and pulmonary embolism. They should share equal recognition for their contribution to the early study of SLE. To complete the transition to SLE from discoid lupus was the recognition of the occurrence of SLE without skin disease as reported in 1936 by Freidberg, Gross, and Wallach.6 There were other landmarks for the studies on SLE and they have been summarized by Benedek.2 The familial study by Arnett and Shulman in 1976 emphasized the importance of genetic factors and their interaction with environmental factors in the pathogenesis of SLE.7 The discovery of drug induced lupus further supports the role of environmental factors in this disorder. These studies provide the basis for the recent efforts on the elucidation of the genetics of SLE.

History of laboratory investigations Development of clinical tests The first laboratory test that was found to be helpful in the diagnosis SLE is the biological false positive test for syphilis that was first described to be associated with lupus by A Reinhart in 1909.8 In 1952, Haserick and Long described 5 cases of SLE with a biological false positive test that preceded the onset of SLE by as much as 8 years.9 This lag time between serological positivity and clinical manifestation is similar to that reported more recently by Arbuckle et al.10 with other lupus-related auto-antibodies (Auto-Abs). Hargraves, Richmond, and Morton described the “LE cells” in the bone marrow of SLE patients in 1948.11 Because the LE cell test is positive in 50%–70% of the patients and seen in other diseases, it is no longer used as a laboratory test for SLE. However, the LE cell test led Holman and Kunkel12 to identify the LE factor as antibodies (Abs) against complexes formed by nuclear nucleoprotein and DNA. These anti-DNA/nucleoprotein complex Abs were shown to differ from those reactive with ds-DNA.13,14 It is of special interest that Deicher et al.13 demonstrated the presence of at least two types of anti-dsDNA Abs by immunoprecipitation in SLE patients. Thus far it remains to be determined whether these two types of anti-dsDNA Abs have clinical significance. It is revealing to revisit the 1974 paper published by Gershwin and Steinberg15 stating that “Patients with lupus nephritis had either precipitating antibodies to DNA, or a mixture of precipitating and nonprecipitating, whereas those patients without nephritis had only nonprecipitating, antibodies to DNA. Furthermore the avidity for DNA was greatest in sera from patients with nephritis. The antigen-binding capacity of sera from patients with and without lupus nephritis was similar, suggesting that qualitative differences in anti-DNA activity may be as important as quantitative ones.” Thus, it appears that the heterogeneity of anti-dsDNA Abs measured by the current binding assays render them to be one of the many lupusrelated autoantibodies.16 Friou et al.17 reported the development of the indirect immunofluorescence technique to detect antinuclear antibodies (FANA) in 1958. For historical reasons, he recalled that their experiments reported in Friou et al. were completed in February 1957.18 Although positive FANA tests were not specific for SLE, it was accepted as a better screening test because of its less technical demand in comparison with the LE cell test. These Abs are also found in approximately 15% of the normal population irrespective of their ages.19 Despite the use human Hep2 cells as the substrate and the improvement of optics in immunofluorescence microscopy, a small percentage of SLE patients remain ANA negative. Thus, the specificity and sensitivity issue remains, rendering the use of positive ANA as an entry criterion for patient

History of systemic lupus erythematosus with an emphasis on certain recent major issues Chapter | 1

selection in the new EULAR/ACR classification criteria for SLE20 problematic. HR Holman pioneered the method for the preparation of extractable nuclear antigens (ENA) to study auto-Abs in SLE.21 Anti-Sm Abs were the first auto-Abs shown to be reactive with ENA by Tan and Kunkel22 by immunoprecipitant analysis with the serum from a young woman, Ms. Smith, who succumbed to lupus nephritis at the age of 21 years.23 It is specific for SLE and remains one of the 11 criteria in the 1982/1997 modified-ACR criteria for the classification of SLE.24,25 Sm is one of the components of snRNP.22 RNP was the second component of snRNP to be recognized as an autoantigen. With an agglutination assay using red cells coated with ENA, Sharp et al.26 showed that a population of patients with overlapping features of SLE, progressive systemic sclerosis, and polymyositis, had high titers of anti-RNP Abs with a distinct clinical course. These patients have mixed-connective tissue disease (MCTD). It is important to emphasize the presence of high titers for anti-RNP Abs to be diagnostic of MCTD. Anti-Ro/SSA Abs were first identified by Clark, Reichlin, and Tomasi27 with the serum from patient Ro by immunodiffusion analysis. The Ro Ag was later identified to be a 60 KD nucleoprotein binding to RNA.28 Anti-Ro Abs are the most common lupus-related auto-Abs in healthy individuals.19 The presence of these Abs in normal young females may result in fetal heart block or neonatal lupus. It should be stressed that the earlier described autoAbs were detected initially by immunodiffusion analyses. Their usefulness in diagnosing SLE was based on clinical correlation with these auto-Abs detected by this technique. The recent developed ELISA assay and the BioRad Multiplex Assays do not correlate exactly with the results by immunodiffusion. Thus interpretation of the current clinical serological assay results in the diagnosis of SLE should be done with caution. Clinically patients with isolated Abs to the auto-Ag panel in the BioRad Multiplex system without positive ANA are often encountered. As of 2015, more than 180 auto-Abs have been described in SLE to diverse organ and cell constituents.29 Those chosen to be included in the classification criteria for SLE are those available in clinical laboratories. These small groups of auto-Abs are employed to measure autoimmune activity in SLE patients. Their absence does not indicate the absence of autoimmunity and does not exclude the diagnosis of SLE.

History of genetics of SLE As stated earlier, the familial occurrence of multiple SLE cases suggests that genetics plays a significant role in the pathogenesis of SLE. The HLA complex was the first genetic locus identified to be linked to SLE susceptibility in 1970.30 With the genome-wide association studies (GWAS), more than 100

5

genetic loci have been confirmed to be associated with SLE.31 With few exceptions most identified alleles have OR between 1.2 and 16. To achieve the threshold for clinical SLE many combinations of these genes are plausible in any given individual patient. The complexity of lupus genetics contributes significantly to the heterogeneity of the disease clinical presentation and responses to therapies.

History of therapy in SLE with an emphasis on the use of steroids The history of therapies for SLE is also a torturous one. The most controversial tissues are how much steroid and for how long steroid should be used in the treatment of SLE. Shortly after the demonstration of remarkable steroid effects on rheumatoid arthritis by Hench et al.,32 ACTH was demonstrated to be effective in treating some cases of SLE.33,34 The choice of ACTH was due to the limited availability of synthetic cortisone. With the availability of prednisone, this medication was used by Pollack et al. in the early 1960s to treat lupus nephritis.35 40–60 mg prednisone for 6 months was effective to treat patients with active proliferative LN. In many patients this high dose could be tapered to 15–20 mg daily with controlling the disease activity. In comparison those treated with 15–20 mg daily doses of prednisone were not effective. This finding might have been the basis for treating lupus patients with moderate to severe symptoms with high doses of prednisone initially and then taper the prednisone to 15–20 mg daily. Today daily doses of prednisone below 10 mg remain acceptable. The effectiveness of using immunosuppressive agents in the treatment of SLE were demonstrated to be effective in the early 1970s. It was initially shown in 1970 that a shortterm use of cyclophosphamide as a single agent was not effective.36 One year later, Steinberg et al.37 concluded from a control clinical trial that “with concurrent corticosteroid therapy, up to 30 mg/day of prednisone, was permitted. Patients receiving cyclophosphamide had greater improvement than did placebo-treated patients in five indexes: antiDNA antibodies, serum complement, urine sediment, proteinuria, and extra-renal disease. There was no difference in creatinine clearance. There was a strong positive correlation between cyclophosphamide dosage and number of indexes improved. Toxic side effects of cyclophosphamide were noted.” In 1986, Austin et al.38 published the results of a long-term therapeutic trial of LN patients treated with high doses of oral prednisone alone versus those treated with an intravenous high-dose of cyclophosphamide plus low-doses of prednisone. Those receiving a high dose of intravenous cyclophosphamide have reduced risk of progressing to end stage of renal disease. Because of the ethical concern of toxicity,39 immunosuppressives have remained steroid-sparing agents and are not used as the primary agents.40

6 PART | I  Epidemiology and diagnosis

During the last two decades, the long-term detrimental effects of moderate/low doses of prednisone41 have been recognized. This prompted observational trials without the use of oral prednisone in LN.42,43 Recently, a multi-target therapy with tacrolimus and mycophenolate mofetil (MMF) plus pulse methylprednisolone with tapering a course of oral prednisone to from 1 mg/kg to 10 mg/day as induction therapy was superior to pulse methylprednisolone with intravenous cyclophosphamide.44 Tacrolimus, MMF plus 10 mg/day oral prednisone was also shown to be superior in the maintenance therapy phase of LN.45 Unfortunately in these studies, prednisone was used at a moderately high dose. It remains to be determined whether oral steroid can be eliminated completely in the multitarget therapy in the maintenance phase with more rapid tapering in the induction phase. The latter multitarget approach may receive acceptance when biomarkers are developed to guide the use of prednisone such as circulating inflammatory cytokine levels after steroid pulses. It is apparent that more than 60 years after the demonstration of usefulness of glucocorticoid in the treatment of lupus, how much steroid and for how long steroid should be used in the treatment of SLE remains controversial. However, it is clear that most patients would chose immunosuppressive agents with lower/no doses of prednisone after experiencing the side effects of moderate doses of prednisone.

History of classification criteria for SLE It is not surprising that committees were needed and were formed to determine the classification criteria of SLE because of its marked protean clinical presentations and clinical courses with highly varied serological laboratory findings. The 1982/1997 Revised ACR Criteria for the Classification of SLE24,25 have been proven to be moderately useful. The 1982/1997 ACR criteria separate the nine criteria for end organ damage from autoimmunity manifestation such as ANA and anti-dsDNA Abs. This separation represents a foresight of the committee realizing that autoimmunity alone needs not to progress to autoimmune disease and that these are two genetically determined and interactive pathways in the pathogenesis of SLE.46 Although it is clearly stated that the classification criteria were for the use of recruiting patients for clinical research and not for clinical use, they have been often used for clinical classification. The misuse of these criteria in clinical practice creates a significant obstacle in providing quality care to our patients, especially in the case that a significant proportion of primary care physicians consider the presence of anti-dsDNA to be diagnostic of lupus. With the failure of many clinical trials for therapeutic agents in SLE, the pressure to recruit patients for clinical trial mounts. This leads to the pressure to revise the 1982/1997 revised ACR criteria for the classification of

SLE and the result of the formation of a new committee in 2017 jointly appointed by EULAR and ACR. The proposed EULAR/ACR classification criteria incorporated most of the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. The criteria are more cumbersome. With adult SLE populations in both Europe and in the Americas, the EULAR/ACR classification criteria for SLE do not appear to be superior to the 1982/1997 revised ACR classification.47,48 It appears that the new criterion is more sensitive but less specific. This preliminary conclusion is disappointing in that the proposed EULAR/ACR criteria classification for SLE did not achieve the initial goal to have a more sensitive and specific classification system for SLE. As I reviewed the literature for this chapter, I came across an article by H. Holman49 that recorded his reflection on the discovery of anti-dsDNA Abs. He lamented the long failure of recognition of autoimmunity by citing a plausible explanation in the 1962 book “The Structure of Scientific Revolution” by Thomas Kuhn. H Holman wrote “Exploring the histories of astronomy and physics, Kuhn argued that dominant concepts in a scientific field (e.g., Earth-centered vs. Sun-centered astronomy, mechanical vs. relativistic physics) did not change as a result of steady, longitudinal growth of knowledge. Rather, they changed when the powerful authority figures in the field, who adhered to the prevailing theoretical view, departed. This allowed younger people with contrary evidence and views to be recognized. The Kuhnian analysis was applied to many fields of science and provoked much controversy. However, the Kuhnian notions of theoretical concepts as paradigms, and paradigm replacement as a consequence of changing of the guards, persist. Whether that explains the dominance of “horror autotoxicus” for a half century despite contrary evidence is a matter of conjecture.” His reflection on autoimmunity may be applicable here.

References 1. Smith CD, Cyr M. The history of lupus erythematosus. From Hippocrates to Osler. Rheum Dis Clin North Am 1988;14:1–14. 2. Benedek TG. History of lupus. Dubois’ Lupus Erythematosus and Related Syndromes. 9th ed. In: Wallace DJ, Hanh BH., editors. Elsevier Inc; 2019. pp. 1–14. 3. Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch Dermatol 1979;115:1409–15. 4. Michelson HE. The history of lupus vulgaris. J Invest Dermatol 1946;7:61–7. 5. Scofield RH, Oates J. The place of William Osler in the description of systemic lupus erythematosus. Am J Med Sci 2009;338:409–12. 6. Friedberg CK, Gross L, Wallach K. Nonbacterial thrombotic endocarditis. Arch Intern Med 1936;58:662–84. 7. Arnett FC, Shulman LE. Studies in familial systemic lupus erythematosus. Medicine (Baltimore) 1976;55:313–22. 8. Reinhart A. Erfahrungen mit der Wassermann Neisser-bruckschen syphilis reaction. Munch Med Wochenschr 1909;41:1092–7.

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9. Haserick JR, Long R. Systemic lupus erythematosus preceded by false-positive serologic tests for syphilis: presentation of five cases. Ann Intern Med 1952;37:559–65. 10. Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003;349:1526– 33. 11. Hargraves MM, Richmond H, Morton R. Presentation of two bone marrow elements; the tart cell and the L.E. cell. Proc Staff Meet Mayo Clin 1948;23:25–8. 12. Holman HR, Kunkel HG. Affinity between the lupus erythematosus serum factor and cell nuclei and nucleoprotein. Science 1957;126:162– 3. 13. Deicher HR, Holman HR, Kunkel HG. The precipitin reaction between DNA and a serum factor in systemic lupus erythematosus. J Exp Med 1959;109:97–114. 14. Holman HR, Deicher HR, Kunkel HG. The LE cell and the LE serum factors. Bull N Y Acad Med 1959;35:409–18. 15. Gershwin ME, Steinberg AD. Qualitative characteristics of anti-DNA antibodies in lupus nephritis. Arthritis Rheum 1974;17:947–54. 16. Fu SM, Dai C, Zhao Z, Gaskin F. Anti-dsDNA antibodies are one of the many autoantibodies in systemic lupus erythematosus. F1000Res 2015;4 (F1000 Faculty Rev). 17. Friou GJ, Finch SC, Detre KD. Interaction of nuclei and globulin from lupus erythematosus serum demonstrated with fluorescent antibody. J Immunol 1958;80:324–9. 18. Friou GJ. Setting the scene: a historical and personal view of immunologic diseases, autoimmunity and ANA. Clin Exp Rheumatol 1994;12(Suppl. 11):S23–5. 19. Satoh M, Chan EK, Ho LA, Rose KM, Parks CG, Cohn RD, et al. Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. Arthritis Rheum 2012;64:2319–27. 20. Tedeschi SK, Johnson SR, Boumpas D, Daikh D, Dörner T, Dayne D, et al. Developing and refining new candidate criteria for systemic lupus erythematosus classification: an international collaboration. Arthritis Care Res 2018;70:571–81. 21. Holman HR. Partial purification and characterization of an extractible nuclear antigen which reacts with SLE sera. Ann N Y Acad Sci 1965;124:800–6. 22. Tan EM, Kunkel HG. Characteristics of a soluble nuclear antigen precipitating with sera of patients with systemic lupus erythematosus. J Immunol 1966;96:464–71. 23. Tsokos GC. In the beginning was Sm. J Immunol 2006;176:1295–6. 24. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7. 25. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725. 26. Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972;52:148–59. 27. Clark G, Reichlin M, Tomasi Jr TB. Characterization of a soluble cytoplasmic antigen reactive with sera from patients with systemic lupus erythematosus. J Immunol 1969;102:117–22. 28. Yamagata H, Harley JB, Reichlin M. Molecular properties of the Ro/ SSA antigen and enzyme-linked immunosorbent assay for quantitation of antibody. J Clin Invest 1984;74:625–33.

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29. Yaniv G, Twig G, Shor DB, Furer A, Sherer Y, Mozes O, et al. A volcanic explosion of autoantibodies in systemic lupus erythematosus: a diversity of 180 different antibodies found in SLE patients. Autoimmun Rev 2015;14:75–9. 30. Grumet FC, Coukell A, Bodmer JG, Bodmer WF, McDevitt HO. Histocompatibility (HL-A) antigens associated with systemic lupus erythematosus. A possible genetic predisposition to disease. N Engl J Med 1971; 285: 193–6. 31. Deng Y, Tsao BP. Updates in lupus genetics. Curr Rheumatol Rep 2017;19:68. 32. Hench PS, Kendall EC, Slocumb CH, Polley HF. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: compound E) and of pituitary adrenocortical hormone in arthritis: preliminary report. Ann Rheum Dis 1949;8:97–104. 33. Thorn GW, Bayles TB, Massell BF, Hill Jr SR, Smith 3rd S, Warren JE. Studies on the relation of pituitary-adrenal function to rheumatic disease. N Engl J Med 1949;241:529–37. 34. Boland EW. Relation of the adrenal cortex to rheumatic disease: a review of some recent investigations. Ann Rheum Dis 1950;9:1–21. 35. Pollak VE, Pirani CL, Schwartz FD. The natural history of the renal manifestations of systemic lupus erythematosus. J Lab Clin Med 1964;63:537–50. 36. Fries JF, Sharp GC, McDevitt HO, Holman HR. A control trial of cyclophosphamide therapy in connective tissue disease. Arthritis Rheum 1970;13:316–7. 37. Steinberg AD, Kaltreider HB, Staples PJ, Goetzl EJ, Talal N, Decker JL. Cyclophosphamide in lupus nephritis: a controlled trial. Ann Intern Med 1971;75:165–71. 38. Austin HA3rd, Klippel JH, Balow JE, le Riche NG, Steinberg AD, Plotz PH, et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 1986;314:614–9. 39. Steinberg AD. Efficacy of immunosuppressive drugs in rheumatic diseases. Arthritis Rheum 1973;16:92–6. 40. Ad Hoc Working Group on Steroid-Sparing Criteria in Lupus. Criteria for steroid-sparing ability of interventions in systemic lupus erythematosus: report of a consensus meeting. Arthritis Rheum 2004;50:3427–31. 41. Apostolopoulos D, Morand EF. It hasn’t gone away: the problem of glucocorticoid use in lupus remains. Rheumatology (Oxford) 2017;56(Suppl. 1):i114–22. 42. Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, et al. Prospective ob-servational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis 2013;72:1280–6. 43. Roccatello D, Sciascia S, Baldovino S, Rossi D, Alpa M, Naretto C, et al. A 4-year observation in lupus nephritis patients treated with an intensified B-lymphocyte depletion without immunosuppressive maintenance treatment-clinical response compared to literature and immunological re-assessment. Autoimmun Rev 2015;14:1123–30. 44. Liu Z, Zhang H, Liu Z, Xing C, Fu P, Ni Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med 2015;162:18–26. 45. Zhang H, Liu Z, Zhou M, Liu Z, Chen J, Xing C, et al. Multitarget therapy for maintenance treatment of lupus nephritis. J Am Soc Nephrol 2017;28:3671–8. 46. Fu SM, Deshmukh US, Gaskin F. Pathogenesis of systemic lupus erythematosus revisited 2011: end organ resistance to damage, autoantibody initiation and diversification, and HLA-DR. J Autoimmun 2011;37:104–12.

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47. Dahlström Ö, Sjöwall C. The diagnostic accuracies of the 2012 SLICC criteria and the proposed EULAR/ACR criteria for systemic lupus erythematosus classification are comparable. Lupus 2019;28:778–82. 48. Mosca M, Costenbader KH, Johnson SR, Lorenzoni V, Sebastiani GD, Hoyer BF, et al. Brief report: how do patients with newly diagnosed

systemic lupus erythematosus present? a multicenter cohort of early systemic lupus erythematosus to inform the development of new classification criteria. Arthritis Rheumatol 2019;71:91–8. 49. Holman H. The discovery of autoantibody to deoxyribonucleic acid. Lupus 2011;20:441–2.

Chapter 2

The patient Donald E. Thomas, Jr.a,b a

Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, United States; bArthritis and Pain Associates of Prince Georges County, Greenbelt, MD, United States

Any idiot can prescribe antibiotics to treat an ear infection, but that’s not what makes you a good physician. Dr Levana Sinai in Vital Conversations: Improving Communications Between Doctors and Patients1

Health care providers are usually good at keeping up with the pathophysiology, diagnosis, and management of diseases. Yet, we typically spend little time learning how to best communicate with patients. In fact, many of us never receive formal training in this subject. This chapter will provide you with important tools for taking care of patients who have systemic lupus erythematosus (SLE). If you put all of these measures to work in your own practice, you will take better care of your patients.

Improve the interactions with your patients Here are some concrete steps you can take to improve your interactions with your patients.

Do not make your patient wait One of the biggest complaints that patients have about their physician visits is long wait times.2 We must remember that our patient’s time is just as valuable as our own. We cannot control some problems, such as needing to answer important phone calls or needing to spend a longer amount of time on a particularly ill patient. However, we do have control over other potential causes of running behind. I recommend not overbooking patient appointments. Some physicians double-book patients in the same time slot just to ensure that their work time is kept busy. However, I am not at all a fan of this practice, which I believe is disrespectful of the patient’s time. I also do my best in preventing a late patient from causing me to run behind on my schedule; I don’t want this to keep other patients waiting longer than they should have to. In Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00002-7 Copyright © 2020 Elsevier Inc. All rights reserved.

these situations, I will see the late patient toward the end of the clinic, or at least get their laboratory work, refill their medications, and reschedule them to see me as soon as possible. If you are running behind due to something out of your control, make sure that someone on your staff informs the patient of the delay; if you have a moment, stick your head in the room yourself to give the message. When you eventually enter the room and greet your waiting patient, make sure to apologize and explain why you are running behind. These simple measures let the patients know that you respect them and value their time. If you were tending to a particularly ill patient, this lets them know that you would do the same for them if they were in a similar unfortunate situation.

Smile as you enter the patient’s room Smiling as you enter the room can help set the stage for the rest of the encounter. A smile as you enter the room lets your patient know that you are glad to be there, that the patient is important, and that you are eager to help. It is not uncommon to have to give bad news to patients who have lupus, such as a new onset of nephritis or worsening of a known manifestation. Initially smiling is important, even when you know that you need to give bad news. If you begin the encounter on a positive note, your patient will feel more comfortable, and this can help decrease any preexisting anxiety. As you enter the part of the conversation where you need to discuss bad test results, then your body language and speech can change appropriately.

Make a visible show of hand washing One of my most vivid memories of being a patient was when I had an appointment with a surgeon. I clearly heard him wash his hands outside my examination room. Then, when he examined me, I could smell the aroma of soap on his hands. This made a strong impression, making me believe 9

10 PART | I  Epidemiology and Diagnosis

that cleanliness was important to him. I automatically had confidence in him. Hand washing is so important that I have had patients even complain to me of other physicians not doing so before examining them. By overtly exhibiting hand washing, we can automatically increase their trust. This is not merely an empty performance; our patients have good reason to question our attention to cleanliness. Health care providers have low rates of hand washing before and after contact with patients.3 Infections continue to be among the top three causes of death in patients who have SLE,4 and hand washing is an important measure in decreasing the transmission of infections.

Shake hands After greeting your patient with a smile and washing your hands, shake the patient’s hand. This immediately adds a welcoming gesture to your patient and provides that first human touch to the encounter. Shaking hands allows you to immediately connect nonverbally with the patient and, along with the smile, sets the stage for a positive, open experience. Shaking the patient’s hand at the end of the encounter also helps to “seal the deal” regarding what was discussed and what the plan for management is.

Acknowledge and greet others in the room I recall the time that I accompanied my grandfather to an appointment with his ophthalmologist. The doctor never acknowledged my presence in the room the entire visit. I was there to help my grandfather understand what the doctor said and to communicate back to our family regarding his condition. I felt uncomfortable during the entire visit as the doctor rushed through the examination. At the end of the encounter, I introduced myself at what seemed to be the first opportune time, and the doctor still barely spoke to me as he rushed out of the room. If he had acknowledged me initially and found out I was the physician grandson, I would have felt more included in the visit and the doctor may have explained things to me more thoroughly in medical terminology so that I could then discuss the findings in layperson’s terms with my grandfather and family. If you acknowledge other people in the examination room, including children, it creates a more positive environment for everyone involved.

Ask open-ended questions When rushed for time, it is easy to ask questions that only require a yes-or-no answer (closed-ended questions). However, this makes it more difficult for the patient to truly communicate. A patient with lupus often has fears or concerns that should be addressed. If you only ask closedended questions, it is difficult for the patient to open up. However, if you train yourself to ask open-ended questions

(e.g., “Why are you here today, and how can I help you?”), you immediately show sincere concern and allow patients to bring up issues that are important to them. Our predetermined agenda for the meeting may be very different than what the patient wishes and needs. We often review other doctors’ and hospital records on our patients with SLE. If you have reviewed records, it can be helpful to say something to the effect, “I have reviewed the records from _______, and I understand you were ________. However, I’d like to hear from you, in your own words, why you are here today and how I can help you.” This shows that you care enough about the patient to have taken time to read over the records beforehand, and that you are interested in the patient’s concerns and personal points of view.

Provide a mechanism for your patient to set the agenda At each patient visit, we usually have our own agenda. This typically revolves around assessing lupus disease activity and making changes in management aimed at striving for remission or low disease activity while preventing complications from treatment and of the disease. However, we must allow our patients to have input regarding the visit agenda as well. Our patients usually will have questions about their care that are important to them. It can be difficult for them to remember these concerns during the appointment. In my office, we have found that an easy way of encouraging our patients to express additional concerns is by including a question on the patient’s intake paperwork that asks, “What questions do you have for your doctor today?” This allows our patients to list questions before the visit during a relaxed time period. This simple addition to the patients’ intake paperwork can add considerable value to their appointment.

Speak in nonmedical terms One of the most important aspects of the visit is to ensure that patients comprehend their medical condition and your instructions. If patients do not understand, they will be more likely to be less adherent to your recommendations. You should speak in nonmedical terms and avoid medical jargon so that the patient can fully understand you. It is important to tell patients their diagnoses and problems using the proper medical terms, but make sure to also write them down so that the patient can see these terms in print. Then, define the terms in easy-to-understand language. This is especially important in a disease such as lupus, where the test results and complications can be confusing. Write down your instructions and ask the patient to repeat what he or she is to do. Studies show that most patients do not understand what is discussed by their doctors and what their instructions are after their visits. One

The patient Chapter | 2

study showed that 72% of patients could not name their medications, and another 63% did not understand what the medications were even for.5 Patients can feel shame, anxiety, or be overwhelmed with information, preventing them from knowing what their doctor tells them. This can keep them from asking their doctor for clarification. If you ask your patients to repeat your instructions, then you can be assured that they understand you. If not, then you can adjust how you explain your instructions to make them more easily understood.

Be honest You are only human and are bound to make mistakes. Hopefully, you challenge yourself to constantly improve over time to minimize future mistakes. When physicians or staff cause a medical mistake, it is important to deal with this mistake directly and honestly. Studies show that admitting to mistakes helps significantly in preventing anger and litigation.6 I especially like the approach of Harvard-affiliated hospitals, which recommends three elements in addressing medical errors—take responsibility, apologize, and then discuss preventative measures with the patient or the family.7 I have found this approach to be very helpful when problems arise in my own office. For example, if a patient states that she had great difficulty contacting me and left unanswered messages, I will acknowledge the problem as well as voice how frustrating it had to be for her. I will apologize for it occurring and then discuss my plan for looking into the matter with my office manager to ensure that this does not recur in the future. This approach shows the patient that I care about her and want to improve and supply the best care possible.

to a patient’s suffering, empathy is more complex and involves learning to share the patient’s emotional struggles in a two-way relationship, actively gaining insight into the patient’s concerns, letting them know that they matter, imagining what it is like to be the patient, respecting the patient as an individual with dignity, then acting appropriately to help the patient based upon this gained understanding.10 An excellent method in learning how to be empathetic is to use Dr. Helen Riess’ approach: utilizing the acronym “E.M.P.A.T.H.Y.”11,12 This is easy to remember check-list that all of us can use before and during our patient encounters in order to enhance the experience and outcomes. l

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Learn to be empathetic Everyone can learn to be more empathetic. Putting forth the effort to do so will automatically make you a better physician. Few things can be more difficult for a patient who is dealing with an illness than to be confronted by a health care provider who appears uncaring or distant. Most patients state that having good bedside manner and exhibiting sincere empathy are important factors in choosing a physician.8 Not only does empathy improve the provider– patient relationship, it also improves the health outcomes of our patients. A 2016 study showed that when nurses proactively engaged in empathy with very ill SLE patients, those patients had significantly better quality of lives compared to those who only received the usual standard of medical care treatment.9 Learning to be empathetic is a skill that all physicians need to strive for, and it is worth noting that empathy is a learnable art. While compassion is an automatic reaction

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“E” stands for “Eye contact”: When someone makes eye contact with us (and vice-versa) this is the first nonverbal indication that we have been noticed. It is paramount that the patient realizes they have been noticed and have our full attention. “M” stands for “Muscles of facial expression”: This has a two-fold purpose. Firstly, emotions are subconsciously revealed by way of facial expressions (as well as by tone of voice). We need to pay attention to these subtle cues in our patient in order to decode how our patient is feeling, especially when it comes to emotions that should be dealt with delicately, such as fear. In addition, mimicking those facial expressions can result in a higher positive perception of empathy by your patient.13 “P” stands for “Posture”: Imagine performing one simple thing that would immediately cause you to appear warmer and more caring, as well as allowing your patient to perceive that you’ve spent significantly longer amounts of time with them than you actually did. Simply sit throughout your patient visit, both in the out-patient as well as in-patient setting. These were the results of studies comparing sitting doctors to standing doctors, even when using the same words during the encounters.14,15 Face your patient squarely, attempt to be close to eye level and make direct eye contact. Lean toward your patient in a relaxed posture in order to let her know that you are truly interested and that she is indeed the center of your attention. Body position is also important if you are rounding with a group of other healthcare providers. The senior person of the group should try to sit during the encounter and face the patient. Before talking about the patient with the group, it is polite to ask permission first, and then make sure to angle your body in such a way that you address the group as well as your patient. Turning your back on the patient while you speak can appear demeaning and can provoke anxiety. “A” stands for “Affect”: A person’s affect is his expressed emotions. Consciously strive to assess your patient’s affect. Doing so helps you achieve additional

12 PART | I  Epidemiology and Diagnosis

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understanding of your patient’s situation. Correctly interpreting your patient’s affect has even been shown to result in improved patient satisfaction, lower anxiety, and better adherence to therapy.16 “T” stands for “Tone of voice”: As with muscles of facial expression, tone is a two-way street. First, concentrating on your patient’s tone of voice is important in order to understand what emotional setting they are coming from. In addition, actively adjusting our own tone to sound warm and understanding is essential to showing our patient that we truly care. Try to match your verbal volume and pace as if you were having a conversation with a friend or relative during a difficult time. Avoid the habit of having a dominating voice; a 2002 study showed that simply having a dominating tone increases the risk for malpractice litigation as a physician.17 “H” stands for “Hear the whole person”: Truly be in the moment. Make your patient the most important person in your life at the time, and truly engage and listen. Concentrate both on nonverbal as well as verbal clues from your patient. Be openly curious about them; try to understand where they are coming from. “Y” stands for “Your response”: Try to absorb your patient’s emotions and feelings, respond to them and mirror them. It is important to put together all the above to shape your understanding of your patient’s situation. If your patient’s emotions are running high, avoid the natural tendency to respond defensively; instead, take a step back and don’t interrupt. Respond with compassion and without judgment.

Always examine your patient Of course, you should perform a physical examination on patients with SLE regularly. Picking up the pulmonary crackles of early interstitial lung disease, hearing the loud P2 sound of early pulmonary hypertension, noting periungual erythema, or observing painless palatal ulcers may provide insights to active disease. Do not forget to examine the concha of the outer ear; it is an area commonly involved in discoid lupus that is easily missed. Although physical examinations are not clinically necessary at every encounter (though I would argue that they should be done with SLE patients), it is important to note that the simple laying on of hands during the examination can provide immense meaning to our patient beyond what we feel is clinically needed. Many patients will assume that a proper visit is not complete without an examination. I have heard patients complain that another doctor did not do a good job because he did not examine them at each visit, and that they did not feel confident in the physician. Even a quick auscultation of the lungs and heart can impart a big sense of confidence.

End the visit with, “Do you have any other concerns or questions?” Most of us dread hearing, “Oh, by the way doctor, I also have been having this other problem,” just as we are heading out the door. It can then be difficult not to appear hurried as you try to quickly address this last-minute issue. However, if you ask this question at a moment when you do have some extra time left, you will be able to address these concerns in a more thoughtful, unrushed manner. Some patients may have problems that they may be ashamed or embarrassed about. If you offer one last chance to ask, it can show that you truly care.

Consulting in the hospital All of the above recommendations also apply when you have been consulted upon in a hospital setting. I have heard from my own family members about how upset they were when they received a bill from the hospital charging them for visits from doctors who they never even remembered seeing or interacting with. One study found that 85% of patients admitted to the hospital could not even name the physician taking care of them.18 I myself have been in situations where healthcare providers have entered my stall in the emergency room (where I was a patient), asked me some quick questions, yet never introduced themselves or stated why they were even there. These abrupt, anonymous encounters make the experience less than satisfactory. It is important to make every patient visit a positive one by following the above recommendations. Even if it is a consultation that you know will end up not requiring your continued help, make sure to introduce yourself, write down your name, explain why the admitting physician asked for your assistance and explain your assessment. Make sure to discuss your role in the patient’s care. This will let patients know why it is important that you see them and will provide value to your consultation on their case.

Improving adherence You should ask your patients at each visit how often they forget to take their medications. Only 50% of patients voluntarily admit to medication nonadherence on their own.19 I prefer to ask, “How often do you forget to take (name of medication)?” rather than, “Do you take your medicines regularly?” The former implies that I understand that it is impossible to take medicines 100% of the time and allows my patient to give a more honest answer. The latter is more apt to get a less-than-honest “yes” for an answer. One of the most important tools in improving adherence is education. If your patient understands why you recommend a treatment (e.g., how sunscreen prevents ultraviolet damage to

The patient Chapter | 2

skin cells, therefore decreasing immune system overactivity; how low vitamin D levels increase lupus disease activity), he or she will be more likely to abide by your recommendations. It is also important to investigate other potential barriers. Some patients may have difficulty affording their medicines, pills may be too large or cause side effects, or the patient may be so busy that she keeps forgetting to take them. Once the reasons for poor adherence are identified, you can address the problems with practical solutions. It is important to also ask your patients about stressors that may be interfering with good health. The more you know about your patients’ lifestyles, the more insight you can have into how they deal with their disease. If you do not understand their difficulties, it can be easy to make statements that are insensitive and unrealistic. For example, telling a young woman with SLE complaining of fatigue to “just go home and rest,” when she is a single parent of two young children and works a full-time job, would not be a reasonable recommendation.

Disability Unfortunately, SLE can be severe in many patients, preventing them from continuing in their line of work.20,21 As physicians, few of us are trained in how to deal with disability. Applying for and obtaining disability can be very difficult and frustrating for patients. There are some simple habits that we can get into as physicians that can simplify the process. In fact, these habits can also make our jobs as the physician much easier in the disability process. If you follow these suggestions, your progress notes on your patient can often suffice in the support of disability, possibly eliminating the need for you to write extensive letters or filling out a lot of paperwork. It is important to clearly designate how your patient was diagnosed with SLE. I recommend documenting the manifestations and laboratory abnormalities of your patient’s SLE on each progress note. I am in this habit primarily because it reminds me of the clinical aspects to pay attention to my patients at each visit. I will then add any new manifestations to this list as they occur over time. From a disability standpoint, this habit makes it easier for reviewing officials to ascertain if a proper diagnosis was made rather than having to sift through mounds of medical paperwork. The United States Social Security Administration (SSA) lists SLE in Section 14.02 of its “Blue Book” as one of its listed conditions. It states that a person with SLE needs to have two of the following constitutional symptoms in order to be disabled—severe fatigue, fever, malaise, and involuntary weight loss. These are common problems in our patients, yet it is easy for us to forget to document them. Therefore, do not forget to also include these in your list of lupus manifestations. For example, most SLE patients feel malaise, yet we typically do not note it as a symptom

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or manifestation. Mosby’s Medical Dictionary defines malaise as “a vague uneasy feeling of body weakness, distress, or discomfort.”22 The SSA also requires involvement of at least two organ systems, one of which must be of at least moderate severity. Simply having SLE is insufficient for obtaining disability. The SSA requires that lupus cause severe limitations in the person’s activities of daily living, social functioning, or in “completing tasks in a timely manner due to deficiencies in concentration, persistence, or pace” in order to be considered disabled.23 On your office visit intake sheet, ask your patients about what difficulties they have at home or work due to their condition. If any difficulties are occurring, add this information to your clinic note. This should suffice for documenting how lupus may or may not limit a patient’s daily activities. We do this regularly in our office; it is an easy and useful habit. It is also important to include in your note that the condition, SLE, is permanent and lifelong because these are also required for SSA disability. (This section was written in consultation with Sharon Christie, Esq, a disability attorney in Baltimore, MD.)

Patient education Today, patients have more access to patient education than ever before, thanks to the internet. Unfortunately, much of what patients encounter online is incorrect. Therefore, it is up to physicians to lead them in the right direction. SLE is complex and requires patients to do much more than take medications. Proper treatment includes using sunscreen regularly, avoiding substances that can worsen lupus, eating a proper diet, getting proper vaccinations to prevent infections, and taking vitamin D regularly (often lifelong) if deficient. Due to this long list of recommendations, I have come up with a list that I call “The Lupus Secrets” that I hand out to all my patients. It is a checklist of what patients should be doing regularly in order to ensure good health with their lupus. A copy of my “Lupus Secrets” is provided at the end of this chapter.24 I encourage you to consider making copies of this list and giving it to your patients as well. In addition, some accurate patient resources that I recommend are provided here. Books l

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The Lupus Encyclopedia: A comprehensive guide for patients and families, by Donald Thomas, Johns Hopkins University Press, 2014. The Lupus Book: A guide for patients and their families, 6th edition, by Daniel Wallace, Oxford University Press, 2019. Lupus Q&A Revised and Updated, 3rd edition: Everything you need to know, by Robert Lahita and Robert Phillips, Avery Trade, 2014.

14 PART | I  Epidemiology and Diagnosis

The lupus secrets 1. Avoid sulfa antibiotics (Bactrim); include them in your allergy list. 2. Keep a personal record of your lab and biopsy results, x-rays, and doctors’ notes (especially those that established your diagnosis of SLE). 3. See a rheumatologist or other lupus specialist regularly, commonly every 3 months, even if you feel great. Kidney inflammation occurs in around 40% of SLE patients and doctors can identify it at early stages when it is easy to treat. 4. Take 81 mg of aspirin in a day to decrease the risk for heart attacks and strokes (check with your doctor first). 5. Get 8 hours of quality sleep daily. (Get a list of sleep hygiene recommendations from your doctor if sleep is a problem.) 6. Tell your doctor if you feel depressed or down in the dumps, especially if you have thoughts about hurting yourself. 7. If you have problems with dryness, ask your doctor if you could have Sjögren’s syndrome. Treatment is important and available. 8. Keep blood pressure consistently 90%) markers for SLE, although the prevalence and sensitivity in SLE is only 5%–30%. The Sm antigen was defined as an snRNP by Lerner and Steitz,24 and the B’/B and D1/D2/D3 proteins bound to U-rich small nuclear RNAs (snRNAs) became known as the primary protein targets.25 Consequently, these autoantibodies have served as useful probes to help investigate the molecular and cellular functions of the spliceosome, which is responsible for premRNA splicing of heterogeneous nuclear RNA to mature messenger RNA (mRNA). In this section, we discuss the major classes of autoantibodies to snRNP including antiSm (Smith), anti-U1RNP (also known as anti-nRNP), antiU1/U2RNP, and briefly review minor autoantibodies to other classes of UsnRNPs, such as LSm (Like Sm) and RNPC3 (U11/12) proteins.

Cellular localization and function of snRNP Components of snRNPs snRNPs are classified according to their association with specific snRNAs, including the most abundant U1, U2, U4, U5, and U6 RNAs (Fig. 28.2A). Each snRNP is an RNA-protein macromolecule of corresponding UsnRNA complexed with several proteins. Common anti-snRNPs autoantibodies are classified into anti-U1RNP that recognize U1snRNPs and anti-Sm that recognize U1, U2, U4-6, and U5 snRNPs (Fig. 28.2A, see specificity). The Sm core proteins B or B’ (27/28 kDa), D1/D2/D3 (14 kDa), E (12 kDa), F (11 ), and G (9 kDa), which are organized as seven-member ring structures (Fig. 28.2B, Sm ring, Sm core particle) are shared by U1, U2, U4/U6, and U5 snRNPs. Since these shared Sm core proteins are recognized by anti-Sm antibodies, U1, U2, U4/U6, and U5 snRNAs are immunoprecipitated by anti-Sm antibodies, whereas only U1RNA is immunoprecipitated by anti-U1RNP antibodies (Fig. 28.2A). In addition to the Sm core particle, each snRNP is associated with several unique proteins. U1snRNPs (U1RNP) has U1snRNP specific proteins U1-70k (68/70 kD), A (33 kD), and C (22 kD). U2snRNP has two unique proteins, U2-A’ and B”. U4/U6snRNP and U5snRNP have several unique proteins in addition to the Sm core particle which, except the U5-200 kD doublet, are not included in Fig. 28.2A.

Antihistone and antispliceosome antibodies Chapter | 28

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FIGURE 28.2  Structure and components of snRNPs. (A) RNA and protein components of snRNPs: specificity of anti-Sm (red), -U1RNP (blue), -U1/U2RNP, and -U2RNP (green), and RNA and protein components of each snRNP are illustrated as bands displayed in a typical radiolabeled protein immunoprecipitation gel analysis. (B) Components of Sm ring: seven-member Sm ring has structural similarity to a doughnut. The center of the structure is involved in binding to single-stranded RNA.

Reactivity of anti-snRNPs autoantibodies Following immunoprecipitation (IP) using human autoimmune sera with anti-snRNP autoantibodies, RNA and protein components can be analyzed (Fig. 28.3). U1RNA is seen in anti-U1RNP immunoprecipitates (lane U1RNP), whereas U1, U2, U4, U5, and U6 RNAs are seen with anti-Sm immunoprecipitates (lane Sm, Fig. 28.3A). The protein components are usually visualized by radiographs of immunoprecipitated cell extracts metabolically labeled with 35S-methionine (Fig. 28.3B). To identify which proteins are directly recognized, western blot using affinity-purified snRNPs is the standard method. Anti-U1RNP sera frequently react in various combinations with U1-70k, A, B′/B, and less frequently with C proteins. Anti-Sm antibodies react with Sm-B′/B and D1/D2/D3 proteins. Because the majority of SLE anti-Sm sera also have anti-U1RNP antibodies, reactivity with U1 unique proteins are also seen in anti-Sm positive sera. In contrast to short linear epitopes for T cells, classic characteristic of autoimmune B-cell epitopes are discontinuous conformational epitopes within each polypeptide of the snRNPs.26 In addition, autoantibodies that recognize the conformational structure of the multiprotein complexes, possibly quaternary structure, have been described, including EFG complex27 and U1-C-Sm core particle.28 Autoantibodies to LSm4 and LSm complex (complex of highly conserved “like Sm” proteins) also were reported.29

History of detection of autoantibodies to snRNPs and potential problems Our understanding of the difference in reactivity of antiU1RNP versus anti-Sm is incomplete, and changes in technology further complicate the issue. Diagnostic assay technologies started with Ouchterlony double immunodiffusion (DID) followed by passive hemagglutination, IP detection of UsnRNA and protein components, western blot detection of reactivity to individual protein components, eventually evolving to LIA, ELISA, ALBIA, chemiluminescence immunoassay (CIA), and other solid-phase multianalyte immunoassays (SPMAIA). The source of antigens (analytes) used in various immunoassays has evolved over time; antigens have spanned the spectrum from purified extracts of calf or rabbit thymus to human cell lines and eventually the large-scale production of recombinant proteins. Historically, DID was the assay used to detect antiSm reactivity.23 Anti-U1RNP was originally reported as anti-Mo that recognized soluble nuclear ribonucleoprotein (nRNP) and produced a distinctive precipitin line from antiSm in DID. At about the same time, the same group of specificities (anti-snRNPs) were reported as anti-ENA that was based on a classification into RNase sensitive anti-ENA (correspond to anti-U1RNP) and RNase-resistant anti-ENA (correspond to anti-Sm). In initial studies, Sm was distinguished from RNP based on the ribonuclease sensitivity of the latter in hemagglutination and other assays.30 After this

242 PART | II  Pathogenesis

FIGURE 28.3  Immunoprecipitation using anti-snRNPs antibodies. (A) RNA components immunoprecipitated from cell extract by human sera were extracted, run on urea-polyacrylamide gel, and identified by silver staining. (B) snRNPs-associated proteins metabolically radiolabeled with 35 S-methionine were immunoprecipitated from cell extract of K562 cells by human autoimmune sera and fractionated by 12.5% or 8% SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and visualized by autoradiography.

period, the source of antigens used for immunoassays gradually shifted from calf or rabbit thymus tissues to human cell lines and recombinant human proteins. This was paralleled by a switch in ANA substrates from cryopreserved animal tissues to human culture cell lines such as HEp-2 (laryngeal cancer).

Detection of antibodies to snRNPs in clinical practice In the contemporary clinical setting autoantibodies to Sm and U1RNP are detected by a staged approach. First, the IIF assay using HEp-2 cells is considered the screening method of choice. By IIF, anti-U1RNP and anti-Sm autoantibodies show a large/coarse nuclear speckled pattern (AC5, Fig. 28.1B and C). There are many other autoantibody specificities that show a similar ANA pattern but, certainly, anti-U1RNP and Sm should be considered when the coarse nuclear speckled pattern is observed. The titer of ANA

IIF for these two target is often very high, >1:1280, particularly in patients with mixed connective tissue diseases (MCTD)—as well as in SLE or undifferentiated connective tissue disease (UCTD). To confirm anti-U1RNP or -Sm specificities, a variety of SPMAIA31,32 using recombinant or affinity purified antigens are commonly used in modern, high-throughput diagnostic laboratories. Other mono-analyte assays such as ELISA, and counterimmunoelectrophoresis, and DID continue to be used in other laboratories. Although ELISA will identify majority of true positives, it may be troubled by a significant percentage of false positives, in particular anti-Sm.33 Improved sensitivity of the anti-U1RNP ELISA and SPMAIA using recombinant U1-70k, A, and C proteins was accomplished by adding U1RNA, via the formation of new epitopes resulted from interaction of U1RNA with the proteins antigens.34 Other improvement in ELISA was the use of symmetric dimethylarginine modified Sm-D derived peptide to detect anti-Sm antibodies35 based on earlier

Antihistone and antispliceosome antibodies Chapter | 28

studies indicating the importance of this posttranslational modification in anti-Sm antibody reactivity. With recent emergence of large, high-throughput laboratories, the emphasis has shifted to SPMAIA, such as ALBIA, CIA, and LIA, which can be automated, effecting cost savings, and rapid turnaround times.31,36 LIA, which is similar to dot blot immunoassay but contains multiple autoantigens individually printed on membrane strips, has been adopted by some laboratories. Other new types of assay include ALBIA and CIA in which individual antigens are covalently bound to beads of different composition. Advantages of these assays include the detection of multiple autoantibodies in a single assay and the requirement for only small amounts (typically 85% of the female mice in R314-1, R503-10, R286-7 and R290-2 have severe proteinuria. The incidence of severe proteinuria is more than that in the parental line. This suggests that certain gene(s) in NZM2328 within the region of 169.22-172.16 Mb on chromosome 1 may have suppressive function. Similarly, there appears to be a suppressor gene within 171.14-178.21 Mb on chromosome 1 within NZM2328. Thus, there are significant interactions within the c1 region within NZM. The finding of resistance genes to end organ damage in the mouse may have translational potential. The human homolog of the genetic region of interest is depicted in Fig. 35.2D. With the exception of 170000P17Rik the human homolog of Cgnz1 region has identical genes in the exact gene order as that of mouse Cgnz1. This suggests that evolution pressure keeps these genes together. The complexity of the genetics of the NZM2328 mouse model of LN provides an explanation for the marked variation of the clinical course of human LN. These genetic factors should be taken into consideration of our understanding of the pathogenesis of LN.

Human genetics on lupus susceptibility genes

Silent LN

Origin of SLE-related auto-Abs

Human LN has been considered to be the prototype of IC mediated diseases.11 The nature of IC deposition has been studied intensively. Clinically IC deposition alone may not lead to declining renal function. Clinically this is exemplified by the natural history of “silent LN.”23 These patients have little proteinuria and no significant cellular elements in their urine and their renal biopsies showed pathology compatible with LN. It is of interest to note that most patients with proliferative LN (class III and class IV) who had second renal biopsies did not develop further changes in their histopathology. “Silent LN” may have relevance to end organ resistance to damage.

Nature of T cell epitopes in lupus-related auto-Ags and HLA-DR determines auto-Ab initiation and diversification. It was determined that mice with DR3 transgene respond best to immunization with recombinant Ro60 and SmD.28,29 In addition, NZM2328.DR3 were shown to have spontaneous lupus-like nephritis with auto-Abs to SmD.30 These observations provide the basis to use mice with the DR3 transgene to map T cell epitopes on SmD and Ro60. With the generation of T-T hybridomas reactive to SmD, seven regions of SmD were shown to contain unique T cell epitopes that are restricted by DR3.31 Each T-T hybridoma uses a unique TCR, which recognizes slightly different T

Most susceptibility genes in man affect autoantigen (autoAg) expression and IC clearance, innate immunity and adaptive immunity.24,25 These genes can be classified into four categories. The first category are genes that contribute to auto-Ag expression, apoptosis, autophagy, DNA repair, lysosome function and IC clearance, and auto-Ag clearance. The second category are genes involving innate immunity that involve toll like receptor (TLR) function, type 1 interferon (IFN) signaling and pro-inflammatory cytokine production that involves NFkB signaling. They may also be involved in neutrophil and macrophage functions. The third category are genes involving adaptive immunity. These genes determine Ag presentation, and T and B cell signaling and activation. These three categories of genes determine the immune responses to pathogens and Ags that may illicit autoimmune responses. In addition they may control the effector functions that are crucial to organ damage. The fourth category of genes have functions yet to be determined. Each gene confers a small effect with odds ratio (OR) usually  5’ DNA exonuclease develop inflammatory myocarditis. Mol Cell Biol 2004;24:6719–27. 25. Scolding NJ, Joseph FG. The neuropathology and pathogenesis of systemic lupus erythematosus. Neuropathol Appl Neurobiol 2002;28:173–89. 26. Daly D. Central nervous system in acute disseminate lupus erythematosus. J Nerv Ment Dis 1945;102:461–5. 27. Joseph FG, Scolding NJ. Neurolupus. Pract Neurol 2010;10:4–15. 28. Wiseman SJ, Ralston SH, Wardlaw JM. Cerebrovascular disease in rheumatic diseases: a systematic review and meta-analysis. Stroke 2016;47:943–50. 29. Hanly JG, Walsh NM, Sangalang V. Brain pathology in systemic lupus erythematosus. J Rheumatol 1992;19:732–41. 30. Ellis SG, Verity MA. Central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 1955–1977. Semin Arthritis Rheum 1979;8:212–21. 31. Sibbitt Jr WL, Brooks WM, Kornfeld M, Hart BL, Bankhurst AD, Roldan CA. Magnetic resonance imaging and brain histopathology in neuropsychiatric systemic lupus erythematosus. Semin Arthritis Rheum 2010;40:32–52. 32. Wiseman SJ, Bastin ME, Jardine CL, et al. Cerebral small vessel disease burden is increased in systemic lupus erythematosus. Stroke 2016;47:2722–8. 33. Arkema EV, Svenungsson E, Von Euler M, Sjowall C, Simard JF. Stroke in systemic lupus erythematosus: a Swedish population-based cohort study. Ann Rheum Dis 2017;76:1544–9. 34. Hahn BH, Grossman J, Chen W, McMahon M. The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. J Autoimmun 2007;28:69–75. 35. 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;74:480–9. 36. Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet 2010;376:1498–509. 37. Salmon JE, de Groot PG. Pathogenic role of antiphospholipid antibodies. Lupus 2008;17:405–11. 38. Hunt D, Kavanagh D, Drummond I, et al. Thrombotic microangiopathy associated with interferon beta. N Engl J Med 2014;370:1270–1. 39. Kavanagh D, McGlasson S, Jury A, et al. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature. Blood 2016;128:2824–33. 40. Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med 2013;19:1584–96. 41. Stock AD, Gelb S, Pasternak O, Ben-Zvi A, Putterman C. The blood brain barrier and neuropsychiatric lupus: new perspectives in light of advances in understanding the neuroimmune interface. Autoimmun Rev 2017;16:612–9. 42. Hammer C, Stepniak B, Schneider A, et al. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity. Mol Psychiatry 2014;19:1143–9.

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43. Kowal C, DeGiorgio LA, Nakaoka T, et al. Cognition and immunity; antibody impairs memory. Immunity 2004;21:179–88. 44. Nishimura K, Harigai M, Omori M, Sato E, Hara M. Blood-brain barrier damage as a risk factor for corticosteroid-induced psychiatric disorders in systemic lupus erythematosus. Psychoneuroendocrinology 2008;33:395–403. 45. Jacob A, Hack B, Bai T, Brorson JR, Quigg RJ, Alexander JJ. Inhibition of C5a receptor alleviates experimental CNS lupus. J Neuroimmunol 2010;221:46–52. 46. Jacob A, Hack B, Chiang E, Garcia JG, Quigg RJ, Alexander JJ. C5a alters blood-brain barrier integrity in experimental lupus. FASEB J 2010;24:1682–8. 47. Kraus J, Voigt K, Schuller AM, et al. Interferon-beta stabilizes barrier characteristics of the blood-brain barrier in four different species in vitro. Mult Scler 2008;14:843–52. 48. Gaynor B, Putterman C, Valadon P, Spatz L, Scharff MD, Diamond B. Peptide inhibition of glomerular deposition of an anti-DNA antibody. Proc Natl Acad Sci USA 1997;94:1955–60. 49. DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 2001;7:1189–93. 50. Fragoso-Loyo H, Cabiedes J, Orozco-Narvaez A, et al. Serum and cerebrospinal fluid autoantibodies in patients with neuropsychiatric lupus erythematosus. Implications for diagnosis and pathogenesis. PLoS One 2008;3:e3347. 51. Kowal C, Degiorgio LA, Lee JY, et al. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc Natl Acad Sci USA 2006;103:19854–9. 52. Faust TW, Chang EH, Kowal C, et al. Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. Proc Natl Acad Sci USA 2010;107:18569–74. 53. Probstel AK, Thanei M, Erni B, et al. Association of antibodies against myelin and neuronal antigens with neuroinflammation in systemic lupus erythematosus. Rheumatol (Oxford) 2018;. 54. Hanly JG, Robichaud J, Fisk JD. Anti-NR2 glutamate receptor antibodies and cognitive function in systemic lupus erythematosus. J Rheumatol 2006;33:1553–8. 55. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7:1091–8. 56. Husebye ES, Sthoeger ZM, Dayan M, et al. Autoantibodies to a NR2A peptide of the glutamate/NMDA receptor in sera of patients with systemic lupus erythematosus. Ann Rheum Dis 2005;64:1210–3. 57. Schwarting A, Mockel T, Lutgendorf F, et al. Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies. Ann Rheum Dis 2019;78:1226–34. 58. Lennox BR, Pollak T, Palmer-Cooper EC, et al. Serum neuronal cellsurface antibodies in first-episode psychosis-Authors’ reply. Lancet Psychiatry 2017;4:187–8. 59. Lennox BR, Palmer-Cooper EC, Pollak T, et al. Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study. Lancet Psychiatry 2017;4:42–8. 60. Bonfa E, Golombek SJ, Kaufman LD, et al. Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl J Med 1987;317:265–71. 61. Karassa FB, Afeltra A, Ambrozic A, et al. Accuracy of anti-ribosomal P protein antibody testing for the diagnosis of neuropsychiatric sys-

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temic lupus erythematosus: an international meta-analysis. Arthritis Rheum 2006;54:312–24. 62. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85:177–89. 63. Alexopoulos H, Kampylafka EI, Fouka P, et al. Anti-aquaporin-4 autoantibodies in systemic lupus erythematosus persist for years and induce astrocytic cytotoxicity but not CNS disease. J Neuroimmunol 2015;289:8–11. 64. Asgari N, Jarius S, Laustrup H, et al. Aquaporin-4-autoimmunity in patients with systemic lupus erythematosus: A predominantly population-based study. Mult Scler 2017:1352458517699791. 65. Pittock SJ, Lennon VA, de Seze J, et al. Neuromyelitis optica and non organ-specific autoimmunity. Arch Neurol 2008;65:78–83. 66. Damato V, Evoli A, Iorio R. Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders: a systematic review and meta-analysis. JAMA Neurol 2016;73:1342–8. 67. Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci 1957;147:258–67. 68. McGlasson S, Jury A, Jackson A, Hunt D. Type I interferon dysregulation and neurological disease. Nat Rev Neurol 2015;11:515–23. 69. International Consortium for Systemic Lupus Erythematosus G, Harley JB, Alarcon-Riquelme ME, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008;40:204-10. 70. Gunther C, Kind B, Reijns MA, et al. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J Clin Invest 2015;125:413–24. 71. Rodero MP, Decalf J, Bondet V, et al. Detection of interferon alpha protein reveals differential levels and cellular sources in disease. J Exp Med 2017;214:1547–55. 72. Khamashta M, Merrill JT, Werth VP, et al. Sifalimumab, an anti-interferon-alpha monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis 2016;75:1909–16. 73. Banchereau R, Hong S, Cantarel B, et al. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell 2016;165:551–65. 74. Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: the type I interferonopathies, a conceptual overview. J Exp Med 2016;213:2527–38. 75. Heinze S, Egberts F, Rotzer S, et al. Depressive mood changes and psychiatric symptoms during 12-month low-dose interferon-alpha treatment in patients with malignant melanoma: results from the multicenter DeCOG trial. J Immunother 2010;33:106–14. 75a. Williams J, McGlasson S, Irani S, et al. Neuromyelitis optica in patients with elevated interferon-alpha concentrations. Lancet Neurol 2020;19:31–3 Available from: https://www.thelancet.com/journals/ laneur/article/PIIS1474-4422(19)30445-4/fulltext. 76. Santer DM, Yoshio T, Minota S, Moller T, Elkon KB. Potent induction of IFN-alpha and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. J Immunol 2009;182:1192–201. 77. Bialas AR, Presumey J, Das A, et al. Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature 2017;546:539–43. 78. Wiseman SJ, Bastin ME, Hamilton IF, et al. Fatigue and cognitive function in systemic lupus erythematosus: associations with white

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matter microstructural damage. A diffusion tensor MRI study and meta-analysis. Lupus 2017;26:588–97. 79. Campbell IL, Abraham CR, Masliah E, et al. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci USA 1993;90:10061–5. 80. Stock AD, Wen J, Putterman C. Neuropsychiatric lupus, the blood brain barrier, and the TWEAK/Fn14 pathway. Front Immunol 2013;4:484.

81. Wen J, Xia Y, Stock A, et al. Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway. J Autoimmun 2013;43:44–54. 82. Ransohoff RM, El Khoury J. Microglia in health and disease. Cold Spring Harb Perspect Biol 2015;8:a020560. 83. Wang J, Yang C, Zhao Q, Zhu Z, Li Y, Yang P. Microglia activation induced by serum of SLE patients. J Neuroimmunol 2017;310: 135–42.

Chapter 39

Constitutional symptoms and fatigue in systemic lupus erythematosus Syahrul Sazliyana Shaharira and Caroline Gordon,b a

Rheumatology Unit, Department of Internal Medicine, National University of Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia; bRheumatology Research Group, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom

Introduction

Fatigue

Constitutional symptoms are very common in systemic lupus erythematosus (SLE) but are rather nonspecific; therefore, they are not taken into account in the classification criteria for SLE. Fatigue is the most common constitutional symptom associated with SLE, affecting up to 90% of patients. Other constitutional symptoms such as fever, anorexia, lymphadenopathy, and splenomegaly are less common. The presence of constitutional symptoms may reflect ongoing active disease. It is one of the systems assessed in British Isles Lupus Assessment Group (BILAG) 2004 disease activity index, which includes the assessment of fever, anorexia, lymphadenopathy, and splenomegaly but not fatigue1,2 because attribution to lupus is difficult and fatigue is often multifactorial, as will be discussed later. In the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), fever is the only variable that is taken into account for disease activity scoring.3 Clinicians should be aware that constitutional symptoms have an exhaustive list of differential diagnoses that need to be excluded before attributing the symptoms to the underlying lupus. Other differential diagnoses that need to be considered include infection, metabolic disorders, malignancy, primary hematological disorders, and other systemic rheumatic diseases. This chapter discusses each of the constitutional symptoms that may occur in SLE in more detail, focusing the potential differential diagnosis and the potential underlying cause of the constitutional symptoms in lupus patients.

Fatigue is defined as “an uncommon, abnormal or extreme whole bodily tiredness disproportionate or unrelated to activity or exertion.”4,5 It is one of the most common and often most disabling symptoms, affecting up to 80%–90% of patients.4 It causes significant morbidity with negative impact on quality of life (QoL). Studies have shown that fatigue correlates moderately or strongly with all components of the SF-366 and is a major component of vitality domain. Fatigue is multifactorial5–14 and is only related in part to lupus disease activity.6 Even patients with quiescent lupus continue to experience marked fatigue.7 Physical inactivity and obesity are found to be significantly associated with fatigue among SLE patients.15 In addition to that, a decrease in the deformability of the red blood cells membrane due to the C4d deposition and complement activation in SLE may further reduce their ability to flow through small capillaries in the brain and muscle.8 Hence, the defective oxygen delivery may partly explain the chronic fatigue experienced by SLE patients. Psychosocial variables have also been found to have compelling associations with fatigue levels.7,12 It is associated with high scores on subscales for depression and hysteria on the Minnesota Multiphasic Personality Inventory-2, as well as with high scores in Beck Depression Inventory.12 Due to the various factors that are associated with fatigue in SLE, the underlying causes need to be investigated so that appropriate intervention can be initiated (Fig. 39.1). In view of the substantial impact of fatigue on SLE patients, the Outcomes Measures in Rheumatology (OMERACT) initiative recommended the measurement of fatigue

Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00039-8 Copyright © 2020 Elsevier Inc. All rights reserved.

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352 PART | IV  Clinical aspects of the disease

FIGURE 39.1  Factors and associations of fatigue in systemic lupus erythematosus.

as one of the patient-reported outcomes (PROs) in SLE clinical trials.16 During the period of 1970-2006, the Fatigue Severity Scale (FSS) was commonly used and therefore it was recommended by the working group and expert panels of the Ad Hoc Committee on SLE Response Criteria for Fatigue. 17 This instrument was developed in patients with SLE, has a valid psychometric property, and is commonly used in SLE studies.17 Both the US Food and Drug Administration and the European Medicines Agency have also recommended the use of PROs instruments to measure fatigue as an endpoint in SLE clinical trials. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale has been increasingly used as it demonstrated greater sensitivity to detect differences in fatigue levels compared with the FSS and the Medical Outcomes Study Short Form 36 (SF-36) Vitality domain.18 Both FACIT-Fatigue and SF-36 were used in phase III Belimumab trials and were found to be able to detect the improvements, consistent with the clinical endpoints.19 Recently, there is an increasing interest on

the Patient-Reported Outcomes Measurement Information System (PROMIS) as a tool to measure fatigue in SLE.20 PROMIS offers effective PRO measurement in various QoL domains and can be used for both adult and pediatric populations.20 Besides fatigue, disease activity and damage, psychosocial factors are among the important predictors of poor QoL in SLE (Fig. 39.2). Important factors include psychological disorders (anxiety, depression), which may be exacerbated by active disease and damage and lead to poor QoL (greater pain, helplessness and physical disability)21 and poor social support22 (Chapter 6).

Management of fatigue in SLE Despite being the most frequent disabling symptom in SLE, there are very few clinical trials that have addressed both pharmacologic and non-pharmacologic management of fatigue. A number of psychological interventions that have been reported to be effective included cognitive–behavior

Constitutional symptoms and fatigue in systemic lupus erythematosus Chapter | 39

353

FIGURE 39.2  Association and relationship between psychosocial factors with fatigue and poor quality of life in SLE.

therapy,23 psychoeducational programs,24 relaxation, and self-management course.25 Patients with SLE may adopt the aerobic exercise programs that begin with low-intensity activities and avoid provoking symptoms. Subsequently the intensity can be increased gradually by combining aerobic and resistance training. Ideally, exercise should be performed at least 3 times weekly for 15–30 minutes as tolerated.26 Systematic reviews on non- pharmacological interventions for the management of fatigue as mentioned above revealed that both psycho-educational interventions and aerobic exercise were effective in reducing fatigue in patients with SLE.27,28 However, due to the diversity of the fatigue instruments and psychological intervention methods, the outcomes were not always consistent and solid conclusions could not be drawn.27,29 Since obesity is associated with fatigue in SLE patients, losing weight may be an appropriate strategy to alleviate fatigue. Dietary modification with lower glycemic index or low calorie diet were equally helpful in reducing weight and fatigue in a small study involving 23 SLE patients.30 Dietary vitamin D3 supplementation at 400–1,200 IU per day was shown to help in reducing fatigue in an open-label observational study.31 N-acetylcystein (an amino acid precursor of glutathione) intake of 2.4 gm/day was well tolerated and has favorable effect on disease activity and fatigue as compared to placebo in a small study involving 36 patients.32 However, the number of subjects in these studies were small and hence future larger studies with preferably randomized controlled trials are needed before making strong recommendations. The benefit of pharmacological treatment in fatigue is also weak. There is some evidence that stopping hydroxychloroquine results in increased fatigue.33 The role of dehydroepiandrosterone (DHEA) in SLE patients with fatigue showed inconsistent results 25 and the use of DHEA are largely limited due to the side effects include acne, hirsutism, weight gain, and menstrual changes. Belimumab improved fatigue in the BLISS (Study of Belimumab in Subjects with Systemic Lupus Erythematosus) trials as assessed

by the Functional Assessment of Chronic Illness Therapy Fatigue scale (secondary end point).34 Improvement in QoL measured by Short Form-36 survey was observed in a randomized control trial of epratuzumab in SLE patients.35 Unfortunately, the high cost and potential side effects of these new biologic agents limit their use for the exclusive treatment of fatigue in SLE. There are many causes of fatigue in SLE patients, and most commonly many factors contribute to fatigue in lupus patients rather than a single factor. Therefore, the treatment strategy should be tailored to the individual’s main underlying cause, and will include physical and psychosocial health factors and other comorbidities that are associated with fatigue in SLE.

Fever The prevalence of fever in lupus patients has declined over the years. Earlier reviews in the 1950s–1960s reported a prevalence of up to 86%.36 However, it has declined to 41% in studies between 1980 and 1989.37 In the Euro-lupus cohort, fever was observed in 36% of patients at disease onset and in 52% during the course of the disease.38 Although an earlier report postulated that the availability and use of nonsteroidal anti-inflammatory drugs and steroids were the reason behind the reducing frequency of fever among SLE patients, the phenomenon is most likely explained by the greater awareness among clinicians to exclude other causes of fever (i.e., infection and malignancy). Fever is more common in childhood-onset lupus as compared to adultonset lupus,39 and patients with late-onset lupus (onset of more than 50 years old) experienced much less fever, with the reported prevalence of 8% at presentation.40 Although fever is becoming less common in SLE, its presence has always been a challenge and often creates a clinical conundrum for the clinicians. This is particularly the case when the symptoms occur at disease onset, prior to the diagnosis of SLE. Apart from SLE, fever may indicate the presence of many other conditions, such as infections, malignancies, or drug reactions41,42 (Table 39.1). It is

354 PART | IV  Clinical aspects of the disease

TABLE 39.1 Possible etiology of fever in systemic lupus erythematosus. Acute lupus

Usually associated with other manifestations of SLE

Infection

Viral Bacterial Mycobacterial Fungal Protozoal Nematodes

Malignancy

Lymphoma (Hodgkin’s or non-Hodgkin’s Primary carcinoma (e.g., renal) Metastatic carcinoma Myeloma

imperative to exclude these differential diagnoses because immunosuppressive treatment that is commonly used to treat SLE will cause detrimental effects to the patients in these situations. Careful history taking, physical examination and thorough investigations may help to identify the potential causes of fever, including atypical infections. To further complicate matters, an infectious process may also trigger SLE, and the two can occur concomitantly. Current biomarkers have poor specificity and sensitivity to differentiate between lupus activity and infection but nonetheless can provide some useful information. The features that favor infection include presence of chills/rigors, leukocytosis in the absence of steroid therapy,42 persistent fever despite improvement of other lupus signs or symptoms43 neutrophilia with increased numbers of band forms or metamyelocytes44 and high C-reactive protein (CRP).44 The median level of CRP in patients with SLE flares without serositis appears to be around 1.4–1.6 mg/dL, with a range of 0–6 mg/dL.45 However, in lupus serositis45 and synovitis,46 the serum CRP levels can be mild-moderately elevated above 6.0 mg/dl. High-sensitivity CRP (hsCRP) is found to be more reliable as values above 6 mg/dl may be associated with active infection with an 84% specificity in SLE patients.47 In addition to that, a ratio of erythrocyte sedimentation rate/ C-reactive protein (ESR/CRP ratio) above 15 was demonstrated to be significantly correlated with disease activity and a ratio below two was associated with infection.47 Serum procalcitonin (PCT) may also help in discriminating between infection and lupus activity as raised PCT levels ≥0.5 µg/L strongly suggest bacterial infection in febrile SLE patients.48 However, the number of studies included in the systematic review were small with a limited data available in case of hemophagocytic syndrome.48 Serum PCT levels may also increase in non-infectious

inflammatory conditions such as post-surgery, post-resuscitation, cardiogenic shock, severe pancreatitis or rhabdomyolysis.49 The effect of corticosteroids in suppressing fever in SLE is not well studied. However, in a study of small cohort of 22 SLE patients with fever, 28 mg (20–40 mg) prednisone completely suppressed SLE fever, usually within 24 h.43 In a study by Zhou et al., a prednisolone dose of ≤100 mg/d was able to suppress SLE fever in 80.6% of the patients within 1–5 days. When the maximum steroid dose was increased to ≥100 mg/d, only 5.3% of patients remained febrile.41 Therefore, a refractory fever despite a low-moderate dose of glucocorticoids, acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) should prompt the clinicians to further investigate for other potential causes, especially infections, in immunosuppressed SLE patients. A persistent fever despite a higher dose of steroids (>150 mg/ day) may be associated with lupus encephalopathy and hemophagocytosis.41 SLE patients are immunosuppressed due to the underlying disease and treatment, thus making them susceptible to various other less common pathogens, including opportunistic infections (Table 39.1), such as tuberculosis, Pneumocystis carinii, fungal infections, viral infections, nematodes, toxoplasmosis, and other protozoal infections (Chapter 45). Lupus patients are at increased risk of such infections because SLE patients often have antibodies to CD4+ T cells. Consequently, they can have low CD4+ T cell counts and reversed CD4:CD8 lymphocyte ratios, and they may even be misdiagnosed initially as suffering from human immunodeficiency virus (HIV; Chapter 13). Therefore, SLE patients with fever should be investigated thoroughly with multiple blood cultures, appropriate swabs of any potential sites of infection, and cultures and examination of urine, stool, and sputum. Further investigation may include white cell scans, ultrasound, and computed tomography or magnetic resonance imaging scans to exclude abscesses or cancers. Apart from infection, the possibility of malignancy and lymphoma should also be considered (Table 39.1 and Fig. 39.3). Studies have shown that there is a slightly increased risk for malignancy in SLE patients, compared to the general population, particularly non-Hodgkin’s lymphoma50 (Chapter 46). After all of the possible non-lupus causes of pyrexia have been ruled out, the fever can be attributed to the underlying SLE and can be recorded as part of the disease activity assessment, using standardized disease activity indices.2 However, it is important to note that different levels of fever are recorded in the various validated disease activity indices. The SLEDAI requires a documented temperature of more than 38°C.3 Meanwhile, the BILAG Index and the European Consensus Lupus Assessment Measure (ECLAM) record a documented fever of greater than 37.5°C.1,2 However, the ECLAM specifically requires

Constitutional symptoms and fatigue in systemic lupus erythematosus Chapter | 39

355

FIGURE 39.3  Algorithm of Approach to Fever in SLE.

that this should be the documented base or morning temperature.2 In all cases, the temperature must have been documented and not estimated by the patient or doctor, and infection should have been excluded as a cause. Fig. 39.3 illustrated the suggested approach and management of fever in SLE patients.51–53

Lymphadenopathy The estimated prevalence is between 5% and 7% at the onset of the disease, and 12%–15% at any time during course of the disease.54,55 Patients with lymphadenopathy are likely to have other constitutional symptoms, such as fever, weight loss, and lethargy.56 Therefore, it is pivotal

to exclude underlying infection and malignancy as well (as discussed above). Other common associated features of SLE patients with lymphadenopathy are more cutaneous and mucosal signs (malar rash, vasculitis, skin ulcers, mouth ulcers, discoid lesions, alopecia, and subcutaneous lupus erythematosus), higher rate of hepatomegaly and splenomegaly, increased anti-dsDNA antibodies titers, and decreased complement levels.56 Lymph nodes in SLE are usually soft, non-tender, mobile, generalize, and of varying size.57 Importantly, the size tends to fluctuate over time particularly with SLE disease exacerbations. In the BILAG Index palpable lymph nodes greater than 1 cm in diameter are recorded, providing that the cause is attributed to lupus.1,2 However, other

356 PART | IV  Clinical aspects of the disease

disease activity indices, such as SLEDAI, Systemic Lupus Activity Measure (SLAM), and ECLAM, do not record lymphadenopathy as part of their disease activity assessment.2 Malignancy, particularly lymphoma, should be suspected if the nodes steadily increase in size. This is particularly important because SLE patients have almost up to fourfold increase risk of non-Hodgkin’s lymphoma.50 Other infrequent infective causes of lymphadenopathy need to be excluded, including viral (cytomegalovirus [CMV], Epstein–Barr virus [EBV], parvovirus, varicella zoster virus [VZV], hepatitis, HIV), bacterial (brucellosis, syphilis, mycobacterial), fungal (histoplasmosis, toxoplasmosis, leishmaniosis), and rickettsial infection. A number of studies have confirmed a high frequency of previous EBV and CMV infection in SLE patients, but the role of these viruses in the lymphadenopathy and onset of lupus remains unclear. Clinical presentation of viral infections, especially CMV and EBV, may be difficult to distinguish from manifestations of active SLE58 (Chapter 45). In case of significant lymphadenopathy, lymph node biopsy is indicated to rule out infections, especially tuberculosis, or malignancy. Lymphadenopathy secondary to SLE represents a benign finding, with a mononucleosis-like behavior.58 Biopsy is nonspecific and commonly shows reactive follicular hyperplasia, increased vascularity, scattered immunoblast and plasma cells, with or without atypical cells.58 Coagulative necrosis with hematoxylin bodies, which is the unique finding in SLE, is rarely seen.59,60 Lymph node lesions of SLE patients may also be similar to those of hyaline-vascular or intermediate types of Castleman’s disease or T-zone dysplasia with hyperplastic follicles.61 Kikuchi–Fujimoto syndrome is also one of the important differential diagnoses as it shares the typical features of SLE, such as fever, arthralgia, and leukopenia, and it commonly affects young women. Biopsy of the lymph nodes typically shows granulomatous necrotizing lymphadenitis and sometimes can be difficult to distinguish from with lupus lymphadenopathy.59 In addition, about 30% of patients presenting with this form of necrotizing lymphadenitis have or go on to develop SLE or discoid lupus.61 However, it may be possible to identify differences in the histology between those that are really SLE from the onset of

lymphadenopathy and those that are true Kikuchi–Fujimoto syndrome62 (Table 39.2). Lymphadenopathy appears to be most common in the first few years of lupus and is rare later in the disease course. The development of lymphadenopathy for the first time in a patient who has had SLE for more than 5 years should prompt further investigations due to broader differential diagnoses, including lymphoma.

Splenomegaly Splenomegaly occurs in 10–45% of patients, particularly during active disease. It is usually mild-moderate degree and gross or massive enlargement of the spleen is extremely rare.63 Mild to moderate splenomegaly may be recorded in the BILAG index but not in other indices, such as SLEDAI and ECLAM.2 It usually develops as a result of lymphoid hyperplasia with enlarged white pulp lymphoid follicles, and a buildup of macrophages and plasma cells around the arterioles and cells of the red pulp.63 Presence of periarterial thickening in an “onion skin” pattern have also been described in the pathologic examination, suggestive of healed vasculitis.64 Its occurrence is often associated with hepatomegaly and/or lymphadenopathy; therefore, it may herald many other differential diagnoses (Table 39.3). However, the presence of splenomegaly is not necessarily associated with cytopenia.

Weight loss Unexplained weight loss of at least 5% body weight can be a manifestation of active disease. However, it is also a nonspecific finding of many other diseases, such as malignancy, chronic infection, endocrinopathy (thyrotoxicosis), and other rheumatic diseases. The BILAG index records both anorexia and unintentional weight loss (>5%) under constitutional or general features.1 In the SLAM-R Index,65 weight loss can be recorded as mild if it is up to 10% of preexisting body weight, and it is recorded as severe if it is greater than 10% of body weight. SLEDAI and ECLAM do not record weight loss.2,3 Loss of appetite or anorexia usually precedes the development of weight loss. Apart from that, weight loss can be attributed to gastrointestinal (GI) disturbance, particularly

TABLE 39.2 Histological differences between SLE and Kikuchi–Fujimoto syndrome. Histological features

SLE lymphadenitis

Kikuchi–Fujimoto syndrome

Necrosis

Present

Present

Hematoxylin bodies

Present

Not present

Cytotoxic T cells (CD8+ lymphocytes)

Sparse

Abundant

Plasma cells

Abundant

Sparse

a

a

Degenerated nuclei that have reacted with antinuclear antibodies, and the Azzopardi phenomenon (i.e., encrustation of blood vessel walls with nuclear material).

Constitutional symptoms and fatigue in systemic lupus erythematosus Chapter | 39

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TABLE 39.3 Differential diagnosis of splenomegaly in SLE. Neoplastic and lymphoproliferative disease

• Lymphoma • Leukemia or hematological cytopathologies • Splenic tumors (primary splenic lymphoma/tumors, metastatic)

Hepatic

• Liver cirrhosis with portal hypertension (associated with autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis)

Vascular occlusive

• Splenic vein thrombosis • Portal vein thrombosis

Immunological

• Autoimmune hemolytic anemia • Immune thrombocytopenic purpura

Infection

• Viral (EBV, CMV, hepatitis virus) • Malaria • Endocarditis • Splenic abscess

Inherited hemoglobinopathies

• Thalassemia • Cytoskeletal defects: hereditary sphero- or elliptocytosis

nausea and vomiting. Anorexia, nausea, and vomiting are frequent and can affect up to 50% of patients with SLE.66 They can occur as an early manifestation of new-onset lupus or lupus flare in the absence of GI features. Apart from disease activity, they may be due to the consequences of disease complications (e.g., uremia in lupus nephritis) or side effects of medication. Other rarer causes of weight loss in SLE include other GI involvement in SLE, such as malabsorption or gut vasculitis. Specific investigations of the gastrointestinal tract may be required to exclude comorbid disease and to look for evidence of localized lupus involvement that is interfering with absorption of nutrients (Table 39.4). Weight loss usually responds to treatment given for other manifestations of lupus, particularly when corticosteroids are involved. However, as with fever and lymphadenopathy, such treatment should not be given or increased until infection and malignancy have been excluded (Chapter 44).

Conclusion Constitutional features of SLE are common during the initial presentation and recurrence of active SLE flares. However, these clinical features are very nonspecific and have a broad differential diagnosis. As discussed in this chapter, it is essential to consider the differential diagnosis of each symptom and sign in turn. Only by having excluded other possibilities can the various features be attributed to lupus and treated as such. Constitutional symptoms are the important features of the disease that need to be assessed and managed appropriately as they cause considerable distress to the patient.

TABLE 39.4 Differential diagnosis of weight loss in SLE. Infection

Tuberculosis, fungal, opportunistic infections.

Malignancy

Lymphoma, solid tumors

Gastrointestinal

Nausea, vomiting, decreased appetite Malabsorption (celiac disease, fat malabsorption) Protein-losing enteropathy Dysphagia (overlapping features of scleroderma or CREST) Lupus enteritis (colitis or vasculitis) Pancreatitis

Organ damage

Uremia from renal failure

Medications

Mycophenolic acid or mycophenolate mofetil (GI side effects: diarrhea, nausea, abdominal pain) Nonsteroidal anti-inflammatory drugs

CREST, calcinosis, Raynaud’s, esophageal dysmolitility, sclerodactyl, telangiectasia.

Immunosuppression and antimalarial therapy are important in the treatment of fever, weight loss, and lymphadenopathy due to lupus. However, because fatigue may not necessarily be attributed to the active disease, a careful search for and treatment of comorbid conditions including depression, fibromyalgia, and sleep disorders should be undertaken. Therefore, the treatment of fatigue may require additional measures, such as an aerobic exercise program, self-management plan, or psychoeducational intervention.

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References 1. Yee CS, Farewell V, Isenberg DA, Griffiths B, Teh LS, Bruce IN, et al. The BILAG-2004 index is sensitive to change for assessment of SLE disease activity. Rheumatology (Oxford) 2009;48(6):691–5. 2. Griffiths B, Mosca M, Gordon C. Assessment of patients with systemic lupus erythematosus and the use of lupus disease activity indices. Best Pract Res Clin Rheumatol 2005;19(5):685–708. 3. Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002;29(2):288–91. 4. Cleanthous S, Tyagi M, Isenberg DA, Newman SP. What do we know about self-reported fatigue in systemic lupus erythematosus? Lupus 2012;21(5):465–76. 5. Balsamo S, Santos-Neto LD. Fatigue in systemic lupus erythematosus: an association with reduced physical fitness. Autoimmun Rev 2011;10(9):514–8. 6. Tench CM, McCurdie I, White PD, D’Cruz DP. The prevalence and associations of fatigue in systemic lupus erythematosus. Rheumatology (Oxford) 2000;39(11):1249–54. 7. Zonana-Nacach A, Roseman JM, McGwin Jr G, Friedman AW, Baethge BA, Reveille JD, et al. Systemic lupus erythematosus in three ethnic groups. VI: factors associated with fatigue within 5 years of criteria diagnosis. LUMINA Study Group. LUpus in MInority populations: NAture vs Nurture. Lupus 2000;9(2):101–9. 8. Ghiran IC, Zeidel ML, Shevkoplyas SS, Burns JM, Tsokos GC, Kyttaris VC. Systemic lupus erythematosus serum deposits C4d on red blood cells, decreases red blood cell membrane deformability, and promotes nitric oxide production. Arthritis Rheum 2011;63(2):503–12. 9. Da Costa D, Dritsa M, Bernatsky S, Pineau C, Menard HA, Dasgupta K, et al. Dimensions of fatigue in systemic lupus erythematosus: relationship to disease status and behavioral and psychosocial factors. J Rheumatol 2006;33(7):1282–8. 10. Kozora E, Ellison MC, West S. Depression, fatigue, and pain in systemic lupus erythematosus (SLE): relationship to the American College of Rheumatology SLE neuropsychological battery. Arthritis Rheum 2006;55(4):628–35. 11. Jump RL, Robinson ME, Armstrong AE, Barnes EV, Kilbourn KM, Richards HB. Fatigue in systemic lupus erythematosus: contributions of disease activity, pain, depression, and perceived social support. J Rheumatol 2005;32(9):1699–705. 12. Omdal R, Waterloo K, Koldingsnes W, Husby G, Mellgren SI. Fatigue in patients with systemic lupus erythematosus: the psychosocial aspects. J Rheumatol 2003;30(2):283–7. 13. Ruiz-Irastorza G, Egurbide MV, Olivares N, Martinez-Berriotxoa A, Aguirre C. Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology (Oxford) 2008;47(6):920–3. 14. Oeser A, Chung CP, Asanuma Y, Avalos I, Stein CM. Obesity is an independent contributor to functional capacity and inflammation in systemic lupus erythematosus. Arthritis Rheum 2005;52(11):3651–9. 15. Mancuso CA, Perna M, Sargent AB, Salmon JE. Perceptions and measurements of physical activity in patients with systemic lupus erythematosus. Lupus 2011;20(3):231–42. 16. Strand V, Gladman D, Isenberg D, Petri M, Smolen J, Tugwell P. Outcome measures to be used in clinical trials in systemic lupus erythematosus. J Rheumatol 1999;26(2):490–7. 17. Ad Hoc Committee on Systemic Lupus Erythematosus Response Criteria for Fatigue. Measurement of fatigue in systemic lupus erythematosus: a systematic review. Arthritis Rheum 2007; 57 (8): 1348–1357.

18. Lai JS, Beaumont JL, Ogale S, Brunetta P, Cella D. Validation of the functional assessment of chronic illness therapy-fatigue scale in patients with moderately to severely active systemic lupus erythematosus, participating in a clinical trial. J Rheumatol 2011;38:672–9. 19. Elvira Bangert, Laura Wakani, Mehveen Merchant, Vibeke Strand, Zahi Touma. Impact of belimumab on patient-reported outcomes in systemic lupus erythematosus: review of clinical studies. Patient Relat Outcome Meas 2019; 10:1–7. 20. Kasturi S, Szymonifka J, Burket JC, et al. Validity and reliability of patient reported outcomes measurement information system computerized adaptive tests in systemic lupus erythematosus. J Rheumatol 2017;44:1024–31. 21. Seawell AH, Danoff-Burg S. Psychosocial research on systemic lupus erythematosus: a literature review. Lupus 2004;13(12):891–9. 22. Sutcliffe N, Clarke AE, Levinton C, Frost C, Gordon C, Isenberg DA. Associates of health status in patients with systemic lupus erythematosus. J Rheumatol 1999;26(11):2352–6. 23. Navarrete-Navarrete N, Peralta-Ramirez MI, Sabio-Sanchez JM, Coin MA, Robles-Ortega H, Hidalgo-Tenorio C, et al. Efficacy of cognitive behavioural therapy for the treatment of chronic stress in patients with lupus erythematosus: a randomized controlled trial. Psychother Psychosom 2010;79(2):107–15. 24. Karlson EW, Liang MH, Eaton H, Huang J, Fitzgerald L, Rogers MP, et al. A randomized clinical trial of a psychoeducational intervention to improve outcomes in systemic lupus erythematosus. Arthritis Rheum 2004;50(6):1832–41. 25. Sohng KY. Effects of a self-management course for patients with systemic lupus erythematosus. J Adv Nur 2003;42(5):479–86. 26. Neill J, Belan I, Ried K. Effectiveness of non-pharmacological interventions for fatigue in adults with multiple sclerosis, rheumatoid arthritis, or systemic lupus erythematosus: a systematic review. J Adv Nur 2006;56(6):617–35. 27. del Pino-Sedeño T, Trujillo-Martín MM, Ruiz-Irastorza G, CuellarPompa L, de Pascual-Medina AM, Serrano-Aguilar P. Effectiveness of nonpharmacologic interventions for decreasing fatigue in adults with systemic lupus erythematosus: a systematic review. Arthritis Care Res (Hoboken) 2016;68(1):141–8. 28. Wu ML, Yu KH, Tsai JC. The effectiveness of exercise in adults with systemic lupus erythematosus: a systematic review and meta-analysis to guide evidence-based practice. Worldviews Evid Based Nurs 2017;14(4):306–15. 29. Yuen HK, Cunningham MA. Optimal management of fatigue in patients with systemic lupus erythematosus: a systematic review. Therap Clin Risk Manag 2014;10:775–86. 30. Davies RJ, Lomer MC, Yeo SI, Avloniti K, Sangle SR, D’Cruz DP. Weight loss and improvements in fatigue in systemic lupus erythematosus: a controlled trial of a low glycaemic index diet versus a calorie restricted diet in patients treated with corticosteroids. Lupus 2012;21(6):649–55. 31. Ruiz-Irastorza G, Gordo S, Olivares N, Egurbide M-V, Aguirre C. Changes in vitamin D levels in patients with systemic lupus erythematosus: effects on fatigue, disease activity, and damage. Arthritis Care Res (Hoboken) 2010;62(8):1160–5. 32. Lai Z-W, Hanczko R, Bonilla E, Caza TN, Clair B, Bartos A, et al. Nacetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: A randomized, double-blind, placebo-controlled trial. Arthritis Rheumatism 2012;64(9):2937–46.

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33. The Canadian Hydroxychloroquine Study Group. The Canadian Hydroxychloroquine Study Group. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med1991;324 (3):150–154. 34. Strand V, Levy RA, Cervera R, Petri MA, Birch H, Freimuth WW, et al. Improvements in health-related quality of life with belimumab, a B-lymphocyte stimulator-specific inhibitor, in patients with autoantibody-positive systemic lupus erythematosus from the randomised controlled BLISS trials. Ann Rheum Dis 2013;73(5):838–44. 35. Strand V, Petri M, Kalunian K, Gordon C, Wallace DJ, Hobbs K, et al. Epratuzumab for patients with moderate to severe flaring SLE: healthrelated quality of life outcomes and corticosteroid use in the randomized controlled ALLEVIATE trials and extension study SL0006. Rheumatology (Oxford) 2014;53(3):502–11. 36. Dubois EL, Tuffanelli DL. Clinical manifestations of systemic lupus erythematosus. Computer analysis of 520 cases. JAMA 1964;190:104–11. 37. Pistiner M, Wallace DJ, Nessim S, Metzger AL, Klinenberg JR. Lupus erythematosus in the 1980s: a survey of 570 patients. Semin Arthritis Rheum 1991;21(1):55–64. 38. Font J, Cervera R, Ramos-Casals M, Garcia-Carrasco M, Sents J, Herrero C, et al. Clusters of clinical and immunologic features in systemic lupus erythematosus: analysis of 600 patients from a single center. Semin Arthritis Rheum 2004;33(4):217–30. 39. Livingston B, Bonner A, Pope J. Differences in clinical manifestations between childhood-onset lupus and adult-onset lupus: a meta-analysis. Lupus 2011;20(13):1345–55. 40. Lalani S, Pope J, de Leon F, Peschken C. Clinical features and prognosis of late-onset systemic lupus erythematosus: results from the 1000 faces of lupus study. J Rheumatol 2010;37(1):38–44. 41. Zhou WJ, Yang CD. The causes and clinical significance of fever in systemic lupus erythematosus: a retrospective study of 487 hospitalised patients. Lupus 2009;18(9):807–12. 42. Stahl NI, Klippel JH, Decker JL. Fever in systemic lupus erythematosus. Am J Med 1979;67(6):935–40. 43. Rovin B, Tang Y, Sun J, et al. Clinical significance of fever in the systemic lupus erythematosus patient receiving steroid therapy. Kidney Int. 2005;68:747–59. 44. Inoue T, Takeda T, Koda S, Negoro N, Okamura M, Amatsu K, et al. Differential diagnosis of fever in systemic lupus erythematosus using discriminant analysis. Rheumatol Int 1986;6(2):69–77. 45. ter Borg EJ, Horst G, Limburg PC, van Rijswijk MH, Kallenberg CG. C-reactive protein levels during disease exacerbations and infections in systemic lupus erythematosus: a prospective longitudinal study. J Rheumatol 1990;17(12):1642–8. 46. Gabay C, Roux-Lombard P, de Moerloose P, Dayer JM, Vischer T, Guerne PA. Absence of correlation between interleukin 6 and C-reactive protein blood levels in systemic lupus erythematosus compared with rheumatoid arthritis. J Rheumatol 1993;20(5):815–21. 47. Firooz N, Albert DA, Wallace DJ, Ishimori M, Berel D, Weisman MH. High-sensitivity C-reactive protein and erythrocyte sedimentation rate in systemic lupus erythematosus. Lupus. 2011;20(6):588–97. 48. Serio I, Arnaud L, Mathian A, Hausfater P, Amoura Z. Can procalcitonin be used to distinguish between disease flare and infection in patients with systemic lupus erythematosus: a systematic literature review. Clin Rheumatol. 2014;33(9):1209–15. 49. Meisner M. Update on procalcitonin measurements. Ann Lab Med. 2014;34(4):263–73.

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50. Bernatsky S, Boivin JF, Joseph L, Rajan R, Zoma A, Manzi S, et al. An international cohort study of cancer in systemic lupus erythematosus. Arthritis Rheum 2005;52(5):1481–90. 51. Badsha H, Kong KO, Lian TY, Chan SP, Edwards CJ, Chng HH. Lowdose pulse methylprednisolone for systemic lupus erythematosus flares is efficacious and has a decreased risk of infectious complications. Lupus 2002;11(8):508–13. 52. Karim MY, Pisoni CN, Khamashta MA. Update on immunotherapy for systemic lupus erythematosus–what’s hot and what’s not! Rheumatology (Oxford) 2009;48(4):332–41. 53. Pagnoux C, Korach JM, Guillevin L. Indications for plasma exchange in systemic lupus erythematosus in 2005. Lupus. 2005;14(11):871–7. 54. Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore) 1993;72(2):113–24. 55. Pons-Estel BA, Catoggio LJ, Cardiel MH, Soriano ER, Gentiletti S, Villa AR, et al. The GLADEL multinational Latin American prospective inception cohort of 1,214 patients with systemic lupus erythematosus: ethnic and disease heterogeneity among “Hispanics”. Medicine (Baltimore) 2004;83(1):1–17. 56. Shapira Y, Weinberger A, Wysenbeek AJ. Lymphadenopathy in systemic lupus erythematosus. Prevalence and relation to disease manifestations. Clin Rheumatol 1996;15(4):335–8. 57. Calguneri M, Ozturk MA, Ozbalkan Z, Akdogan A, Ureten K, Kiraz S, et al. Frequency of lymphadenopathy in rheumatoid arthritis and systemic lupus erythematosus. J Int Med Res 2003;31(4):345–9. 58. Sekigawa I, Nawata M, Seta N, Yamada M, Iida N, Hashimoto H. Cytomegalovirus infection in patients with systemic lupus erythematosus. Clin Exp Rheumatol 2002;20(4):559–64. 59. Melikoglu MA, Melikoglu M. The clinical importance of lymphadenopathy in systemic lupus erythematosus. Acta Reumatol Port 2008;33(4):402–6. 60. Kojima M, Motoori T, Asano S, Nakamura S. Histological diversity of reactive and atypical proliferative lymph node lesions in systemic lupus erythematosus patients. Pathol Res Pract 2007;203(6):423–31. 61. Santana A, Lessa B, Galrao L, Lima I, Santiago M. Kikuchi-Fujimoto’s disease associated with systemic lupus erythematosus: case report and review of the literature. Clin Rheumatol 2005;24(1):60–3. 62. Bosch X, Guilabert A, Miquel R, Campo E. Enigmatic KikuchiFujimoto disease: a comprehensive review. Am J Clin Pathol 2004;122(1):141–52. 63. Milder MS, Aptekar RG, Larson SM, Decker JL, Johnston GS. Letter: Spleen size in SLE. Arthritis Rheum 1974;17(2):190–1. 64. Tolaymat A, Al-Mousily F, Haafiz AB, Lammert N, Afshari S. Spontaneous rupture of the spleen in a patient with systemic lupus erythematosus. J Rheumatol 1995;22(12):2344–5. 65. Liang MH, Socher SA, Larson MG, Schur PH. Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 1989;32(9):1107–18. 66. Sultan SM, Ioannou Y, Isenberg DA. A review of gastrointestinal manifestations of systemic lupus erythematosus. Rheumatology (Oxford) 1999;38(10):917–32.

Chapter 40

The musculoskeletal system in SLE Maria-Louise Barilla-LaBarca, Diane Horowitz, Galina Marder and Richard Furie Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States

Along with cutaneous disease, musculoskeletal manifestations predominate in SLE with large series observing more than a 90% cumulative involvement,1 whereas some musculoskeletal complications, such as myositis and arthritis, reflect disease activity, others, such as osteonecrosis and osteoporosis, are typically adverse effects of treatment. In this chapter, we review common musculoskeletal manifestations that affect patients with SLE.

Arthritis Clinical trials confirmed the high prevalence of arthritis in lupus, with 60%–65% of subjects entering BLISS-52 and BLISS-76 with musculoskeletal disease activity.2–4 The ALMS study, a trial that focused on the treatment of lupus nephritis, documented a 16% frequency of BILAG A or B musculoskeletal involvement.5 There are three historically recognized clinical patterns of joint involvement: nonerosive, erosive (rhupus) and Jaccoud’s arthropathy (JA).6,7 However, information from advanced imaging techniques, such as MRI and ultrasound (US), have recently challenged these subsets with new patterns of involvement being proposed.8 Furthermore, abnormalities can be identified using these more sensitive imaging tests even in the absence of active joint symptoms, suggesting the presence of subclinical musculoskeletal disease affecting joints and soft tissues.9

Nonerosive arthritis The most common pattern of lupus arthritis has historically been described as a nonerosive, nondeforming inflammatory arthritis. Insidious in onset, it is an early disease manifestation causing inflammatory joint symptoms such as erythema, tenderness, and/or effusion. Usually symmetric with a predilection for hands, wrists, and knees, it can be confused with early rheumatoid arthritis (RA). Therefore it is vital during the diagnostic evaluation of patients with inflammatory arthritis to include lupus serologies. Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00040-4 Copyright © 2020 Elsevier Inc. All rights reserved.

Patients with lupus arthritis do not develop voluminous synovial effusions. When obtained, the fluid is clear to mildly opaque, and viscosity may be normal or slightly reduced. The white cell count of synovial fluid is low, rarely exceeding 10,000 cells/ml.10 Lymphocytes and monocytes predominate, although neutrophils may be abundant in fluids with marked leukocytosis. Serologic tests on synovial fluid are of no diagnostic value, but it is imperative to culture the fluid if circumstances warrant. Radiographs may demonstrate soft tissue swelling, but erosive changes and joint space narrowing are typically absent.11 The concept of nonerosive arthritis in lupus has been challenged recently with the advent of sensitive imaging techniques, such as high-resolution US with power Doppler and MRI. The development of consensus-driven definitions of musculoskeletal pathology by the OMERACT 7 US special interest group allows reproducibility and comparison between study results that was not before possible.12 Recently it has been shown that US has a high specificity (98.7%) but only fair sensitivity (35.9%) in detecting erosions in lupus patients compared to CT.13 The sensitivity of US in this study was found to be better at MCP joints (57.1%), compared to wrist. In a recent meta-analysis of US studies of lupus patients performed by Lins and Santiago, a total of 1091 joints, representing 610 SLE patients, were studied sonographically.9 Hands and wrists represented approximately 80% of the studies. Effusions were observed in 55% of joints, synovitis in 20%, and synovial hypertrophy in 14%. Joint synovitis on US was correlated with patient’s symptoms or tender/swollen joints on physical exam. Notably, erosions were present in a small but measurable subset, with a range of 26% to 47%, despite removing patients with serologic markers typical of RA from the analysis.14,15 Importantly, the correlation of sonographic features of lupus with various standard disease activity indices has been inconsistent between studies.9,14,16 361

362 PART | IV  Clinical aspects of the disease

Yet unanswered is whether subclinical synovitis is predictive of future arthropathy, can be used as a biomarker of flare, and its prognostic implications of long term outcome measurements. Yoon et al. utilized gray-scale US and power Doppler to identify subclinical inflammatory changes in the joints of 48 SLE patients without clinically overt musculoskeletal involvement.17 Synovitis, found in 58.3% of patients, was noted at the wrist (33.3%), second MCP joint (29.2%), and the third MCP joint (31.3%). New musculoskeletal symptoms subsequently developed in 22.9% of patients, and among predictive risk factors was a higher baseline US synovitis index. The degree, or grade, of synovitis in many US studies is not standardized and/or reported and therefore must be interpreted with caution as low-grade synovitis can be found in noninflammatory arthritis.18 The prevalence of erosions identified by US in historically nonerosive disease sets is supported by data from MRI from several studies. Chiara et al. reported MRI findings in 50 SLE patients with arthritis who underwent hand and wrist MRI’s without contrast.19 Bone marrow edema was observed in two patients in the hand (4%) and in 15 in the wrist (13%). Erosions were observed in the hands in 24 patients (48%) and in the wrists in 41 (82%) patients. They concluded that involvement of the wrist in SLE is similar in frequency to RA, but involvement of the hand in SLE is significantly less frequent compared to RA. Similarly, in their study of 34 patients with SLE arthritis, Ball et al. demonstrated the presence of erosions at the wrist in 93% of subjects and at the MCP’s in 61% using contrast-enhanced MRI.20 In total, 93% of patients had at least grade 1 synovitis at one or more MCP joints, and wrist synovitis was present in all. In contrast to RA, synovium from patients with lupus does not demonstrate exuberant inflammatory changes. Natour et al. examined 30 percutaneous synovial knee biopsies from lupus patients and noted: (1) synoviocyte hyperplasia, (2) scarce inflammatory infiltrates, (3) vascular proliferation, (4) edema and congestion, (5) fibrinoid necrosis and intimal fibrous hyperplasia of blood vessels, and (6) fibrin on the synovial surface.21 Insight into the mechanism by which lupus patients with arthritis are generally spared from significant erosions was provided by Mensah et al.22 They postulated that an interferon-rich milieu, as is seen in most lupus patients, supports the differentiation of myelomonocytic precursors to myeloid dendritic cells as opposed to osteoclasts.

Erosive arthritis (rhupus) An uncommon subset of lupus arthritis, referred to as “rhupus”, is marked by articular features of RA, namely erosive arthritis, and serologic features of lupus.23,24 Findings may include synovitis, synovial proliferation, rheumatoid nodules, and malalignment. Predictors for the development

of erosive arthritis are poorly understood. Amezcua-Guerra et al. demonstrated a median C-reactive protein (CRP) concentration in erosive arthritis of 14.5 mg/L compared to 0.8 in nonerosive arthritis. AntiCCP antibodies were also significantly associated with erosive arthritis, but serum IL-6, interferon-gamma, IL-4 and IL-10, while numerically greater in erosive arthritis, were not statistically different.25 Similar observations were made by Chan et al. who compared the presence of antiCCP antibodies in 104 SLE patients with either erosive or nonerosive/no arthritis.26 While only 6 patients had major erosive arthritis, 4 (67%) of those patients did had antiCCP2 antibodies; only 4 of the other 98 patients were CCP2 antibody positive. Kakumanu et al. compared the frequency of antiCCP antibodies (>1.7 units) in patients with RA (68%) to those with SLE (17%). Their presence was over two-fold higher in SLE patients with erosive arthritis (38%). AntiCCP antibodies were less commonly observed (8.8%) in the SLE cohort described by Ball et al.20

Jaccoud’s arthropathy Francois-Sigismond Jaccoud, a Swiss physician living in Paris in the 1800s, originally described an arthritis associated with rheumatic fever. Characterized by reducible deformities on exam, there is a notable absence of erosions on plain radiographs in patients with JA. Bleifeld and Inglis published their observations of the hands of 50 lupus patients.27 Abnormalities included laxity (50%) and reducible deformities (38%), but radiographs failed to demonstrate erosive changes. Prevalence figures for JA from two SLE cohorts were 3.47% and 6.1%.28,29 The most frequent joint deformities include swan neck, thumb subluxation (z-thumb), ulnar deviation, hallux valgus, and boutonniere deformity.28,30 Spronk et al developed a JA index that has been used to standardize classification of patients.30,16 Clinical features of lupus in JA do not differ from patients with other types of lupus arthropathy. In fact, SLE disease activity scores are comparable.28,30,31 Interestingly, Spronk et al. found that CRP, which classically does not increase in lupus disease flares, was significantly higher in JA compared with nonJA patients.31 JA could be mistaken for RA as these patients share clinical features, such as ulnar deviation and subluxation at the MCP’s. Features that distinguish JA from RA include the reducibility of the deformities and the lack of erosions on x-ray although more recent studies have demonstrated a small rate of erosions utilizing US, MRI, and CT.13,14,30 Lins et al. demonstrated at least 1 US finding at the hand and wrist in 50% of their 40 patients.30 In this cohort of SLE patient with only JA, synovial hypertrophy was found in 48%, tenosynovitis in 23%, and bony erosions in 5%. More current studies have suggested erosion rates of greater than 50% when including the fifth MCP joint, an area not

The musculoskeletal system in SLE Chapter | 40

typically studied in earlier reports or using MRI.13,32 Erosions viewed with these advanced imaging studies in JA have a characteristic hook-shaped appearance.13,33 Severe JA may compromise hand function as a result of contractures or ulnar deviation. Severe contractures may lead to maceration of the palmar skin. The pathogenesis of joint laxity in JA is not understood. Though rarely obtained, biopsy specimens have shown normal synovium. Whereas JA is generally observed in the hands, it has been reported in feet and knees.34

Tendons and entheses The presence of tendon involvement particularly in asymptomatic patients has been increasingly recognized through US. Tendon involvement largely consists of tenosynovitis, though tendon dislocation, tendon tear, tendonitis, enthesitis, and tendon thinning also occur.8 The presence of tenosynovitis ranges between 20% and 65% in US studies and is often found in patients without active joint symptoms.8,9,14,15 Recent US studies therefore suggest that utilizing patients’ symptoms or the physical exam alone may underrecognize musculoskeletal pathology.9,35 At least one author has proposed rescoring a C on MS-BILAG, but with positive US power Doppler signal on tendon or joints, as a B and considered having intermediate active musculoskeletal disease.14 Spontaneous tendon rupture, albeit rare, occurs in patients with lupus.36 Ruptures may be acute and are sometime bilateral with the most commonly affected tendons being the patellar and Achilles tendons. Predisposing factors include trauma and steroids. Histology, reported in a limited number of cases, has shown variable degrees of inflammatory changes, ranging from no inflammation to exuberant synovial proliferation.

Treatment Arthritis activity dictates how aggressively the clinician will need to intervene. Nonsteroidal antiinflammatory drugs and low dose corticosteroid (e.g.., prednisone 5–10 mg daily) are often effective for mild symptoms. For those failing minor interventions, hydroxychloroquine or immunosuppressives may be warranted. Wong and Esdaile noted inconsistent effects in their review of methotrexate in controlled and uncontrolled studies.37 Fortin et al. demonstrated the steroid-sparing effects of methotrexate in a randomized, double-blind placebo-controlled study of 86 SLE patients.38 While the study did not focus solely on articular manifestations, 90% of participants had musculoskeletal involvement at baseline. Azathioprine represents yet another treatment option. A trial comparing the efficacy of mycophenolate to cyclophosphamide in lupus nephritis yielded data on extra-

363

renal responses.5 Of those with baseline BILAG A or B musculoskeletal domain scores, over 85% of the patients in both arms had improvements in their domain scores at 24 weeks. However, despite the greater use of mycophenolate for both renal and extra-renal disease, lupus experts polled in a 2015 survey recommended sequential use of hydroxychloroquine, methotrexate, and rituximab for the treatment of lupus arthritis.39 In post hoc analyses of the phase 3 belimumab data, Manzi et al. published that those subjects who entered BLISS-52 and BLISS-76 studies with musculoskeletal domain activity had statistically significant improvement when belimumab, as opposed to placebo, was added to standard of care.40 While most rheumatologists shy away from off-label use of tumor necrosis factor (TNF) inhibitors in lupus because of fear of disease exacerbations, anecdotal experience suggests that some patients with lupus arthritis benefit. It must be remembered that TNF inhibitors can promote the synthesis of antiDNA antibodies, thus confusing the picture for those clinicians whose assessment of disease activity is guided by serologies. Favorable effects on musculoskeletal disease activity, albeit not statistically significant, have been demonstrated with tocilizumab and abatacept.41,42 Laquinimod, in development for multiple sclerosis, was studied in lupus arthritis; however, study results were never presented. Rituximab, while not approved for SLE, is favored by some for refractory arthritis. Splints will correct the maligned digits in a patient with JA. However, it is the authors’ experience that deformities recur once splints are removed. Similarly, pharmacologic interventions, while capable of reducing inflammation in the more typical subset of lupus arthritis, do not affect deformities associated with JA. On occasion, surgical intervention of the hand is required. Reported results have been variable.43 The traditional teaching that lupus arthritis is not associated with erosions has been contested in recent years with the introduction of sensitive imaging modalities. These findings further confound the classification of joint disease in SLE. Ball and Bell emphasized that lupus arthritis remains largely understudied in comparison to RA. It is this lack of understanding of SLE arthritis pathogenesis and classification that may thwart therapeutic advances for this disease.44

Myalgia/myopathy/myositis Muscular involvement in SLE ranges from commonly seen myalgia to less frequently observed inflammatory myopathy or myositis.

Fibromyalgia The prevalence of fibromyalgia in lupus is 6.2%.45 In their recent study, Torrente-Segarra and coworkers showed that

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disease duration of more than 5 years was associated with slightly higher prevalence rates. Furthermore, patients with SLE-FMS had more depression, secondary Sjogren’s, photosensitivity, and oral ulcers compared to their nonFMS matched controls.

Medication-related myopathy It is important to recognize when myopathic process occurs as a complication of therapies used, most commonly steroids and antimalarials. Antimalarials including both chloroquine and hydroxychloroquine are the cornerstone of lupus therapy with well-recognized benefits to both lupus disease activity and damage as well as cardiovascular health. Although neuromyotoxicity and cardiomyopathy are recognized side effects of treatment, they are considered rare; existing largely as case reports in the literature, longitudinal studies are lacking. Tselios and coworkers recently investigated the relationship between these drugs and myopathy in the largest series to date.46 They determined a frequency of creatinine phosphokinase (CPK) elevation in their large cohort to be 16.3%, of antimalarial users. Chronic use was a risk factor for the biochemical alteration but evolution to clinical myopathy with weakness was only 2.5%.46 CPK elevation generally is low and proximal muscle weakness, if it occurs, tends to be mild with an occasional neuropathic component.46,47 Electron microscopy demonstrates a vacuolar myopathy with curvilinear bodies, which on immunohistochemistry is acid phosphatase positive and consistent with an autophagic vacuolar process.47,48 It is believed that antimalarials accumulate within lysosomes, decreasing their acidity and function, resulting in autophagy. Toxicity is reversible as discontinuation of drug results in symptom improvement. Renal failure is an important risk factor.49 Steroid induced myopathy presents as a chronic, insidious, painless, proximal muscle weakness that is associated with higher levels of steroid use. Muscle enzymes are typically normal and histologic features consistent of type II myofiber atrophy without inflammation. The challenge with patients on steroids for autoimmune disease is whether the muscle weakness is a reflective of disease activity or drug toxicity. Lowering the dose of steroid if possible is the best way to distinguish between the two as strength improves several weeks after drug discontinuation.

Myositis Clinical and laboratory features of lupus myositis are no different than idiopathic inflammatory myopathy (IIM) and include proximal muscle weakness with or without myalgia as well as elevated muscle enzymes, typically CPK. In about 5% of SLE patients, myositis may be a first manifestation of lupus,50 but more frequently, it is observed years after the diagnosis of SLE has been established. Rayn-

aud’s phenomena, anemia, alopecia, oral ulcers, erosive arthritis, and interstitial lung disease are associated with SLE myositis.29,51,52 Lupus nephritis, conversely, occurred less often in lupus myositis.51 It has been suggested that serositis and lymphopenia are predictive of the subsequent development of myositis.53 Garton and Isenberg compared the clinical and laboratory features of lupus myositis to primary IIM. Relapsing and remitting courses were common in both, whereas monophasic disease was the least frequent pattern. There were no significant differences in muscle strength and serum CPK levels between groups of patients.54 RNP antibodies are more prevalent in SLE patients with myositis as opposed to SLE patients without myositis.50 Indeed, a multitude of other myositis-associated antibodies have been reported in patients with and without an overlap syndrome.55 Recently, the cytosolic 5′-nucleotidase 1A (cN-1A) antibody, traditionally thought of as a marker of inclusion body myositis, has been identified in up to 30% of SLE patients independent of muscular symptoms.56 It was initially suggested that lupus myositis follows a much milder course than IIM. Foote et al. reported significantly lower mortality rates in patients with lupus myositis compared to those with polymyositis complicating scleroderma or RA (18% vs. 47%).57 However, Garton and Isenberg concluded lupus myositis can be as severe as in IIM with similar mortality rates.54 Dayal and Isenberg later observed that mortality in lupus patients with myositis was no different from lupus patients without myositis; however, lupus patients with myositis had a shorter life expectancy than lupus patients without myositis (24.7 vs. 51 years).51 The prognosis of lupus patients with myositis depends on other manifestations of SLE.

Histologic features Histological findings from biopsy and autopsy series of lupus myositis include: (1) lymphocytic and plasma cell infiltrates in perivascular, perimysial, and endomysial locations; (2) mononuclear and lymphocytic vasculitis but rare vessel wall necrosis; (3) perifasicular atrophy; (4) vacuolar myopathy (in the absence of corticosteroid or chloroquine exposure).58,59 Oxenhandler et al. demonstrated immunoglobulin and complement deposition in the skeletal muscle of SLE patients, highlighting similar mechanisms of injury in lupus myositis as is described for cutaneous and renal involvement.58 Moreover, histologic evidence of inflammatory myopathy was found even in clinically uninvolved muscles of lupus patients.58 Furthermore, SLE patients with nonspecific arthralgia and myalgia were more likely to have type II fiber atrophy and vessel wall thickening on muscle biopsy than patients with fibromyalgia (87% vs. 58%); lymphocytic vasculitis and myositis were reported in 38% of SLE patients with muscular symptoms in contrast to 0%

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in fibromyalgia.59 Increased capillary basement membrane thickness associated with C3d-g deposition and endothelial microtubular inclusions were also observed.60,61

Treatment Just as with designing treatment plans for other manifestations of lupus, the treatment regimen for myositis needs to be customized according to disease severity. Corticosteroids, the mainstay of therapy for lupus myositis, are used in doses that range from 0.5–1.5 mg/kg to intravenous “pulse” methylprednisolone. Even as our therapeutic arsenal expanded, there has been no consensus regarding an immunosuppressive regimen for induction or maintenance. Hence, for patients refractory to corticosteroids, azathioprine, methotrexate, or mycophenolate are often used. Rituximab has been reported to be useful in refractory cases of SLE myositis.62 Overexpression of the type I interferon signature in the serum and tissue of patients with either SLE or inflammatory myositis has been observed.63 These findings suggest a common pathway in disease pathogenesis and may explain clinical similarities between the two diseases. Results of a phase 1b clinical trial was to evaluate sifalimumab, a human antiinterferon-alpha monoclonal antibody in development for SLE, in myositis showed that the interferon gene signature was suppressed by 50% in blood and in muscle specimens postsifalimumab administration.64 These preliminary observations require confirmation in a larger trial powered to evaluate efficacy. With lupus and myositis clinical trial activity at unprecedented levels, the lupus community eagerly awaits the further development of targeted therapies.

Osteonecrosis Osteonecrosis, also known as ischemic necrosis of bone, avascular necrosis, osteochondriits dissecans, and aseptic necrosis, compromises the structural integrity of bone architecture. While there are numerous etiologies and varied clinical presentations of avascular necrosis, cell death due to interrupted blood supply to periarticular bone is the common pathogenic mechanism.65,66 Osteonecrosis, which can cause substantial pain and disability, represents a significant challenge in the SLE patient.

Clinical impact Clinicians should view osteonecrosis as a spectrum ranging from the asymptomatic patient with abnormal findings on imaging to the patient with severe disease with pain and disability from advanced cortical destruction. Asymptomatic or silent osteonecrosis is usually found incidentally on imaging. While asymptomatic osteonecrosis is associated with less severe changes on imaging than symptomatic osteonecrosis, patients with asymptomatic disease have the

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potential to progress to symptomatic disease. A prospective study of hip MRIs in 23 SLE patients on glucocorticoids for SLE discovered asymptomatic osteonecrosis at baseline in 35% of subjects. At the 3-year follow up, 25% of subjects had progression of osteonecrosis on MRI, and 12.5% developed hip pain.67 In a case-control study of 95 SLE patients, those with osteonecrosis had higher HAQ scores and lower scores on the physical functioning domain of the SF-20.68

Epidemiology SLE is an independent risk factor for the development of osteonecrosis. The prevalence of symptomatic and asymptomatic osteonecrosis in patients with SLE is 4%–15% and 40%–50%, respectively.68,69–78 While osteonecrosis has been reported in almost every bone, the most common site is the hip. The approximately 50% of patients will have multi-site involvement.78

Pathogenesis There are multiple proposed mechanisms of ischemia in osteonecrosis1: intravascular occlusion2; diminished blood flow from increased extravascular pressure, or3 inhibition of angiogenesis and osteogenesis.79–82 Intravascular occlusion can stem from thrombosis associated with inflammation-mediated elevations in homocysteine, anticardiolipin antibody activity, small vessel vasculitis, vasospasm, and fat emboli. Corticosteroids can increase adipocytes in the marrow, which can cause intracortical pressure leading to decreased blood flow in the cortical vessels. Finally, the proinflammatory cytokine milieu induces osteoclast formation, decreases osteoblast activity, and reduces angiogenic factors.79

Risk factors While there is a strong association between corticosteroids and osteonecrosis, other factors such as, black race,78 elevated cholesterol,78 high disease activity,77 disease damage,78 use of cytotoxic agents,83,84 Raynaud’s phenomenon,85 vasculitis, and antiphosopholipid antibodies86,87 have been found to be risk factors in SLE.75 Multiple studies have evaluated the pattern of steroid use in relation to the development of osteonecrosis. In a study of 539 patients, each two-month exposure to highdose prednisone conferred a 1.2-fold increased risk of developing osteonecrosis.76 The development of osteonecrosis occurred in temporal proximity to high dose steroid use.87,88 A meta-analysis of 23 studies showed that osteonecrosis was associated with higher cumulative steroid dose, higher daily steroid dose, higher highest daily steroid dose, use of pulse dose steroids, and cushingoid appearance.89 While a metaanalysis of eight studies of patients

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with Lupus demonstrated a protective effect of antimalarial therapies on the risk of development of osteonecrosis.77 another metaanalysis of 23 studies did not show a protective effect of antimalarial therapy.89 Neither of these studies corrected for other factors such as disease severity and concomitant medications and that may be a reason for the discrepancy. Susceptibility to osteonecrosis is not understood. Supporting the multifactorial nature of the risk for osteonecrosis, there is variability in the risk factors identified that contribute to the development of osteonecrosis in various lupus cohorts. As with many conditions, it is likely there are genetic factors that contribute to susceptibility to corticosteroid-induced osteonecrosis. Polymorphisms in MDR1 (ABCB1) have been shown to be associated with steroid-induced osteonecrosis in patients with SLE.90,91

Diagnosis Symptomatic osteonecrosis presents with pain localized to the involved bone and is exacerbated by weight bearing. While CT, MRI, radionucleotide bone scan, and radiographs are all used to detect osteonecrosis, radiographs are the least sensitive and MRI the most sensitive.67,92 Radiographs are used for initial screening, but MRIs are ordered when radiographs are normal.

Treatment Asymptomatic osteonecrosis is treated conservatively and by reducing modifiable risk factors, whereas symptomatic osteonecrosis can be treated conservatively or surgically. Conservative measures include modification of activity with restricted weight bearing, stimulation of repair with US or electrical signals, and pharmacologic treatment.79,81 Convincing data are not available to support the routine use of pharmaceutical treatments other than to control pain. The prevention of osteonecrosis in lupus patients with statins, anticoagulants or bisphosphonates has been studied in small studies. However, additional studies are needed prior to the adoption of these therapies.88,93 Surgical treatment of osteonecrosis is reserved for patients with severe symptoms and/or collapse on imaging. Options include joint replacement or joint-preserving procedures such as support of sub-chondral bone, vascularized, and nonvascularized bone grafting, cementation, implantation of trabecular metal rods, core decompression, or osteotomy.80,81 Given the interest in stem cell therapy, a systematic review was performed by Lau et al. They noted that stem cell therapy was associated with a significant improvement in patient reported outcomes, but there were no statistically significant changes in joint survival.94

Osteoporosis The importance of bone health in lupus has come into focus as both long-term survival rates in lupus increase and the diagnostic modalities to assess bone mineral density have become more refined. In addition to traditional risk factors, lupus patients have additional risk factors for low bone density. These risk factors are associated with disease activity and pharmacotherapy.95,96

Epidemiology of osteopenia and osteoporosis Data collected from 2005–2010 in adults over the age of 65 demonstrated the prevalence of osteopenia to be 44% in men, the prevalence of osteopenia to be 52.3% in women, the prevalence of osteoporosis in men to be 5.6% and the prevalence of osteoporosis in women to be 24.8%.97 Recent studies of patients with lupus yielded prevalence figures for osteopenia as high as 50.8% and for osteoporosis as high as 23%.98,99 In a North American Cohort, in premenopausal women the prevalence of low bone mineral density was 17.3% and in postmenopausal women the prevalence of osteoporosis was 43.2% and the prevalence of low bone mineral density was 12.3%.100 In a study of 702 women with lupus followed over 5951 person-years, there was an almost five-fold increase in fracture risk seen in the subjects with lupus compared to the general female population.101 In these studies, the average age was under 50, although the majority of patients were postmenopausal male lupus patients have a higher prevalence of osteopenia and osteoporosis than healthy males, but lower prevalence of osteopenia and osteoporosis than female lupus patients.98,99,102 Children with juvenile systemic lupus erythematosus also have a significant risk of osteopenia with a reported prevalence of approximately 40% in two studies.103,104

Risk factors and pathophysiology of bone loss After peak bone mass is achieved between ages 20 and 30, bone is remodeled through a balance between osteoclastic and osteoblastic activities. In the general population, an imbalance caused by hormonal changes associated with menopause and aging leads to osteoporosis.105–107 Inflammation, metabolic changes and corticosteroid use are more detrimental to trabecular bone than cortical bone due to the higher turnover rate of trabecular bone. The ratio of trabecular bone to cortical bone is greater in the lumbar spine compared to the hip.106–108 Traditional risk factors that are more prevalent in the lupus population include female sex, premature menopause, low vitamin D levels, and sedentary lifestyle. Independent traditional risk factors include: weight less than 58 kilograms, age 65 or greater, personal or family history of fractures as an adult, inadequate calcium intake, excessive alcohol use and smoking.

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Lupus-related risk factors include inflammatory-mediated bone loss, glucocorticoid use, nonglucocorticoid medications, reduced mobility, and corresponding decline in muscle mass, myopathy, renal disease, endocrine factors, amenorrhea, low plasma androgen levels, hyperprolactinemia, chronic induction of bone-resorbing cytokines and therapy with anticoagulants or antiepileptic medications.100,109,110

Glucocorticoids Bone loss associated with corticosteroid use is greatest in the first year of treatment, but does continue throughout treatment.111,112 Glucocorticoids are thought to adversely affect bone formation, bone resorption, and calcium metabolism (both vitamin D-dependent and vitamin D-independent).113,114 Glucocorticoids decrease the number of functional osteoblasts.115,116 Both the maximum daily dose and the cumulative dose of steroids have been associated with bone loss in lupus patients.98,112

Other factors There are risk factors other than corticosteroid exposure that contributes to the increased prevalence of osteopenia and osteoporosis in this population. Bone loss is stimulated by activation of RANKL-OPG (receptor activator of nuclear factor kappa B ligand-osteoprotegerin), and cytokines, such as IL-1, IL-6 and TNFα, vitamin D3, and IL-11, are thought to affect RANKL-OPG. In addition, TNF also stimulates osteoclast maturation.95,96,109 Hormonal factors such as amenorrhea, low androgen levels, premature menopause, and hyperprolactinemia have been associated with low bone mineral density in lupus.95,117–120 Medications such as anticoagulants, cyclophosphamide, mycophenalate mofetil, and cyclosporine have been associated with reduced bone density.

Treatment Patients should maintain adequate calcium intake, monitor vitamin D levels, avoid tobacco, avoid alcohol, and engage in muscle-building exercises. Multiple pharmacologic options are available for bone loss. Bisphosphonates, including etidronate, risedronate, and alendronate, have been shown to mitigate bone loss in both postmenopausal and glucocorticoid-induced osteoporosis.96,109 The long halflife of bisphosphonates, which bind bone hydroxyapatite and inhibit osteoclastic activity, raises concerns about their use in premenopausal women desirous of future child-bearing.106,107,121 Other pharmacologic interventions such as teriparitide, raloxifine, denosumab, and abaloparatide have been shown to be effective in mitigation of bone loss, but there are no large clinical trials of these medications in lupus patients with osteoporosis or low bone mineral density.

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53. Jacobsen S, Petersen J, Ullman S, Junker P, Voss A, Rasmussen JM, et al. A multicentre study of 513 Danish patients with systemic lupus erythematosus. Disease manifestations and analyses of clinical subsets. Clin Rheumatol 1998;17(6):468–84. 54. Garton MJ, Isenberg DA. Clinical features of lupus myositis versus idiopathic myositis: a review of 30 cases. Br J Rheum 1997;36:1067–74. 55. Aguila LA, Lopes MR, Pretti FZ, Sampaio-Barros PD, Carlos de souza FH, Borba EF, et al. Clinical and laboratory features of overlap syndromes of idiopathic inflammatory myopathies associated with systemic lupus erythematosus, systemic sclerosis, or rheumatoid arthritis. Clin Rheumatol 2014;33:1093–8. 56. Rietveld A, van den Hoogen LL, Bizzaro N, Blokland SLM, Dahnrich C, Gottenberg JE, et al. Autoantibodies to cytosolic 5’-nucleotidase 1A in primary Sjogren’s Syndrome and systemic lupus erythematosus. Front Immunol 2018;9:1200. 57. Foot RA, Kimbrough SM, Stevens JC. Lupus myositis. Muscle Nerve 1982;5:65–8. 58. Oxenhandler R, Hart MN, Bickel J, Scearce D, Durham J, Irvin W. Pathologic features of muscle in systemic lupus erythematosus. Hum Pathol 1982;13:745–57. 59. Lim KL, Abdul-Wahab R, Lowe J, Powell RJ. Muscle biopsy abnormalities in systemic lupus erythematosus: correlation with clinical and laboratory parameters. Ann Rheum Dis 1994;53:178–82. 60. Pallis M, Lowe J, Powell R. An electron microscopic study of muscle capillary wall thickening in systemic lupus erythematosus. Lupus 1994;3(5):401–7. 61. Bronner IM, Hoogendijk JE, Veldman H, Ramkema M, van den Bergh, Weerman MA, et al. Tubuloreticular structures in different types of myositis: implications for pathogenesis. Ultrastruct Pathol 2008;32(4):123–6. 62. Ramos-Casals M, Garcia-Hernandez FJ, de Ramon E, Callejas JL, et al. Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases. Clin Exp Rheumatol 2010;28(4):468–76. 63. Walsh RJ, Kong SW, Yao Y, Jallal B, Kiener PA, Pinkus JL, et al. Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis. Arthritis Rheum 2007;56(11):3784–92. 64. Higgs BW, Zhu W, Morehouse C, White WI, Brohawn P, Guo X, et al. A phase 1b clinical trial evaluating sifalimumab, an anti-IFNα monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients. Ann Rheum Dis 2014;73(1):256–62. 65. Zizic TM, Marcoux C, Hungerford DS, Stevens MB. The early diagnosis of ischemic necrosis of bone. Arthritis Rheum 1986;29(10):1177– 86. 66. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32(2):94–124. 67. Nagasawa K, Tsukamoto H, Tada Y, Mayumi T, Satoh H, Onitsuka H, et al. Imaging study on the mode of development and changes in avascular necrosis of the femoral head in SLE: long-term observations. Br J Rheumatol 1994;33:343–7. 68. Gladman DD, Chaudhry-Ahluwalia V, Ibañez D, Bogoch E, Urowitz MB. Outcomes of symptomatic osteonecrosis in 95 patients with SLE. J Rheumatol 2001;28:2226–9. 69. Abeles M, Urman JD, Rothfield NF. Aseptic necrosis of bone in SLE: Relationship to corticosteroid therapy. Arch Intern Med 1978;138:750–4. 70. Petri M. Musculoskeletal complications of SLE in the Hopkins Lupus Cohort: an update. Arthritis Rheum 1995;8(3):137–45.

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71. Urowitz MB, Gladman DD, Tom BDM, Ibañez D, Farewell VT. Changing patterns in mortality and disease outcomes for patients with SLE. J Rheum 2008;35(11):2152–8. 72. Zizic TM, Marcoux C, Hungerford DS, Dansereau JV, Stevens MB. Corticosteroid therapy associated with ischemic necrosis of bone in SLE. Am J Med 1985;79:596–604. 73. Joo YB, Sung YK, Shim JS. Prevalence, incidence and associated factors of avascular necrosis in Korean Patients with Systmic Lupus Erythematosus: a nationwide epidemiologic Study. Rheumatol. Inter 2015;35:879–86. 74. Kunyakham W, Foocharoen C, Mahakkanukrauh, et al. Prevalance and risk factor for symptomatic avascular necrosis development in thai systemic lupus erythematosus patients. Asian Pac J Allergy Immunol. 2012;30:152–7. 75. Sayarlioglu M, Yuzbasioglu, Inanc M, et al. Risk Factors for Avascular Bone Necrosis in patients with systemic lupus erythematosus. Rheumatol Int 2012;32:177–82. 76. Zonana-Nacach A, Barr SG, Magder LS, Petri M. Damage in SLE and its association with corticosteroids. Arthritis Rheum 2000;43(8): 1801–8. 77. Zhang K, et al. Systemic lupus erythematosus patients with high disease activity are associated with accelerated incidence of osteonecrosis: a systematic review and meta-analysis. Clin Rheumatol 2018;37(1):5–11. 78. Gladman DD, et al. Osteonecrosis in SLE: prevalence, patterns, outcomes and predictors. Lupus 2018;27(1):76–81. 79. Lane NE. Therapy insight: Osteoporosis and osteonecrosis in SLE. Nat Clin Pract Rheum 2006;2(10):562–9. 80. Jones LC, Hungerford DS. Osteonecrosis: etiology, diagnosis, and treatment. Curr Opin Rheumatol 2004;16:443–9. 81. Mont MA, Jones LC. Management of osteonecrosis in SLE. Rheum Dis Clin N Am 2000;26(2):279–309. 82. Wang, A, Ren M, Wang J. The pathogenesis of steroid-induced osteonecrosis of the femoral head: a systematic review of the literature. Gene 2018;671:103–9. 83. Calvo-Alen J, McGwin G, Toloza S, Fernandez M, Roseman JM, Bastian HM, et al. SLE in a multiethnic US cohory (LUMINA): XXIV. Cytotoxic treatment is an additional risk factor for the development of symptomatic osteonecrosis in lupus patients: results of a nested matched case-control study. Ann Rheum Dis 2006;65:785–90. 84. Sweet DL, Roth DG, Desser RK, et al. Avascular necrosis of the femoral head with combination therapy. Ann Intern Med 1976;85:67–8. 85. Rueda JC, Duque MA, Mantilla RD, Iglesias-Gamarra A. Osteonecrosis and antiphospholipid syndrome. J Clin Rheumatol 2009;15(3):130– 2. 86. Tektonidiou MG, Malagari K, Vlachoyiannopoulos PG, Kelekis DA, Moutsopoulos HM. Asymptomatic avascular necrosis in patients with primary antiphospholipid syndrome in the absence of corticosteroid use. Arthritis Rheum 2003;48(3):732–6. 87. Oinuma K, Haradaa Y, Nawatab Y, Takabayashib K, Abea I, Kamikawaa K, et al. Osteonecrosis in patients with SLE develops very early after starting high dose corticosteroid treatment. Ann Rheum Dis 2001;60:1145–8. 88. Nagasawa K, Tada Y, Koarada S, et al. Prevention of steroid-induced osteonecrosis of femoral head in SLE by anti-coagulant. Lupus 2006;15:354–7. 89. Hussein S, et al. Monitoring of osteonecrosis in systemic lupus erythematosus: a systematic review and meta-analysis. J Rheumatol 2018;45(10):1462–76.

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90. Yang XY, Xu DH. MDR1(ABCB1) gene polymorphisms associated with steroid-induced osteonecrosis of femoral head in SLE. Pharmazie 2007;62(12):930–2. 91. Asano T, Takahashi KA, Fujioka M, et al. ABCB1 C3435T and G2677T/A polymorphism decreased the risk for steroid induced osteonecrosis of the femoral head after kidney transplantation. Pharmacogenetics 2003;13(11):675–82. 92. Zhang Y-Z, et al. Accuracy of MRI diagnosis of early osteonecrosis of the femoral head: a meta-analysis and systematic review. J Orthop. Sur Res 2018;13(1):167. 93. Lydon EJ, Schweitzer M, Godberg JD, Belmont HM. Atorvastatin to prevent avascular necrosis of bone in systemic lupus erythematosus. Arthritis Rheum 2008; abstract. 94. Lau RL, Perruccio AV, Evans HMK, et al. Stem cell therapy for the treatment of early stage avascular necrosis of the femoral head: a systematic review. BMC Musculoskeletal Dis 2014;15:156. 95. Di Munno O, Mazzantini M, Delle Sedie A, et al. Risk factors for osteoporosis in female patients with systemic lupus erythematosus. Lupus 2004;13:724–30. 96. Lee C, Ramsey-Goldman R. Bone health and systemic lupus erythematosus. Curr Rheumatol Rep 2005;7:482–9. 97. National Health and Nutrition Survey. CDC/NHANES. 2005–2010. Available from: https://www.cdc.gov/nchs/data/hestat/osteoporsis/ osteoporosis2005_2010.pdf 98. Yee CS, Crabtree N, Skan J, et al. Prevalence and predictors of fragility fractures in systemic lupus erythematosus. Ann Rheum Dis 2005;64:111–3. 99. Almehed K, Forsblad d’Elia H, Kvist G, et al. Prevalence and risk factors for osteoporosis in female SLE patients – extended report. Rheumatology 2007;46:1185–90. 100. Cramarossa G, et al. Prevalence and associated factors of low bone mass in adults with systemic lupus erythematosus. Lupus 2017;26(4):365–72. 101. Ramsey-Goldman R, Dunn JE, Huang CE, et al. Frequency of fractures in women with systemic lupus erythematosus: comparison with United States population data. Arthritis Rheum 1999;42(5):882–90. 102. Mok CC, Yee SK, Ying Y, et al. Bone mineral density and body composition in men with systemic lupus erythematosus: a case control study. Bone 2008;43:327–31. 103. Lilleby V, Lien G, Frey Froslie K, et al. Frequency of osteopenia in children and young adults with childhood-onset systemic lupus erythematosus. Arthritis Rheum 2005;52:2051–9. 104. Compeyrot-Lacassagne S, Tyrrell PN, Atenafu E, et al. Prevalence and etiology of low bone mineral denisty in juvenile systemic lupus erythematosus. Arthritis Rheum 2007;56(6):1966–73.

105. Alele JD, Kamen DL. The importance of inflammation and vitamin D status in SLE-associated osteoporosis. Autoimmun Rev 2009;9(3):137–9. 106. Lane N. Osteoporosis: Is there a rational approach to fracture prevention? B Hosp Joint Dis Ort 2006;64:67–71. 107. Lane NE. Therapy insight: osteoporosis and osteonecrosis in systemic lupus erythematosus. Nat Clin Pract Rheum 2006;2(10): 562–9. 108. Lane NE, Rehman Q. Osteoporosis in the rheumatic disease patient. Lupus 2002;11:675–9. 109. Lee C, Ramsey-Goldman R. Osteoporosis in systemic lupus erythematosus mechanisms. Rheum Dis Clin N Am 2005;31:363–85. 110. Carli L, et al. Risk factors for osteoporosis and fragility fractures in patients with systemic lupus erythematosus. Lupus Sci Med 2016;3(1):e000098. 111. Lo Cascio V, Bonucci E, Imbimbo B, et al. Bone loss in response to long-term glucocorticoid therapy. Bone Miner 1990;8:39–51. 112. Jardinet D, Lefebvre C, Depresseux G. Longitudinal analysis of bone mineral density in pre-menopausal female systemic lupus erythematosus patients: deleterious role of glucocorticoid therapy at the lumbar spine. Rheumatology 2000;39:389–92. 113. Reid IR. Glucocorticoid osteoporosis – mechanisms and management. Eur J Endocrinol 1997;137:209–17. 114. Klein RG, Arnaud SB, Gallagher JC, et al. Intestinal calcium absorption in exogenous hypercortisolism. Role of 25-hydroxyvitamin D and corticosteroid dose. J Clin Invest 1977;60:253–9. 115. Manolagas SC, Weinstein RS. New developments in pathogenesis and teratment of steroid induced osteoporosis. J Bone Miner Res 1999;14:1061–6. 116. Weinstein RS, Jilka RL, Parfitt AM, et al. Inhibition of osteoblastogenesis and promotion of apoptosis of osteopblasts and osteocytes by glucocorticoids. J Clin Invest 1998;102:274–82. 117. Sinigaglia L, Varenna M, Binelli L, et al. Bone mass in systemic lupus erythematosus. Clin Exp Rheumatol 2000;18(2):19:S27. 118. Lahita RG, Bradlow HL, Ginzler E, et al. Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum 1987;30:241–8. 119. Lahita RG. Sex hormones and systemic lupus ertythematosus. Rheum Dis Clin N Am 2000;26(4):951–68. 120. Shabanova SS, Ananieva LP, Alekberova ZS, Guzov II. Ovarian function and disease activity in patients with systemic lupus erythematosus. Clin Exp Rheumatol 2008;26(3):436–41. 121. Saag KG, Zanchetta JR, Devogelaer JP, et al. Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis. Arthritis Rheum 2009;60(11):3346–55.

Chapter 41

Cutaneous lupus erythematosus Annegret Kuhna,b, Aysche Landmannb and Gisela Bonsmannc a

Interdisciplinary Center for Clinical Trials (IZKS), University Medical Center Mainz, Mainz, Germany; bDivision of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany; cDepartment of Dermatology, University of Muenster, Muenster, Germany

Epidemiology Cutaneous manifestations occur in approximately 75% of patients with systemic lupus erythematosus (SLE) during the course of the disease and are the first sign in about 25% of patients.1 Epidemiological data of the different subtypes of cutaneous lupus erythematosus (CLE) have rarely been investigated, as most studies rather evaluate the incidence of SLE.2 In 2007, a study from Stockholm County, Sweden, reported that subacute cutaneous lupus erythematosus (SCLE) with anti-Ro/SSA antibodies has an incidence of 0.7 per 100,000 persons per year compared with an incidence of SLE of 4.8 per 100,000 persons per year.3

Classification criteria for SLE The criteria developed by the American College of Rheumatology (ACR) for the classification of SLE comprise 11 clinical and laboratory features and provide some degree of uniformity to the patient population of clinical studies.4 However, 4 of the 11 ACR criteria include mucocutaneous manifestations (malar rash, discoid lesions, photosensitivity, and oral ulcers) and therefore may result in an overestimation of SLE.5 In particular, the ACR criteria poorly define photosensitivity as “a result of an unusual reaction to sunlight by patient's history or physician's observation.”4 Furthermore, photosensitivity is not specific for SLE, as it is also observed in other photodermatoses, such as polymorphous light eruption.5 To improve the clinical relevance and to incorporate new knowledge in SLE immunology, the Systemic Lupus Collaborating Clinics (SLICC) revised the ACR criteria in 2012.6 The SLICC criteria include 11 clinical criteria (e.g., nonscarring alopecia or synovitis) and 6 immunological Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00041-6 Copyright © 2020 Elsevier Inc. All rights reserved.

criteria (e.g., decreased complement and antiphospholipid antibodies), whereas photosensitivity is no longer listed. The SLICC criteria have still to be assessed in routine clinical practice, and it is unclear how much impact these criteria will have on the validity of the diagnosis of SLE.

Photosensitivity The importance of photosensitivity as one of the most common environmental triggers in lupus erythematosus (LE) has been outlined by different groups from Europe, Japan, and the United States.7–11 In SLE patients, even induction of systemic organ involvement, such as lupus nephritis, has been reported as a result of extensive sun exposure.10,12 Moreover, consistent sunscreen protection in patients with SLE is associated with better clinical outcomes, as well as a decreased need for immunosuppressive agents.13 In addition, several studies with a high number of CLE patients have been performed to show a clear relationship between ultraviolet (UV) radiation and disease-specific skin manifestations using a standardized photoprovocation protocol.14–16 Meanwhile, photoprovocation has been accepted as a diagnostic procedure to evaluate photosensitivity in CLE.17 In two retrospective studies of more than 400 patients with different subtypes of CLE, skin lesions induced by UVA and/or UVB radiation were observed in 54.0% and 61.7% of patients, respectively.15,18 The more recent analysis suggests that the reaction to UV light may change during the course of the disease and that photosensitivity should not be defined only on the basis of patients’ history.18 Moreover, a randomized, vehicle-controlled, intraindividual, comparative, double-blind study demonstrated that the application of a broad-spectrum sunscreen with a high protection factor prevented the appearance of disease-specific skin 371

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lesions in all tested patients with photosensitive CLE.14 A further study confirmed these results.19 In addition, immunohistological analysis of skin biopsy specimens taken from patients with CLE after UV exposure demonstrated that sunscreen protection reduces lesional tissue damage and inhibits the typical interferon-driven inflammatory response.20 The published studies imply that patients with CLE should receive thorough advice (i.e., information that UVA passes window glass) and instructions on photoprotective measures (i.e., information on suitable clothing).14,19–21 Sunscreens with a high sun protection factor (≥50) should be applied in a sufficient amount (2 mg/cm2) 20–30 minutes before sun exposure.22

TABLE 41.1 Subtypes of cutaneous lupus erythematosus (CLE). Acute cutaneous lupus erythematosus (ACLE) Localized Generalized Subacute cutaneous lupus erythematosus (SCLE) Annular Papulosquamous/psoriasiform Chronic cutaneous lupus erythematosus (CCLE) Discoid lupus erythematosus (DLE) Localized Disseminated

Cutaneous manifestations Skin lesions associated with LE show great heterogeneity and have led to the differentiation into LE-specific and LE-nonspecific manifestations by clinical parameters and histological analysis of skin biopsy specimens.23 LE-nonspecific cutaneous manifestations, which may also appear in other diseases, are preferably associated with higher disease activity in SLE.24,25 These include cutaneous vascular lesions, such as periungual telangiectasia, red lunula, livedo racemosa, Raynaud's phenomenon, acral occlusive vasculopathy, thrombophlebitis, and leukocytoclastic vasculitis, which can occur as palpable purpura or urticarial vasculitis (especially hypocomplementemic urticarial vasculitis). Other nonspecific skin lesions include papular mucinosis, calcinosis cutis, nonscarring alopecia (i.e., “lupus hair”), and erythema multiforme, among others.26 LE-specific cutaneous manifestations comprise the different subtypes of CLE, which are defined by a constellation of clinical and histological features, serological parameters, such as antinuclear antibodies, and the course of the disease.23 Since the first classification system of Gilliam including acute CLE (ACLE), SCLE, and chronic CLE (CCLE) more than 3 decades ago, several approaches have been made to further develop this system and to present a more detailed classification of the different CLE subtypes.23,27–29 For example, the subtype named LE tumidus (LET) with specific clinical, histological, and photobiological features has been analyzed and defined as a separate entity of CLE in the past years.30–32 Its course and prognosis is generally more favorable compared to other subtypes of CLE; therefore, a revised classification system, including LET as the intermittent, non-chronic subtype of CLE, was suggested as the “Duesseldorf Classification” (Table 41.1).27,33 In 2004, the European Society of Cutaneous Lupus Erythematosus (EUSCLE) was founded to further differentiate and assess the various subtypes of CLE and to achieve a general consensus concerning evidence-based clinical

Lupus erythematosus profundus/panniculitis (LEP) Chilblain lupus erythematosus (CHLE) Intermittent cutaneous lupus erythematosus (ICLE) Lupus erythematosus tumidus (LET) Source: Modified after Ref. [27].

standards for disease evaluation. A study group of EUSCLE defined a core set of variables for the evaluation of the characteristic features of the disease and developed the EUSCLE Core Set Questionnaire, which includes various parameters considered the most relevant features of CLE.34,35 Data of 1002 patients with CLE from 30 centers in Europe were collected using the EUSCLE Core Set Questionnaire, and statistical analysis of clinical and laboratory features, as well as an evaluation of treatment options and their efficacies was performed.36,37 In addition, an analysis of the smoking behavior and the efficacy of antimalarials in part of the study population suggests that smoking is a risk factor for the disease, in particular for LET, and negatively influences CLE disease activity and the efficacy of antimalarial treatment.38

Scores in cutaneous lupus erythematosus To determine disease activity in everyday clinical practice and during clinical trials, several disease activity scores Systemic Lupus Erythematosus Disease Activity Index (SLEDAI); European Consensus Lupus Activity Measurement (ECLAM); British Isles Lupus Assessment Group (BILAG) have been established for SLE.39,40 In addition, the damage should be assessed once a year by the SLICC/ACR Damage Index.41 Although these scores include dermatological manifestations (e.g., butterfly rash, generalized erythema, oral ulcers), they are not suitable for evaluating the activity and damage of the different CLE subtypes. Therefore, the scoring system Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) has been developed for patients with cutaneous

Cutaneous lupus erythematosus Chapter | 41

manifestations to assess disease activity and damage, taking into account anatomical regions (e.g., face, chest, arms) and morphological aspects (e.g., erythema, edema, infiltration, scarring, atrophy).42 By increasing the accuracy of existing parameters, such as scaling/hypertrophy and dyspigmentation, and by including several new parameters, such as edema/infiltration and subcutaneous nodule/plaque, the CLASI was revised in 2010.43 Thus, the revised CLASI is a validated scoring system for the clinical evaluation of activity and damage in different CLE subtypes, and is currently applied in several clinical trials.

Subtypes of cutaneous lupus erythematosus Acute cutaneous lupus erythematosus Acute cutaneous lupus erythematosus (ACLE) may occur as a localized, occasionally transient, or generalized widespread form.44 Most common is localized ACLE, which presents as a malar rash (butterfly rash) in approximately 50% of patients during the course of SLE (Fig. 41.1).25 The erythema symmetrically affects the bridge of the nose and cheeks, typically sparing the nasolabial folds, and can be misdiagnosed as sunburn. It commonly starts with discrete small, erythematous macules or papules, which subsequently become confluent. Generalized ACLE is less common and often occurs concomitantly with systemic disease activity. The erythematous to violaceous, maculopapular widespread exanthema symmetrically involves the trunk and extremities, in particular UV-exposed areas (V-area of the neck and extensor aspects of the arms). On the hands, the knuckles are typically spared; telangiectasia and periungual erythema occur at the nail fold and may be associated with a red lunula. Skin lesions in ACLE usually heal without scarring or dyspigmentation. Diffuse thinning of the hair (lupus hair) along the hairline is frequently associated with ACLE.45 Superficial mucosal ulcers may affect the hard palate, but they may also be found anywhere in the

FIGURE 41.1  ACLE: butterfly rash with symmetrical erythema on malar areas and back of the nose sparing the nasolabial folds.

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oral cavity, on the lips, and in the nose. However, the highly acute form of generalized ACLE characterized by toxic epidermal necrolysis (TEN)-like lesions and described as “Acute Syndrome of Apoptotic Panepidermolysis” is rarely seen in patients with the disease.46

Subacute cutaneous lupus erythematosus (SCLE) In the cohort evaluated by EUSCLE, SCLE was diagnosed in 236 of 1002 patients and was associated with discoid LE (DLE) in 53 patients.36 Drug-induced CLE was found in 6% of the 1002 patients, with the highest prevalence of druginduced SCLE (31 of 236 patients). In annular SCLE, the lesions are characterized by a ring-shaped erythema with peripheral collarette scaling at the inner border, central clearing, and polycyclic confluence of the annular lesions (Fig. 41.2).47 In rare cases, vesiculobullous lesions develop at the periphery of annular SCLE lesions. The papulosquamous/psoriasiform SCLE shows psoriasis- or eczema-like lesions. Both forms, the annular and the papulosquamous/ psoriasiform type of SCLE, can be concurrently present in the same patient. The recurrent, non-scarring skin lesions of SCLE usually appear in a symmetric distribution on sunexposed areas, such as the V-area of the neck (often sparing the area under the chin), the upper ventral and/or the dorsal part of the trunk and extensor aspects of the extremities; face and scalp are rarely involved. A diagnostic “clue” of this subtype can be the healing with vitiligo-like, sometimes permanent hypopigmentation, especially if treatment is delayed.45 Patients with SCLE are typically photosensitive and UV radiation can induce and/or exacerbate skin manifestations.15 Similar to ACLE, a TEN-like picture can rarely occur in patients with SCLE, especially after exposure to UV light.46 In particular in genetically susceptible individuals, SCLE can be triggered by different drugs, such as anti-diuretics/anti-hypertensives (i.e., hydrochlorothiazide, calcium channel blockers, ACE inhibitors) and anti fungals (up to now, terbinafine is considered the most

FIGURE 41.2  SCLE: polycyclic confluence of the annular lesions with central clearing and collarette staining at the inner border of the lower back.

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common cause of drug-induced SCLE).48,49 SCLE shows a characteristic immunogenetic disposition and is associated with the HLA-A1, -B8, -DR3 haplotype and the -308A TNF promoter polymorphism.50 Characteristic serological features of SCLE are anti-Ro/SSA (in 70%–90%) and antiLa/SSB antibodies (in 30%–50%, nearly always together with anti-Ro/SSA antibodies).51–53 SLE with often milder course will develop in 10%–15% of SCLE patients.47 The immunogenetic background of SCLE is similar to Sjögren's syndrome; therefore, patients with SCLE are reported to be at higher risk to develop features of Sjögren's syndrome in the course of the disease.47,54

Chronic cutaneous lupus erythematosus (CCLE) CCLE includes three different forms: discoid LE (DLE), LE profundus/LE panniculitis (LEP), and chilblain LE (CHLE).

pitted acneiform (vermicular) scarring.55 Mucosal DLE with chronic buccal plaques, presenting typically as roundish lesions with peripheral white hyperkeratotic striae and central atrophy, erosion or ulceration, has to be differentiated from lichen planus.45 In anatomically specific regions (e.g., ear, tip of the nose, margin of eyelid), mutilations can occur resulting in high burden of the disease. Palmoplantar involvement can present as discoid and erythematous scaly plaques or rarely painful erosions. Exposure to the sun or irritating stimuli (Koebner phenomenon or isomorphic response), such as trauma, tattoos, scratching, and various types of dermatitis, can provoke or exacerbate the disease.56,57 DLE lesions occur in approximately 15%–25% in the course of SLE, but more than 95% of patients with DLE lesions suffer from cutaneous lesions only. Disseminated DLE has an increased risk to develop systemic organ manifestations.25,44,58

Discoid lupus erythematosus (DLE)

Lupus erythematosus profundus/ panniculitis (LEP)

In the study published by EUSCLE, DLE was diagnosed in 397 of 1002 patients.36 DLE is the most common form of CCLE and occurs as localized form (ca. 80%) with lesions on the face and scalp, especially the cheeks, forehead, ears, nose, and upper lip or as disseminated/generalized form (ca. 20%) with lesions involving the upper part of the trunk and the extensor aspects of the extremities.44 The lesions of DLE develop unilaterally or bilaterally and consist of sharply-demarcated, coin-shaped (discoid) indurated erythematous plaques with adherent follicular hyperkeratosis (Fig. 41.3). Removal of the keratotic spikes causes pain and is termed “carpet tack sign.”45 Slowly, the lesions expand at the periphery with an active erythematous border and hyperpigmentation, resulting in atrophy, scarring, telangiectasia and hypopigmentation in the center of the lesions. At the scalp, eyebrows and bearded regions of the face, DLE can progress to total, irreversible scarring alopecia. In the perioral region, DLE lesions can lead to characteristic

LEP is a rare variant of CCLE and is associated with DLE in 70% of patients,44 but is rarely (less than 3%) present in the context of SLE.25,44 This subtype clinically presents with single or multiple well-defined, persistent asymptomatic and sometimes painful indurated subcutaneous nodules and plaques, which may later firmly adhere to the overlying skin. The surface of the LEP lesions may appear without clinical changes or can show signs of DLE. In the course of the disease, the nodules develop into deep, asymptomatic lipatrophy or deep retracted scars; ulceration is rare (Fig. 41.4). Skin lesions of LEP are typically located in areas of increased fat deposition, such as the gluteal region, the thighs or the upper and lower extremities, but face, scalp, and chest can also be involved. Rarely, periorbital edema may be an initial presenting symptom prior to the development of typical skin changes.45 LEP can also be induced by irritative stimuli but usually not by UV exposure.44

FIGURE 41.3  DLE: several active discoid lesions with erythematous border and white hyperkeratotic center on the left part of the face.

FIGURE 41.4  LEP: typical deep lipatrophy after resolution of lesions on the upper right arm.

Cutaneous lupus erythematosus Chapter | 41

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FIGURE 41.5  CHLE: erythematous inflammation with scaling and hyperkeratosis at fingertips and palmar sites of D2.

FIGURE 41.6  LET: urticaria-like, erythematous, annular and semilunar plaques and papules on the upper arm.

Chilblain lupus erythematosus (CHLE)

by UV radiation in more than 70% of patients.10,68 The analysis of 1002 patients by EUSCLE revealed that smoking is a risk factor for the development of this subtype.38 Association with SLE seems to be extremely rare in patients with LET, only a few cases have been reported.31 Therefore, this subtype has a good prognosis with a variable course of the disease in the majority of patients.30 The identification of the specific clinical, histological, and photobiological criteria has resulted in the definition of LET as a distinct entity and has therefore been included in the “Duesseldorf Classification” as “intermittent cutaneous LE” (ICLE).27

CHLE is a further manifestation of CCLE, which is influenced by environmental factors, such as cold, damp weather or a critical drop in temperature, and often clinically and histologically difficult to distinguish from frostbites (chilblains). Association of CHLE with other CLE subtypes, such as DLE, has been described in the literature; in up to 20% of patients, CHLE is associated with SLE.59–61 This subtype is characterized by symmetrically distributed, circumscribed pruriginous or painful bluish plaques and nodules.45 Edematous plaques and nodules may develop central erosions or ulcerations, which affect the acral surfaces, especially fingers, toes, heels, nose, ears, elbows, knees, and calves (Fig. 41.5).62 The description of a monogenic autosomal dominant, inherited familial chilblain lupus presenting in early childhood and usually caused by mutations in TREX-1, has provided novel insights into the molecular pathogenesis and on our understanding of the disease.63–65 Recently, associations with mutations in TREX-1 have also been described in single SLE patients.65

Intermittent cutaneous lupus erythematosus (ICLE) Lupus erythematosus tumidus (LET) LET is characterized by sharply-bordered, “succulent,” urticaria-like, single or multiple erythematous papules and plaques with a smooth surface without epidermal involvement (Fig. 41.6).66 In the course of the disease, the lesions may be semilunar or annular with swelling in the periphery and flattening in the center.30 In contrast to annular SCLE, the lesions of LET show no scaling and resolve without residual defects, such as scarring or dyspigmentation. The lesions of LET patients are typically found in sun-exposed areas (e.g., face, upper back, upper chest, extensor aspects of the upper arms), but rare reports exist describing LET below the waist.67 LET is the most photosensitive subtype of CLE, as skin lesions can be experimentally induced

Conclusion Skin manifestations are one of the most frequent symptoms in patients with SLE, can develop at any stage of the disease and are the first sign in approximately 25% of patients. To differentiate SLE from other connective tissue diseases, the 11 ACR criteria can be helpful, but the comparative high number of dermatological criteria (malar rash, discoid lesions, photosensitivity, and oral ulcers) may result in an overestimation of SLE.4,5 The recently developed SLICC criteria have still to be evaluated in everyday clinical practice. Skin manifestations in SLE are divided in LE-nonspecific manifestations, such as urticarial vasculitis, and LE-specific manifestations comprising the four CLE subtypes including ACLE, SCLE, CCLE, and ICLE. Patients should be advised that UV exposure can induce and exacerbate existing skin lesions. Sun protection, such as protective clothing and daily application of broad-spectrum sunscreens, continuous avoidance of the sun, and elimination of potentially photosensitizing drugs are of high importance in the prevention of the disease.

Acknowledgment The figures were kindly provided by the Photographic Laboratory (with thanks to J. Bueckmann and P. Wissel), Department of Dermatology, University of Muenster, Germany.

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References 1. Jimenez S, Cervera R, Ingelmo M, Font J. The epidemiology of cutaneous lupus erythematosus. In: Kuhn A, Lehmann P, Ruzicka T, editors). Cutaneous lupus erythematosus. Springer-Verlag: Berlin; pp. 45–52, 2005. 2. Tebbe B, Orfanos CE. Epidemiology and socioeconomic impact of skin disease in lupus erythematosus. Lupus 1997;6:96–104. 3. Popovic K, Nyberg F, Wahren-Herlenius M. A serology-based approach combined with clinical examination of 125 Ro/SSA-positive patients to define incidence and prevalence of subacute cutaneous lupus erythematosus. Arthritis Rheum 2007;56:255–64. 4. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7. 5. Albrecht J, Berlin JA, Braverman IM, et al. Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus. Lupus 2004;13:839–49. 6. Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677–86. 7. Kuhn A, Beissert S. Photosensitivity in lupus erythematosus. Autoimmunity 2005;38:519–29. 8. Scheinfeld N, Deleo VA. Photosensitivity in lupus erythematosus. Photodermatol Photoimmunol Photomed 2004;20:272–9. 9. Furukawa F. Photosensitivity in cutaneous lupus erythematosus: lessons from mice and men. J Dermatol Sci 2003;33:81–9. 10. Kuhn A, Ruland V, Bonsmann G. Photosensitivity, phototesting, and photoprotection in cutaneous lupus erythematosus. Lupus 2010;19:1036–46. 11. Foering K, Chang AY, Piette EW, et al. Characterization of clinical photosensitivity in cutaneous lupus erythematosus. J Am Acad Dermatol 2013;69:205–13. 12. Schmidt E, Tony HP, Brocker EB, Kneitz C. Sun-induced life-threatening lupus nephritis. Ann NY Acad Sci 2007;1108:35–40. 13. Vila LM, Mayor AM, Valentin AH, et al. Association of sunlight exposure and photoprotection measures with clinical outcome in systemic lupus erythematosus. P R Health Sci J 1999;18:89–94. 14. Kuhn A, Gensch K, Haust M, et al. Photoprotective effects of a broadspectrum sunscreen in ultraviolet-induced cutaneous lupus erythematosus: a randomized, vehicle-controlled, double-blind study. J Am Acad Dermatol 2011;64:37–48. 15. Kuhn A, Sonntag M, Richter-Hintz D, et al. Phototesting in lupus erythematosus: a 15-year experience. J Am Acad Dermatol 2001;45:86–95. 16. Sanders CJ, Van Weelden H, Kazzaz GA, et al. Photosensitivity in patients with lupus erythematosus: a clinical and photobiological study of 100 patients using a prolonged phototest protocol. Br J Dermatol 2003;149:131–7. 17. Kuhn A, Wozniacka A, Szepietowski JC, et al. Photoprovocation in cutaneous lupus erythematosus: a multicenter study evaluating a standardized protocol. J Invest Dermatol 2011;131:1622–30. 18. Ruland V, Haust M, Stilling RM, et al. Updated analysis of standardised photoprovocation in patients with cutaneous lupus erythematosus. Arthritis Care Res 2012;65:767–76. 19. Patsinakidis N, Wenzel J, Landmann A, et al. Suppression of UVinduced damage by a liposomal sunscreen: a prospective, open-label study in patients with cutaneous lupus erythematosus and healthy controls. Exp Dermatol 2012;21:958–61.

20. Zahn S, Graef M, Patsinakidis N, et al. Ultraviolet light protection by a sunscreen prevents interferon-driven skin inflammation in cutaneous lupus erythematosus. Exp Dermatol 2014;23:516–8. 21. Gutmark EL, Lin DQ, Bernstein I, Wang SQ, Chong BF. Sunscreen use in cutaneous lupus erythematosus patients. Br J Dermatol 2015;173:831–4. 22. Faurschou A, Wulf HC. The relation between sun protection factor and amount of suncreen applied in vivo. Br J Dermatol 2007;156: 716–9. 23. Gilliam JN, Sontheimer RD. Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J Am Acad Dermatol 1981;4:471–5. 24. Uva L, Miguel D, Pinheiro C, et al. Cutaneous manifestations of systemic lupus erythematosus. Autoimmune Dis 2012;(2012):834291. 25. Obermoser G, Sontheimer RD, Zelger B. Overview of common, rare and atypical manifestations of cutaneous lupus erythematosus and histopathological correlates. Lupus 2010;19:1050–70. 26. Provost TT. Nonspecific cutaneous manifestations of systemic lupus erythematosus. In: Kuhn A, Lehmann P, Ruzicka T, editors. Cutanoeus lupus erythematosus. Springer: Heidelberg, pp. 93–106, 2005. 27. Kuhn A, Ruzicka T. Classification of cutaneous lupus erythematosus. In: Kuhn A, Lehmann P, Ruzicka T, editors. Cutaneous lupus erythematosus. Springer: Heidelberg, pp. 53–58, 2005. 28. Werth VP. Cutaneous lupus: insights into pathogenesis and disease classification. Bull NYU Hosp Jt Dis 2007;65:200–4. 29. Sontheimer RD. The lexicon of cutaneous lupus erythematosus—a review and personal perspective on the nomenclature and classification of the cutaneous manifestations of lupus erythematosus. Lupus 1997;6:84–95. 30. Schmitt V, Meuth AM, Amler S, et al. Lupus erythematosus tumidus is a separate subtype of cutaneous lupus erythematosus. Br J Dermatol 2010;162:64–73. 31. Kuhn A, Bein D, Bonsmann G. The 100th anniversary of lupus erythematosus tumidus. Autoimmun Rev 2009;8:441–8. 32. Rodriguez-Caruncho C, Bielsa I. Lupus erythematosus tumidus: a clinical entity still being defined. Actas Dermosifiliogr 2011;102: 668–74. 33. Kuhn A, Landmann A. The classification and diagnosis of cutaneous lupus erythematosus. J Autoimmun 2014;48–49:14–9. 34. Kuhn A, Kuehn E, Meuth AM, et al. Development of a core set questionnaire by the European Society of Cutaneous Lupus Erythematosus (EUSCLE). Autoimmun Rev 2009;8:702–12. 35. Kuhn A, Patsinakidis N, Bonsmann G. The impact of the EUSCLE Core Set Questionnaire for the assessment of cutaneous lupus erythematosus. Lupus 2010;19:1144–52. 36. Biazar C, Sigges J, Patsinakidis N, et al. Cutaneous lupus erythematosus: first multicenter database analysis of 1002 patients from the European Society of Cutaneous Lupus Erythematosus (EUSCLE). Autoimmun Rev 2013;12:444–54. 37. Sigges J, Biazar C, Landmann A, et al. Therapeutic strategies evaluated by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) Core Set Questionnaire in more than 1000 patients with cutaneous lupus erythematosus. Autoimmun Rev 2013;12:694–702. 38. Kuhn A, Sigges J, Biazar C, et al. Influence of smoking on disease severity and antimalarial therapy in cutaneous lupus erythematosus: analysis of 1002 patients from the EUSCLE database. Br J Dermatol 2014;171:571–9. 39. Griffiths B, Mosca M, Gordon C. Assessment of patients with systemic lupus erythematosus and the use of lupus disease activity indices. Best Pract Res Clin Rheumatol 2005;19:685–708.

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40. Ward MM, Marx AS, Barry NN. Comparison of the validity and sensitivity to change of 5 activity indices in systemic lupus erythematosus. J Rheumatol 2000;27:664–70. 41. Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum 1996;39:363–9. 42. Albrecht J, Taylor L, Berlin JA, et al. The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus. J Invest Dermatol 2005;125:889–94. 43. Kuhn A, Meuth AM, Bein D, et al. Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI): a modified outcome instrument for cutaneous lupus erythematosus. Br J Dermatol 2010;163:83–92. 44. Costner MI, Sontheimer RD, Provost TT. Lupus erythematosus. In: Sontheimer RD, Provost TT, editors. Cutaneous manifestations of rheumatic diseases. Williams & Wilkins: Philadelphia, pp. 15–64, 1996. 45. Kuhn A, Sticherling M, Bonsmann G. Clinical manifestations of cutaneous lupus erythematosus. J Dtsch Dermatol Ges 2007;5:1124–37. 46. Ting W, Stone MS, Racila D, Scofield RH, Sontheimer RD. Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus and the spectrum of the acute syndrome of apoptotic pan-epidermolysis (ASAP): a case report, concept review and proposal for new classification of lupus erythematosus vesiculobullous skin lesions. Lupus 2004;13:941–50. 47. Sontheimer RD. Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings. Autoimmun Rev 2005;4:253–63. 48. Sontheimer RD, Henderson CL, Grau RH. Drug-induced subacute cutaneous lupus erythematosus: a paradigm for bedside-to-bench patient-oriented translational clinical investigation. Arch Dermatol Res 2009;301:65–70. 49. Gronhagen CM, Fored CM, Linder M, Granath F, Nyberg F. Subacute cutaneous lupus erythematosus and its association with drugs: a population-based matched case-control study of 234 patients in Sweden. Br J Dermatol 2012;167:296–305. 50. Werth VP, Zhang W, Dortzbach K, Sullivan K. Association of a promoter polymorphism of tumor necrosis factor-alpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription. J Invest Dermatol 2000;115:726–30. 51. Sontheimer RD, Maddison PJ, Reichlin M, et al. Serologic and HLA associations in subacute cutaneous lupus erythematosus, a clinical subset of lupus erythematosus. Ann Intern Med 1982;97:664–71. 52. Chlebus E, Wolska H, Blaszczyk M, Jablonska S. Subacute cutaneous lupus erythematosus versus systemic lupus erythematosus: diagnostic criteria and therapeutic implications. J Am Acad Dermatol 1998;38:405–12.

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53. Lee LA, Roberts CM, Frank MB, McCubbin VR, Reichlin M. The autoantibody response to Ro/SSA in cutaneous lupus erythematosus. Arch Dermatol 1994;130:1262–8. 54. Black DR, Hornung CA, Schneider PD, Callen JP. Frequency and severity of systemic disease in patients with subacute cutaneous lupus erythematosus. Arch Dermatol 2002;138:1175–8. 55. Chang YH, Wang SH, Chi CC. Discoid lupus erythematosus presenting as acneiform pitting scars. Int J Dermatol 2006;45:944–5. 56. Ueki H. Koebner phenomenon in lupus erythematosus with special consideration of clinical findings. Autoimmun Rev 2005;4: 219–23. 57. Kuhn A, Aberer E, Barde C, et al. Leitlinien kutaner lupus erythematodes (Entwicklungsstufe 1). In: Korting HCCR, Reusch M, Schlaeger M, Sterry W, editors). Dermatologische qualitätssicherung: leitlinien und empfehlungen. ABW Wissenschaftsverlag GmbH: Berlin, pp. 214–257, 2009. 58. Tebbe B, Mansmann U, Wollina U, et al. Markers in cutaneous lupus erythematosus indicating systemic involvement. A multicenter study on 296 patients. Acta Derm Venereol 1997;77:305–8. 59. Viguier M, Pinquier L, Cavelier-Balloy B, et al. Clinical and histopathologic features and immunologic variables in patients with severe chilblains. A study of the relationship to lupus erythematosus. Medicine 2001;80:180–8. 60. Hedrich CM, Fiebig B, Hauck FH, et al. Chilblain lupus erythematosus–a review of literature. Clin Rheumatol 2008;27:949–54. 61. Millard LG, Rowell NR. Chilblain lupus erythematosus (Hutchinson). A clinical and laboratory study of 17 patients. Br J Dermatol 1978;98:497–506. 62. Helm TN, Jones CM. Chilblain lupus erythematosus lesions precipitated by the cold. Cutis 2002;69:183–4. 63. Lee-Kirsch MA, Gong M, Schulz H, et al. Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am J Hum Genet 2006;79:731–7. 64. Gunther C, Berndt N, Wolf C, Lee-Kirsch MA. Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3′ repair exonuclease 1 (TREX1). JAMA Dermatol 2015;151:426–31. 65. Rice GI, Rodero MP, Crow YJ. Human disease phenotypes associated with mutations in TREX1. J Clin Immunol 2015;35:235–43. 66. Kuhn A, Richter-Hintz D, Oslislo C, et al. Lupus erythematosus tumidus - a neglected subset of cutaneous lupus erythematosus: report of 40 cases. Arch Dermatol 2000;136:1033–41. 67. Stead J, Headley C, Ioffreda M, Kovarik C, Werth V. Coexistence of tumid lupus erythematosus with systemic lupus erythematosus and discoid lupus erythematosus: a report of two cases of tumid lupus. J Clin Rheumatol 2008;14:338–41. 68. Kuhn A, Sonntag M, Richter-Hintz D, et al. Phototesting in lupus erythematosus tumidus-review of 60 patients. Photochem Photobiol 2001;73:532–6.

Chapter 42

The clinical evaluation of kidney disease in systemic lupus erythematosus Brad H. Rovina, Isabelle Ayouba and Swati Arorab a

Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, OH, United States; bDivision of Nephrology, Allegheny Health Network, Pittsburgh, PA, United States

Introduction Kidney disease is common in patients with systemic lupus erythematosus (SLE). This is most often due to lupus nephritis (LN). LN is one of the major causes of morbidity and mortality in SLE patients and is associated with poorer outcomes than in those patients with no kidney involvement.1,2 This poor prognosis is explained only in part by the risk of chronic kidney disease (CKD) and end-stage kidney disease (ESKD), suggesting that LN is a manifestation of a more severe form of SLE. In LN anti-double stranded DNA and other autoantibodies bind to self-antigens, including chromatin released during glomerular cell injury, and form immune complexes that accumulate in all compartments of the glomeruli. Immune complex deposits in the mesangium or subendothelial space lead to activation of the classical pathway of complement and initiate an inflammatory response that can also involve the renal interstitium. This process may result in injury to the entire kidney parenchyma (Chapter 35). Clinically, this is often manifested by an active, inflammatory urine sediment (described as follows), proteinuria, and sometimes renal insufficiency. Immune complex deposits can also accumulate in the subepithelial space, which is separated from the blood by the glomerular basement membrane. Subepithelial immune deposits primarily damage the glomerular epithelial cells (podocytes), leading to proteinuria, but generally do not result in in flammatory findings on urinalysis and most often kidney function is preserved. Besides LN, other mechanisms may lead to kidney damage in SLE, such as thrombotic microangiopathy, lupus podocytopathy, or superimposed ANCA associated glomerulonephritis.3 Kidney biopsy plays a crucial role in discerning underlying pathology and in choosing an appropriate treatment Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00042-8 Copyright © 2020 Elsevier Inc. All rights reserved.

regimen. LN is often treatable. The best outcomes occur with early recognition and prompt treatment. Early recognition requires a high index of suspicion and the appropriate use of screening tests for kidney involvement followed by confirmatory tests and a kidney biopsy.

The scope of lupus nephritis Examination of kidney tissue from SLE patients who had no clinical signs of kidney disease suggested that LN may be present in up to 90% of lupus patients.4,5 Most of this clinically silent LN was associated with very mild histologic changes, but about 15% of patients had moderate to severe pathology, many of whom did eventually develop proteinuria, an abnormal urine sediment, or renal insufficiency. Silent LN may represent the earliest stage in the natural history of LN.6 The incidence of clinically overt kidney disease in all lupus populations is about 38%, but this varies greatly among racial and ethnic groups. The incidence of LN in non-white SLE patients is 50% or more, whereas only 12%33% of white patients (European, European Americans) develop LN.7 LN is reported in 40%-69% of black patients (African American, Afro-Caribbean), and 47%-53% of Asian patients, and occurs frequently (36%-61%) in Hispanic patients.7 Adverse kidney outcomes, such as ESKD or doubling of serum creatinine (a surrogate marker of ESKD), are also more frequent in black and Hispanic patients as compared to white patients.7 The incidence of ESKD attributed to LN in adults is 4.9 cases per million in the general population, but is 17-20 per million in black patients and 6 per million in Hispanics compared to 2.5 per million in white patients.7 379

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According to the 2018 United States Renal Data System report, about 1.9% of the prevalent patients receiving renal replacement therapy have ESKD attributable to LN, but in children with ESKD lupus accounts for 5.6% of ESKD. Beyond ESKD, the prevalence of CKD in patients with LN is difficult to quantify. However, if it is assumed that, at a minimum, a complete clinical renal response after treatment is needed to prevent CKD from developing, the prevalence of CKD is likely to be high, as many LN patients achieve only a partial renal response. Defining CKD as a serum creatinine greater than 1.0 mg/dL with estimated glomerular filtration rate (eGFR) less than 60 mL/min/m2, the prevalence of CKD was estimated to be 4.5%.8 CKD in LN is important because it may progress to ESKD. Currently, progression to ESKD 5, 10, and 15 years after the diagnosis of LN occurs in about 11%, 17%, and 22% of patients in developed countries and 12%, 19%, and 26% in developing countries.9 Progression to ESKD is higher among black, Asian, and Hispanic patients compared to white patients.10,11 CKD is also a nontraditional risk factor for cardiovascular morbidity, as is lupus itself.12,13 The highest mortality in LN is seen in patients with chronic kidney damage.1,2

The diagnosis of lupus nephritis The systemic lupus international collaborating clinics (SLICC) proposed that the diagnosis of SLE can be made with a kidney biopsy showing LN in the presence of antinuclear or antidouble-stranded DNA antibodies.14 This

facilitates the diagnosis of the kidney disease as LN. The SLICC criteria are more sensitive of the diagnosis of lupus than the American College of Rheumatology criteria (100% vs. 94%), but less specific (91% vs. 100%).15 However a kidney biopsy cannot be diagnosed as LN in isolation. Rather, a biopsy can show immune-complex mediated glomerulonephritis consistent with LN in the appropriate clinical setting. The early diagnosis and treatment of LN is critical to preserve kidney function.16-18 The key to early diagnosis is maintaining a high index of suspicion for renal involvement in every SLE patient. Patients who present with LN when SLE is first diagnosed have higher rates of prolonged remission and a lower frequency of chronic kidney damage than those whose LN presents later. This may be because of early recognition, but only about half of LN patients have the evidence of kidney disease at the initial presentation of SLE.19,20 An algorithm to identify kidney involvement in SLE patients is shown in Fig. 42.1.

Evaluation of kidney function Kidney function should be assessed during the initial evaluation of SLE, during SLE flares, and whenever a renal flare is suspected. Traditionally, renal function has been evaluated by the serum creatinine level or by calculating creatinine clearance from a 24-hours urine collection. Because it is difficult to reliably determine the completeness of a 24-hours urine collection, equations to estimate

FIGURE 42.1  An algorithm for the evaluation of the kidney in patients with SLE. Note that patients with a history of LN and previous kidney biopsy may not need a repeat biopsy (Fig. 42.4). Kidney biopsy should be done for new diagnoses of kidney involvement. Acanthocytes are dysmorphic red blood cells specific for glomerular bleeding (Fig. 42.2). SCr, serum creatinine; GFR, glomerular filtration rate; uPCR, protein-to- creatinine ratio in a urine sample.

The clinical evaluation of kidney disease in systemic lupus erythematosus Chapter | 42

creatinine clearance and, more recently, the glomerular filtration rate (GFR) have been incorporated into clinical practice. Nonetheless, all methods used to estimate kidney function in place of measuring GFR (which is not clinically practical) have limitations that affect their interpretation (Table 42.1). Creatinine production is proportional to muscle mass. Individuals with small to moderate muscle mass, like many women with SLE, may normally have low serum creatinine levels (even below the lower limit of the clinical laboratory’s range). In such individuals, a serum creatinine that falls at the clinical laboratory’s upper limit may reflect impaired renal function. Conversely, individuals with high muscle mass may have normal kidney function despite a serum creatinine that is above the clinical laboratory’s upper limit. Additionally, tubular secretion of creatinine increases in hypoalbuminemic nephrotic patients, lowering serum creatinine, and giving the impression that GFR is better than it really is.21 Finally, muscle metabolism can be affected by the high-dose glucocorticoids used in the treatment of LN, and this may acutely increase serum creatinine levels.22 Although cystatin C has been suggested as a superior endogenous marker of GFR than serum creatinine, it too can be affected by medications used to treat LN, such as corticosteroids and cyclosporine A.23 The Cockcroft-Gault formula has been used to estimate creatinine clearance for years. Now, however, many clinical laboratories provide an eGFR value whenever serum creatinine is measured. The eGFR is calculated using serum creatinine, sex, race, and age in equations derived from the Modification of Diet in Renal Disease (MDRD) study or the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi). CKD-Epi is more accurate than MDRD at eGFR >60 mL/min and is now the preferred GFR estimating equation for patients with CKD.24 GFR estimating equations have several limitations. All estimating equations assume that patients of a given serum creatinine, sex, race, and age have similar body surface areas and rates of creatinine production.25 None of the equations were developed using a typical SLE population of young women. Two studies compared the accuracy and precision of the Cockcroft-Gault and MDRD equations to directly measured creatinine clearance, one in Chinese patients with LN26 and the other in Caucasian and African American patients with LN.27 In Asian patients with impaired kidney function, the MDRD equation was a modestly better estimate of creatinine clearance than Cockcroft-Gault, but the opposite was found in Caucasian and African American patients. A third study compared creatinine clearance and several estimating equations to CKD-Epi in an LN cohort and recommended CKD-Epi.28 However, none of the studies compared calculated and measured eGFR, so none of the GFR equations have truly been compared to a gold standard GFR measurement in SLE patients.

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In summary, serial serum creatinine measurements remain useful in the management of individual patients. For individuals who are obese, have extremes of muscle mass, or have skewed diets (vegetarian, high meat intake), the Cockcroft-Gault formula adjusted for actual body surface area is a better estimate of GFR than the creatinine-based equations that do not include body weight and size.29 After determining that a lupus patient has impaired GFR, other common causes of acute kidney injury (Table 42.2) should be excluded to attribute the reduced function to LN.

Evaluation of the urine A comprehensive urinalysis should be done in all SLE patients at initial diagnosis, whenever renal involvement is suspected because of other symptoms or signs, such as edema, and at every extra-renal flare. While the clinical laboratory may be used for reporting the urine dipstick, urine microscopy should be done by a qualified individual. The urine dipstick is a commonly used screening test, and kidney involvement in SLE should be considered if the dipstick is positive for blood and/or protein. A positive test for blood is usually the result of hematuria. However, if the test for blood is strongly positive but there are only rare red blood cells in the urine sediment, the patient may have hemoglobinuria or myoglobinuria. If the urine is very dilute (e.g., specific gravity of 1.005 or less), red cells will lyse, mimicking hemoglobinuria. Hematuria may be due to several conditions unrelated to LN. For example, in the SLE population, menstruation is an important consideration. The urine sediment should be examined to verify the source of hematuria. Glomerular bleeding, which is expected to be present in a glomerulonephritis like LN, is suggested by the morphology of the urine red blood cells. Red cells indicative of glomerular bleeding are called acanthocytes and are dysmorphic cells that show cell-membrane blebs (Fig. 42.2). In addition to acanthocytes, red blood cell casts, as well as white blood cells and white blood cell casts in the absence of infection are indicative of glomerulonephritis (Fig. 42.2). Glomerular hematuria in the absence of proteinuria and/or renal insufficiency does not require an immediate kidney biopsy for evaluation, but it needs to be followed closely for accompanying changes in kidney function and protein excretion.

Evaluation of proteinuria At present, the most sensitive indicator of kidney involvement in SLE is proteinuria, and its magnitude is a key biomarker of relapse and response to treatment. Therefore accurate measurement of proteinuria is crucial to the optimal management of LN. The gold standard for estimating the magnitude of proteinuria is the protein content of a 24-hours urine collection. However, 24-hours urines are

Method

Rationale

Strengths

Weaknesses

(1) Serum creatinine (SCr)

Creatinine is usually produced at a constant rate, excreted almost entirely by the kidney, and mainly by glomerular filtration. Thus changes in SCr usually reflect change in GFR.

Simple and relatively inexpensive

There are many conditions that can increase or decrease SCr independent of GFR. The most common are: • Changes in intake of cooked meat (cooking converts creatine to creatinine). SCr is about 25% lower on a vegetarian diet. • Drugs that decrease tubular secretion of creatinine (trimethoprim and cimetidine) raise SCr by 10%-30%. • Hypoalbuminemia in severely nephrotic patients is associated with an increase in tubular secretion of creatinine. • Drugs that affect muscle metabolism Small changes in SCr (e.g., ±0.3 mg/dL) when SCr is in the normal range correspond to very large changes in GFR (about ±20%). Confounding this interpretation is that the 95% confidence intervals of the measurement of SCr are also about ±0.2 mg/dL for SCr values around the normal range. Thus often it is necessary to measure SCr 2 or 3 times to assess whether a real change in GFR has occurred versus a spontaneous laboratory variation.

(2) Creatinine clearance (CCr)

CCr refers to the renal clearance of creatinine, which is usually a close estimate of GFR. CCr = (amount of creatinine in a complete 24-hours urine collection)/(average SCr during the period that the urine was collected). In most patients SCr is stable. Thus SCr measured at the start or end of the 24-hours collection reflects the average SCr during the urine collection. If SCr is changing (as in acute renal failure), the SCr measured at the midpoint of the collection is a good estimate of the average SCr during the collection.

CCr estimate of GFR is not affected by changes in creatinine production so long as the patient is in a steady state (serum creatinine is stable).

An accurate estimate of CCr is dependent on a complete 24-hours collection. Thus the error in estimating GFR from CCr is directly proportional to the completeness of the intended 24-hours collection. • CCr underestimates GFR if the patient is receiving trimethoprim or cimetidine. See weaknesses of SCr (aforementioned). • At low GFR (e.g., 60 mL/min/1.73 m2. Thus a single measure in patients with serum creatinine at or near the normal range is not a reliable measure of GFR. Multiple measures, however, improve precision. The MDRD-4 eGFR assumes everyone of the same age, race, and sex has the same rate of creatinine production. Thus MDRD-4 underestimates GFR in large persons (or those with other mechanisms of increased creatinine production) and overestimates GFR in those with low creatinine production. MDRD-4 eGFR also suffers from confounding by all of the other factors that influence SCr, independent of GFR. See weaknesses, SCr (aforementioned). The MDRD-4 eGFR is most useful in comparing GFR between large populations where the influence of body size, diet, etc. can be expected to be similar in the groups being compared.

CKD-EPI

This is the latest version of eGFR. It is calculated from a complex formula similar to that of MDRD-4 eGFR. However, CKD-Epi used a larger and more diverse data set.

CKD-EPI eGFR is somewhat more accurate than MDRD4 eGFR in those with GFR >60 mL/min/1.73 m2.

The weaknesses are the same as MDRD-4 eGFR.

Iothalamateclearance (CIothal) Inulin clearance (CIn), Iohexol clearance (CIohex)

These molecules are true markers of glomerular filtration. They are freely filtered at the glomerulus and there is little or no tubular secretion or absorption of these markers. Thus their renal clearance reflects GFR.

CIothal, CIn and CIohex are true measures of GFR.

A single measure is not a reliable estimate of the patient’s prevailing GFR, particularly in those with GFR >60 mL/min/1.73 m2. • Expensive. Time consuming. • Not useful in individual patients to decide whether GFR is normal based on a single measure.

The clinical evaluation of kidney disease in systemic lupus erythematosus Chapter | 42

MDRD-4

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384 PART | IV  Clinical aspects of the disease

TABLE 42.2 Etiologies of acute renal insufficiency in SLE other than LN. Infections including bacteremia and sepsis Volume depletion Hypotension Nephrotoxin exposure (e.g., radiographic contrast) Hemolysis Thrombosis Cardiac failure Commonly prescribed medications: Nonsteroidal antiinflammatory drugs Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers Allergic interstitial nephritis (e.g., from antibiotics) Other, non-lupus glomerular diseases

often over- or under-collected, with a strong bias toward undercollection.30 Because of these issues with 24-hours urine collections, the random spot urine protein-to-creatinine ratio (uPCR) is endorsed by nephrology and rheumatology societies to estimate and monitor 24-hours proteinuria in clinical practice.31,32 However, random spot uPCR has hour-to-hour variability mainly attributed to changes in urine protein excretion rates.30,33 A study comparing random spot uPCR variability to 24-hours urine PCR in LN and CKD cohorts found that, especially in LN with subnephrotic proteinuria (the most common level of proteinuria), random spot uPCR is unreliable.34 In contrast to random spot uPCR, a uPCR from a first morning void urine provides an accurate estimate of 24-hours urine PCR.35 A reasonable and straightforward approach to assessing proteinuria in individual patients is to follow trends in the first morning void uPCR (Fig. 42.3). If a change in first morning void uPCR is observed that would warrant a change in therapy, the magnitude of proteinuria should be

verified in a 24-hours urine collection. Similarly, a 24-hours collection should be used to declare a renal remission or diagnose a renal flare in an individual. To correct for overand under-collections, the uPCR of the intended 24-hours urine collection should be multiplied by the individual’s expected 24-hours urine creatinine excretion (Fig. 42.3).36

The kidney biopsy A kidney biopsy is essential to plan the management of kidney disease in SLE. A kidney biopsy should be considered if proteinuria above 500 mg/day is confirmed, especially in the presence of hematuria or abnormal urine sediment. Survey studies of SLE kidney biopsies have shown significant kidney pathology with levels of proteinuria in this range or higher.37-39 The main reasons to perform a biopsy are to establish the correct diagnosis and determine the activity of the kidney disease. In this regard, the clinical utility of the kidney biopsy depends on obtaining an adequate sample of renal cortex so the clinician and renal pathologist are confident that the histology is representative of what is occurring globally within the kidney.40 An algorithm for using the kidney biopsy in LN is shown in Fig. 42.4. Although the findings of proteinuria and glomerular hematuria, with or without red or white blood cell casts, are highly suggestive of LN in a patient with SLE, not all kidney disease in lupus is classic, immune-complex-mediated glomerulonephritis. Other glomerular diseases do occur, and they often require therapies distinct from those used in LN. In a series of 252 SLE patients, 5% were found to have pathologies such as focal segmental glomerulosclerosis, minimal change disease, thin glomerular basement membrane disease, hypertensive nephrosclerosis, and amyloidosis.41 Minimal change disease and focal segmental glomerulosclerosis are considered diseases of the podocyte and are called podocytopathies. The incidence of podocytopathies in LN appears to be higher than the general population.42 Differentiating these glomerulopathies from LN is important for treatment decisions.

FIGURE 42.2  Urine sediment findings in LN. Two acanthocytes under brightfield microscopy are shown in the left frame. A red blood cell cast is shown in the middle frame. A white blood cell cast is shown in the right frame.

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FIGURE 42.3  An approach to monitoring proteinuria in lupus nephritis. Individual patients can be followed with the urine protein-to-creatinine ratio (uPCR) of first morning void urine specimens. Trends in the uPCR that would warrant a change in therapy, such as a decline in proteinuria consistent with remission, or a worsening of proteinuria consistent with renal flare should be verified with a 24-hours urine collection. To avoid over- or underestimating proteinuria because of incomplete collection or over collection of the 24-hours specimen, the protein content of the 24-hours urine should be corrected for the expected 24-hours creatinine excretion of the individual.

FIGURE 42.4  Algorithm for kidney biopsy in lupus nephritis. A diagnostic kidney biopsy should be done to guide therapy when a lupus patient presents with clinical evidence of new kidney injury. A repeat biopsy could be considered to confirm complete histologic remission in patients who have achieved complete clinical renal response so maintenance immunosuppression may be stopped. A repeat biopsy should be considered to guide changes in therapy for patients who have incompletely responded. A repeat kidney biopsy should be considered at LN flare if there is suspicion that histology changed and therapy may need to be modified.

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Additionally, there are other important kidney lesions found in SLE patients. For example, patients with antiphospholipid antibodies, a lupus anticoagulant or anticardiolipin antibodies are hypercoagulable and can develop glomerular and vascular thrombi that lead to insidious and progressive renal insufficiency.43,44 Antiphospholipid syndrome (APS) nephropathy may occur in the presence or absence of LN, and is not infrequent. APS nephropathy is discussed later, but identifying it by kidney biopsy is critical because treatment requires anticoagulation and not immunosuppression. Lupus can also cause a predominantly interstitial nephritis without glomerulonephritis. Although pure interstitial nephritis is rare, it can be associated with an active urine sediment and renal insufficiency.45 Not all LN needs to be treated with aggressive immunosuppression. Clinical findings, including GFR, amount of proteinuria, urine sediment abnormalities, complement levels, and serologies cannot predict the underlying kidney histology.46 The kidney biopsy assesses the degree of active and chronic kidney injury. Each kidney biopsy is given a score based on the activity and chronicity index (Table 42.3).47 In contrast to active lesions (e.g., cellular proliferation, glomerular crescents, interstitial inflammation), chronic renal injury-which is recognized as glomerular sclerosis, tubular atrophy, and interstitial fibrosis-does not respond to immunosuppression. The kidney biopsy can thus be used to tailor immunosuppressive therapy to the activity and severity of an individual’s disease process. If, however, scarring is the dominant finding on biopsy, even with some areas of active inflammation, the risk of immunosuppression may outweigh its benefits in terms of renal survival. Such patients

TABLE 42.3 Modified NIH lupus nephritis activity and chronicity index. NIH activity index

Score

Endocapillary hypercellularity

0-3

Karyorrhexis

0-3

Fibrinoid necrosis

(0-3) × 2

Hyaline deposits

0-3

Cellular/fibrocellular crescents

(0-3) × 2

Interstitial inflammation

0-3

Total

0-24

NIH chronicity index Global/segmental glomerulosclerosis

0-3

Fibrous crescents

0-3

Tubular atrophy

0-3

Interstitial fibrosis

0-3

Total

0-12

may be more appropriately treated with kidney-protective therapies.48 There are no established recommendations for if and when kidney biopsies should be repeated in lupus patients. A repeat biopsy may be helpful in patients who have not responded as expected to one or more therapeutic regimens, patients who flare after a period of disease quiescence and there is concern that histology may have changed, or to differentiate between active disease and chronic injury. Several studies have shown that patients may have ongoing histologic activity despite no clinical activity.40 A recent prospective observational study showed that an NIH activity index over 2 and duration of SLE at repeat biopsy were independent predictors of future LN flare.49 A repeat kidney biopsy may be useful to identify such patients when there is consideration of discontinuing maintenance immunosuppressive therapy.

Antiphospholipid syndrome and the kidney APS (Chapters 58–60) can result in kidney injury by causing noninflammatory occlusions of renal blood vessels, including the intrarenal microvasculature. APS is seen in about 30% of patients with SLE, often (but not always) accompanied by LN and antiphospholipid antibodies such as anticardiolipin and antiβ2-glycoprotein I antibodies, or lupus anticoagulants.50 It is important to consider the diagnosis of renal APS and verify with a kidney biopsy because the usual immunosuppression used for LN does not treat renal APS, which requires anticoagulation. Failure to treat APS can lead to CKD or ESKD.

Pregnancy and lupus nephritis Pregnancy is an important consideration for patients with SLE and is discussed in detail elsewhere (Chapter 52). LN can significantly compromise a pregnancy and pregnancy can adversely affect the kidneys in LN patients. To protect the fetus and the kidneys, it is recommended that SLE patients with LN wait at least 6 months after complete renal remission before trying to become pregnant. This recommendation is based on a fetal loss rate of 8%-13% in quiescent LN, but which is as high as 35% in active LN.51,52 Additionally, renal flare rates of 10%-69% have been reported during or after pregnancy, and risk of renal flare or progressive renal impairment appears to be higher in patients who have achieved only a partial renal remission.51-53 If a pregnant patient with history of SLE develops worsening hypertension, proteinuria, elevated serum creatinine then renal biopsy could be pursued up to 32 weeks of gestation to delineate underlying etiology, especially when it is likely to affect the approach to treatment. In a systematic

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review of 243 kidney biopsies during pregnancy, minor complications occurred in 7% of females during pregnancy as compared to 1% postpartum. There was a therapeutic change in 66% patients based on kidney biopsy findings.54 Kidney biopsy is contraindicated if suspicion is high for preeclampsia because of heightened risk of complications such as development of coagulopathies. If the patient has serological workup consistent with lupus flare a biopsy may be less critical, especially if high risk.55 If kidney biopsy is deferred during pregnancy, it should be delayed approximately 4-6 weeks postpartum for complete resolution of coexisting endotheliosis.

Childhood lupus nephritis About 15% of all SLE is diagnosed before the age of 16.56 Briefly, the incidence of LN in pediatric SLE patients appears to be between 64% and 87%, and children tend to have more proliferative LN than adults.57-59 In pediatric LN, the incidence of CKD ranges from 16% to 45%, and ESKD from 4% to 19%.56,58,59 In multivariate analyses unfavorable prognostic factors for renal survival in children with LN were male sex, hypertension, and inability to achieve remission, but not class IV LN.56,59,60

Conclusion LN is a severe manifestation of SLE and is associated with significant morbidity and mortality. To improve outcomes, early evaluation and treatment of patients with LN is necessary. This requires the treating physician to maintain a high level of suspicion for kidney involvement, both at the time of initial diagnosis of SLE and during followup. When LN is diagnosed, consultation with a nephrologist experienced in autoimmune diseases is appropriate, and a co-management approach for patient care should be initiated.

References 1. Reich HN, Gladman DD, Urowitz MB, et al. Persistent proteinuria and dyslipidemia increase the risk of progressive chronic kidney disease in lupus erythematosus. Kid Int 2011;79:914–20. 2. Mok CC, Kwok RC, Yip PS. Effect of renal disease on the standardized mortality ratio and life expectancy of patients with systemic lupus erythematosus. Arthritis Rheum 2013;65:2154–60. 3. Hu W, Chen Y, Wang S, et al. Clinical-morphological features and outcomes of lupus podocytopathy. Clin J Am Soc Nephrol 2016;7(11):585–92. 4. Gonzalez-Crespo MR, Lopez-Fernandez JI, Usera G, et al. Outcome of silent lupus nephritis. Semin Arthritis Rheum 1996;26:468–76. 5. Valente de Almeida R, Rocha de Carvalho JG, de Azevedo VF, et al. Microalbuminuria and renal morphology in the evaluation of subclinical lupus nephritis. Clin Neprol 1999;52:218–29. 6. Zabaleta-Lanz ME, Munoz LE, Tapanes FJ, et al. Further description of early clinically silent lupus nephritis. Lupus 2006;15:845–51.

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7. Rovin BH, Stillman IE. The kidney in systemic lupus erythematosus. In: Lahita RG, editor. Systemic lupus erythematosus. 5th ed. London: Academic Press; 2011. p. 769–814. 8. Moroni G, Vercelloni PG, Quaglini S, et al. Changing patterns in clinical-histological presentation and renal outcome over the last five decades in a cohort of 499 patients with lupus nephritis. Annal Rheumat Dis 2018;77:1318–25. 9. Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1971-2015, a systemiatic review and bayesian meta-analysis. Arthritis Rheum 2016;68:1432–41. 10. Adler M, Chambers S, Edwards C, et al. An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25-year period. Rheumatol 2006;45:1144–7. 11. Ward MM. Changes in the incidence of endstage renal disease due to lupus nephritis in the united states, 1996-2004. J Rheumatol 2009;36:63–7. 12. Sinicato NA, da Silva PA, Appenzeller S. Risk factors in cardiovascular disease in systemic lupus erythematosus. Curr Cardiol Rev 2013;9:15–9. 13. Sozeri B, Deveci M, Dincel N, et al. The early cardiovascular changes in pediatric patients with systemic lupus erythematosus. Pediatr Nephrol 2013;28:471–6. 14. Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677–86. 15. Rijnink EC, Teng YKO, Kraaij T, et al. Validation of the systemic lupus international collaborating clinics classification criteria in a cohort of patients with full house glomerular deposits. Kidney Int 2018;93:214–20. 16. Faurschou M, Starklint H, Halbert P, et al. Prognosis factors in lupus nephritis: Diagnostic and therapeutic delay increases the risk of terminal renal failure. J Rheumatol 2006;33:1563–9. 17. Fiehn C. Early diagnosis and treatment in lupus nephritis: How we can influence the risk for terminal renal failure. J Rheumatol 2006;33:1464–6. 18. Fiehn C, Hajjar Y, Mueller K, et al. Improved clinical outcome of lupus nephritis during the past decade: Importance of early diagnosis and treatment. Ann Rheum Dis 2003;62:435–9. 19. Bastian HM, Roseman JM, McGwin Jr G, et al. Systemic lupus erythematosus in three ethnic groups. Xii. Risk factors for lupus nephritis after diagnosis. Lupus 2002;11:152–60. 20. Seligman VA, Lum RF, Olson JL, et al. Demographic differences in the development of lupus nephritis: a retrospective analysis. Am J Med 2002;112:726–9. 21. Branten AJW, Vervoort G, Wetzels JFM. Serum creatinine is a poor marker of GFR in nephrotic syndrome. Nephrol Dial Transplant 2005;20:707–11. 22. van Acker BA, Prummel MF, Weber JA, et al. Effect of prednisone on renal function in man. Nephron 1993;65:254–9. 23. Risch L, Herklotz R, Blumberg A, et al. Effects of glucocorticoid immunosuppression on serum cystatin c concentrations in renal transplant patients. Clin Chem 2001;47:2055–9. 24. Levey AS, Inker LA, Coresh J. Gfr estimation: from physiology to public health. Am J Kidney Dis 2014;63:820–34. 25. Hebert LA, Nori U, Hebert PL. Measured and estimated glomerular filtration rate. N Engl J Med 2006;355:1068 author reply 1069-70. 26. Leung YY, Lo KM, Tam LS, et al. Estimation of glomerular filtration rate in patients with systemic lupus erythematosus. Lupus 2006;15:276–81.

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27. Kasitanon N, Fine DM, Haas M, et al. Estimating renal function in lupus neprhitis: comparison of the modification of diet in renal disease and cockcroft-gault equations. Lupus. 2007;16:887–95. 28. Martinez-Martinez MU, Borjas-Garcia JA, Magana-Aquino M, et al. Renal function assessment in patients with systemic lupus erythematosus. Rheumatol Int 2012;32:2293–9. 29. Hebert PL, Nori US, Bhatt UY, et al. A modest proposal for improving the accuracy of creatinine-based gfr-estimating equations. Nephrol Dial Transplant 2011;26:2426–8. 30. Birmingham DJ, Rovin BH, Shidham G, et al. Spot urine protein/ creatinine ratios are unreliable estimates of 24 h proteinuria in most systemic lupus erythematosus nephritis flares. Kidney Int 2007;72: 865–70. 31. Levey AS, Coresh J, Balk E, et al. National kidney foundation practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Annal Inter Med 2003;15(139):137–47. 32. Hahn BH, McMahon MA, Wilkinson A, et al. American college of rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthrit Care Res 2012;64:797–808. 33. Hebert LA, Birmingham DJ, Shidham G, et al. Random spot urine protein/creatinine ratio is unreliable for estimating 24-hour proteinuria in individual systemic lupus erythematosus nephritis patients. Nephron Clin Pract 2009;113:c177–82. 34. Birmingham DJ, Shidham G, Perna A, et al. Spot pc ratio estimates of 24-hour proteinuria are more unreliable in lupus nephritis than in other forms of chronic glomerular disease. Annal Rheumat Dis 2014;73:475–6. 35. Fine DM, Ziegenbein M, Petri M, et al. A prospective study of 24-hour protein excretion in lupus nephritis: adequacy of short-interval timed urine collections. Kidney Int 2009;76:1284–8. 36. Glassock RJ, Fervenza FC, Hebert L, et al. Nephrotic syndrome redux. Nephrol Dial Trans 2015;30:12–7. 37. Grande JP, Balow JE. Renal biopsy in lupus nephritis. Lupus 1998;7:611–7. 38. Christopher-Stine L, Siedner MJ, Lin J, et al. Renal biopsy in lupus patients with low levels of proteinuria. J Rheumatol 2007;34:332–5. 39. Ding J, Zheng Z, Feng Y, et al. Urinary albumin levels are independently associated with renal lesion severity in pateints with lupus nephritis and little or no proteinuria. Med Sci Monit 2017;23:631–9. 40. Rovin BH, Parikh SV, Alvarado A. The kidney biopsy in lupus nephritis: Is it still relevant? Ginzler EM, Dooley MA, editors. Systemic lupus erythematosus, vol. 40. Philadelphia: Elsevier; 2014. p. 537–52. 41. Baranowska-Daca E, Choi Y-J, Barrios R, et al. Non-lupus nephrritides in patients with systemic lupus erythematosus: a comprehensive clinicopathologic study and review of the literature. Hum Pathol 2001;32:1125–35. 42. Kraft SW, Schwartz MM, Korbet SM, et al. Glomerular podocytopathy in patients with systemic lupus erythematosus. J Am Soc Nephrol 2005;16:175–9. 43. Tektonidou MG, Sotsiou F, Moutsopoulos HM. Antiphospholipid syndrome nephropathy in catastrophic, primary, and systemic lupus erythematosus-related APS. J Rheumatol 2008;35:1983–8.

44. Daugas E, Nochy D, Huong DL, et al. Antiphospholipid syndrome nephropathy in systemic lupus erythematosus. J Am Soc Nephrol 2002;13:42–52. 45. Mori Y, Kishimoto N, Yamahara H, et al. Predominant tubulointerstitial nephritis in a patient with systemic lupus nephritis. Clin Exp Nephrol 2005;9:79–84. 46. Alvarado A, Malvar A, Lococo B, et al. The value of repeat kidney biopsy in quiescent argentinian lupus nephritis patients. Lupus 2014;8:840–7. 47. Bajema IM, Wilhelmus S, Alpers CE, et al. Revision of the international society of nephrology/renal pathology society classification for lupus nephritis: Clarification of definitions, and modified national institutes of health activity and chronicity indices. Kidney Int 2018;93:789–96. 48. Neusser MA, Lindenmeyer MT, Edenhofer I, et al. Intrarenal production of b-cell survival factors in human lupus nephritis. Mod Pathol 2011;24:98–107. 49. De Rosa M, Azzato F, Toblli JE, et al. A prospective observational cohort study highlights kidney biopsy findings of lupus nephritis patients in remission who flare following withdrawal of maintenance therapy. Kidney Int 2018;94:788–94. 50. Tektonidou MG. Renal involvement in the antiphospholipid syndrome (aps)-aps nephropathy. Clin Rev Allergy Immunol 2009;36:131–40. 51. Imbasciati E, Tincani A, Gregorini G, et al. Pregnancy in women with pre-existing lupus nephritis: Predictors of fetal and maternal outcome. Nephrol Dial Transplant 2009;24:519–25. 52. Wagner SJ, Craici I, Reed D, et al. Maternal and foetal outcomes in pregnant patients with active lupus nephritis. Lupus 2009;18:342–7. 53. Tandon A, Ibanez D, Gladman D, et al. The effect of pregnancy on lupus nephritis. Arthritis Rheum 2004;50:3941–6. 54. Piccoli GB, Daidola G, Attini R, et al. Kidney biopsy in pregnancy: evidence for counselling? A systematic narrative review. BJOG 2013;120:412–27. 55. Blom K, Odutayo A, Bramham K, et al. Pregnancy and glomerular disease: a systematic review of the literature with management guidelines. Clin J Am Soc Nephrol 2017;7(12):1862–72. 56. Hagelberg S, Lee Y, Bargman J, et al. Longterm followup of childhood lupus nephritis. J Rheumatol 2002;29:2635–42. 57. Brunner HI, Gladman DD, Ibanez D, et al. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum 2008;58:556–62. 58. Tucker LB, Uribe AG, Fernandez M, et al. Adolescent onset of lupus results in more aggressive disease and worse outcomes: results of a nested matched case-control study within lumina, a multiethnic us cohort (lumina lvii). Lupus 2008;17:314–22. 59. Lee BS, Cho HY, Kim EJ, et al. Clinical outcomes of childhood lupus nephritis: a single center’s experience. Pediatr Nephrol 2007;22: 222–31. 60. Vachvanichsanong P, Dissaneewate P, McNeil E. Diffuse proliferative glomerulonephritis does not determine the worst outcome in childhood-onset lupus nephritis: A 23-year experience in a single centre. Nephrol Dial Trans 2009;24:2729–34.

Chapter 43

The pathology of lupus nephritis Isaac Ely Stillman Director, Renal Pathology Service – Beth Israel Deaconess Medical Center, Associate Professor of Pathology – Harvard Medical School, Boston, MA, United States

Introduction The kidney, an “innocent bystander” in the pathogenesis of SLE, nevertheless bears the brunt of the morbidity and mortality of the disease. Indeed the majority of patients with lupus eventually develop some degree of renal involvement, which in some cases precedes (occasionally by years) the diagnosis of SLE. This clinically oriented chapter will focus on the varied expressions of SLE associated renal disease, their classification and relationship to treatment.

Introduction to nephropathology The diagnostic utility of the renal biopsy is a direct function of the skills of those procuring and interpreting the sample, as well as the communication between them.1Nephrologist and nephropathologist should review the findings together to ensure that clinical concerns have been addressed and that the biopsy has been appropriately interpreted. Biopsies are evaluated using three techniques—light microscopy (LM, typically formalin fixed), immunofluorescence microscopy (IF, performed on fresh frozen tissue) and electron microscopy (EM, typically glutaraldehyde fixed). These complementary techniques should be evaluated by the same nephropathologist to maximize the integration of all findings. The bedrock of pathologic evaluation is LM, performed on 2 micron serial sections, suitably stained with Hematoxylin and Eosin (H&E), as well as the “special” stains that supplement it—Periodic AcidSchiff reaction (PAS), Masson trichrome (MT) and Jones (methenamine silver-periodic acid) (Figure 43.1). Most labs in North America continue to use the IF technique, (in contrast to immunohistochemistry on the paraffin block) as it remains more sensitive, reliable, and reproducible. Frozen tissue is routinely “stained” for IgG, IgA, IgM, C3, C1q, fibrin (including fibrinogen and breakdown products), kappa and lambda (light chains) and albumin (which serves as a control) using FITC-conjugated antibodies. An important Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00043-X Copyright © 2020 Elsevier Inc. All rights reserved.

limitation of EM is its sample size (far smaller than LM and IF); ultrastructural findings must therefore always be interpreted in context.

Introduction to the nephropathology of SLE The pathogenesis of autoantibody formation and immune complex (IC) formation and deposition in SLE and in lupus nephritis (LN) is addressed elsewhere in this book and its nephropathology has been detailed in two references, one encyclopedic2 and the other diagnostic.3 It is critical to recall that the renal biopsy findings, per se, cannot be used to establish a diagnosis of SLE in a patient.4 Lupus nephritis is by definition an IgG dominant IC disease and the distribution of the deposits determines the resulting histopathological pattern. The pathologic pleomorphism that is the hallmark of LN reflects the multiple possible patterns of deposition, themselves a function of the diversity of the autoantibodies/complexes involved and their deposition kinetics. While many autoantibodies have been eluted from LN renal tissue, anti-dsDNA antibodies directed against nucleosomes are thought to predominate.5 Autoantibodies may form in situ with endogenous or exogenous antigens, or alternatively, deposit from the circulation as preformed IC. Factors determining the location of deposition include immunoglobulin class and subclass, and ability to activate complement and / or cellular immunity. Other factors include avidity, charge, size, ratio of antibody to antigen, as well as specificity and rate of production and clearance. Relatively small amounts of IC may deposit in the mesangium alone, larger amounts may progress to subendothelial deposits. Low-avidity cationic deposits may be more likely to transverse the anionic glomerular basement membrane and accumulate in the subepithelial space. Thus, while the overwhelming majority of glomerular lesions in LN are due to one process—IC

389

390 PART | IV  Clinical aspects of the disease

FIGURE 43.1  Normal glomerulus (Class I pattern). Note the delicate and patent capillary loops with a mildly conspicuous mesangium. There is no hypercellularity within the tuft of capillaries or in the open urinary space. The montage demonstrates the difference between routine H&E (starting on left), Masson Trichrome, and the matrix stains PAS and the higher contrast Jones (right) which both highlight mesangial matrix and basement membranes (glomerular and tubular). Original magnification 40X.

deposition, the range of lesions produced is extraordinarily varied. While LM is the primary technique for evaluating lesions resulting from IC deposition, it is not ideal at identifying the deposits themselves, particularly when they are small. Eosin stains cytoplasm, membranes, and IC alike. In contrast, the “special stains” PAS and Jones delineate both basement membranes and mesangial matrix (they are biochemically similar) but not cytoplasm (Figure 43.2). Small IC are also usually negative and may be appreciated by their “spaces” within the tissue. In contrast, larger deposits may be identified by their glassy (“hyaline”) appearance on H&E and are visible on “special stains” as PAS positive (particularly when IgM rich), red (MT) or pink (Jones) deposits (Figure 43.3). MT stains fibrin and necrosis intensely red and is especially helpful in assessing chronicity by highlighting interstitial collagen blue. IF defines the nature of the deposits and to a lesser degree, their location. While IgG is dominant in LN, other immunoglobulins are frequently codeposited. The “full-house pattern”, when present, consisting of all three (IgG, IgA, and IgM), as well as two complement fractions (C1q and C3) is classic for LN. However it can never be used by itself to diagnose a patient with SLE.6 When IgG and IgA are codominant the possibility of IgA nephropathy must be considered. C1q implies activation of the classic complement pathway and when strongly present suggests LN.7 Immune complex staining in LN is typically granular or confluent and is graded from 0 to 4 + . The location of glomerular

FIGURE 43.2  High power image of a glomerulus stained with PAS showing endocapillary hypercellularity with occlusion of capillary lumens. Note that the cytoplasm is PAS negative, as are the immune complexes, seen as mottled areas within the mesangial matrix. Basement membranes are PAS positive. Tubule in upper right corner shows some cytoplasmic PAS positive protein resorption droplets. Original magnification 100X.

deposition is described—urinary space, mesangial, and capillary wall (deposits with a smooth outer contour are more likely to be subendothelial as they lay against the GBM, as opposed to the more ragged edges of subepithelial deposits). Another distinctive feature of LN is the presence of vascular, interstitial, and tubular basement membrane staining for IgG.

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391

the extracellular space—the electron dense deposits appear within matrix or basement membranes, but are never cell-membrane bound (intracytoplasmic). Their location is described as mesangial, subendothelial, intramembranous, and subepithelial. The simultaneous presence of deposits in multiple sites is suggestive of LN. On occasion, foci within otherwise typical granular deposits show varying degrees of substructure, such as alternating bands measuring 10–15 nm in a crystalline pattern, which may be curved (“fingerprinting”), tubular, or straight (Figure 43.4). Some deposits are similar to that seen with cryoglobulinemia (typically Type III – mixed) and indeed such antibodies are common in lupus patients.

Renal biopsy and SLE FIGURE 43.3  High power image of a glomerulus stained with Jones (methenamine silver) showing segmental endocapillary hypercellularity (with occlusion of capillary lumens) protruding across the urinary pole. Note that cytoplasm is silver negative, as are the immune complexes, which are seen as hypereosinophilic endocapillary deposits within the mesangium and along the silver positive (black) capillary membranes (in the subendothelial zone). Endocapillary lesions are thus always delineated by the glomerular basement membranes. Within the urinary space podocyte nuclei show reactive changes secondary to injury. Original magnification 100X.

EM complements IF, as it excels at precisely localizing deposits and their accompanying ultrastructural lesions, but is poor at defining their nature (they all appear similarly granular and amorphous).8 IC deposition is in

The renal biopsy plays a fundamental role in the diagnosis of LN.9 It provides information regarding the activity and chronicity of renal lesions that is otherwise unobtainable, and required to determine therapy and prognosis. Guidelines for biopsy indications are discussed elsewhere. Given the variation in glomerular involvement at least 20 glomeruli may be necessary for reproducible classification.10 Nevertheless, a minimum of 10 glomeruli are advised, and there is uncertainty how to count partial glomeruli (increasingly common as the gauge of needle biopsies decreases). Given the plasticity of lesions, repeat biopsy (uncommon in other diseases) plays an important role (see later).

FIGURE 43.4  Transmission Electron Microscopy of Deposits with Substructure. (A) Short curved cylindrical structures with the typical appearance of cryoglobulins (usually Type III – mixed, in LN) deposited within the mesangial matrix (MM) which is surrounded by membrane-bound mesangial cell cytoplasm (MC). Original magnification 25,000X. (B) Tubular basement membrane “fingerprint deposits” with curved parallel arrays, arising out of amorphous granular deposits that are typical of immune complexes. This substructure is highly suggestive of LN; their relationship to cryoglobulins is uncertain. Arrowhead points to a Type III Collagen bundle, present in the renal interstitium. Original magnification 50,000X

392 PART | IV  Clinical aspects of the disease

The lesions of lupus nephritis Glomeruli

FIGURE 43.5  Ultrastructural appearance of two adjacent glomerular capillary loops that are within normal limits. Note that the mesangium (M) is continuous with the subendothelial space. The peripheral capillary wall is comprised of the fenestrated endothelium, the glomerular basement membrane and the podocyte (Pod) foot processes. CL = capillary lumen, US= urinary space. Original magnification 8,000X

A normal glomerulus (Figures 43.1 and 43.5) shows delicate patent capillary loops, and a mesangium that is no more than mildly conspicuous. LM evaluation begins with an assessment of glomerular cellularity. Increased glomerular cellularity (historically, but inaccurately called “proliferation”) is primarily due to an influx of exogenous inflammatory cells, although there may be a component of an increase in native cells as well. Hypercellularity may be noted in the mesangial, endocapillary or extracapillary (crescent) zones. The distribution of glomerular lesions is described within individual glomeruli (segmental vs. global) as well as their total population (focal vs. diffuse). Table 43.1 contains a glossary of basic pathological terminology. The fundamental glomerular lesion of LN is mesangial IC deposition, with all other glomerular lesions superimposed on it. Mesangial IC deposition is identified by IF and EM (Figures 43.6 and 43.7) and is usually associated with

TABLE 43.1 Glossary of pathologic terms terms in bold = as defined by the revised ISN/RPS classification. Adhesion – An area of isolated continuity of extracellular matrix material between the tuft and capsule even when the underlying segment does not have overt sclerosis Crescent – extracapillary hypercellularity composed of a variable mixture of cells. Fibrin and fibrous matrix may be present; 10% or more of the circumference of Bowman’s capsule should be involved   Cellular crescent – More than 75% cells and fibrin and less than 25% fibrous matrix   Fibrocellular crescent – 25%–75% cells and fibrin and the remainder fibrous matrix   Fibrous crescent – More than 75% fibrous matrix and less than 25% cells and fibrin Diffuse – A lesion involving most (≥50%) glomeruli Double Contours – Thickened glomerular capillary walls with duplication of the basement membrane due to the growth of an inner neomembrane; usually in response to chronic subendothelial deposition Endocapillary hypercellularity – Increase in cells within the glomerular capillaries, primarily due to the influx of inflammatory cells causing narrowing of the glomerular capillary lumina; endothelial swelling alone is insufficient for this designation. Formerly called “proliferation”. Focal – A lesion involving ) along their basement membranes, a common finding in LN. A peri-tubular capillary (*) also shows deposits. IF, anti-IgG, original magnification 40X.

FIGURE 43.14  Segmental endocapillary hypercellularity (Class III or IV Pattern). The hypercellularity occludes the capillary lumen and obscures the mesangial / capillary lumen architecture, but is bounded by the peripheral capillary wall and only involves a minority of the tuft. While these lesions are often (but not always) seen in association with overt segmental necrosis their overall clinical significance remains unclear. The other glomerular lobules show mesangial prominence. H&E original magnification 40X.

FIGURE 43.16  Segmental fibrinoid necrosis (Class III or IV Pattern). This lesion typically incites cellular crescent formation. The other glomerular lobules show only mesangial prominence (Class II pattern). H&E original magnification 40X.

and are comprised of basophilic nuclei coated with antinuclear antibodies. Although highly specific for SLE, they are also highly rare (Figure 43.13). Hypercellular endocapillary lesions are most associated with “active lesions” and particularly necrosis of the glomerular tuft (Figures 43.14 and 43.15). Necrosis is usually segmental, and is identified by the presence of fibrin,

neutrophilic exudation, apoptosis, karyorrhexis, and / or fragmentation of the basement membrane (Figure 43.16). Severe inflammation and especially fibrinoid necrosis results in glomerular capillary rupture with hemorrhage into Bowman’s space and formation of cellular crescents (extracapillary hypercellularity) (Figure 43.17). Cellular crescents, (a variable combination of proliferating epithelial cells and infiltrating mononuclear inflammatory cells), indicate severe glomerular injury and when persistent organize into fibrocellular and then fibrous crescents (often

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FIGURE 43.17  Segmental necrosis with rupture of the capillary wall and release of fibrin and other inflammatory mediators into the urinary space (Class III or IV Pattern). An early cellular crescent is seen at 5-6 o’clock. The remainder of the glomerulus is intact. These active lesions may heal as segmental sclerosis. Jones, original magnification 40X.

seen with glomerular obsolescence) (Figure 43.18). More than one type of crescent can be seen in the same glomerulus. Despite their association, both segmental necrosis and cellular crescents may be seen alone. Extracapillary hypercellularity seen in association with collapsing lesions of the tuft is likely due to podocytes, and is not designated as a crescent.

Chronic subendothelial deposition may result in a membranoproliferative pattern, reflecting reactive basement membrane/“double contour” formation (Figure 43.19). In addition to neo-membrane covering the subendothelial deposits, EM may reveal cells in that space, in continuity with the mesangium (so-called “mesangial interposition,” although they are likely to be leukocytes) (Figure 43.20). Scattered subepithelial IC deposition is common in LN and may be associated with reactive changes of the lamina densa. Such “membranous” changes are best identified on IF and EM, and when more extensive on Jones stain (Figure 43.21). Deposits in this “protected” location, (walled off from the circulation), may activate complement, but are not associated with inflammatory cell influx (hypercellularity). When this pattern dominates, the appearance may suggest idiopathic membranous GN. Often however, subepithelial deposition is combined with endocapillary hypercellularity due to deposits at other sites. The active changes noted above (immune deposition, hypercellularity, necrosis, etc.) may progress to chronic scarring. Serial biopsies suggest that segmental necrosis heals as segmental scars (sclerosis) (Figure 43.22). More severe glomerular injury or crescent formation may result in global sclerosis. The percentage of sclerotic glomeruli (global and segmental) is an important metric of chronicity. Similar chronic changes may also result from unrelated processes such as hypertension and aging. Only glomerulosclerosis that can be attributed to post-inflammatory scarring is

FIGURE 43.18  Circumferential cellular crescent filling the urinary space and compressing the glomerular tuft, which shows endocapillary hypercellularity (Class III or IV Pattern). The PAS (right) by delineating the membranes, allows for easier discrimination between the positive tuft and the negative cells in the urinary space than H&E (left). Comprised primarily of native glomerular cells, macrophages, and lymphocytes, cellular crescents may completely resolve in response to therapy. If they persist, however, these crescents scar and lead to glomerulosclerosis. Original magnification 40X.

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FIGURE 43.19  Membranoproliferative pattern of glomerular injury by PAS (left) and Jones (right) (Class III or IV Pattern). In the context of LN, this pattern results from chronic subendothelial immuno-deposits, inciting the formation by the endothelial cells of an inner neo-membrane and the resultant “double contour” or “tram track” lesion. The space between the membranes appears clear because the cytoplasm and deposits present there do not stain. Original magnification 100X.

FIGURE 43.20  Membranoproliferative pattern of glomerular injury by EM (Class III or IV Pattern). Subendothelial granular electron dense deposits are seen within a markedly thickened capillary wall, and in continuity with the mesangium (Mes). Cellular elements are also embedded within the deposits and interposed between the outer basement membrane and neo-membrane (seen on LM as “double contours”). Endothelial cells (Endo) encircle a reduced capillary lumen (CL). US= urinary space. Original magnification 8,000X.

FIGURE 43.21  Membranous changes involving the glomerular basement membranes to varying degrees. Areas of reactive changes, with growth of the lamina densa (of the basement membrane) in between the subepithelial deposits are seen as “spikes” and “holes”, as the deposits themselves are sliver negative. Some of the membranes appear uninvolved, a finding more typical of a lupus rather than primary membranous pattern. No hypercellularity is present. The epithelial cells (podocytes) show reactive changes suggestive of acute injury. Jones, original magnification 100X.

classified as LN involvement. Unfortunately, that distinction may be difficult to make on morphologic grounds. EM usually shows frequent tubuloreticular structures (or inclusions), most commonly in glomerular endothelial cells (Figure 43.23). These 24 nm interanastamosing structures located within the endoplasmic reticulum are

associated with elevated levels of circulating interferon and can also be seen in viral infections. Their association with LN underscores the central role of interferon in this disease.11 Their presence in a case of otherwise primary membranous GN may portend the subsequent development of SLE.

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FIGURE 43.22  Segmental sclerosis by PAS (left) and MT (right). There is segmentally increased PAS positive matrix effacing the glomerular capillary architecture and forming an adhesion to a small fibrous crescent (1-2 o’clock). This scar, likely the sequel of prior necrosis and crescent formation, is incompatible with a Class II designation, and is indicative of Class III or IV. This lesion will not respond to anti-inflammatory therapy. Original magnification 40X.

Tubulointerstitium

FIGURE 43.23  Granular electron dense immune complex deposition in the glomerular capillary wall. CL= capillary lumen. Pod= podocyte cell body. A tubuloreticular inclusion is present within a glomerular endothelial cell. These 24 nm structures, relating to the rough endoplasmic reticulum, are associated with elevated levels of circulating interferon, and their frequent occurrence in LN underscores the central role of interferon in this disease. Subendothelial deposits are seen to connect through the lamina densa to subepithelial deposits (trans- membranous deposition), a pattern suggestive of LN. Podocytes show injury with widespread foot process effacement. The simultaneous presence of extensive subepithelial and subendothelial immune deposits warrants the addition of Class III or IV (focal or diffuse LN) to the Class V (membranous) designation. EM may be necessary to identify such cases, which have a significantly worse prognosis than pure Class V. EM Original magnification 30,000X

Tubules and interstitium share a tight anatomical association and their lesions (either acute or chronic) are often considered together. Interstitial edema (appearing as clear space) and inflammation, predominantly comprised of mononuclear cells (lymphocytes, plasma cells, and macrophages) are acute changes seen to varying degrees in LN, and in association with tubulitis and other forms of acute tubular injury (degenerative and regenerative) including red cell and/or “pus” casts. While interstitial infiltrates are rarely seen alone, the extent of inflammation usually parallels the severity of glomerular disease. The degree of inflammation has been correlated with both reduction in GFR and serologic activity.12 Studies immunophenotyping the infiltrates have not yielded consistent results. Staining for CD45+ cells may improve assessment for intermediate grades of tubulointerstitial inflammation.13 Macrophage infiltration may correlate with both current and future renal function.14 Inflammation leads to fibrosis, and macrophages play a role in both. This complex subject is discussed more fully elsewhere in this text. A recent biopsy study using single-cell RNA sequencing reviews these issues and reveals the complexity of immune populations in LN kidneys.15 Work in recent years has led to the realization that tubulointerstitial inflammation in SLE may be an entirely independent process from the systemic autoimmunity that results in glomerular damage. Investigation in this important area has been hampered by the fact that two

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FIGURE 43.24  Left: Nuclei of tubular epithelium showing diffuse coating by IgG (“tissue ANA”). This finding confirms the presence of autoantibodies. IF, anti-IgG, original magnification 40X. Right: Granular immune-complex deposition along tubular basement membranes, a finding that is highly suggestive of LN. EM Original magnification 8,000X

important features of human tubulointerstitial disease, the formation of tertiary lymphoid structures, and tubular basement membrane IC deposition, are not seen in most murine models. IF and EM often reveal deposits (most commonly IgG) along tubular basement membranes (always suggestive of LN or another autoimmune condition) and even within the interstitium (Figure 43.24). While tubulointerstitial deposits can rarely be seen in the absence of glomerular deposition, typically their extent parallels glomerular hypercellularity.16 Nevertheless, deposits along the TBM might arise from different pathogenic mechanisms than those resulting in glomerular deposition. This is underscored by data showing that TBM deposits are associated with a poor renal outcome especially in patients with non-proliferative glomerular lesions.17 Interstitial inflammation in lupus nephritis does not appear to be related to tubulointerstitial immune deposits but may be caused by autoantibodies to interstitial antigens, particularly vimentin.18 Finally, nuclei may show staining for IgG on IF (“tissue ANA,” perhaps an artifact of tissue sectioning) which when strong may obscure other deposits (Figure 43.24). Evaluation of interstitial fibrosis (and tubular atrophy) is critical to define the extent of chronic injury. It is best assessed on MT, where expansion of the normally inconspicuous interstitium appears as varying intensities of blue, reflecting the density of collagen deposition (Figure 43.25). As in other renal diseases, the degree of tubulointerstitial scarring is the histologic parameter that best correlates with both current and future renal function. Morphometric

FIGURE 43.25  Cortical tubulo-interstitium with chronic renal injury. The normally inconspicuous interstitium is markedly expanded by fibrosis (blue). Some proximal tubules show dilation and cytological features of acute injury. Others show atrophy and thickened basement membranes. The condition of the tubulo-interstitium is the histological feature that best correlates with current and future GFR. MT, original magnification 40X.

evaluation has been shown to improve the assessment, but has not been adopted in clinical practice.19 As tubules progress from acute injury to chronic atrophy they undergo changes that result in diminished cytoplasm and diameter, thickening of basement membranes (best seen on PAS stain) and cast formation. Like interstitial fibrosis, these processes are thought to be irreversible.

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TABLE 43.2 Vascular lesions. Lupus specific   Uncomplicated immune complex deposition   Lupus Vasculopathy Lupus related   Necrotizing arteritis (? ANCA associated)   Thrombotic Microangiopathy   HUS/TTP   Scleroderma    Lupus anti-coagulant / Antiphospholipid syndrome   Malignant Hypertension Non-lupus related  Arteriosclerosis  Arteriolarsclerosis

FIGURE 43.26  “Uncomplicated immune complex deposition” in the intima and media of an arteriole (lower right) and artery (left). The lumen is not compromised. This finding is highly suggestive of LN and may not carry an adverse prognosis. IF, anti-IgG, original magnification 40X.

Vessels Nonspecific chronic lesions (secondary to hypertension, aging, etc.) are the most common changes seen. Lesions specific to SLE receive insufficient attention, in part because they (like tubulointerstitial changes) are absent from LN classifications and their terminology has not been standardized. Their clinical significance ranges from trivial to profound.20 A schema is presented in Table 43.2.21 The most common lesion, uncomplicated vascular immune deposits, is recognized by irregular deposition of immunoreactants (most commonly IgG although other immunoglobulins and complement components may be present) in vessel walls (predominantly small arteries and arterioles) as seen by IF (Figure 43.26). The presence of IgM and/or complement alone may reflect nonspecific injury and is not diagnostic of a lupus-related process. Vessel walls may display IC on LM but the lumen is not compromised by them. EM localizes

the deposits to the intimal basement membrane and medial matrix. The degree of deposition roughly correlates with glomerular hypercellularity and tubulointerstitial deposition. These deposits are usually clinically silent and may not carry negative prognostic implications.22 Lupus vasculopathy (noninflammatory necrotizing vasculopathy) in contrast, is far less common, and is associated with a bad prognosis.23 Seen most commonly in the setting of severe hypercellular LN, vessels (usually arterioles) show lumenal narrowing by IC deposition accompanied by endothelial and medial injury. Fibrin and necrosis is typically present but inflammation (by definition) is absent. (Figure 43.27) Literal vasculitis, that is, fibrinoid necrosis of the vessel wall with associated inflammation is a very rare finding in LN. Its histologic appearance is indistinguishable from a systemic vasculitis of the ANCA type, and may represent the simultaneous occurrence of an unrelated systemic or “renal limited” vasculitis. Thrombotic microangiopathy (TMA) in the lupus setting may be seen in association with any of its related clinical entities (such as malignant hypertension, systemic sclerosis, HUS/TTP), or with the antiphospholipid antibody nephropathy/lupus anticoagulant syndrome. However, TMA can be present without any systemic syndrome (“renal limited”). Small arteries and arterioles may show thrombosis, fibrinoid necrosis, and mucoid intimal hyperplasia (“onion skinning”) (Figure 43.28). As opposed to lupus vasculopathy, lesions show no significant IgG immune deposition (IgM and C3 may be present, secondary to vascular injury). Glomeruli show typical TMA changes such as thrombosis, mesangiolysis, and double contour formation that may be superimposed on other glomerular changes of LN. Studies have shown a strong relationship between the presence of glomerular micro-thrombi and intensity of C4d staining; suggesting a role for the classical complement pathway in LN associated TMA.24 The presence of TMA in LN is associated with more severe clinical and histological activity, and significantly inferior long-term renal outcome.25 Anti-phospholipid antibody syndrome may be primary or lupus (or “lupus-like”) associated, and is a clinically important cause of systemic and renal thrombosis, resulting in systemic and renal infarctions and subsequent organization and recanalization of the vessels.26 The acute form of the SLE associated variant is more likely to also involve smaller vessels and display more typical findings of TMA (Figure 43.29). TMA lesions are significantly more common in lupus patients with anti-phospholipid antibodies.27 However, many patients may be antibody positive without demonstrating the syndrome. The chronic form, which may be clinically smoldering and unrecognized shows only chronic injury in the form of zonal cortical scarring and tubular thyroidization. This insensitive finding, when present, greatly increases the likelihood of an underlying

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FIGURE 43.27  Lupus vasculopathy, seen on LM by H&E (left) and MT (right): Occlusive immune deposits (70%).73 Not surprisingly, the FSGS group had the worst renal prognosis. They noted that the fact that the nephrotic syndrome relapsed in three patients with no glomerular immune deposits, and concurrent with extrarenal and serological activity, strongly supports the idea that podocytopathy is associated with SLE, rather than the idea that SLE coexists with idiopathic MCD. APOL1 risk alleles strongly associate with collapsing GN in African American SLE patients.74 The vast majority of African Americans with LN-associated ESRD who possessed two APOL1 renal risk variants failed cytotoxic therapy.75 Proposed criteria to diagnose lupus podocytopathy are:1 clinical presentation of full nephrotic syndrome in a patient with SLE,2 diffuse and severe foot process effacement, and3 the absence of subendothelial or subepithelial immune deposits. Mesangial deposits and mesangial proliferation are not part of the criteria; if these findings are present, then the additional diagnosis of LN Class I or II is merited. Lupus podocytopathy is further subdivided into patients who would otherwise meet criteria for MCD or FSGS, including the morphologic subtypes of FSGS (collapsing, tip lesion, etc.).76

Other renal diseases and SLE Renal disease in SLE patients cannot be assumed to represent LN. Biopsy may reveal another process, either alone, or superimposed on LN. At least 5% of biopsies in lupus patients may reveal lesions unrelated to LN and virtually every disease has appeared as a case report.77 Drug-induced lupus is relatively common; fortunately, renal involvement is not. Many drugs have been implicated and all Classes have been noted. A high index of suspicion is warranted as there are no specific histologic features suggesting a drug related process. Patients with both HIV and SLE may show lesions related to either or both entities. In contrast, HIV associated “lupus-like” immune complex GN shows multiple site deposits and other morphologic features of LN without positive lupus serologies.78 The glomerular lesions of mixed connective tissue disease may be indistinguishable from LN. Vessels may display TMA changes similar to systemic sclerosis. Patients with both SLE and Sjogren’s syndrome may have milder renal disease than those with SLE alone.79

Transplantation Studies suggest that both patient and allograft survival are comparable to nonlupus cohorts.80 The rate of detection of

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recurrent disease is a direct function of the use of IF and EM on allograft biopsies with a recent study suggesting that it may be more common than previously thought, although most recurrences are sub-clinical.81 Of note, a significant percentage of the recurrent lesions may not involve immune complex deposition.82

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lupus erythematosus revisited. J Am Soc Nephrol 2004;15(2):241–50 Epub 2004/01/30. 33. Bajema IM, Wilhelmus S, Alpers CE, Bruijn JA, Colvin RB, Cook HT, et al. Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices. Kidney Int 2018;93(4):789–96 doi: 10.1016/j. kint.2017.11.023. 34. Nasr SH, D’Agati VD, Park HR. Necrotizing and crescentic lupus nephritis with antineutrophil cytoplasmic antibody seropositivity. Clin J Am Soc Nephrol 2008;3:682–90. 35. Jennette JC, Iskandar SS, Dalldorf FG. Pathologic differentiation between lupus and nonlupus membranous glomerulopathy. Kidney Int 1983;24(3):377–85 Epub 1983/09/01. 36. Larsen CP, Messias NC, Silva FG, Messias E, Walker PD. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Mod Pathol 2013;26(5):709–15 doi: 10.1038/modpathol.2012.207. 37. Garcia-Vives E, Sole C, Moline T, Alvarez-Rios AM, Vidal M, Agraz I, et al. Antibodies to M-type phospholipase A2 receptor (PLA2R) in membranous lupus nephritis. Lupus 2019;28(3):396–405 Epub 2019/02/15. doi: 10.1177/0961203319828521. 38. Najafi CC, Korbet SM, Lewis EJ, Schwartz MM, Reichlin M, Evans J, et al. Significance of histologic patterns of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis. Kidney Int 2001;59(6):2156–63 doi: 10.1046/j.1523-1755.2001.00730.x. 39. Mittal B, Hurwitz S, Rennke H, Singh AK. New subcategories of class IV lupus nephritis: are there clinical, histologic, and outcome differences? Am J Kidney Dis 2004;44(6):1050–9 Epub 2004/11/24. doi: S0272638604012624 [pii]. 40. Haring CM, Rietveld A, van den Brand JA, Berden JH. Segmental and global subclasses of class IV lupus nephritis have similar renal outcomes. J Am Soc Nephrol 2012;23(1):149–54 doi: 10.1681/ASN. 2011060558. 41. Wilhelmus S, Cook HT, Noel LH, Ferrario F, Wolterbeek R, Bruijn JA, et al. Interobserver agreement on histopathological lesions in class III or IV lupus nephritis. Clin J Am Soc Nephrol 2015;10(1):47–53 doi: 10.2215/CJN. 03580414. 42. Furness PN, Taub N. Interobserver reproducibility and application of the ISN/RPS classification of lupus nephritis-a UK-wide study. Am J Surg Pathol 2006;30(8):1030–5 Epub 2006/07/25. doi: 00000478200608000-00015 [pii]. 43. Yokoyama H, Wada T, Hara A, Yamahana J, Nakaya I, Kobayashi M, et al. The outcome and a new ISN/RPS 2003 classification of lupus nephritis in Japanese. Kidney Int 2004;66(6):2382–8 Epub 2004/12/01. doi: KID66027 [pii] 10.1111/j.1523-1755.2004.66027.x. 44. Dasari S, Chakraborty A, Truong L, Mohan C. A systematic review of interpathologist agreement in histologic classification of lupus nephritis. Kidney Int Rep 2019; doi: https://doi.org/10.1016/j. ekir.2019.06.011. 45. Lu J, Tam LS, Lai FM, Kwan BC, Choi PC, Li EK, et al. Repeat renal biopsy in lupus nephritis: a change in histological pattern is common. Am J Nephrol 2011;34(3):220–5 doi: 10.1159/000330356. 46. Moroni G, Pasquali S, Quaglini S, Banfi G, Casanova S, Maccario M, et al. Clinical and prognostic value of serial renal biopsies in lupus nephritis. Am J Kidney Dis 1999;34(3):530–9 Epub 1999/09/02. doi: 10.1053/AJKD03400530 S0272638699003200 [pii]. 47. Daleboudt GMN, Bajema IM, Goemaere NNT, van Laar JM, Bruijn JA, Berger SP. The clinical relevance of a repeat biopsy in lupus

nephritis flares. Nephrol Dial Transplant 2009; gfp359. doi: 10.1093/ ndt/gfp359. 48. Bajaj S, Albert L, Gladman DD, Urowitz MB, Hallett DC, Ritchie S. Serial renal biopsy in systemic lupus erythematosus. J Rheumatol 2000;27(12):2822–6. 49. Christopher-Stine L, Siedner M, Lin J, Haas M, Parekh H, Petri M, et al. Renal biopsy in lupus patients with low levels of proteinuria. J Rheumatol 2007;34(2):332–5 Epub 2006/12/22. doi: 06/13/1215 [pii]. 50. Chagnac A, Kiberd BA, Farinas MC, Strober S, Sibley RK, Hoppe R, et al. Outcome of the acute glomerular injury in proliferative lupus nephritis. J Clin Invest 1989;84(3):922–30 doi: 10.1172/JCI114254. 51. Pagni F, Galimberti S, Goffredo P, Basciu M, Malachina S, Pilla D, et al. The value of repeat biopsy in the management of lupus nephritis: an international multicentre study in a large cohort of patients. Nephrol Dial Transplant 2013;28(12):3014–23 doi: 10.1093/ndt/gft272. 52. Austin HA3rd, Muenz LR, Joyce KM, Antonovych TT, Balow JE. Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int 1984;25(4):689–95. 53. Schwartz MM, Lan SP, Bernstein J, Hill GS, Holley K, Lewis EJ. Irreproducibility of the activity and chronicity indices limits their utility in the management of lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis 1993;21(4):374–7 Epub 1993/04/01. doi: S0272638693000563 [pii]. 54. Austin HA, 3rd, Boumpas DT, Vaughan EM, Balow JE. Predicting renal outcomes in severe lupus nephritis: contributions of clinical and histologic data. Kidney Int 1994;45(2):544–50. 55. Hill GS, Delahousse M, Nochy D, Remy P, Mignon F, Mery JP, et al. Predictive power of the second renal biopsy in lupus nephritis: significance of macrophages. Kidney Int 2001;59(1):304–16 Epub 2001/01/03. doi: kid492 [pii] 10.1046/j.1523-1755.2001.00492.x. 56. Hiramatsu N, Kuroiwa T, Ikeuchi H, Maeshima A, Kaneko Y, Hiromura K, et al. Revised classification of lupus nephritis is valuable in predicting renal outcome with an indication of the proportion of glomeruli affected by chronic lesions. Rheumatology (Oxford) 2008;47(5):702–7 Epub 2008/04/09. doi: ken019 [pii] 10.1093/rheumatology/ken019. 57. Hill GS, Delahousse M, Nochy D, Tomkiewicz E, Remy P, Mignon F, et al. A new morphologic index for the evaluation of renal biopsies in lupus nephritis. Kidney Int 2000;58(3):1160–73 Epub 2000/09/06. doi: kid272 [pii] 10.1046/j.1523-1755.2000.00272.x. 58. Pasquali S, Banfi G, Zucchelli A, Moroni G, Ponticelli C, Zucchelli P. Lupus membranous nephropathy: long-term outcome. Clin Nephrol 1993;39(4):175–82 Epub 1993/04/01. 59. Vachvanichsanong P, Dissaneewate P, McNeil E. Diffuse proliferative glomerulonephritis does not determine the worst outcome in childhood-onset lupus nephritis: a 23-year experience in a single centre. Nephrol Dial Transplant 2009;24(9):2729–34 Epub 2009/04/28. doi: gfp173 [pii] 10.1093/ndt/gfp173. 60. Yu F, Haas M, Glassock R, Zhao MH. Redefining lupus nephritis: clinical implications of pathophysiologic subtypes. Nat Rev Nephrol 2017;13(8):483–95 doi: 10.1038/nrneph.2017.85. 61. Broder A, Mowrey WB, Khan HN, Jovanovic B, Londono-Jimenez A, Izmirly P, et al. Tubulointerstitial damage predicts end stage renal disease in lupus nephritis with preserved to moderately impaired renal function: a retrospective cohort study. Semin Arthritis Rheum 2018;47(4):545–51 doi: 10.1016/j.semarthrit.2017.07.007. 62. Clark MR, Trotter K, Chang A. The pathogenesis and therapeutic implications of tubulointerstitial inflammation in human lupus nephritis. Semin Nephrol 2015;35(5):455–64 Epub 2015/11/18. doi: 10.1016/j. semnephrol.2015.08.007.

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63. Leatherwood C, Speyer CB, Feldman CH, D’Silva K, Gómez-Puerta JA, Hoover PJ, et al. Clinical characteristics and renal prognosis associated with interstitial fibrosis and tubular atrophy (IFTA) and vascular injury in lupus nephritis biopsies. Semin Arthritis Rheum 2019; doi: 10.1016/j.semarthrit.2019.06.002. 64. Yu F, Wu LH, Tan Y, Li LH, Wang CL, Wang WK, et al. Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system. Kidney Int 2010;77(9):820–9 doi: 10.1038/ki.2010.13. 65. Takahashi Y, Mizoue T, Suzuki A, Yamashita H, Kunimatsu J, Itoh K, et al. Time of initial appearance of renal symptoms in the course of systemic lupus erythematosus as a prognostic factor for lupus nephritis. Mod Rheumatol 2009;19(3):293–301 Epub 2009/03/12. doi: 10.1007/s10165-009-0154-4. 66. Rijnink EC, Teng YKO, Wilhelmus S, Almekinders M, Wolterbeek R, Cransberg K, et al. Clinical and histopathologic characteristics associated with renal outcomes in lupus nephritis. Clin J Am Soc Nephrol 2017;12(5):734–43 Epub 2017/05/06. doi: 10.2215/cjn.10601016. 67. Parikh SV, Alvarado A, Malvar A, Rovin BH. The kidney biopsy in lupus nephritis: past, present, and future. Sem Nephrol 2015;35(5):465– 77 doi: 10.1016/j.semnephrol.2015.08.008. 68. Wakasugi D, Gono T, Kawaguchi Y. Frequency of class III and IV nephritis in systemic lupus erythematosus without clinical renal involvement: an analysis of predictive measures. J Rheumatol 2012;39:79–85. 69. Zabaleta-Lanz ME, Munoz LE, Tapanes FJ, Vargas-Arenas RE, Daboin I, Barrios Y, et al. Further description of early clinically silent lupus nephritis. Lupus 2006;15(12):845–51. 70. Wang Y, Huang X, Cai J, Xie L, Wang W, Tang S, et al. Clinicopathologic characteristics and outcomes of lupus nephritis with antineutrophil cytoplasmic antibody: a retrospective study. Medicine (Baltimore) 2016;95(4):e2580 Epub 2016/01/31. doi: 10.1097/ md.0000000000002580. 71. Li C, Wang J-J, Zhou M-L, Liang D-D, Yang J, Zhu H-X, et al. Differences in clinico-pathological characteristics and outcomes between proteinase 3-ANCA positivity and myeloperoxidase-ANCA positivity in lupus nephritis. Lupus 2019;28(9):1111–9 doi: 10.1177/0961203319861680. 72. Sen D, Isenberg DA. Antineutrophil cytoplasmic autoantibodies in systemic lupus erythematosus. Lupus 2003;12(9):651–8 Epub 2003/09/30.

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73. Hu W, Chen Y, Wang S, Chen H, Liu Z, Zeng C, et al. Clinical-morphological features and outcomes of lupus podocytopathy. Clin J Am Soc Nephrol 2016;11(4):585–92 Epub 2016/03/18. doi: 10.2215/ cjn.06720615. 74. Larsen CP, Beggs ML, Saeed M, Walker PD. Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy. J Am Soc Nephrol 2013;24(5):722–5 doi: 10.1681/ASN. 2012121180. 75. Freedman BI, Langefeld CD, Andringa KK, Croker JA, Williams AH, Garner NE, et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol 2014;66(2):390–6 doi: 10.1002/art.38220. 76. Bomback AS, Markowitz GS. Lupus podocytopathy: a distinct entity. Clin J Am Soc Nephrol 2016;11(4):547–8 doi: 10.2215/cjn.01880216. 77. Baranowska-Daca E, Choi YJ, Barrios R, Nassar G, Suki WN, Truong LD. Nonlupus nephritides in patients with systemic lupus erythematosus: a comprehensive clinicopathologic study and review of the literature. Hum Pathol 2001;32(10):1125–35 Epub 2001/10/27. doi: S0046-8177(01)52911-1 [pii] 10.1053/hupa.2001.28227. 78. Haas M, Kaul S, Eustace JA. HIV-associated immune complex glomerulonephritis with “lupus-like” features: a clinicopathologic study of 14 cases. Kidney Int 2005;67(4):1381–90 doi: 10.1111/j.15231755.2005.00215. 79. Baer AN, Maynard JW, Shaikh F, Magder LS, Petri M. Secondary Sjogren’s syndrome in systemic lupus erythematosus defines a distinct disease subset. J Rheumatol 2010;37(6):1143–9 doi: 10.3899/ jrheum.090804. 80. Contreras G, Li H, Gonzalez-Suarez M, Isakova T, Scialla JJ, Pedraza F, et al. Kidney allograft survival of African American and Caucasian American recipients with lupus. Lupus 2014;23(2):151–8 doi: 10.1177/0961203313513819. 81. Norby GE, Strom EH, Midtvedt K, Hartmann A, Gilboe IM, Leivestad T, et al. Recurrent lupus nephritis after kidney transplantation: a surveillance biopsy study. Ann Rheum Dis 2010;69(8):1484–7 doi: 10.1136/ard.2009.122796. 82. Meehan SM, Chang A, Khurana A, Baliga R, Kadambi PV, Javaid B. Pauci-immune and immune glomerular lesions in kidney transplants for systemic lupus erythematosus. Clin J Am Soc Nephrol 2008;3(5):1469–78 doi: 10.2215/CJN. 00790208.

Chapter 44

Cardiovascular disease in systemic lupus erythematosus: an update Stephanie Saelia, Tanmayee Bichilea, Payal Thakkarb and Susan Manzia a

Department of Medicine, Medicine and Autoimmunity Institute, Allegheny Health Network, Pittsburgh, PA, United States; bAllegheny Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, United States

Burden of cardiovascular disease in lupus Despite therapeutic advances, cardiovascular disease (CVD) remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE, lupus). Although a nationwide population-based study from 1968–2013 found improving mortality in SLE, with a consistent downtrend since 1999, SLE-related mortality continues to remain high compared to non-SLE-related mortality.1 Furthermore, significant disparities in mortality based on sex, race/ethnicity, age, and geographic region were noted. Patients with lupus have an increased risk of death from any cause compared to the general population, with a three-fold greater risk of death from CVD.2 A study conducted from 1996 to 2012 that examined national trends in hospitalization rates for CVD events found that the rate of myocardial infarction and ischemic stroke hospitalizations went up over time in patients with SLE but decreased in the general population.3 In 2011 the American Heart Association (AHA) first acknowledged SLE as a unique risk factor for CVD.4 This increased cardiovascular risk cannot be fully explained by traditional risk factors alone5 or conventional risk scores like the Framingham 10-year risk score or the 2013 ACC/ AHA risk score.6 Some authors in North America and Europe have proposed 10-year CVD risk stratification scores specific to lupus, by incorporating disease-specific variables. A modified Framingham risk score, where each item is multiplied by 2, was shown to more accurately predict CVD in SLE.7 Other investigators have proposed using the PREDICTS (Predictors of Risk for Elevated Flares, Damage Progression and Cardiovascular Disease in Patients with SLE) score, a panel of biomarkers and risk factors to better identify who will have progression of atherosclerosis using carotid imaging.8 Specifics of this panel are further detailed below. Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00044-1 Copyright © 2020 Elsevier Inc. All rights reserved.

In the United Kingdom QRISK2/3 scores (clinical and immunological/biochemical measures specific to SLE) more accurately identified lupus patients with an increased 10-year risk of CVD as compared to healthy controls.9 In fact, since 2008, the United Kingdom has used QRISK 2 scores as a standard practice to calculate the 10-year risk of a major cardiovascular event in patients with lupus. A score ≥10% is considered high risk necessitating clinical intervention. QRISK3 scores specifically incorporate markers for endothelial dysfunction and steroid use, making it more sensitive to capture lupus patients at an increased 10-year risk of CVD compared to QRISK2 scores; it is expected to replace QRISK2 scores in time. It is likely that composite risk scores, like those discussed here, are needed to accurately predict 10-year CVD risk in lupus patients. In this review, we will discuss the evidence to support the role of traditional risk factors, SLE-specific risk factors, and novel biomarkers in predicting who is at risk for CVD. Furthermore, we will review recent updates in our understanding of atherogenesis, the use of imaging modalities for early detection, and management strategies.

Traditional risk factors for cardiovascular disease in SLE CVD in lupus likely includes an interplay of traditional risk factors and disease-specific immune and inflammatory factors.10 Traditional risk factors, such as hypertension, diabetes, smoking, hyperlipidemia, obesity, and a sedentary lifestyle, are prevalent in SLE and clearly contribute to the increased risk of CVD. Hypertension in lupus patients is associated with a 2.6-fold increased risk of cardiovascular events and coronary artery disease as well as progression 415

416 PART | IV  Clinical aspects of the disease

of carotid plaque.11,12 Diabetes has been shown to double the risk of cardiovascular events in this population.11 Furthermore, smoking is associated with a three-fold increase in cardiovascular events in lupus.13 A prospective European study found that smoking was the only traditional risk factor to predict mortality from CVD.14 In the Toronto lupus cohort, there was a 2.07-fold increase in CVD with persistently elevated total cholesterol levels.15 Although sedentary lifestyle and obesity, influenced by limitations in physical activity and glucocorticoid use, are common in lupus and regarded as traditional risk factors, their effects on cardiovascular events in these patients are not well defined.16 A recent study by Rodríguez-Carrio et al. found that a low bone mineral density, defined as either osteopenia or osteoporosis, was independently associated with an increased risk of CVD. In the same study, a paradoxical effect of body mass index (BMI) on subclinical atherosclerosis was found. BMI 30 kg/m2 had less carotid plaques, despite increased CIMT sometimes labeled as an “obesity paradox.”17 On the other hand, patients with high BMI can develop metabolic syndrome, which is well documented in lupus and may be related to the inflammation that drives the metabolic changes.18

SLE-specific risk factors for cardiovascular disease The premature and accelerated atherosclerosis seen in young women with lupus supports mechanisms beyond traditional risk factors.19,20 SLE-specific risk factors, including disease activity, renal disease and proteinuria,16 presence of antiphospholipid antibodies (aPLs), antidouble stranded DNA, and glucocorticoid use, increase cardiovascular risk early in the disease.21 SLE disease activity and damage may influence CVD risk as found in a recent study in which patients with prolonged SLE remission of >5 years (defined as no clinical disease activity with or without serologic activity and stable doses of immunosuppressive agents) had a higher probability of CVD-free survival over 17 years of follow-up.22 Conversely, lupus patients with more extensive disease damage (plaques on carotid ultrasound) were likely to be reclassified from low or moderate risk to a high-risk CVD group.23 The European study described earlier that found that smoking was the only traditional risk factor to predict mortality from CVD also found that high levels of cystatin C, high soluble vascular cell adhesion molecule-1 (sVCAM-1), high sensitivity C-reactive protein (hsCRP), and any antiphospholipid antibody were other important risk factors for CVD and increased cardiovascular mortality.14 Cystatin C levels, which are high in patients with abnormal renal function, were elevated in lupus patients with and

without nephritis and proved to be a strong predictor of cardiovascular mortality. Furthermore, sVCAM levels, which may serve as a marker of endothelial dysfunction, were also elevated in lupus patients with CVD, and they predicted increased mortality.14 Unfortunately, certain treatment strategies for lupus can also increase a patient's risk for development of CVD. Specifically, glucocorticoid use, one of the most commonly used therapies for lupus, has well known adverse effects that increase traditional cardiovascular risk factors. This is detailed in the discussion on available therapies. Of note, certain nontraditional risk factors may also contribute to cardiovascular risk and subclinical atherosclerosis in SLE. Ethnicity may play a role, suggesting an intricate and complex influence of genetics, diet, socioeconomic status, and access to care. Barbhaiya and coworkers24 conducted a study among patients with SLE within the Medicaid Analytic eXtract from 2000 to 2010, and found that Blacks were at an increased risk of CVD compared to Whites, whereas Hispanics and Asians had a lower risk of myocardial infarction compared to Whites. Furthermore, Blacks had the highest, whereas Asians had the lowest risk of cardiovascular events (defined as myocardial infarction or stroke).24 Depression is more common in patients with SLE as compared to the general population.25 In the Study of Lupus Vascular and Bone Long-term Endpoints cohort from Chicago, which included women >18 years of age with lupus and matched controls, after controlling for traditional cardiovascular risk factors, the presence of depression was associated with progression of subclinical atherosclerosis (as measured by CIMT) in the SLE group but not the control group.26 In another study, increased coronary artery calcification (CAC) and carotid plaque was seen in patients with lupus who were also suffering from depression.27 Data on vitamin D and its effect on CVD risk in lupus are conflicting. In the general population, vitamin D deficiency is associated with increased cardiovascular risk factors and events. In lupus, lower vitamin D is associated with traditional cardiovascular risk factors like hypertension, hyperlipidemia, and elevated CRP with a trend toward higher likelihood of CVD events.28 Interestingly, over supplementation of both calcium and vitamin D may have deleterious effects as well. Mellor-Pita et al. found an association between increased arterial wall stiffness and combined vitamin D and calcium supplementation. This was, however, a small study and proposed to be secondary to increased calcium levels.29 Women with lupus are at increased risk for adverse pregnancy outcomes, which may confer a unique risk factor for future cardiovascular events. In one study, pregnant women with lupus who developed maternal placental syndromes (any hypertensive disorders in pregnancy, stillbirth, placental abruption, or delivery of a small-for-gestational-age infant) and delivery at 40% of patients with SLE had abnormal findings.67 CMR has many promising implications in the risk stratification for ischemic heart disease in patients with lupus. Not all myocardial disease in patients with lupus is secondary to ischemia. CMR imaging is useful for detecting inflammatory myocarditis in symptomatic and asymptomatic patients. Subclinical perimyocardial inflammation was found in asymptomatic patients with lupus by T1 mapping, even in the setting of normal echocardiography.68 CMR is appealing because of the lack of radiation exposure and the ability to evaluate multiple structural and functional abnormalities related to heart disease.

Treatment of cardiovascular disease in SLE Despite the evidence supporting an increased risk of CVD in patients with SLE, there are no lupus-specific guidelines on prevention and treatment of CVD that have been widely accepted. While the treatment and prevention of traditional cardiac risk factors still applies to patients with lupus, disease-specific treatment is not well understood. To date, there have been few randomized controlled trials for the treatment of CVD in lupus. Table 44.2 summarizes the current evidence for potential treatment options and their impact on cardiovascular events and progression of atherosclerosis. There is evidence to support that low-dose aspirin is effective in secondary prevention of coronary events in the general population, while primary prevention is limited to certain high-risk groups. Iudici et al. followed 167 patients with SLE over a median of 8 years and found that low-

Cardiovascular disease in systemic lupus erythematosus: an update Chapter | 44

421

TABLE 44.2 Treatment and potential targets of atherosclerosis in SLE. Drug

Year 69

Study design

Conclusions

Statins

Petri et al. Yu et al.70 Sahebkar et al.71

Randomized, placebo-controlled, 2-year followup; 200 SLE; 1° outcome: CAC, 2° outcomes: CIMT/plaque and biomarkers Observational study, 4095 SLE with hyperlipidemia; association between statin and all-cause mortality, CAD, CVD, and ESRD Systematic review and bibliographic search with data synthesis

No reduction in calcified plaques or biochemical measures of inflammation with the use of statin therapy Statin use was associated with reduced risk of mortality, CVD, and ESRD Statin use had significant reduction in hs-CRP and is relatively safe

Low dose Aspirin

Iudici et al.72 Nugraha et al.73

Observational study, 167 SLE, ASA treated = 146, nonASA treated = 21; 1° outcome: CV events Meta-analysis of 12 randomized controlled trials; 1° outcome: incidence of ASCVD in SLE patients on low dose aspirin

Low dose aspirin was beneficial for primary prophylaxis of cardiovascular events Significant decrease in atherosclerotic cardiovascular events with use of low dose aspirin

HCQ

Cairoli et al.74 Fang et al.75

Longitudinal observation study, SLE 24; lipids measured before and after 3 months of treatment n = 140; SLE = 90, age and sex matched controls = 50; comparison of blood levels of PCSK9 after three months of HCQ therapy

HCQ use resulted in beneficial effect on reduction in lipid levels after only three months of treatment HCQ use was associated with lower levels of PCSK9

Aspirin + HCQ

Fasano et al.76

Longitudinal observation study, n = 189; occurrence of thrombotic events recorded

Long term use of HCQ plus low dose aspirin was found to be thromboprotective

MMF

Kiani et al.77

Post hoc analysis from a randomized trial of atorvastatin in lupus n = 187, n = 25 on MMF during the 2-year follow-up; Outcomes: CAC and CIMT

No improvement in progression of CIMT or CAC. No benefit seen in those on MMF

Azathioprine

Toloza et al.13

Longitudinal observation study, n = 546; assessment for traditional and nontraditional risk factors for vascular events

Vascular events were common in patients on azathioprine

Methotrexate

Ridker et al.78

Randomized, double blind; non SLE population, patients with previous MI or multi-vessel CAD who also had either T2DM or metabolic syndrome; 1° end point: number of nonfatal MI, nonfatal CVA, or CV death (trial was stopped after median 2.3 year follow-up)

No reduction in IL-6, IL-1 beta, or CRP No decrease in CVD events versus placebo

AntiBAFF/ BLyS

Tsiantoulas et al.79

CVD mouse model with (Apoe−/−) and (Ldlr−/−) mice were treated with an antiBAFF antibody (mice model not specific to lupus)

AntiBAFF treatment in CVD mice model increased atherosclerotic plaques with necrosis and decreased collagen. In the absence of human and SLE specific data, we cannot extrapolate the findings to SLE patients with CVD

Cyclophosphamide

Roldan et al.80

TEE to assess aortic IMT, 47 SLE versus 21 controls

CYC was a negative predictor of aortic IMT; 5.8 times less likely risk of developing aortic atherosclerosis

Cyclosporine A

Oryoji et al.81

CIMT in 94 SLE and 427 healthy controls

Cyclosporine A use was protective against increased CIMT

AntiCD 20

Ait-Oufella et al.82

Mouse model (Apoe−/−) and (Ldlr−/−)

Reduced production of IgG antiOxLDL antibodies, decreases T cell, macrophage accumulation in atherosclerotic lesions, decreased INF gamma secretion

dose aspirin may be beneficial in preventing cardiovascular events; however, the small cohort studied makes these results only suggestive.72 Of note, approximately 20% of these patients were positive for aPL antibodies. While large studies on aspirin use in SLE are lacking, a meta-analysis of 12 randomized controlled trials showed a significant de-

crease in CVD, transient ischemic attacks, and peripheral arterial disease.73 The use of statins in reducing CVD risk in the general population is well recognized, but the data in lupus are conflicting, with some studies reporting less progression of coronary calcification and reduction in CVD events and others

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showing no benefit. In a metaanalysis of three randomized controlled trials of statins in lupus, total cholesterol levels were significantly reduced and there was a trend toward improvement in CIMT progression.83 Sahebkar et al. reviewed seven controlled studies on the use of statins in patients with lupus and showed that atorvastatin use significantly reduced hsCRP independent of the drug's effects on LDL.71 However, in the Lupus Atherosclerosis Prevention Study (LAPS trial) of 200 SLE patients with no baseline CVD, atorvastatin was not shown to reduce calcified plaque progression or biochemical measures of inflammation.69 Even with the inconsistent findings, trials show that statins are well tolerated and effectively reduce lipid levels without a deleterious effect on disease activity. Using a large National Health Insurance Research Database of over 4000 lupus patients with hyperlipidemia, statin users had significant reduction in all-cause mortality as compared to those who had never taken a statin.1,70 Hydroxychloroquine (HCQ) is considered a mainstay of treatment in SLE. The beneficial effects of HCQ on traditional risk factors of CVD such as dyslipidemia have been well established. HCQ has also been found to have beneficial effects on atherosclerosis in patients with SLE due to mechanisms affecting both traditional and diseasespecific risk factors.84 Antimalarial use has been associated with lower lipid levels, reduced vascular stiffness, improved glucose metabolism, less thrombovascular events, and improved survival in multiethnic lupus cohorts. A more recently discovered benefit of HCQ is its effects on proprotein convertase subtilisin-kexin type 9 (PCSK9), a protease with a known association with CVD risk. PCSK9 inhibits the clearance of LDL from the blood and also plays a role in increasing inflammation in the body, and it has become a subject of interest in the world of cardiology pharmacotherapy. HCQ use is associated with lower levels of PCSK9, providing another cardiovascular benefit to this commonly used medication.75 Data from clinical trials to address the role of immunosuppressive therapies and biologics on the development of atherosclerosis are scarce. Previous animal studies support the role of mycophenolate mofetil (MMF) in reducing CVD progression by inhibition of NADPH-oxidase; however, in a human study, MMF did not improve either CIMT or CAC progression over a 2-year period in a prospectively followed lupus cohort randomized to atorvastatin or placebo. A limitation of this study was that only 25 of the 187 patients were on MMF, which emphasizes the common problem of small sample size in many of the therapeutic trials evaluating CVD in lupus.77 Oxidative stress is a well-known factor in the pathophysiology of both atherosclerosis and acute thrombosis. Even so, pooled data from large randomized trials of vitamin E, vitamin C, and beta carotene in CVD risk reduction in the general population have been disappointing.85 Simi-

larly, in one small trial in lupus, there was no significant effect on endothelial function after 12 weeks of vitamin C and vitamin E therapy. On the other hand, omega-3 fatty acids, which exert favorable pleiotropic, cardiometabolic effects on the cardiovascular system, have demonstrated beneficial outcomes and are recommended in current guidelines for CVD risk reduction. The supplementation of up to 1 gram daily is generally well tolerated and encouraged in populations at high risk for CVD events. Similar benefits were noted in a small study of patients with lupus, where omega-3 fatty acids improved flow mediated vasodilation after 24 weeks.86 Glucocorticoids, one of the cheapest and most effective therapies in lupus, have long been implicated in promoting CVD.47 Although glucocorticoids effectively reduce overall inflammation and disease activity, longer duration of use and higher cumulative dosing are associated with a greater risk for atherosclerosis.87 This greater risk is likely explained by the well-known adverse effects of steroid use. Glucocorticoid use is associated with the development of hypertension, diabetes, and obesity, all traditional risk factors for CVD. A 2012 study revealed that even short-term glucocorticoid use of ≥20 mg/day resulted in a greater risk of cardiovascular events.11 One study showed a directly proportional relationship between cumulative steroid dose and increase in the Framingham Risk score over a period of 7 years.88 These findings reinforce the concept of limiting glucocorticoid exposure in favor of other therapeutics, including antimalarials and immunoregulatory agents.89,90 As new treatment options for SLE arise, their effect on cardiovascular disease is an important topic of concern. AntiB cell activating factor (antiBAFF) therapy was approved by the US Food and Drug administration in 2011 for the treatment of patients with SLE. In a recent study by Tsiantoulas et al., antiBAFF treatment led to increased atherosclerotic plaque size in mice.79 However, this study was done in a CVD mouse model and was not replicated in mice models of lupus. Additionally, human data to support the relationship between antiBAFF therapy and its effect on subclinical atherosclerosis in SLE are lacking.79 Further research into the effect of antiBAFF therapy on CVD in humans is needed. Many of the studies on prevention and treatment are observational studies. Randomized, prospective, controlled trials are needed to refine our approach to CVD risk reduction in lupus. Not surprisingly, lifestyle changes to mitigate traditional risk factors remains first-line for prevention and treatment of CVD, even in patients with lupus. The AHA recommends moderate exercise, smoking cessation, blood pressure monitoring and control, weight reduction and a healthy diet to promote heart health. Risk stratification and management of CVD in lupus may be extrapolated from data on similar at-risk populations such as rheumatoid arthritis. The recently updated

Cardiovascular disease in systemic lupus erythematosus: an update Chapter | 44

European League Against Rheumatism (EULAR) recommendations for rheumatoid arthritis CVD prevention may have applications to lupus. Interestingly the risk of CVD decreases with low disease activity in rheumatoid arthritis. In contrast, CVD risk remains high in patients with SLE regardless of disease activity, excluding those who have obtained long-term remission.22,91 This observation may reflect the highly effective biologic therapies in rheumatoid arthritis and the potential long-term impact on inflammation and endothelial activation. Current recommendations for CVD prevention in lupus focus on optimal disease control, adapting and incorporating SLE-specific CVD risk calculators, screening for asymptomatic atherosclerosis with imaging modalities, promoting healthy lifestyle modifications, and avoiding potential therapies that may negatively impact CVD risk such as long-term glucocorticoid use.92

Summary Despite therapeutic advances and improved survival, CVD remains a major cause of morbidity and mortality in SLE. In the past decade, the AHA recognized lupus as an at-risk population for CVD for the first time. Conventional CVD risk scores are not adequate in lupus and have led to the development of a CVD risk panel of traditional, clinical, and immunological biomarkers specific to lupus. These new CVD risk panels coupled with imaging techniques will likely serve as stratification tools to identify those patients at highest risk for CVD events. The immunological and inflammatory pathways integral to lupus also play a role in atherogenesis and likely explain the ‘lupus factor’ that accounts for the increased risk of CVD beyond traditional risk factors. Even with the widely recognized increased risk of CVD in lupus, we lack reliable data from lupus-specific clinical trials to support the most effective interventions for primary and secondary prevention. Until evidence-based guidelines are established, we should focus our efforts on optimizing control of lupus disease activity, minimizing use of glucocorticoids, and applying general lifestyle modifications and management of traditional risk factors.

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38. Pons-Estel GJ, Gonzalez LA, Zhang J, et al. Predictors of cardiovascular damage in patients with systemic lupus erythematosus: data from LUMINA (LXVIII), a multiethnic US cohort. Rheumatology (Oxford) 2009;48(7):817–22. 39. Divard G, Abbas R, Chenevier-Gobeaux C, et al. High-sensitivity cardiac troponin T is a biomarker for atherosclerosis in systemic lupus erythematous patients: a cross-sectional controlled study. Arthritis Res Ther 2017;19(1):132. 40. Petri M. Update on anti-phospholipid antibodies in SLE: the Hopkins’ Lupus Cohort. Lupus 2010;19(4):419–23. 41. Haque S, Skeoch S, Rakieh C, et al. Progression of subclinical and clinical cardiovascular disease in a UK SLE cohort: the role of classic and SLE-related factors. Lupus Sci Med 2018;5(1):e000267. 42. Conti F, Spinelli FR, Alessandri C, et al. Subclinical atherosclerosis in systemic lupus erythematosus and antiphospholipid syndrome: focus on beta2GPI-specific T cell response. Arterioscler Thromb Vasc Biol 2014;34(3):661–8. 43. Urowitz MB, Gladman D, Ibanez D, et al. Atherosclerotic vascular events in a multinational inception cohort of systemic lupus erythematosus. Arthritis Care Res 2010;62(6):881–7. 44. Grönwall C, Akhter E, Oh C, Burlingame RW, Petri M, Silverman GJ. IgM autoantibodies to distinct apoptosis-associated antigens correlate with protection from cardiovascular events and renal disease in patients with SLE. Clin Immunol 2012;142(3):390–8. 45. Grönwall C, Reynolds H, Kim JK, et al. Relation of carotid plaque with natural IgM antibodies in patients with systemic lupus erythematosus. Clin Immunol 2014;153(1):1–7. 46. McMahon M, Grossman J, FitzGerald J, et al. Proinflammatory highdensity lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 2006;54(8):2541–9. 47. Agarwal S, Elliott JR, Manzi S. Atherosclerosis risk factors in systemic lupus erythematosus. Curr Rheumatol Rep 2009;11(4):241–7. 48. Kahlenberg JM, Kaplan MJ. The interplay of inflammation and cardiovascular disease in systemic lupus erythematosus. Arthritis Res Ther 2011;13(1):203. 49. Somers EC, Zhao W, Lewis EE, et al. Type I interferons are associated with subclinical markers of cardiovascular disease in a cohort of systemic lupus erythematosus patients. PloS One 2012;7(5):e37000. 50. McMahon M, Skaggs BJ, Sahakian L, et al. High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids. Ann Rheum Dis 2011;70(9):1619–24. 51. Baker JF, Morales M, Qatanani M, et al. Resistin levels in lupus and associations with disease-specific measures, insulin resistance, and coronary calcification. J Rheumatol 2011;38(11):2369–75. 52. Castejon R, Jimenez-Ortiz C, Valero-Gonzalez S, Rosado S, Mellor S, Yebra-Bango M. Decreased circulating endothelial progenitor cells as an early risk factor of subclinical atherosclerosis in systemic lupus erythematosus. Rheumatology (Oxford) 2014;53(4):631–8. 53. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001;103(13):1813–8. 54. McMahon M, Grossman J, Skaggs B, et al. Dysfunctional proinflammatory high-density lipoproteins confer increased risk of atherosclerosis in women with systemic lupus erythematosus. Arthritis Rheum 2009;60(8):2428–37. 55. Winau L, Hinojar Baydes R, Braner A, et al. High-sensitive troponin is associated with subclinical imaging biosignature of inflammatory car-

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diovascular involvement in systemic lupus erythematosus. Ann Rheum Dis 2018;77(11):1590–8. 56. Motoki Y, Nojima J, Yanagihara M, et al. Anti-phospholipid antibodies contribute to arteriosclerosis in patients with systemic lupus erythematosus through induction of tissue factor expression and cytokine production from peripheral blood mononuclear cells. Thromb Res 2012;130(4):667–73. 57. Murthy V, Willis R, Romay-Penabad Z, et al. Value of isolated IgA anti–β2-glycoprotein I positivity in the diagnosis of the antiphospholipid syndrome. Arthritis Rheum 2013;65(12):3186–93. 58. Bartels CM, Buhr KA, Goldberg JW, et al. Mortality and cardiovascular burden of systemic lupus erythematosus in a US population-based cohort. J Rheumatol 2014;41(4):680–7. 59. Croca SC, Rahman A. Imaging assessment of cardiovascular disease in systemic lupus erythematosus. Clin Dev Immunol 2012;2012. 60. Kao AH, Lertratanakul A, Elliott JR, et al. Relation of carotid intima-media thickness and plaque with incident cardiovascular events in women with systemic lupus erythematosus. Am J Cardiol 2013;112(7):1025–32. 61. Polak JF, Pencina MJ, Pencina KM, O’Donnell CJ, Wolf PA, D’Agostino RB, Sr. Carotid-wall intima-media thickness and cardiovascular events. N Engl J Med 2011;365(3):213–21. 62. Hou ZH, Lu B, Gao Y, et al. Prognostic value of coronary CT angiography and calcium score for major adverse cardiac events in outpatients. JACC Cardiovasc Imaging 2012;5(10):990–9. 63. Khan A, Arbab-Zadeh A, Kiani AN, Magder LS, Petri M. Progression of noncalcified and calcified coronary plaque by CT angiography in SLE. Rheumatol Int 2017;37(1):59–65. 64. Captur G, Manisty C, Moon JC, Cardiac MRI. evaluation of myocardial disease. Heart 2016;102(18):1429–35. 65. Ishimori ML, Martin R, Berman DS, et al. Myocardial ischemia in the absence of obstructive coronary artery disease in systemic lupus erythematosus. JACC Cardiovasc Imaging 2011;4(1):27–33. 66. Mavrogeni S, Koutsogeorgopoulou L, Markousis-Mavrogenis G, et al. Cardiovascular magnetic resonance detects silent heart disease missed by echocardiography in systemic lupus erythematosus. Lupus 2018;27(4):564–71. 67. Burkard T, Trendelenburg M, Daikeler T, et al. The heart in systemic lupus erythematosus - A comprehensive approach by cardiovascular magnetic resonance tomography. PloS One 2018;13(10):e0202105. 68. Puntmann VO, D’cruz D, Smith Z, et al. Native myocardial T1 mapping by cardiovascular magnetic resonance imaging in subclinical cardiomyopathy in patients with systemic lupus erythematosus. Circulation 2013;6(2):295–301. 69. Petri MA, Kiani AN, Post W, Christopher-Stine L, Magder LS. Lupus atherosclerosis prevention study (LAPS). Ann Rheum Dis 2011;70(5):760–5. 70. Yu HH, Chen PC, Yang YH, et al. Statin reduces mortality and morbidity in systemic lupus erythematosus patients with hyperlipidemia: a nationwide population-based cohort study. Atherosclerosis 2015;243(1):11–8. 71. Sahebkar A, Rathouska J, Derosa G, Maffioli P, Nachtigal P. Statin impact on disease activity and C-reactive protein concentrations in systemic lupus erythematosus patients: a systematic review and metaanalysis of controlled trials. Autoimmun Rev 2016;15(4):344–53. 72. Iudici M, Fasano S, Gabriele Falcone L, et al. Low-dose aspirin as primary prophylaxis for cardiovascular events in systemic lupus erythematosus: a long-term retrospective cohort study. Rheumatology (Oxford) 2016;55(9):1623–30.

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91. Kravvariti E, Konstantonis G, Sfikakis PP, Tektonidou MG. Progression of subclinical atherosclerosis in systemic lupus erythematosus versus rheumatoid arthritis: the impact of low disease activity. Rheumatology (Oxford) 2018;57(12):2158–66.

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Chapter 45

The lung in systemic lupus erythematosus Lindsy Forbessa, Daniel J. Wallacea and Caroline Jefferiesa,b a

Division of Rheumatology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, United States; bDepartment of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, United States

Introduction

Role of inflammation in SLE lung

Systemic lupus erythematosus (SLE) is an autoimmune disorder that can affect virtually every organ of the body, including the lung. Depending on the sensitivity of the tools used to detect disease and the populations studied, the incidence of pulmonary involvement in SLE varies. However, it is likely that 60% and higher of SLE patients experience lung involvement at some stage in the course of their disease and any of the respiratory compartments can be impacted (Table 45.1).1,2 Clinical severity varies from asymptomatic imaging or pulmonary function test (PFT) abnormalities to fulminant, life-threatening disease. Lung disease in SLE has been associated with an increased risk of mortality.3 Little is known about the natural history of, or predispositions to, SLE lung disease or how to best manage its various manifestations. Inflammation and dysregulation of immune responses are important drivers of lung pathology in autoimmune disease.4 Although the precise mechanisms underlying the pathology of SLE-associated lung inflammation are unknown, a number of features associated with SLE, such as elevated levels of systemic type I interferons (IFN), circulating immune complexes (IC) and the presence of a subset of highly inflammatory neutrophils point to a role for these factors in driving lung inflammation and ultimately fibrosis and tissue damage. This review will discuss how these features may promote lung inflammation in SLE, in addition to discussing clinical presentations of pulmonary manifestations of SLE and treatment. It will also briefly review pulmonary features associated with interferonopathies, a group of monogenic autoinflammatory diseases categorized as having high levels of type I IFN and discuss how features associated with these diseases promote lung involvement and interstitial lung disease (ILD).

SLE patients with lung involvement are reported to have increased levels of systemic pro-inflammatory cytokines such as IFN-γ, TNF-α, and IL-6 compared with patients with no lung involvement, supporting a role for inflammation as a potential driver.5 While the role of inflammation in the progression of pulmonary fibrosis has been challenged,6 cellular inflammation, particularly in the early stages of disease, has been consistent with pathological findings.7,8 As a result of an initial inflammatory insult (injury, infection, antibody deposition, complement activation) damaged or activated epithelial or endothelial cells release proinflammatory cytokines or chemokines (such as TNF-α, IL-1, IL-8) resulting in the attraction and homing of neutrophils initially, followed by monocytes, macrophages and T and B lymphocytes. Once at the site neutrophils degranulate releasing anti-microbial proteins such as neutrophil elastase, defensins and proteinase 3, in addition to pro-inflammatory mediators such as IL-1, TNF, and reactive oxygen species.9 In SLE, neutrophils further contribute to autoimmune lung inflammation by virtue of their ability to release DNA and histones in a process called NETosis, revealing autoantigens and selfDNA to further exacerbate inflammatory responses.10 Type I IFNs also play an important role—driving neutrophil NETosis, autoantibody production and helping break immune tolerance in the lung. This complex interplay between initiating factors (IFNs, autoantibodies and immune complexes, infectious insult or injury) and downstream responses (complement activation, neutrophil accumulation and activation) play important roles in driving SLE-associated lung involvement as outlined in Figure 45.1.

Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00045-3 Copyright © 2020 Elsevier Inc. All rights reserved.

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TABLE 45.1 Pulmonary manifestations associated with SLE (Prevalence Estimates %). Infection Adverse effects of drugs used to treat systemic disease Nonpulmonary causes of respiratory symptoms Thoracic chondritis Lupus myositis Anemia cardiac ischemia, valvular heart disease and cardiomyopathies Pericardial disease Deconditioning Gastro-esophageal reflux disease/aspiration Pleural disease (30%–45%) Pleuritis (45%) Pleural effusion (30%) Parenchymal Acute lupus pneumonitis (up to 9%) Chronic interstitial lung disease (3%) Diffuse alveolar hemorrhage (up to 2%) Acute reversible hypoxemia Shrinking lung syndrome (up to 10%) Pulmonary vascular disease Pulmonary hypertension (0.5%–14%) Thromboembolism (up to 25%) Lung vasculitis Airways disease (up to 20%) Upper airways (e.g., cricoarytenoid arthritis) Lower airways (small airways disease)

IFN-driven autoimmune lung inflammation In recent years a type I IFN (IFNα and IFNβ) gene signature in the peripheral blood of SLE patients has been described which correlates with increased disease activity.11–15 Elevated IFNα is observed in over 50% of patients and correlates with disease severity, flare and tissue involvement (specifically skin, kidney, and central nervous system). In

the lung, type I IFNs are induced in response to infection and injury (such as that associated with smoking, etc.), with lung epithelial cells and cells of the innate immune system being involved; depending on the stimulus IFNs in the lung exacerbate inflammation via inducing chemokine expression and production of inflammatory cytokines (presumably by upregulating signaling components that will enhance their expression) and will promote adaptive immune responses via enhancing antigen presentation and costimulatory molecule upregulation.16 As mentioned above, type I IFNs can help break tolerance and drive the production of autoantibodies. Deposition of circulating autoantibodies and immune complexes on lung tissue has been suggested as a leading cause of inflammation in the lung in SLE and rheumatoid arthritis (RA).17 Type I IFNs (IFNα and IFNβ) are produced in response to RNA and DNA detection primarily: both Toll-like receptors (TLRs) and cytosolic RNA and DNA sensors are involved (discussed in detail in Chapter 23).18,19 One IFNinducing pathway that has recently been associated with lung involvement is the cGAS-STING pathway. cGAS is an intracellular, cytosolic DNA sensor which once activated produces cyclic dinucleotides which then activate the ER-resident adaptor protein STING (stimulator of interferon genes).20 STING homodimerizes and activates the IRF3 kinase TBK1, resulting in IRF3 activation and nuclear translocation and subsequent activation of IFNβ gene expression. Activating mutations in the gene encoding STING, TMEM173, give rise to enhanced expression of IFNβ and a systemic autoinflammatory/autoimmune disease termed SAVI (STING associated vasculopathy with onset in infancy). SAVI is part of a collection of autoinflammatory/autoimmune diseases termed interferonopathies which all feature single gene mutations in regulators of the cGAS-STING pathway.21, 22 However, despite the similarities in IFN dysregulation among the interferonopathies, clinically only SAVI and another novel syndrome called

FIGURE 45.1  Overview of immune aspects that drive lung involvement in autoimmune disease.

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COPA syndrome,23,24 are associated with lung involvement. Thus, perhaps another mechanism may be at play here. Recently endoplasmic reticulum (ER) stress has emerged as a driver of autoimmune lung inflammation.23 ER stress responses in lung epithelia leads to the release of cytokines that aid recruitment of cells to the damaged area and remodeling of the local environment.25 A recent report identified ER stress as the principle mechanism behind a hereditary autoimmune syndrome of severe lung disease, where mutations in COPA disrupt protein transport, causing ER stress and subsequent activation of inflammation and recruitment of Th17 cells to the lung.23 Interestingly, ER stress has been shown to prime IFN production via the activation of the transcription factor IRF3, indicating the potential for cross-talk between IFN and ER stress pathways and potential relevance to IFN driven diseases such as SLE.26 The clinical features of SAVI and COPA syndrome are discussed in detail further.

Immune complex involvement The most common conditions associated with immune complexes (ICs) are autoimmune diseases such as SLE and RA.27 Patients with SLE have various lab abnormalities including high titer autoantibodies against DNA, ribonucleoprotein complexes, Smith antigen, Ro/SSA and La/ SSB (reviewed in [28]). Autoantibodies associated with lung disease in SLE include anti-Smith, anti-RNP, and antiSSA1 (or TRIM21/Ro52).29,30 Anti-SSA1/TRIM21 is associated with poor outcome in a number of interstitial lung diseases including SLE.31 Interestingly SSA-1 or TRIM21 is an interferon regulated gene, indicating in patients with high levels of type I IFN then levels of this autoantigen are high.32 Immune complexes are antigen-antibody complexes formed by binding of IgM or IgG to soluble antigen. They mediate their effects in two ways primarily:1 triggering complement activation via the classical pathway involving recognition of antibody by C1q, activation of C3 and generation of the C5b-9 membrane attack complex,33,342 binding to Fcγ receptors on monocytes, resident macrophages and neutrophils to enhance phagocytosis, release or produce reactive oxygen species (ROS) production and degranulation of neutrophils to release proteases, inflammatory cytokines and ROS to further exacerbate inflammation35. Immune complexes can also trigger neutrophil NETosis—a process whereby neutrophils release decondensed chromatin (DNA and histones) and granular contents to the extracellular space.17,36 Thus immune complex-mediated inflammation and injury is at the heart of lung involvement in diseases such as SLE and RA.

Neutrophils and NETosis SLE patients have a specific inflammatory subset of neutrophils called low density neutrophils (LDNs) or granulocytes

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that are primed to be activated by immune complexes and IFNs. They produce IL-1β and also IFN in response to being activated and are also highly susceptible to undergoing NETosis—targeted release of self-DNA from within the neutrophil as a result of decondensation of nucleosomes.10,37,38 Release of histones and self-DNA from neutrophils during NETosis is highly inflammatory and damaging to the lung39— both acting as a source of autoantigens (histones and self-DNA) but also driving IFN production through recognition of self-DNA by DNA sensing cGAS-STING pathway.40 Extracellular histones can also drive cytotoxicity of alveolar epithelial cell lines, exacerbating lung damage and inflammation.41 Acute lung inflammation that drives alveolar hemorrhage is driven primarily by the release of inflammatory cytokines and chemokines that result in stimulating an influx of neutrophils into the airways. Recently work from our group showed that an inflammatory cytokine IL-16 plays a role in this process.42 IL-16 is released during systemic inflammation and induces CXCL10 expression from alveolar epithelial cells, promoting the influx of neutrophils in a mouse model of IFN-driven disease. Our work also showed that enhanced IL-16 levels associated with lung involvement in SLE patients, suggesting IL-16 may act as a marker or driver of IFN-driven autoimmune lung inflammation. As to whether IL-16 contributes to altered neutrophil function in SLE is currently under investigation. Thus, many mechanisms that are known to drive tissue pathology in SLE– immune complex deposition, neutrophil activation and NETosis, dysregulation of IFN production and signaling contribute to autoimmune lung inflammation, and specifically SLE-associated lung inflammation. The relative contribution of RNA/DNA sensing pathways in regulating these responses and driving exacerbation of lung inflammation and process of fibrosis remains underappreciated and under studied. As discussed below in detail our analysis of monogenic diseases such as COPA syndrome and SAVI may provide additional information that may better guide therapeutic intervention and management.

Clinical presentations of lung involvement in SLE Lung involvement in SLE is frequently identified. In a cohort of 110 SLE patients, 91.5% had either respiratory symptoms or evidence of pulmonary physiologic impairment, 57.3% reported dyspnea, and 31.8% had pleuritic chest pain.43 PFT abnormalities were noted in 66.4%. The forced vital capacity (FVC) was abnormal in 31.8% of patients and the diffusing capacity of the lung for carbon monoxide (DLCO) was abnormal in 45.9%. PFT abnormalities are common even among asymptomatic SLE individuals,1,44 with decreased DLCO being the most common finding,44, 45 In this regard, in one study of

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70 nonsmoking SLE patients without respiratory symptoms and with normal chest radiography, abnormal PFT were found in 63% of patients (compared with 17% of controls), with isolated decreased DLCO being found in 31% SLE patients (vs. none in controls).6 Small airway disease was relatively common in both groups (SLE 24% vs. controls 17%). None of the 70 asymptomatic SLE patients had chest radiograph abnormalities. In a study of 43 symptomatic SLE patients, abnormal chest radiographic features were observed in 23%.5 Pleural changes appear to be the most common abnormality in SLE patients.46 Thoracic high-resolution computed tomography (HRCT) scan abnormalities (including traction bronchiectasis, interstitial lung disease (ILD), lymphadenopathy, and pleuro-pericardial abnormalities) are seen in the majority of SLE patients, even in the absence of respiratory symptoms or impairment on PFT.47 In the cohort of 110 SLE patients mentioned earlier, among the 95 patients who had a chest radiograph, 25.3% had an abnormal finding (7.4% with possible or definite interstitial infiltrates; 4.2% with pleural thickening). Among the 80 patients who had a chest CT scan, 18.8% displayed interstitial infiltrates, and 11.0% had pleural involvement.43

Pulmonary infection Of all the pulmonary manifestations in SLE, infection is the most common and needs to be excluded. Infection can mimic lung disease, which is part of the connective tissue disease (CTD) process and often requires immunosuppressive therapy; also, infection is associated with appreciable morbidity and mortality.48 Both typical and atypical pathogenic organisms, including fungal and mycobacterial species, may be the cause.48 Due to a patient's immunocompromised state, the clinical presentation may be insidious, particularly if opportunistic organisms are the culprit. Rigorous evaluation that often includes bronchoalveolar lavage (BAL) to exclude infection in SLE patients with any suggestive or unexplained pulmonary abnormality is mandatory. (See Chapter 45 for a thorough review of infectious complications associated with SLE.)

Nonpulmonary involvement as a cause of respiratory symptoms A comprehensive evaluation is needed to exclude nonrespiratory causes of dyspnea and/or cough. For example, cardiac ischemia, cardiomyopathy, valvular heart disease, pericardial disease, anemia, and deconditioning are important etiologies to consider and need to be excluded. Cough may be more likely due to gastroesophageal reflux disease, esophageal dysmotility, or aspiration; these frequentlyencountered comorbid conditions require thorough assessment and appropriate management.

Pleural disease Of all of the intrathoracic presentations of SLE, pleural abnormalities are seen most commonly,28,48 and occur more frequently in SLE than in any other CTD.49 Depending upon the population evaluated and the mode of detection, its prevalence varies greatly. Autopsy studies have reported pleural abnormalities in 78%–93% of cases.48,50 In large nonautopsy studies, a cumulative incidence of 36% (either pleural or pericardial involvement) was identified among a cohort of 1000 SLE patients,51 in a large cohort of 520 SLE patients pleurisy was reported in 45% and pleural effusion in 30%.52 Pleural abnormalities appear to be more common in men13 and in African-Americans.53 Pleural disease may rarely be the presenting manifestation of SLE,54 and it may be unilateral or bilateral.55 Pleuritic pain can herald an SLE flare, can last for several weeks, and can be associated with fever, dyspnea, cough, and/or pain, mostly at the costo-phrenic angle.2 Pleuritic chest pain should prompt evaluation to exclude thromboembolism and evidence of pleural effusion requires investigation to exclude infection, states of volume overload, and malignancy. Pleural effusions are typically small to moderate in size, bilateral, and exudative.55 Pleural glucose level is usually >70 mg/dL, lactate dehydrogenase  7.2,55,56 The role of testing for pleural fluid ANA is not clear.57 There are no evidence-based recommendations for treatment of pleural disease, but we have found that pleurisy often responds rapidly to nonsteroidal anti-inflammatory drugs or corticosteroids (CS) in moderate doses (20–30 mg/ day of prednisone equivalent). Pleural effusions often mandate a more protracted treatment course. In more severe or refractory cases, a CS-sparing agent such as azathioprine (AZA) or methotrexate may be needed.58 Rarely, pleural disease requires intercostal steroid injection, pleurodesis, or pleurectomy.59,60

Parenchymal disease Acute lupus pneumonitis Acute lupus pneumonitis has a similar clinical presentation to infectious pneumonia61 and may be seen in up to 9% of SLE cohorts:1,51 acute onset of fever, cough, dyspnea, tachypnea, and hypoxemia are typical. Chest radiograph and thoracic HRCT scan usually demonstrate bilateral diffuse patchy alveolar infiltrates, which may involve all lung zones but favors the lower zones.49 Given its clinical similarity with infectious pneumonia and their common co-existence,61 a thorough diagnostic evaluation for an infectious etiology is indicated. Bronchoscopy is typically performed and surgical lung biopsy may be required to provide diagnostic certainty. Histopathology demonstrates diffuse alveolar damage (DAD) in the absence of

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vasculitis, capillaritis, or hemorrhage, and the presence of interstitial edema and intra-alveolar hyaline membrane formation.10 The prognosis is variable but with lethal potential (8%–50%).62,63 Corticosteroids are first-line therapy, but more severe cases may require further immunosuppression with AZA,25 cyclophosphamide (CYC),64 or other immunosuppressive agents to reduce the likelihood of recurrent pneumonitis or to help effectively taper the CS dose. In more fulminant, life-threatening scenarios, plasmapheresis should be considered.64

Pulmonary hemorrhage/diffuse alveolar hemorrhage Diffuse alveolar hemorrhage (DAH) is arguably the most debilitating pulmonary manifestation of SLE. Reliable estimates of the prevalence of DAH in SLE are lacking, but some data suggest prevalence as high as 2% and accounting for roughly 3% of all SLE-related hospitalizations, and approximately 20% of hospitalizations for all SLEassociated lung disease.2,65–67 Clinical presentation ranges from mild and insidious to fulminant and life-threatening disease. Presentation may be nonspecific, including acute onset of dyspnea, cough, and fever, but with hemoptysis in only around 65% of patients.67 DAH most often occurs in younger women with preexisting SLE, especially with multisystem disease. The clinical course is often one of rapid respiratory deterioration.2,62,67 With massive hemorrhage, hemoglobin, and hematocrit will drop precipitately. Chest radiograph shows bilateral nonspecific peripheral infiltrates and thoracic HRCT scan reveals diffuse fluffy or nodular ground glass opacification changes due to alveolar filling admixed with areas of consolidation (Figure 45.2). Co-existent acute respiratory infection may be seen in 13%–57% of cases.67 Exclusion

FIGURE 45.2  Diffuse alveolar hemorrhage. Chest CT scan shows patchy ground glass attenuation in a bronchocentric distribution, consistent with intra-alveolar blood. Reproduced from Ref. [20], p. 853.

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of infection and confirmation of the diagnosis of SLEassociated DAH requires bronchoscopy with BAL, demonstrating the presence of blood within the large airways and increasingly bloody returns from successive aliquots. The presence of hemosiderin-laden macrophages in the BAL fluid is a clue to insidious alveolar hemorrhage. Surgical lung biopsy is not usually needed to confirm the diagnosis of DAH but, when performed, histopathology reveals hemosiderin-laden macrophages, diffuse intra-alveolar hemorrhage, co-existent capillaritis, DAD, alveolar edema and necrosis, microvascular thrombi, and vascular intimal proliferative changes.2,67,68 DAH can lead to respiratory failure necessitating mechanical ventilatory support. Therapeutic intervention is based on anecdotal evidence and small case series and typically include pulse-high dose CS65 with early addition of intravenous CYC;69,70 plasmapheresis may improve chances of survival but also increases the risk of serious infection.69,70 Even with such intensive regimens, the overall prognosis is dismal, with a reported overall mortality between 70% and 90%, half dying during their hospitalization.2,67,68

Chronic interstitial lung disease Although chronic interstitial lung disease (ILD) is common in patients with other CTDs, it rarely occurs in SLE; its estimated prevalence is only about 3%.71 Although ILD may be the presenting manifestation of SLE, it typically occurs with long-standing and multisystem disease and is characterized by an insidious onset of cough, exertional dyspnea, and bibasilar crackles. PFT reveals reduced lung volumes, restriction on spirometry (proportionate reduction in forced expiratory volume in 1 second and FVC), and impaired gas exchange (reduced DLCO). BAL shows a mixed neutrophil/eosinophil increase, but a lymphocyte increase may be seen in more cellular disease.72 Whether the underlying histopathologic pattern has prognostic significance in SLE-ILD has yet to be determined.73 Nearly all of the histopathologic patterns encountered in those with idiopathic interstitial pneumonia (IIP) have been encountered in SLE.74 Nonspecific interstitial pneumonia (NSIP) is the most common pattern in SLE (Figure 45.3); less frequently encountered patterns include organizing pneumonia (OP) (Figure 45.4), lymphocytic interstitial pneumonia (LIP) (Figure 45.5), the DAD found in acute lupus pneumonitis (Figure 45.3), and more rarely usual interstitial pneumonia (UIP). Often the pattern contains a combination of features, commonly including co-existing pleural disease, and may not exhibit the classical features of any of the individual chronic ILD. At present, the precise role of surgical lung biopsy in SLE-ILD remains to be determined.75 In our experience, the decision whether to pursue a surgical lung biopsy is made on a case-by-case

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FIGURE 45.4  Organizing pneumonia (OP) pattern. Chest CT scan below the level of the carina shows patchy consolidation and some ground glass attenuation compatible with an OP histopathological pattern.

FIGURE 45.3  Nonspecific interstitial pneumonia (NSIP) pattern. (A) Chest CT scan at the lung bases shows widespread ground glass attenuation with traction bronchiectasis and subpleural sparing, compatible with a fibrotic NSIP histopathological pattern. Note the absence of honeycombing. (B) Coronal view showing the basal predominance of disease.

basis and should be considered when there is an atypical or unclassifiable radiologic pattern or concerns for an alternative etiology to account for the ILD. Patients with SLE-ILD do not always require pharmacologic treatment.76,77 The decision to treat rests upon1 whether the patient is clinically impaired by the ILD,2 whether the ILD is progressive, and3 what contraindications or mitigating factors exist. Therapy for SLE-associated ILD is generally reserved for those patients with clinically significant, progressive disease, based upon a combination of clinical assessment tools, including both subjective and objective measures of respiratory impairment.76,77 There are limited data available to guide the choice of specific pharmacologic agents for the treatment of CTD-ILD as a group, and no controlled data for SLE-ILD.77 Data from small uncontrolled trials in systemic sclerosis (SSc)-ILD

FIGURE 45.5  Lymphocytic interstitial pneumonia (LIP) pattern. Chest CT scan shows marked volume loss in the right lung with pleural thickening and an extensive reticular pattern consistent with diffuse established fibrosis. There are also widespread centrilobular nodules in both lungs, with some low attenuation areas throughout the left lung consistent with small cysts/bullae; both features are compatible with an LIP histopathological pattern.

and other CTD-ILD77 and from three controlled trials in SSc-ILD78–80 provide support for the use of CYC in SLEILD. Retrospective data suggest that AZA or mycophenolate mofetil (MMF) may be effective in CTD-ILD.81 Two retrospective studies demonstrated that MMF was associated with effective CS dose tapering and with longitudinal

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improvements in FVC and DLCO in a diverse spectrum of CTD-ILD.58,82 It is not known whether we can extrapolate from these data to SLE-ILD. Our usual regimen for SLEILD includes the use of CS at a moderate to high dose (30– 60 mg/day of prednisone equivalent) combined with CYC for the most severe or progressive cases, or with AZA or MMF for less severe disease.77

Shrinking lung syndrome Shrinking lung syndrome (SLS) is characterized by unexplained dyspnea and restrictive pulmonary physiology the severity of which is disproportionate to the extent of parenchymal radiographic abnormalities. In our experience, SLE patients with SLS often have long-standing or recurrent symptoms of pleurisy. Elevations of the diaphragms together with bibasilar atelectasis are the hallmark radiographic features.83 Among 110 SLE patients, 10.0% were found to meet the definition of SLS, with increased disease duration, RNP positivity and history of serositis being significant associations.43 The precise pathogenesis remains to be determined. It is usually not progressive, but it is associated with chronic and persistent dyspnea. Inhaled β-agonist or theophylline therapy may favorably impact SLS.84,85 Alternatively, CS or immunosuppressive agents such as AZA, methotrexate, CYC, or rituximab may improve the condition.86

Pulmonary vascular disease Pulmonary hypertension Patients with SLE are at risk for developing several types of pulmonary hypertension (PH): pulmonary arterial hypertension (PAH), PH due to left heart disease, PH due to chronic ILD or chronic thromboembolic-associated PH (CTEPH).87 Severe PH is relatively rare.88 Mild, subclinical PH, however, is relatively common with a reported prevalence of 0.5%–14%,87 SLE-PH presents with exertional fatigue and dyspnea and more severe disease manifests with characteristic features of right-heart failure. Clues to the presence of PH may include a disproportionate reduction in the DLCO, exertional hypoxemia or an elevated brain natriuretic peptide (BNP) level in those with more advanced disease. Echocardiography is the best noninvasive tool for PH assessment but is neither sensitive nor specific, and a right-heart catheterization must be performed for accurate measurement of cardiac hemodynamic parameters and to confirm a diagnosis of PH87. The pathophysiologic mechanisms of SLE-PAH are not known but prevailing theories include pulmonary circulatory vasospasm, intrinsic vasculopathy, in situ thrombosis, and endothelial dysfunction as possible causes.87 In general, the approach to managing SLE-PAH is similar to that of idiopathic PAH and includes monotherapy or

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combination therapy with oral endothelin receptor antagonists, phosphodiesterase-type 5 inhibitors, guanylate cyclase stimulators, parenteral or inhaled prostanoids and is optimized by a multidisciplinary approach that includes an experienced PH-treating cardiologist or pulmonologist. PAH in SLE is unique in that there have been reports in small series suggesting that immunosuppressive therapies (including high-dose CS and CYC) may be useful in selected cases, typically those with more of an inflammatory vasculopathy.89,90 The prognosis of SLE-PAH is better than SSc-PAH.91

Pulmonary Thromboembolism New-onset pleuritic chest pain or acute dyspnea requires evaluation for pulmonary embolism in any SLE patient. Thromboembolism occurs in up to 25% of SLE patients and is a major cause of morbidity and mortality;2 the presence of antiphospholipid syndrome-associated antibodies increases the risk of thromboembolism.92,93 In one study, antiphospholipid antibody positivity was associated with a more than six fold risk of thromboembolism;93 in another study, lupus anticoagulant positivity carried a fivefold risk.92 Evaluation for pulmonary embolism starts with noninvasive assessment that usually includes ventilation/perfusion (V/Q) scan or CT angiography but may require pulmonary angiography for a definitive diagnosis. D-dimer level appears to have limited utility in SLE because nonspecific increase is noted with disease flares, infections, and may be positive in 50% of those without thromboembolism.94 The mainstay of therapy is anticoagulation with heparin followed by warfarin. SLE patients with thromboembolism and positive antiphospholipid syndrome-associated antibodies usually require lifelong anticoagulation.95 (See Chapters 56–58 and 63 for a thorough review of antiphospholipid syndrome in SLE.)

Acute reversible hypoxia syndrome A novel syndrome of acute reversible hypoxemia affecting six SLE patients presenting with dyspnea and pleurisy, acute and reversible hypoxemia, absence of chest radiographic abnormalities, and a wide alveolar-arterial gradient that improved with CS treatment was reported in 1991.96 In 1995, a similar clinical picture was reported in four SLE patients.97 Complement-mediated aggregation and activation of neutrophils within the pulmonary vasculature or increased surface expression of adhesion molecules and a resultant leuko-occlusive pulmonary vasculopathy have been suggested as possible pathophysiologic mechanisms of disease.96,97 Treatment is typically supportive, includes supplemental oxygen, and occasionally mandates a shortterm course of CS.

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Airway disease Airflow limitation involving both the upper and lower airways, as defined by obstructive physiology on PFT, has been observed in patients with SLE, but its clinical significance is not known.45 In a prospective study assessing thoracic HRCT scans from 34 patients with SLE (23% with symptoms), 21% of the scans showed bronchiectasis and bronchial wall thickening.8 Symptomatic obstructive lung (“airways”) disease is uncommon.

Overlap syndromes Many patients with SLE who have pulmonary hypertension and/or ILD have overlapping features of other autoimmune diseases, such as mixed connective tissue disease (MCTD) or Sjogren's syndrome (SS). MCTD is an overlap syndrome including features of SLE, systemic sclerosis, myositis and/or rheumatoid arthritis. Anti-U1 ribonucleoprotein (RNP) antibodies are required for the diagnosis of MCTD. Pulmonary hypertension can develop in MCTD on the basis of ILD or as a result of isolated pulmonary arteriopathy. The development of pulmonary hypertension in MCTD worsens prognosis and is responsible for increased mortality.98 SS is an autoimmune condition with diminished lacrimal and salivary gland function resulting in dryness of the eyes and mouth. It can coexist with SLE patients and is termed secondary SS in this setting. Anti-Ro/SSA and Anti-La/SSB antibodies are commonly found among patients with SS. Extraglandular manifestations occur in SS and approximately 10%–20% of SS patients have clinically significant lung disease, including ILD.99

COPA syndrome and SAVI: Interferonopathies with lung involvement COPA syndrome COPA syndrome is an autoimmune lung and joint disorder first described in 2015 that shares many similarities with SLE, and therefore may provide new insights into pathogenic mechanisms of SLE.23 It is an autosomal dominant disease with incomplete penetrance that is due to missense mutations in the COPA gene.100 The syndrome is characterized by ILD and diffuse alveolar hemorrhage (DAH), arthritis and autoantibodies.101 A majority are positive for anti-nuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) or both, along with rheumatoid factor (RF) and hypocomplementemia. Renal failure can present in combination with DAH and renal pathology shows immune-mediated renal disease. Lung disease in COPA syndrome is characterized by ILD (Figure 45.6), pulmonary hemorrhage, or both. Spirometry reveals mostly restrictive defects with abnormal DLCO % predicted. Chest CT imaging often shows thin-walled cysts scattered throughout the

FIGURE 45.6  Interstitial lungddisease (ILD) in COPA syndrome. Chest CT scan shows irregularity reticulations throughout both lungs with an apical basal gradient with worsening disease at the bases. This is associated with traction bronchiectasis as well as traction bronchiolectasis. Areas of honeycombing are identified predominantly in the right middle and lower lobes consistent with interstitial lung disease.

parenchyma in variable distribution, as well as groundglass opacities and nodules. Pulmonary histopathology commonly reveals follicular bronchiolitis, and sometimes airspace enlargement/cystic changes. Arthritis can affect both large (shoulders, knees) and small joints (MCP, PIP and DIPs) and has been described as both erosive and nonerosive.100,101 Subjects with lung disease, especially those with DAH, have been treated with steroid therapy and immunosuppressive agents (i.e. cyclophosphamide, mycophenolate mofetil and azathioprine).101 This has stopped the hemorrhage and led to radiographic improvement. Subjects, however, despite immunosuppressants, have gone on to lung transplantation, suggesting that data is limited in immunosuppressive therapy's ability to prevent long term disease progression. The lack of ANA sub-serologies (i.e., dsDNA, anti-Ro/ SSA, anti-La/SSB, anti-Smith, and anti-RNP) help distinguish COPA from SLE. ANCA positivity, DAH and renal involvement can be consistent with ANCA-associated vasculitis (AAV), however the lack of upper airway involvement and immune complex deposition on renal biopsy help distinguish COPA from AAV. Whether COPA is a form of SLE or AAV, or a disorder with distinct disease pathogenesis requires further study. Other manifestations reported in those with COPA mutations have been malignancy (pulmonary carcinoid, clear cell renal carcinoma), neuromyelitis optica, extrapulmonary cysts (renal and hepatic),

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nephrolithiasis, pyelonephritis and meningitis.102 This hints that the phenotypic spectrum of this disorder is not yet fully defined. Those with ILD and/or DAH and arthritis, early disease onset, family history and typical autoantibodies (ANA, ANCA, RF) should be identified for targeted sequencing for a COPA mutation to help establish a diagnosis.

SAVI syndrome STING-associated vasculopathy with onset in infancy (SAVI) is an ultra-rare autoinflammatory syndrome caused by gain-of-function mutations in TMEM173, which encodes the stimulator of interferon genes (STING).103 As the name suggests, patients are symptomatic within the first 8 weeks of life. Most develop progressive ILD with variable severity.100 CT chest shows ILD and hilar or paratracheal lymphadenopathy. Lung biopsy shows scattered mixed lymphocytic inflammatory infiltrate, interstitial fibrosis and emphysematous changes. Autopsies of children who died of pulmonary complications and secondary infection showed widespread vasculopathy of the systemic and pulmonary vasculature.103 A vasculopathy/vasculitis develops that affects small vessels in mostly acral areas (cheeks, nose, fingers, toes, soles) leading to vasooclusion and gangrene, often necessitating surgical amputation. Biopsies of lesional skin show marked vascular inflammation in the capillaries, microthrombotic vascular changes in chronic lesions, and immune complex deposition (IgM, C3 and fibrin).103 Low-titer autoantibodies (ANCAs) and antiphospholipid antibodies (anticardiolipin antibodies and antibodies against B2-glycoprotein) are present but disappear over time. Systemic inflammation is present with elevated erythrocyte sedimentation rate and C-reactive protein levels. Immunosuppressant agents (i.e. steroids, azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide, tumor necrosis factor antagonists, IL-1 blockade, IL-6 blockade) have not resulted in sustained responses. A recent clinical trial with Baricitinib, a Janus kinase (JAK) 1/2 inhibitor, in the treatment of autoinflammatory interferonopathies included 4 patients with SAVI syndrome and showed improvement of vasculitis flares and prevention of the development of gangrene, as well as stabilization of ILD, but no normalization of inflammatory markers. In addition, IFN scores decreased but the absolute levels remained elevated.104 JAK inhibition may be a promising treatment approach in type I IFN-mediated diseases but requires further study.

A case for screening for Lung Disease In SLE Given the prevalence and wide range of lung diseases that can be seen in SLE, we would suggest that some degree of screening for lung disease in SLE is indicated, especially to establish a baseline when dealing with a disease

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in which some form of pulmonary manifestation may occur during the course of the disease. In our opinion, it would seem reasonable to perform chest radiography and PFT at first presentation. We also suggest careful assessment for respiratory symptoms or physical examination signs of impairment at each clinical encounter. Any abnormality detected, even if only mild or subtle, will prompt further investigation. High resolution CT chest is the preferred method to evaluate lung parenchyma. CT angiography or VQ scans are used to identify thromboembolic phenomena. Ultrasound can be used to help identify pleural effusions and/or aspirate pleural fluid, especially if loculations are present. Pleural fluid analysis often yields an exudative fluid and pleural fluid cultures, along with bronchoscopy, can help exclude infection. In other words, although we cannot advocate wide-scale screening for lung disease for all SLE patients, we do highlight the importance of clinical vigilance in this situation while maintaining a low threshold to proceed with pulmonary evaluation given the potentially devastating manifestations of lung disease that can occur in SLE.

Summary Lung manifestations in SLE are diverse and can range from asymptomatic physiologic and radiographic abnormalities to severe, life-threatening disease. Given that lung disease is highly prevalent and can be associated with significant morbidity, clinicians should be vigilant about identifying possible lung disease in all patients with SLE. Patients with SLE and respiratory symptoms require a thorough evaluation to assess for both intra- and extrathoracic causes and respiratory infection must be rigorously excluded. Although treatment is not evidence-based, the general approach to management includes early detection and prompt initiation of immunosuppressive therapies for SLE-associated lung disease. Importantly, the breakthroughs in our understanding regarding the immunopathology driving lung involvement in SLE promises to lead to expanded and targeted treatment options for patients.

Acknowledgment We also need to acknowledge the previous authors: Chapter updated by Forbess, Wallace, Jefferies, originally written by Chartrand, Fischer, du Bois

References 1. Grigor R, Edmonds J, Lewkonia R, Bresnihan B, Hughes GR. Systemic lupus erythematosus. A prospective analysis. Ann Rheum Dis 1978;37(2):121–8. 2. Murin S, Wiedemann HP, Matthay RA. Pulmonary manifestations of systemic lupus erythematosus. Clin Chest Med 1998;19(4):641–65 viii.

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3. Bertoli AM, Vila LM, Apte M, Fessler BJ, Bastian HM, Reveille JD, et al. Systemic lupus erythematosus in a multiethnic US Cohort LUMINA XLVIII: factors predictive of pulmonary damage. Lupus 2007;16(6):410–7. 4. Haupt HM, Moore GW, Hutchins GM. The lung in systemic lupus erythematosus. Analysis of the pathologic changes in 120 patients. Am J Med 1981;71(5):791–8. 5. Al-Mutairi S, Al-Awadhi A, Raghupathy R, Al-Khawari H, Sada P, Al-Herz A, et al. Lupus patients with pulmonary involvement have a pro-inflammatory cytokines profile. Rheumatol Int 2007;27(7):621– 30. 6. Selman M, King TE, Pardo A, American Thoracic S, European Respiratory S, American College of Chest P. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134(2):136–51. 7. Crystal RG, Fulmer JD, Roberts WC, Moss ML, Line BR, Reynolds HY. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med 1976;85(6):769–88. 8. Kravis TC, Ahmed A, Brown TE, Fulmer JD, Crystal RG. Pathogenic mechanisms in pulmonary fibrosis: collagen-induced migration inhibition factor production and cytotoxicity mediated by lymphocytes. J Clin Invest 1976;58(5):1223–32. 9. Kruger P, Saffarzadeh M, Weber AN, Rieber N, Radsak M, von Bernuth H, et al. Neutrophils: between host defence, immune modulation, and tissue injury. PLoS Pathogens 2015;11(3):e1004651. 10. Carmona-Rivera C, Kaplan MJ. Low-density granulocytes: a distinct class of neutrophils in systemic autoimmunity. Semin Immunopathol 2013;35(4):455–63. 11. Bauer JW, Petri M, Batliwalla FM, Koeuth T, Wilson J, Slattery C, et al. Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation study. Arthritis Rheum 2009;60(10):3098–107. 12. Crow MK. Type I interferon in systemic lupus erythematosus. Curr Topics Microbiol Immun. 2007;316:359–86. 13. Kennedy WP, Maciuca R, Wolslegel K, Tew W, Abbas AR, Chaivorapol C, et al. Association of the interferon signature metric with serological disease manifestations but not global activity scores in multiple cohorts of patients with SLE. Lupus Sci Med 2015;2(1):e000080. 14. Petri M, Singh S, Tesfasyone H, Dedrick R, Fry K, Lal P, et al. Longitudinal expression of type I interferon responsive genes in systemic lupus erythematosus. Lupus 2009;18(11):980–9. 15. Ronnblom L. The importance of the type I interferon system in autoimmunity. Clin Exp Rheum 2016;34(4 Suppl 98):21–4. 16. Trinchieri G. Type I interferon: friend or foe? J Exp Med 2010;207(10):2053–63. 17. Ward PA, Fattahi F, Bosmann M. New insights into molecular mechanisms of immune complex-induced injury in lung. Front Immun 2016;7:86. 18. Roers A, Hiller B, Hornung V. Recognition of endogenous nucleic acids by the innate immune system. Immunity 2016;44(4):739–54. 19. Wu J, Chen ZJ. Innate immune sensing and signaling of cytosolic nucleic acids. Ann Rev Immun 2014;32:461–88. 20. Tanaka Y, Chen ZJ. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci Signal 2012;5(214):ra20. 21. Lee-Kirsch MA. The Type I Interferonopathies. Annu Rev Med 2017;68:297–315.

22. Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: the type I interferonopathies, a conceptual overview. J Exp Med 2016;213(12):2527–38. 23. Watkin LB, Jessen B, Wiszniewski W, Vece TJ, Jan M, Sha Y, et al. COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nature Genet 2015;47(6):654–60. 24. Clarke SL, Pellowe EJ, de Jesus AA, Goldbach-Mansky R, Hilliard TN, Ramanan AV. Interstitial lung disease caused by STING-associated vasculopathy with onset in infancy. Am J Respir Crit Care Med 2016;194(5):639–42. 25. Suwara MI, Green NJ, Borthwick LA, Mann J, Mayer-Barber KD, Barron L, et al. IL-1alpha released from damaged epithelial cells is sufficient and essential to trigger inflammatory responses in human lung fibroblasts. Mucosal Immun 2014;7(3):684–93. 26. Liu YP, Zeng L, Tian A, Bomkamp A, Rivera D, Gutman D, et al. Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3. J Immun 2012;189(9):4630–9. 27. Levinsky RJ, Cameron JS, Soothill JF. Serum immune complexes and disease activity in lupus nephritis. Lancet 1977;1(8011):564–7. 28. Keane MP, Lynch JP3rd. Pleuropulmonary manifestations of systemic lupus erythematosus. Thorax 2000;55(2):159–66. 29. Yoshimi R, Ueda A, Ozato K, Ishigatsubo Y. Clinical and pathological roles of Ro/SSA autoantibody system. Clin Develop Immun 2012;2012:606195. 30. Migliorini P, Baldini C, Rocchi V, Bombardieri S. Anti-Sm and anti-RNP antibodies. Autoimmunity 2005;38(1):47–54. 31. Sabbagh S, Pinal-Fernandez I, Kishi T, Targoff IN, Miller FW, Rider LG, et al. Anti-Ro52 autoantibodies are associated with interstitial lung disease and more severe disease in patients with juvenile myositis. Ann Rheum Dis 2019;78(7):988–95. 32. Jefferies C, Wynne C, Higgs R. Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease? Nat Rev Immun 2011;11(9):617–25. 33. Karp DR, Complement. Complement and systemic lupus erythematosus. Curr Opin Rheum 2005;17(5):538–42. 34. Kavai M. Immune complex clearance by complement receptor type 1 in SLE. Autoimmun Rev 2008;8(2):160–4. 35. Ben Mkaddem S, Benhamou M, Monteiro RC. Understanding Fc receptor involvement in inflammatory diseases: from mechanisms to new therapeutic tools. Front Immunol 2019;10:811. 36. Behnen M, Leschczyk C, Moller S, Batel T, Klinger M, Solbach W, et al. Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcgammaRIIIB and Mac-1. J Immunol 2014;193(4):1954–65. 37. Knight JS, Kaplan MJ. Lupus neutrophils: ’NET’ gain in understanding lupus pathogenesis. Curr Opin Rheum 2012;24(5):441–50. 38. Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 2011;3(73):73ra20. 39. Grailer JJ, Ward PA. Lung inflammation and damage induced by extracellular histones. Inflamm Cell Signal 2014;1(4). 40. Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 2016;22(2):146–53. 41. Saffarzadeh M, Juenemann C, Queisser MA, Lochnit G, Barreto G, Galuska SP, et al. Neutrophil extracellular traps directly induce

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61. Swigris JJ, Fischer A, Gillis J, Meehan RT, Brown KK. Pulmonary and thrombotic manifestations of systemic lupus erythematosus. Chest 2008;133(1):271–80. 62. Matthay RA, Schwarz MI, Petty TL, Stanford RE, Gupta RC, Sahn SA, et al. Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine (Baltimore) 1975;54(5):397–409. 63. Matthay RA, Hudson LD, Petty TL. Acute lupus pneumonitis: response to azathioprine therapy. Chest 1973;63(1):117–20. 64. Isbister JP, Ralston M, Hayes JM, Wright R. Fulminant lupus pneumonitis with acute renal failure and RBC aplasia. Successful management with plasmapheresis and immunosuppression. Arch Internal Med 1981;141(8):1081–3. 65. Barile LA, Jara LJ, Medina-Rodriguez F, Garcia-Figueroa JL, Miranda-Limon JM. Pulmonary hemorrhage in systemic lupus erythematosus. Lupus 1997;6(5):445–8. 66. Santos-Ocampo AS, Mandell BF, Fessler BJ. Alveolar hemorrhage in systemic lupus erythematosus: presentation and management. Chest 2000;118(4):1083–90. 67. Zamora MR, Warner ML, Tuder R, Schwarz MI. Diffuse alveolar hemorrhage and systemic lupus erythematosus. Clinical presentation, histology, survival, and outcome. Medicine (Baltimore) 1997;76(3):192–202. 68. Mintz G, Galindo LF, Fernandez-Diez J, Jimenez FJ, Robles-Saavedra E, Enriquez-Casillas RD. Acute massive pulmonary hemorrhage in systemic lupus erythematosus. J Rheum 1978;5(1):39–50. 69. Erickson RW, Franklin WA, Emlen W. Treatment of hemorrhagic lupus pneumonitis with plasmapheresis. Semin Arthritis Rheum 1994;24(2):114–23. 70. Euler HH, Schroeder JO, Harten P, Zeuner RA, Gutschmidt HJ. Treatment-free remission in severe systemic lupus erythematosus following synchronization of plasmapheresis with subsequent pulse cyclophosphamide. Arthritis and rheumatism. 1994;37(12): 1784–94. 71. Weinrib L, Sharma OP, Quismorio Jr FP. A long-term study of interstitial lung disease in systemic lupus erythematosus. Semin Arthritis Rheum 1990;20(1):48–56. 72. Greene NB, Solinger AM, Baughman RP. Patients with collagen vascular disease and dyspnea.The value of gallium scanning and bronchoalveolar lavage in predicting response to steroid therapy and clinical outcome. Chest 1987;91(5):698–703. 73. Park JH, Kim DS, Park IN, Jang SJ, Kitaichi M, Nicholson AG, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med 2007;175(7):705–11. 74. American Thoracic S, European Respiratory S. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165(2):277–304. 75. Antoniou KM, Margaritopoulos G, Economidou F, Siafakas NM. Pivotal clinical dilemmas in collagen vascular diseases associated with interstitial lung involvement. Eur Respir J 2009;33(4):882–96. 76. Fischer A, Richeldi L. Cross-disciplinary collaboration in connective tissue disease-related lung disease. Semin Respir Crit Care Med 2014;35(2):159–65.

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77. Solomon JJ, Chartrand S, Fischer A. Current approach to connective tissue disease-associated interstitial lung disease. Curr Opin Pulm Med 2014;20(5):449–56. 78. Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006;54(12):3962–70. 79. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354(25):2655–66. 80. Tashkin DP, Elashoff R, Clements PJ, Roth MD, Furst DE, Silver RM, et al. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med 2007;176(10):1026–34. 81. Dheda K, Lalloo UG, Cassim B, Mody GM. Experience with azathioprine in systemic sclerosis associated with interstitial lung disease. Clin Rheumatol 2004;23(4):306–9. 82. Swigris JJ, Olson AL, Fischer A, Lynch DA, Cosgrove GP, Frankel SK, et al. Mycophenolate mofetil is safe, well tolerated, and preserves lung function in patients with connective tissue disease-related interstitial lung disease. Chest 2006;130(1):30–6. 83. Gibson CJ, Edmonds JP, Hughes GR. Diaphragm function and lung involvement in systemic lupus erythematosus. Am J Med 1977;63(6):926–32. 84. Munoz-Rodriguez FJ, Font J, Badia JR, Miret C, Barbera JA, Cervera R, et al. Shrinking lungs syndrome in systemic lupus erythematosus: improvement with inhaled beta-agonist therapy. Lupus 1997;6(4):412–4. 85. Van Veen S, Peeters AJ, Sterk PJ, Breedveld FC. The “shrinking lung syndrome” in SLE, treatment with theophylline. Clin Rheumatol 1993;12(4):462–5. 86. Oud KT, Bresser P, ten Berge RJ, Jonkers RE. The shrinking lung syndrome in systemic lupus erythematosus: improvement with corticosteroid therapy. Lupus 2005;14(12):959–63. 87. Pope J. An update in pulmonary hypertension in systemic lupus erythematosus - do we need to know about it? Lupus 2008;17(4):274–7. 88. Prabu A, Patel K, Yee CS, Nightingale P, Situnayake RD, Thickett DR, et al. Prevalence and risk factors for pulmonary arterial hypertension in patients with lupus. Rheumatology 2009;48(12):1506–11. 89. Gonzalez-Lopez L, Cardona-Munoz EG, Celis A, Garcia-de la Torre I, Orozco-Barocio G, Salazar-Paramo M, et al. Therapy with intermittent pulse cyclophosphamide for pulmonary hypertension associated with systemic lupus erythematosus. Lupus 2004;13(2):105–12. 90. Sanchez O, Sitbon O, Jais X, Simonneau G, Humbert M. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest 2006;130(1):182–9.

91. Condliffe R, Kiely DG, Peacock AJ, Corris PA, Gibbs JS, Vrapi F, et al. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med 2009;179(2):151–7. 92. Somers E, Magder LS, Petri M. Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of patients with systemic lupus erythematosus. J Rheum 2002;29(12):2531–6. 93. Wahl DG, Guillemin F, de Maistre E, Perret C, Lecompte T, Thibaut G. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus--a meta-analysis. Lupus 1997;6(5):467–73. 94. Wu H, Birmingham DJ, Rovin B, Hackshaw KV, Haddad N, Haden D, et al. D-dimer level and the risk for thrombosis in systemic lupus erythematosus. Clin J Am Soc Nephrol 2008;3(6):1628–36. 95. Cohen D, Berger SP, Steup-Beekman GM, Bloemenkamp KW, Bajema IM. Diagnosis and management of the antiphospholipid syndrome. BMJ 2010;340:c2541. 96. Abramson SB, Dobro J, Eberle MA, Benton M, Reibman J, Epstein H, et al. Acute reversible hypoxemia in systemic lupus erythematosus. Ann Intern Med 1991;114(11):941–7. 97. Martinez-Taboada VM, Blanco R, Armona J, Fernandez-Sueiro JL, Rodriguez-Valverde V. Acute reversible hypoxemia in systemic lupus erythematosus: a new syndrome or an index of disease activity? Lupus 1995;4(4):259–62. 98. Niklas K, Niklas A, Mularek-Kubzdela T, Puszczewicz M. Prevalence of pulmonary hypertension in patients with systemic sclerosis and mixed connective tissue disease. Medicine (Baltimore) 2018;97(28):e11437. 99. Kreider M, Highland K. Pulmonary involvement in Sjogren syndrome. Semin Respir Crit Care Med 2014;35(2):255–64. 100. de Jesus AA, Goldbach-Mansky R. Newly recognized Mendelian disorders with rheumatic manifestations. Curr Opin Rheum 2015;27(5):511–9. 101. Tsui JL, Estrada OA, Deng Z, Wang KM, Law CS, Elicker BM, et al. Analysis of pulmonary features and treatment approaches in the COPA syndrome. ERJ Open Res 2018;4(2). 102. Taveira-DaSilva AM, Markello TC, Kleiner DE, Jones AM, Groden C, Macnamara E, et al. Expanding the phenotype of COPA syndrome: a kindred with typical and atypical features. J Med Genet 2018. 103. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GAM, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med 2014;371(6):507–18. 104. Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest 2018;128(7):3041–52.

Chapter 46

Gastrointestinal, hepatic, and pancreatic disorders in systemic lupus erythematosus Chi Chiu Mok Department of Medicine, Tuen Mun Hospital, New Territories, Hong Kong

Introduction Gastrointestinal (GI) manifestations of systemic lupus erythematosus (SLE) are protean (Table 46.1). Clinical features are noncharacteristic and must be distinguished from infective, thrombotic, therapy-related, and nonSLE causes. Appropriate imaging investigations, endoscopic procedures, and biopsies are indicated. Early recognition and intervention help reduce mortality and morbidity. The prevalence of GI lupus varies widely. Oral symptoms and mucosal lesions are most frequent, whereas acute abdominal pain is most sinister. GI manifestations are likely to be underestimated in SLE because some of these features are indistinct and not gauged by disease activity indices. In the literature, GI lupus appears to be more common in Asian patients.1

The gastrointestinal tract in SLE Buccal cavity Oral ulceration is common in SLE.2 Typically, these ulcers are superficial, painless, and mostly found on the hard palate, buccal cavity, and vermiform border. Oral ulceration is a marker for disease activity3 and remains one of the 2012 revised classification criteria for SLE by the SLICC group of investigators.4 However, painful oral ulcers and mucositis in SLE may be secondary to herpes simplex and candida infection, as well as treatment with cyclophosphamide and methotrexate. Chronic discoid lupus erythematosus (DLE) may develop in the oral cavity.5 It is frequently found in the buccal mucosa

Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00046-5 Copyright © 2020 Elsevier Inc. All rights reserved.

but the palate and tongue may also be involved. Lesion usually begins as a painless, erythematosus patch, and slowly matures into a chronic plaque-like lesion. Mucosal DLE lesions can be severely painful and may be confused with lichen planus or leukoplakia. Tissue biopsy may show lupus-specific histopathology. Topical corticosteroids and the antimalarials are the main treatment but intralesional corticosteroid, azathioprine, thalidomide, dapsone, retinoids, and mycophenolate mofetil (MMF) may be required in refractory cases.5 Secondary Sjogren’s syndrome is reported in 9.2% of SLE patients.6 Dry mouth can be alleviated by air humidification, stimulation of salivary flow by sugarless mints or chewing gums, and artificial saliva preparations. The muscarinic receptor agonists such as pilocarpine and cevimeline may also be considered. SLE patients are prone to have poor dental health because of multiple factors that include mucosal ulceration, reduced salivary flow, bleeding diathesis, and medications such as corticosteroids (gingival infection), nonsteroidal antiinflammatory drugs (NSAIDs) (platelet dysfunction), cyclosporin A (gingivitis, gingival hypertrophy), methotrexate (stomatitis and mucositis), antiepileptic agents (gum hypertrophy), and tricyclic antidepressants (worsen sicca). Case-control studies report a higher incidence of aphthous ulcers, erythema, dental plaques, gingival overgrowth and bleeding, and temporomandibular joint dysfunction in SLE patients.7 Because of the association of periodontal disease with atherosclerosis,8 impaired dental health in SLE patients may further aggravate their cardiovascular risk. SLE patients should receive regular dental checkups and treatment of periodontitis.

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TABLE 46.1 Gastrointestinal and hepatic manifestations of lupus. Oral cavity

Oral ulceration Mucosal discoid lupus Sicca symptoms Chronic periodontitis

Esophagus

Hypomotility Esophageal reflux/ulceration

Stomach

Gastritis, gastric ulceration Pernicious anemia Gastric antral vascular ectasia

Small bowel and peritoneum

Intestinal vasculitis (enteritis) Mesenteric insufficiency Intestinal pseudo-obstruction Protein-losing gastroenteropathy Peritonitis/ascites (serositis) Eosinophilic enteritis Malabsorption

Large bowel

Colitis Inflammatory bowel diseases Collagenous colitis

Liver

Subclinical hepatitis Autoimmune hepatitis (lupus hepatitis) Hemangioma Nodular regenerative hyperplasia Hepatic vein thrombosis Veno-occlusive disease Hepatic arteries and infarction

Biliary tract

Acalculous cholecystitis Primary biliary cirrhosis Autoimmune cholangiopathy Sclerosing cholangitis

Pancreas

Pancreatitis

Esophagus Dysphagia and heartburn in SLE patients may be caused by mucosal dryness, esophageal hypomotility, esophagitis, and esophageal ulceration. Manometry studies reveal functional abnormalities of the esophagus (aperistalsis or hypoperistalsis) in 10%–32% of SLE patients, usually in the upper third.9 Skeletal muscle fiber atrophy, inflammation of the esophageal muscles, and ischemic or vasculitic damage of the Auerbach’s plexus have been postulated to be the mechanisms of impaired esophageal mobility. Esophageal ulceration occurs in 3%–5% of SLE patients2 and is often caused by gastroesophageal reflux

or infections such as Candidia, herpes simplex, and cytomegalovirus (CMV). Vasculitis leading to ulceration is rare. Medications such as the NSAIDs and the oral bisphosphonates are occasionally associated with esophagitis and bleeding esophageal ulcers. Esophageal symptoms in SLE patients are treated with high-dose H2 blockers, proton pump inhibitors, and prokinetic agents.

Stomach Gastritis, gastric erosion, and ulceration in SLE patients may result from treatment with high-dose corticosteroids, NSAIDs, and the bisphosphonates. CMV infection rarely causes gastritis and gastric ulceration that may lead to bleeding and perforation.10 Perforated peptic ulcer is diagnosed in 6%–8% of SLE patients who present with acute abdomen.11 Vasculitis of the gastric mucosa causing ulceration and bleeding is exceedingly rare. Recently, a link between Helicobacter pylori infection of the stomach and autoimmunity has been proposed.12 However, the prevalence of antibodies to H. pylori is not higher in SLE than matched controls and the role of H. pylori infection in SLE remains to be elucidated. Functional upper GI symptoms such as dyspepsia, heartburn, and bloating is fairly prevalent in SLE.13 Gastric emptying is altered in SLE patients and correlated with upper GI symptom index along with stomach wall thickness.14 SLE accounts for 3% of nondiabetic patients diagnosed with “gastroparesis” according to a large database study in the United States.15 Gastric antral vascular ectasia (GAVE) is a rare vascular malformation in the stomach that may cause acute or chronic bleeding. The characteristic endoscopic appearance is a collection of red spots of ectatic vessels arranged in stripes along the antral rugal folds. GAVE is mostly found in scleroderma but has been reported in SLE.16 Endoscopic treatment or open surgery is indicated for persistent bleeding. Pernicious anemia has been reported in 3% of patients with SLE, characterized by low serum cobalamin level, macrocytic anemia, and the presence of antibody against intrinsic factor.17 A recent study showed a prevalence of antigastric parietal cell antibody in 3.6% of SLE patients, but clinical pernicious anemia developed only in 0.5% of patients.18 Finally, a recent metaanalysis reported an increased risk of esophageal, gastric and hepatobiliary cancers by 0.31 to 1.37 fold in SLE patients compared to the general population.19

Small intestine Mesenteric/Intestinal vasculitis/lupus enteritis The prevalence of intestinal vasculitis in SLE patients ranges from 0.2% to 9.7%20,21 and among those who present with

Gastrointestinal, hepatic, and pancreatic disorders in systemic lupus erythematosus Chapter | 46

acute abdominal pain, intestinal vasculitis is diagnosed in 29%–65% of patients.11,22 This manifestation is more commonly observed in Asian patients. Symptoms of mesenteric vasculitis range from mild abdominal bloating with a variable degree of nausea, vomiting, fever, and loose stool to intestinal perforation which manifests as severe diffuse abdominal pain, abdominal distension, rebound tenderness, and paralytic ileus. In serious cases, mucosal ulceration leading to extensive GI bleeding, intussusception, and bowel gangrene may develop.1,2,23 Serological and clinical disease activity in other organs is usually present. An accurate and timely diagnosis of mesenteric vasculitis is essential. Other SLE and nonSLE-related causes of abdominal pain must be excluded. Plain radiograph of the abdomen is insensitive for diagnosing lupus mesenteric vasculitis at its early stage. In established disease, X-rays may demonstrate pseudo-obstruction, ileus, or dilatation of the bowel loops, effacement of the mucosal folds, submucosal edema as a result of bowel ischemia (thumbprinting appearance), and uncommonly pneumatosis cystoids intestinalis (gas cysts within the submucosa or subserosa of the intestine).1 Intraabdominal free gas may be seen after intestinal perforation. Computer tomography (CT) scan of the abdomen is the most useful diagnostic tool for mesenteric vasculitis.1,24 Apart from excluding other intraabdominal pathologies such as abscesses and collections, cholecystitis, and pancreatitis with or without pseudocyst formation, a contrast CT scan may demonstrate focal or diffuse bowel wall thickening with double halo or target sign (enhancing outer and inner rim with hypoattenuation in the center), prominent mesenteric vessels with palisade pattern or comb-like appearance supplying focally or diffusely dilated bowel loops, and ascites.1,24,25 Segmental or multifocal involvement of the small and large bowel loops is highly suggestive of ischemic changes due to vasculitis. Early CT findings of lupus enteritis are reversible on immunosuppressive treatment.25 Besides, CT angiography may help in differentiating lupus enteritis with thrombosis of the major mesenteric vessels. Upper and lower endoscopies in lupus enteritis may show signs of ischemia and mucosal ulceration. The typical histopathological findings are usually observed in the arterioles and venules of the submucosa of the bowel wall rather than the medium-sized mesenteric arteries. Vasculitic lesions tend to be segmental and focal. Immunohistochemical staining of the tunica adventitia and media may reveal immune complex, C3 complement, and fibrinogen deposition. Fibrinoid necrosis, intraluminal thrombosis of affected vessels, acute, or chronic inflammatory infiltrates consisting of lymphocytes, plasma cells, histiocytes, and neutrophils may also be demonstrated.26 Although any vessels can be involved, the territory of the superior mesenteric artery (jejunum and ileum) is most

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frequently affected by lupus enteritis.1,24 The pathogenesis of lupus enteritis remains elusive. Immune complex-mediated vasculitis with complement activation that induces inflammation, microvascular injury, ischemia, and edema of the bowel wall, leading to increase in vascular permeability, is thought to be the mechanism.27 The mortality of lupus enteritis is high, depending on the extent of vascular involvement and the rapidity of diagnosis and treatment.1,23 Aggressive immunosuppressive therapy with high-dose intravenous pulse methylprednisolone should be given early. Patients should be monitored closely and surgical intervention is indicated when a rapid clinical response is not achieved or there is clinical and radiological suspicion of bowel perforation. Lupus enteritis may recur in more than half of patients, especially in those with a bowel wall thickness of >9 mm at presentation.28 Intravenous pulse cyclophosphamide has been used with success in refractory lupus enteritis21 and reducing recurrence.28

Mesenteric insufficiency Atherosclerosis of the mesenteric arteries should be considered in SLE patients who present with chronic intermittent abdominal pain (“intestinal angina”). Symptoms usually start in the postprandial state and persist for several hours. Symptoms may worsen over time and weight loss may develop for fear of eating. Concomitant atherosclerotic disease in the coronary and carotid vessels supports the diagnosis. SLE patients with long-standing disease, traditional vascular risk factors, renal insufficiency, persistent proteinuria, antiphospholipid antibodies, and chronic corticosteroid therapy are at risk. The diagnosis of chronic mesenteric insufficiency relies on a high index of suspicion. Conventional angiography is the gold standard imaging procedure. Digital subtraction angiography and magnetic resonance angiography are adjunctive diagnostic modalities.29 Acute mesenteric ischemia can result from thrombosis of the mesenteric arterial or venous systems. Classically, abdominal pain is persistent and disproportionately severe relative to physical signs. Bowel infarction and perforation may manifest as acute surgical abdomen, fever, bloody diarrhea, melena, and hypotension. SLE patients with underlying chronic mesenteric insufficiency or the antiphospholipid antibodies are prone to acute intestinal ischemia, which may be precipitated by hypoperfusion states. Surgical revascularization and percutaneous transluminal mesenteric angioplasty with or without a stent are treatment options for patients with chronic mesenteric ischemia.29 Acute mesenteric thrombosis causing bowel gangrene should be treated by surgical exploration and embolectomy. Long-term anticoagulation should be given to patients who qualify with the antiphospholipid syndrome.

442 PART | IV  Clinical aspects of the disease

Intestinal pseudo-obstruction Intestinal pseudo-obstruction (IPO) is a syndrome characterized by impaired intestinal motility leading to features of a mechanical bowel obstruction. This condition is rare but more commonly reported in Asian patients with SLE. IPO may be the initial presentation of SLE and usually occurs in the setting of an active lupus.1,2,30 The small bowel is more commonly affected than the large bowel. Common presenting symptoms of IPO are subacute onset of abdominal pain, nausea, vomiting, abdominal distension, and constipation. The abdomen is diffusely tender with sluggish or absent bowel sounds. Rebound tenderness is usually absent unless there is bowel perforation. X-ray and CT examination may demonstrate multiple dilated bowel loops with fluid level and thickened bowel wall (Fig. 46.1). Mechanical causes for intestinal obstruction should be excluded, preferably by nonsurgical means but laparotomy may be necessary in some patients. Manometry motility studies in patients with IPO may demonstrate esophageal aperistalsis and intestinal hypomotility.31 Interestingly, more than two-thirds of the reported cases of SLE-related IPO had concomitant ureterohydronephrosis and contracted/thickened urinary bladder, with the majority demonstrating histological features of chronic interstitial cystitis.1,2,30

The coexistence of ureterohydronephrosis in many patients with SLE-related IPO and dilatation of the biliary tract (megacholedochus) in occasional patients indicates that the basic pathophysiology is dysmotility of the intestinal musculature. The association with autoimmune cystitis and the demonstration of antibodies against proliferating cell nuclear antigen in some patients32 suggest that immune complex-mediated vasculitis may be a mechanism for inflammation and subsequent damage of the visceral smooth muscles, leading to atrophy, fibrosis, and loss of function of the bowel wall. Other postulated mechanisms for visceral smooth muscle dysfunction include a primary myopathy of the bowel musculature, neuropathy of the enteric nerves or the visceral autonomic nervous system, and direct cytotoxicity of antibodies directed against the smooth muscle of the gut wall. SLE-related IPO often responds to high-dose corticosteroids.1,2,23 Additional immunosuppressive agents such as azathioprine, cyclosporin A, and cyclophosphamide have been used with success in some reports.33,34 Other adjunctive therapies for IPO are nasogastric tube insertion, intravenous fluid, parental nutrition, broad spectrum antibiotics, and prokinetic agents such as erythromycin, metoclopramide, and octreotide (a long-acting somatostatin analog).34 Early recognition of IPO in SLE patients and timely initiation of immunosuppressive therapy are important because the condition is potentially reversible with nonsurgical measures. However, some patients may have a relapsing course despite maintenance immunosuppressive treatment.

Malabsorption and celiac disease Malabsorption is reported to occur in 2/21 (9.5%) patients with SLE by standard screening tests.35 In one of these patients, histologic examination revealed flattened and deformed villi with an inflammatory infiltrate. Up to 23% of patients with SLE have been tested positive for IgA or IgM antigliadin antibodies36 and 5.7% of patients have positive IgA antiendomysium antibodies.18 However, biopsy proven celiac disease (gluten-sensitive enteropathy) in SLE patients is extremely rare.37

Protein-losing gastroenteropathy

FIGURE 46.1  An SLE patient presented with intestinal pseudo-obstruction. Plain radiograph of the abdomen shows multiple dilated bowel loops with fluid level.

Protein-losing gastroenteropathy (PLGE) is a condition characterized by hypoalbuminemia secondary to loss of protein from the GI tract. It is usually identified by an elevated clearance of stool α1-antitrypsin or the technetium99m-labeled human serum albumin scan. A variety of pathologies from the stomach down to the colon may be responsible for protein loss. Significant proteinuria should be ruled out. Investigations into the causes of PLGE such as gastrointestinal lymphoma, malabsorption state, bacterial overgrowth, inflammatory bowel disease, chronic infection, polyposis, and lymphatic obstruction are essential.

Gastrointestinal, hepatic, and pancreatic disorders in systemic lupus erythematosus Chapter | 46

Endoscopic examination with mucosal biopsies, barium studies, radiologic examinations, and absorption tests are required. PLGE is an uncommon manifestation of SLE, with an estimated point prevalence of 1.9% to 3.2%.2,38,39 Twothirds of the reported cases in the literature are in Asian patients and in 49% of patients; PLGE is the presenting feature of SLE.40 Disease activity of SLE in other systems is usually present. The most common presenting symptoms of PLGE are generalized or dependent edema (80%), and abdominal symptoms such as pain (27%), nonbloody diarrhea (46%), nausea (22%), and vomiting (19%). Ascites (48%), pleural effusion (38%), and pericardial effusion (21%) related to hypoalbuminemia (96%) may also be present. Protein leakage occurs more frequently from the small bowel (84%) than the large bowel (29%). Investigation findings in SLE-related PGLE are often nonspecific. The most common endoscopic appearance is mucosal edema (50%). Biopsy is either unremarkable or reveals thickened mucosa, submucosal edema, villous atrophy, dilated lacteals, or inflammatory infiltrates.41 Definite lymphangiectasia, vasculitis, or C3 deposition in the capillary walls of the lamina propriae of villi is uncommon. Contrast CT of the abdomen may show ascites, bowel wall thickening, and edema. The exact pathogenesis of PLGE is unknown. Mucosal disruption, increase in mucosal capillary permeability as a result of complement- or cytokine-mediated damage, mesenteric venulitis, and dilated/ruptured mucosal lacteals have been postulated.38 PLGE in SLE often responds to corticosteroid treatment. No controlled trials are available regarding the additional benefit of azathioprine. Our own experience shows that an initial regimen of high-dose prednisolone and azathioprine is well tolerated and effective in most patients with SLErelated PLGE.40 Relapse is uncommon (6%) with low-dose prednisolone and azathioprine maintenance treatment.38 Intravenous pulse cyclophosphamide, cyclosporine A, and azathioprine may be considered in patients with refractory disease. Albumin infusion, diuretics, and nutritional support may help to reduce symptoms of edema. Prophylaxis for thromboembolic complications should be considered in patients with severe and persistent protein loss, especially if the antiphospholipid antibodies are present.

Infective and eosinophilic enteritis Infective enteritis should be considered in SLE patients presenting with abdominal symptoms. Bacterial enteritis is the most common, with nontyphoidal Salmonella infection being most frequently reported. Campylobacter jejuni infection and CMV enteritis may lead to ileal perforation. Eosinophilic gastroenteritis is a rare condition characterized by eosinophilic infiltration of the deep layers of the

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intestinal wall,23 leading to abdominal pain, nausea, vomiting, and diarrhea. Peripheral eosinophilia is usually present. Four cases of eosinophilic enteritis have been reported in patients with SLE. High-dose prednisolone treatment is usually effective and refractory cases may respond to intravenous immunoglobulin.

Ascites and peritonitis Acute peritonitis in SLE may be caused by mesenteric vasculitis, bowel infarction, perforated viscera, pancreatitis, intraabdominal infection, or serositis related to active SLE (lupus peritonitis). Subacute or chronic peritoneal effusion can result from lupus peritonitis, any causes of hypoalbuminemia, right heart failure, hepatic venous thrombosis, malignancy, and more indolent infections such as tuberculosis. About 30% of serositis episodes in patients with SLE are caused by inflammatory peritonitis.42 Abdominal pain is the usual presenting symptom, which may be severe enough to mimic acute surgical abdomen that leads to negative laparotomy. On the other hand, physical signs of peritonitis or ascites may not necessarily be present in mild cases of lupus peritonitis. Lupus peritonitis often responds rapidly to moderate doses of corticosteroids. In patients with massive or refractory ascites, intravenous pulse methylprednisolone and additional immunosuppressive agents such as azathioprine, cyclosporin A, and cyclophosphamide may be needed.

Large intestine Lupus colitis and inflammatory bowel disease The large bowel may occasionally be involved in lupus enteritis, leading to colitis and perforation.11 Active SLE in other organs is often present and the mortality is high. Crohn’s disease and ulcerative colitis (UC) are rarely reported in SLE patients. The prevalence of UC in SLE patients is around 0.4%.43 Clinically and pathologically, lupus colitis may be indistinguishable from UC. Symptoms include lower abdominal discomfort, per rectal bleeding, and persistent diarrhea that may be bloody. Cases of Crohn’s disease presenting with persistent GI bleeding have been described in patients with SLE.44 Recently, a large database study reported an significantly increased prevalence of Crohn’s disease (odds ratio 2.23), but not UC, in patients with SLE compared to matched controls.45

Infective and collagenous colitis Colonic infections should be considered in SLE patients presenting with lower GI symptoms. CMV and amoebic colitis have been reported in patients with SLE.2 Collagenous colitis is a disorder characterized by colonic intraepithelial lymphocytosis, expansion of the lamina propria with acute

444 PART | IV  Clinical aspects of the disease

and chronic inflammatory cells, and a thickened subepithelial collagen band. Patients usually present with chronic watery diarrhea despite normal radiologic and endoscopic findings. Collagenous colitis has been reported in discoid and systemic lupus.2

The liver in SLE Subclinical liver disease Liver function abnormalities are common in patients with SLE. Multiple factors such as the use of aspirin, NSAIDs, azathioprine, and methotrexate, fatty infiltration of liver as a result of corticosteroid treatment, diabetes mellitus, or obesity as well as viral hepatitis and alcoholism may contribute. Persistent and severe liver function abnormalities require further investigations such as ultrasonography and liver biopsy to delineate the underlying causes. Elevation of liver enzymes occurs in 23%–60% of SLE patients during the course of the illness but significant liver disease is not common.46–48 No identifiable cause other than SLE itself is found in around one-third of patients.48 In 80% of cases of persistent “unexplained” liver function derangement, the serial change in liver transaminases correlates with SLE activity.48 Liver biopsy in SLE patients commonly reveals steatotic hepatitis, portal inflammatory infiltrates, and chronic active hepatitis.46,47 Other reported pathologies include chronic granulomatous hepatitis, centrilobular necrosis, chronic persistent hepatitis, and microabscesses (6%).

Autoimmune hepatitis Autoimmune hepatitis (AIH) is characterized histologically by portal and periportal lymphoplasmacytic infiltration and extension of the infiltrates into the lobule (interface hepatitis) and hepatocyte rosette formation (Fig. 46.2). As the disease progresses, the evidence of hepatic injury such as bridging necrosis, panlobular necrosis, multilobular necrosis, and cirrhosis may develop. Hypergammaglobulinemia and a variety of autoantibodies that direct against hepatic antigens or liver–kidney microsomal proteins such as ANA, antismooth muscle antibodies (SMA), and antiliver/kidney microsomal (LKM) antibodies may be present. AIH is classified into three types: (1) Type I AIH (the classical “lupoid hepatitis” described in the 1950s) is the most common form worldwide and is associated with ANA and/or SMA; (2) Type II AIH is associated with antiLKM1 antibody; and (3) Type III AIH is associated with antisoluble liver/liver pancreas antigen (SLA/LP) antibodies. Patients with AIH commonly present with insidious onset of nonspecific symptoms such as fatigue, malaise, and anorexia. Liver enlargement, jaundice, and ascites may be present in severe cases. AIH is associated with SLE-like

FIGURE 46.2  Liver biopsy in an SLE patient showing active interface hepatitis with prominent portal lymphoplasmacytic infiltrates (H&E stain).

features such as arthritis, serositis, thrombocytopenia, hypergammaglobulinemia, and positive ANA and antidsDNA,49 but only 10%–23% of AIH patients fulfill the ACR criteria for SLE.50 The incidence of coexisting AIH in SLE patients is unclear as not all patients will undergo liver biopsy for liver derangement and mild AIH may respond completely to corticosteroids. Differentiation between AIH/SLE overlap and SLE-associated hepatitis can be difficult in the absence of histological information. Lupus-associated hepatitis runs a more benign course with predominant lobular involvement and mild lobular inflammation without piecemeal necrosis on liver histology.50 Antiribosomal P antibody is more commonly found in SLE patients with hepatitis than in those without.51 Features of lupus-associated hepatitis and SLE/AIH overlap are contrasted in Table 46.2. High-dose prednisone alone or a lower dose of prednisone in conjunction with azathioprine is the main stay of treatment for AIH. Remission can be achieved in the majority of patients in the first 3 years of diagnosis. The use of azathioprine may reduce relapses and is corticosteroid sparing. Maintenance therapy with low-dose prednisone and azathioprine is preferred for patients with multiple relapses. MMF, cyclosporin A, or tacrolimus is reserved for refractory cases of AIH.

Viral and drug-induced hepatitis The prevalence of chronic hepatitis B virus infection does not seem to be higher in patients with SLE as compared to the age- and sex-matched general population, even in endemic areas.52 Some studies have reported a higher prevalence of chronic hepatitis C (HCV) infection in SLE patients compared to healthy controls.53 SLE patients with HCV infection were less likely to have cutaneous disease

Gastrointestinal, hepatic, and pancreatic disorders in systemic lupus erythematosus Chapter | 46

445

TABLE 46.2 Main features of lupus-associated hepatitis and idiopathic autoimmune hepatitis (AIH). Features

SLE-associated hepatitis

AIH

Histology

Lobular, rarely periportal

Portal and periportal, piecemeal necrosis

ACR criteria for SLE

100%

10%–23%

Elevated serum IgG

Common

Common

Complements (C3/4)

Normal or depressed

Often normal unless liver failure

ANA

>99%

80% in type I AIH

Anti-dsDNA

60%–70%

20%–50%, low titer

Anti-Ro

30%–60%

11%–14%

Anti-ribosomal P

70%

1000 g, (3) daily dose >400 mg/day (>6.5 mg/ kg ideal body weight for short individuals) for HCQ and >250 mg/day, (4) renal or hepatic dysfunction, (5) elderly, and (6) preexisting retinal disease or maculopathy. The risk factors for chloroquine are similar but with dosing thresholds set at total dose >460 g and daily dose of >250 mg/ day (>3.0 mg/kg/day for short individuals). It is recognized, however, that retinal toxicity is occasionally seen in apparently low-risk individuals.

Conclusion Ocular manifestations of SLE, although infrequently severe, are important both in terms of their direct effects (pain, loss of vision, etc.) and in the information they provide as to overall disease activity. Severe retinal vaso-occlusive disease and optic neuropathy are strongly associated with active CNS involvement. As control of systemic disease activity has improved, severe ocular complications have become uncommon. SLE is, however, still a potentially blinding condition. Any visual symptoms require urgent ophthalmic assessment to identify sight-threatening disease requiring systemic therapy.

References 1. Papagiannuli E, Rhodes B, Wallace G, et al. Systemic lupus erythematosus: an update for ophthalmologists. Surv Ophthalmol 2016;61(1):65–82. 2. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271. 3. Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64(8):2677–86.

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4. Jabs DA, et al. Severe retinal vaso-occlusive disease in systemic lupus erythematous. Arch Ophthalmol 1986;104(4):558–63. 5. Isenberg DA, et al. BILAG 2004. Development and initial validation of an updated version of the British Isles Lupus Assessment Group's disease activity index for patients with systemic lupus erythematosus. Rheumatology (Oxford) 2005;44(7):902–6. 6. Jensen JL, et al. Oral and ocular sicca symptoms and findings are prevalent in systemic lupus erythematosus. J Oral Pathol Med 1999;28(7):317–22. 7. Spaeth GL. Corneal staining in systemic lupus erythematosus. N Engl J Med 1967;276(21):1168–71. 8. Messmer EM, Foster CS. Vasculitic peripheral ulcerative keratitis. Surv Ophthalmol 1999;43:379–96. 9. Yazici AT, Kara Yuksel K, Altinkaynak O, et al. The biomechanical properties of the cornea in patients with systemic lupus erythematosus. Eye 2011;28(8):1005–9. 10. Foster CS. Immunosuppressive therapy for external ocular inflammatory disease. Ophthalmology 1980;87(2):140–50. 11. Hickman RA, Denniston AK, Yee CS, et al. Bilateral retinal vasculitis in a patient with systemic lupus erythematosus and its remission with rituximab therapy. Lupus 2010;19(3):327–9. 12. Huey C, et al. Discoid lupus erythematosus of the eyelids. Ophthalmology 1983;90(12):1389–98. 13. Gupta T, Beaconsfield M, Rose GE, et al. Discoid lupus erythematosus of the periorbita: clinical dilemmas, diagnostic delays. Eye 2012;26(4):609–12. 14. Grimson BS, Simons KB. Orbital inflammation, myositis, and systemic lupus erythematosus. Arch Ophthalmol 1983;101(5):736–8. 15. Stavrou P, et al. Acute ocular ischaemia and orbital inflammation associated with systemic lupus erythematosus. Br J Ophthalmol 2002;86(4):474–5. 16. Stafford-Brady FJ, et al. Lupus retinopathy. Patterns, associations, and prognosis. Arthritis Rheum 1988;31(9):1105–10. 17. Ushiyama O, et al. Retinal disease in patients with systemic lupus erythematosus. Ann Rheum Dis 2000;59(9):705–8. 18. Asherson RA, et al. Antiphospholipid antibodies: a risk factor for occlusive ocular vascular disease in systemic lupus erythematosus and the ‘primary’ antiphospholipid syndrome. Ann Rheum Dis 1989;48(5):358–61. 19. Graham EM, et al. Cerebral and retinal vascular changes in systemic lupus erythematosus. Ophthalmology 1985;92(3):444–8. 20. Nag TC, Wadhwa S. Histopathological changes in the eyes in systemic lupus erythematosus: an electron microscope and immunohistochemical study. Histol Histopathol 2005;20(2):373–82. 21. Yen YC, Weng SF, Chen HA, et al. Risk of retinal vein occlusion in patients with systemic lupus erythematosus: a population-based cohort study. Br J Ophthalmol 2013;97(9):1192–6. 22. Sekimoto M, et al. Pseudoretinitis pigmentosa in patients with systemic lupus erythematosus. Ann Ophthalmol 1993;25(7):264–6.

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23. Chan WM, et al. Bilateral retinal detachment in a young woman. Lancet 2003;361(9374):2044. 24. Cunningham Jr ET, Alfred PR, Irvine AR. Central serous chorioretinopathy in patients with systemic lupus erythematosus. Ophthalmology 1996;103(12):2081–90. 25. Jabs DA, et al. Choroidopathy in systemic lupus erythematosus. Arch Ophthalmol 1988;106(2):230–4. 26. Jabs DA, et al. Optic neuropathy in systemic lupus erythematosus. Arch Ophthalmol 1986;104(4):564–8. 27. Keane JR. Eye movement abnormalities in systemic lupus erythematosus. Arch Neurol 1995;52(12):1145–9. 28. McGalliard J, Bell AL. Acquired Brown's syndrome in systemic lupus erythematosus: another ocular manifestation. Clin Rheumatol 1990;9(3):399–400. 29. Fonseca P, Manno RLMN. Bilateral sequential trochleitis as the pesenting feature of systemic lupus erythematosus. J Neuroophthalmol 2013;33(1):74–6. 30. Galindo M, Pablos JL, Gomez-Reino JJ. Internuclear ophthalmoplegia in systemic lupus erythematosus. Semin Arthritis Rheum 1998;28(3):179–86. 31. Yigit A, et al. The one-and-a-half syndrome in systemic lupus erythematosus. J Neuroophthalmol 1996;16(4):274–6. 32. Brandt KD, Lessell S, Cohen AS. Cerebral disorders of vision in systemic lupus erythematosus. Ann Intern Med 1975;83(2):163–9. 33. Kim JM, Kwok SK, Ju JH, Kim HY, Park SH. Idiopathic intracranial hypertension as a significant cause of intractable headache in patients with systemic lupus erythematosus: a 15-year experience. Lupus April 2012;21(5):542–7. 34. Damato E, Chilov M, Lee R. et al. Plasma exchange and rituximab in the management of acute occlusive retinal vasculopathy secondary to systemic lupus erythematosus. Ocul Immunol Inflamm 2011; 19(5):379–81. 35. Rosenbaum JT, Simpson J, Neuwelt CM. Successful treatment of optic neuropathy in association with systemic lupus erythematosus using intravenous cyclophosphamide. Br J Ophthalmol 1997;81(2):130–2. 36. Hobbs HE, Sorsby A, Freedman A. Retinopathy following chloroquine therapy. Lancet 1959;2:478–80. 37. Marmor MF, Kellner U, Lai TY, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2016;123(6):1386–94. 38. Yusuf IH, Foot B, Galloway J, et al. The Royal College of Ophthalmologists recommendations on screening for hydroxychloroquineand chloroquine users in the United Kingdom: executive summary. Eye (Lond) 2018;32(7):1168–73. 39. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol 2014;132(12):1453–60.

Chapter 52

Fertility and pregnancy in systemic lupus erythematosus Bonnie L. Bermasa and Lisa R. Sammaritanob a

UTSouthwestern Medical Center, Dallas, TX, United States; bHospital for Special Surgery, New York, NY, United States

Systemic lupus erythematosus—A manual Systemic lupus erythematosus (SLE) is a disease of reproductive aged women; as a result, family planning issues such as fertility and pregnancy are an important component of the management of SLE patients. For many years, women who had systemic lupus erythematosus were counseled against becoming pregnant. This directive was informed by the belief that the hormonal and immunologic changes of pregnancy would exacerbate disease activity and contribute to maternal morbidity and poor fetal outcomes. However, with the improved management of SLE, this general prohibition against pregnancy in SLE has become obsolete. While SLE pregnancies are frequently complicated due to higher risk for disease exacerbation in the mother and potential for complications in the fetus, current management that includes careful planning, treatment, and monitoring most often results in successful pregnancy outcomes for these patients.

Fertility and SLE Fertility in stable SLE patients without identifiable risk factors appears to be comparable to that of the general population.1 Studies do show a reduction in family size for women with SLE that may relate to effects of disease activity, disease damage, cytotoxic medications, and psychosocial factors.2

Etiology of infertility in subsets of SLE patients Causes of decreased fertility in some SLE patients include advanced maternal age, active disease or disease-related damage, and medication effects. Many SLE patients are Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00052-0 Copyright © 2020 Elsevier Inc. All rights reserved.

older when they attempt to conceive as they may have been counseled to avoid pregnancy if their disease has not been quiescent, and thus, they may encounter difficulties related to an age-associated loss of ovarian reserve and oocyte quality. Premature ovarian failure, defined as persistent amenorrhea with elevated FSH prior to age 40 years, is sometimes due to autoimmune etiologies but it is rare for these patients to have coexisting systemic autoimmune disease.3 However, SLE patients may have menstrual disturbances or amenorrhea related to active disease.4 Anti-Mullerian hormone (AMH) serum level, a marker of ovarian reserve, has been reported to be lower in a group of non-cyclophosphamidetreated SLE patients than in age-matched healthy controls, although use of oral contraceptives and other medications differed between the two groups.5 Lupus patients with renal insufficiency or failure may develop hypofertility or infertility through a disruption of the hypothalamic–pituitary axis that can reverse with renal transplantation. While early reports proposed an association among anti-phospholipid antibodies (aPL), infertility, and poor in vitro fertilization (IVF) outcome, recent controlled studies do not support this association and so treatment of aPL for infertility in the absence of antiphospholipid syndrome with obstetrical complications is not recommended.6 Cyclophosphamide (CYC), used for severe lupus manifestations including nephritis and central nervous system disease, accounts for the majority of fertility issues in SLE patients. Patients administered CYC are more likely to maintain fertility if they are younger than 30 years old, the total number of monthly intravenous pulses is six or less, the cumulative dose is less than 7 g, and if there is no amenorrhea before or during administration.7

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498 PART | IV  Clinical aspects of the disease

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for control of mild SLE symptoms. Despite experimental and anecdotal data suggesting that these drugs have the potential to interfere with normal follicular rupture and ovulation, systematic clinical data are lacking. Highdose corticosteroids may also affect the menstrual cycle, but it is difficult to distinguish effects of disease activity from those of the corticosteroid itself.

Preservation of fertility Counseling and frank discussion regarding risk and benefit of both the CYC therapy and any suggested fertility prevention must be done with each individual patient. The dose of CYC should be minimized especially in older patients. The use of the Euro-Lupus CYC regimen, mycophenolate mofetil, or other non-CYC combination therapies may be helpful in this regard. Treatment to provide ovarian protection from CYC effects with gonadotrophic hormone receptor (GnRH) agonists has become common practice, although the benefit of this therapy is still somewhat controversial. Administration of the GnRH agonist leuprolide at 10–14 days prior to CYC pulse therapy was shown to be protective against development of persistent amenorrhea in one large series,8 and a recent meta-analysis calculated a 68% increase in rate of preserved ovarian function in treated versus untreated women.9 GnRH-agonist therapy should not be administered immediately before CYC: if given in the follicular part of the cycle, it can stimulate the ovaries (potentially worsening ovarian damage) and increase estrogen levels.10.As a result, patients are rarely treated with GnRH agonists before their first CYC infusion, but can be treated at monthly intervals mid-cycle thereafter. In the past, the traditional measure of infertility after CYC has been the development of amenorrhea; newer objective measures such as AMH level may provide a better assessment of ovarian reserve in the future Long-term preservation of fertility through cryopreservation techniques, while appealing in theory, presents a challenge when administration of CYC is deemed urgent (as is often the case for severe disease). Cryopreservation of oocytes or embryos requires ovarian hyperstimulation, a procedure that involves a time delay in lupus treatment of at least 2 weeks as well as elevated levels of estrogen, both usually contraindicated in the setting of lupus flare. Although patient's psychosocial issues and beliefs and financial constraints may limit use of these techniques, increasing numbers of women in their early to mid-thirties in the general population are pursuing oocyte or freezing for fertility preservation in anticipation of IVF in future years. This fertility-preservation technique can be considered for SLE patients with stable inactive disease who are faced with age-related fertility concerns (discussed later).

Cryopreservation of ovarian tissue is an emerging technique in which ovarian tissue is removed through laparoscopic oophorectomy, without the need for ovarian stimulation or significant time delay. Oocytes from the retrieved tissue may be matured in vitro and then frozen, or the ovarian tissue itself may be frozen in thin strips for later in vitro oocyte maturation or autotransplantation.10 When fertility is not or cannot be preserved with available methods, IVF utilizing a donor oocyte and partner's sperm provides an alternative option for pregnancy during a period of quiescent disease.

Assisted reproductive techniques Ovulation induction (OI) and the controlled ovarian hyperstimulation necessary for IVF may increase risk of flare and/or thrombosis in patients with SLE. Risk appears to be related to degree of elevation in 17β-estradiol levels. While individual case reports describe OI- and IVFrelated flare and thrombosis in SLE and antiphospholipid syndrome (APS) patients,3 two large series report overall positive outcomes in a combined total of 177 OI and IVF cycles in patients with SLE and/or APS.11,12 Flare occurred in 21%–42% of SLE patients but was generally mild and responsive to therapy. Risk of both flare and thrombosis was greater if the diagnosis of SLE was not known at the start of the cycle.11 Flare risk was higher with use of gonadotrophins than with the estrogen antagonist clomiphene, but pregnancy rates for clomiphene were significantly lower. Thrombosis was rare, although almost all patients with positive aPL or APS were treated throughout the cycle with some form of anticoagulation (aspirin and/or heparin). While one group has reported the absence of thrombotic complications in 17 aPL-positive patients undergoing ovulation induction without use of any prophylactic anticoagulation,13 no controlled studies have been performed. Thrombosis risk is higher with IVF protocols than with OI due to the higher estrogen levels generated, with thrombosis risk most closely associated with the complication of ovarian hyperstimulation syndrome, a capillary-leak syndrome resulting in hemoconcentration.14 Options to minimize overall IVF risk for patients with SLE and aPL generally involve modulating the IVF process to avoid very high estrogen levels. Prophylactic heparin therapy for patients with positive aPL is usually recommended, given the likely increase in thrombosis risk and the absence of data-derived guidelines. We recommend that patients with APS on warfarin switch to therapeutic heparin or low molecular weight heparin prior to the start of the cycle and to hold it 12–24 h before oocyte retrieval with resumption 12 h later.14 There are no data to support prophylactic low-dose corticosteroid to reduce risk of lupus flare through IVF cycles; however, patients should be closely observed for

Fertility and pregnancy in systemic lupus erythematosus Chapter | 52

evidence of flare and treated promptly when flare occurs. Importantly, assisted-reproductive techniques should only be performed in lupus patients who have stable inactive disease on pregnancy-compatible medications, that is, those who would otherwise be considered safe to undertake pregnancy. Occasionally, a patient may be considered suitable for IVF but not pregnancy, for example, those with significant renal insufficiency or pulmonary hypertension. Such patients may tolerate ovarian stimulation but not the hemodynamic stress of pregnancy; in this situation, IVF followed by embryo transfer to a gestational carrier can result in a biological child. For every patient, and whatever the specific procedure planned, collaboration among the reproductive medicine specialist, high-risk obstetrician, and rheumatologist is critical for maximizing the potential for a successful outcome while minimizing maternal risk.

Pregnancy in SLE patients During pregnancy, multiple physiologic and immunologic changes occur to maintain the developing fetus. Examples include a 30%–50% increase in intravascular volume that results in physiologic anemia; immune system changes of diminished circulating natural killer cells, altered regulatory T-cell sets, and shift to a T-helper 2 type humoral immunity that lead to increased autoantibody production; and increases in prothrombin levels, plasma fibrinogen, and reduced protein S levels that create a prothrombotic state.15,16 Moreover, common symptoms of pregnancy such as fatigue, joint pain, back aches, headaches, dyspnea, and skin rashes, can easily be confused with symptoms of SLE flare. Standard laboratory assessments of disease activity can be altered by pregnancy as well: sedimentation rate, C-reactive protein, complement components, and white blood cell count all increase during normal pregnancy and can contribute to the challenges in assessing SLE disease activity in pregnancy.15

Pregnancy impact on SLE disease activity There is no consensus opinion regarding the impact of pregnancy on SLE disease activity. Disparate reports likely reflect the lack of uniformity in flare definition and the compounding effect of pregnancy-specific symptoms on disease activity scales. Recent attempts to rectify this include adjustments to standard disease activity metrics such as the SLEDAI, SLAM, and LAI, to account for the symptoms of pregnancy. While a few small scale studies have not revealed increased risk of SLE flare during pregnancy,17 several larger studies suggest that pregnancy flare rates may approach 60%.18,19 The largest observational study to date in 385 pregnant lupus patient with inactive or mild disease

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at conception found that only 19% of these patients had complicated pregnancies.20 The most common disease manifestations during pregnancy include lupus nephritis, cutaneous disease, arthritis, and thrombocytopenia. The type of organ system involvement in the preconception period may predict the type of disease symptoms during pregnancy.21 While most flares during pregnancy are mild, about onefifth of flares will be severe.22 Active disease in the 6 months prior to conception increases the risk of flare during pregnancy several-fold.23 Primagravidas and those patients who have ever had renal disease are likewise vulnerable to flaring during pregnancy.24,25 Other preconception risk factors for increased SLE disease activity during pregnancy include low-complement levels and hematological abnormalities.26 Patients with active renal disease during the 6 months preceding conception and/or a baseline creatinine value of greater than 1.4 mg/dL are particularly vulnerable to disease flare during pregnancy with the risk of progression to end-stage renal disease. They are also at higher risk for preterm delivery, hypertension, preeclampsia, and stroke.2728 Significantly, women with SLE have a 1% maternal mortality rate, 20 times the normal pregnancy mortality risk.29 Severe manifestations of disease damage may preclude pregnancy as it puts the mother at too great a risk. These include cardiomyopathy, cardiac valve disease, pulmonary arterial hypertension (PAH), interstitial lung disease, recent cerebral vascular accident, and significant renal insufficiency. PAH in particular is associated with a high risk of pregnancy-related mortality.30

Preeclampsia and SLE flare Preeclampsia occurs in roughly 25% of women with SLE during pregnancy.31 Distinguishing a lupus flare from preeclampsia and its variants is challenging, as symptoms largely overlap (Table 52.1). While hypertension, edema, proteinuria, and low platelets can be found in both disorders, certain features may help distinguish between them. For example, preeclampsia rarely occurs before 20 weeks and most commonly occurs after 34 weeks of gestation, whereas SLE flares can occur throughout pregnancy. Laboratory testing can also be helpful in differentiating a clinical presentation of SLE flare from preeclampsia— low complements, rising anti-dsDNA antibody titers, low white blood cell count, and an active urine sediment suggest a lupus flare, while elevated liver function tests, elevated uric acid, and proteinuria with an acelluar urine sediment are more suggestive of preeclampsia. Management of these disorders differs, as SLE flare is controlled with immunosuppression whereas preeclampsia is treated with immediate delivery. In practice, the two entities often coexist and patients may require treatment for both.

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TABLE 52.1 Differentiation of SLE Flare from preeclampsia during pregnancy. Clinical finding

SLE flare

Preeclampsia

Timing

All three trimesters

Rare before 20 weeks, most often after 34 weeks

Hypertension

+/−

+++

Edema

+

+++

Proteinuria

++

+++

Thrombocytopenia

++

+++

LFTs

Unchanged or decreased

++

Uric acid

Normal

Normal or high

Rising dsDNA antibody titer

++

–

Complement levels

Low or falling

Normal or high

SLE impact on pregnancy outcome Pregnancy outcome for women with lupus has improved; however, SLE pregnancy is still associated with increased rates of pregnancy loss, preterm delivery, and fetal growth restriction. In general, most of the risk factors affecting maternal health status in lupus pregnancy, such as disease activity, renal disease, and thrombocytopenia, impact fetal and neonatal outcomes as well. Additionally, the presence of anti-phospholipid antibodies (aPL) anti-SS-A/Ro, and anti-SS-B/La antibodies may negatively affect pregnancy outcome. Clark et al. compared their current cohort to historical data and found the pregnancy loss rate decreased from 40% to 17% over 40 years; rate of preterm delivery, however, did not improve significantly (37% vs. 32%, respectively).32 A large meta-analysis of 2751 lupus pregnancies found overall rates of premature birth to be 39.6% and of intrauterine growth restriction to be 12.7%.28 These complications are important because severe preterm delivery and growth restriction can have long-term health implications for offspring, including significant neuro-developmental complications.

Pregnancy loss Rates of pregnancy loss are estimated at 15%–30%. Early miscarriage (pregnancy loss at less than 10 weeks gestation) is common in the general population, whereas fetal loss (greater than 10 weeks gestation), and stillbirth (loss after 20 weeks gestation) are infrequent in the general population and are more characteristic of SLE. Many studies of SLE pregnancy group all losses from the embryonic stage (up to 9–10 weeks gestation) to stillbirth (fetal death at 20 or more weeks) under the term “fetal loss,” making it challenging to interpret the data on SLE pregnancy loss. The effect of SLE on embryonic losses is controversial, with a possible slight increase in risk. Women with SLE are at increased risk of fetal death beyond 10 weeks, particularly in the presence

of active SLE, lupus nephritis, and antiphospholipid syndrome (APS). Overall, fetal loss rates amongst SLE patients have been declining over the last decades, with increased rates of livebirths. A large observational cohort of patients with inactive lupus or mild to moderate disease activity at conception found that 5% of pregnancies ended in fetal or neonatal death (i.e., losses at > 10 weeks).33 For comparison, the population risk of miscarriage at any time less than 20 weeks gestation ranges from 8% to 20%.34 Factors increasing risk for lupus pregnancy loss include high levels of disease activity before and during pregnancy, presence of aPL, lupus nephritis, renal insufficiency, and hypertension.22,28,35,36 Pregnancy loss rates are 3-fold higher in patients with active lupus in the first or second trimester of the pregnancy than in patients with quiescent disease.22 APL, present in up to 30% of SLE patients, is closely associated with adverse pregnancy outcome: obstetric antiphospholipid syndrome (OB-APS) is defined as recurrent early miscarriage, single fetal loss, or early delivery at less than 34 weeks for preeclampsia or placental insufficiency in the presence of persistent lupus anticoagulant (LAC) or high titer anticardiolipin (aCL) or anti-β2 glycoprotein I (aβ2GPI) IgG or IgM antibodies37 (Chapters 58–60). LAC is the most powerful predictor for adverse pregnancy outcome in aPL-positive patients: in the multicenter prospective PROMISSE study (Predictors of pregnancy outcome: biomarker in antiphospholipid antibody syndrome and systemic lupus erythematosus), LAC was associated with a relative risk of 12.33 in a cohort of 144 aPL-positive women with and without SLE. History of thrombosis and concomitant SLE were additional independent risk factors. Overall, adverse outcomes occurred in 39% LAC-positive patients, versus 3% in the LAC-negative group.38 Presence of anti-SS-A/Ro and anti-SS-B/La antibodies are associated with a 15%–20% risk of neonatal lupus in the offspring, with risk of complete congenital heart block about 2% (see Chapter 53). Complete congenital heart block, especially when associated with other

Fertility and pregnancy in systemic lupus erythematosus Chapter | 52

cardiac abnormalities, may result in fetal and/or neonatal death and affected children usually require permanent pacemakers.

TABLE 52.2 Prepregnancy assessment and management during pregnancy. SLE

Assessment

Management of SLE during pregnancy Disease should be in remission on medications compatible with pregnancy (see medications further) for 6 months prior to conception. Pre-pregnancy and early pregnancy evaluation should include assessments for anti-dsDNA and complement levels, anti-SS-A/Ro and anti-SS-B/La antibodies, aPL (including LAC, aCL, and anti-β2GPI), complete blood and platelet count, metabolic panel including renal function and liver function testing, and urinalysis. Patients should be co-managed with a maternal fetal medicine specialist with expertise in SLE. Pregnancy monitoring should be more frequent in SLE pregnancies including non-stress testing and biophysical profiling; in some situations, umbilical artery Doppler testing may be indicated. Complete blood counts with platelets, renal function, liver function testing, complement levels, anti-dsDNA antibody testing, and urinalysis should be performed regularly throughout the pregnancy to monitor for disease flare and preeclampsia. (Table 52.2)

• Evaluate for disease activity • Evaluate for underlying lupusrelated organ damage that may affect pregnancy risk

Preterm birth and intrauterine growth restriction Rates of preterm birth and intrauterine growth restriction are increased in patients with SLE, most commonly for those with high-risk profiles. Intrauterine growth restriction (IUGR) results in infants that are small for gestational age (SGA), defined as being below the 10th percentile of weight for age, and is reported to be more common in SLE pregnancy, especially in the setting of positive aPL and hypertension.39 Preterm birth, defined as delivery prior to 37 weeks, may be medically induced for maternal or fetal safety in the setting of complications such as preeclampsia or fetal distress. Spontaneous preterm delivery also occurs, most commonly from preterm labor or preterm premature rupture of membranes (PPROM). Preterm birth rates for SLE patients range from 14% to 50% and rates for Cesarean delivery are also increased.28,35,36,40 Presence of aPL, lupus disease activity, current or prior nephritis, and hypertension are all associated with earlier delivery. Prednisone use is also significantly associated with PPROM and early delivery.36 Even with previous adverse pregnancy outcome, future pregnancies may be successful in patients with SLE. A population-based cohort study recently reported on 177 women with SLE with a previous pregnancy, 69% of whom went on to have a second pregnancy—89% of second pregnancies resulted in neonates being discharged home. Importantly, 9 of the 10 women with stillbirth or neonatal death in their first pregnancy had a successful second pregnancy.41

501

• Check anti-Ro/SSA and/or anti-La/ SSB antibodies once pre- or early pregnancy • Check aPL (aCL, aβ2GPI, LAC) once pre- or early pregnancy • Check anti-dsDNA and complement levels, complete blood and platelet count, metabolic panel including renal function and liver function testing, and urinalysis • Transition to medications compatible with pregnancy: before pregnancy, allow adequate time after medication transition to assess efficacy of new therapy before conceiving • Set-up co-management team with maternal fetal medicine Management

• Hydroxychloroquine • Low-dose aspirin • Monitor for lupus activity (history, physical, labs) each trimester • Treat recent or current lupus activity with pregnancycompatible medications; • Use prednisone sparingly

Medication management Medication management of SLE during pregnancy and lactation is challenging, as the potential benefits to the mother of any medication must be weighed against the potential risk to the developing fetus. Decisions regarding medication safety unfortunately are often challenging given that information on drug safety is often based on animal studies or case reports. Below is a discussion on the safety of commonly used medications for rheumatologic disorders in pregnancy and lactation (Table 52.3). Aspirin and NSAIDs are often given to manage joint pain and serositis in SLE patients. Low-dose aspirin is also used to manage antiphospholipid syndrome and in preeclampsia prevention. While these medications are teratogenic in rodents, they are not in humans.42 There is insufficient data on COX-2 inhibitors to conclude whether these medications can cause congenital anomalies so they are best avoided. Use of NSAIDs can cause premature closure of the ductus arteriosus and these medications should be discontinued after the 30th week of gestation.43 Both traditional

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TABLE 52.3 Medication compatibility pre-conception, during pregnancy, during lactation. Drug

Preconception

During pregnancy

Breastfeeding

NSAIDs (avoid COXinhibitors)

Discontinue if the woman is having difficulty conceiving

Discontinue third trimester

Compatible (Ibuprofen preferred)

Glucocorticoids

Taper to 6weeks prior to conception

Stop;; refer to MFM or genetics specialist

Contraindicated

Cyclosphosphamide

Avoid

Avoid except in life-threatening circumstances in 2nd/3rd trimester. First trimester exposure: refer to MFM or genetics specialist

Contraindicated

Abatacept

Discontinue at conception

Discontinue during pregnancy

Compatible- expect minimal transfer due to large molecular size but minimal data

Belimumab

Discontinue at conception

Discontinue during pregnancy

Compatible- expect minimal transfer due to large molecular size but minimal data

Rituximab

Discontinue at conception

Discontinue during pregnancy

Compatible- expect minimal transfer due to large molecular size but minimal data

NSAIDs and COX-2-specific inhibitors may interfere with ovulation and implantation; thus in women who are having difficulty conceiving, consideration can be made to avoid these medications during a planned conception cycle.44 There are conflicting data on whether NSAIDs cause an increased risk of early spontaneous miscarriage; therefore it seems prudent to limit use of these medications during the first trimester.45,46 The nonfluorinated glucocorticoids prednisone and prednisolone are mainstays of therapy for SLE symptoms. These steroids cross the placenta in limited amounts and reach the fetus in low concentrations. In contrast, fluorinated glucocorticoids such as betamethasone readily cross the placenta and are used to hasten fetal lung maturity when premature delivery is anticipated.47 Later in pregnancy, steroid use can contribute to PPROM and SGA infants. Mothers taking glucocorticoids during pregnancy have an increased risk of gestational diabetes, hypertension, and osteoporosis, and so dosage should be minimized

when feasible. Prednisone is compatible with nursing,48 although women taking more than 20 mg per day should discard breast milk produced in the first four hours after the dose. The antimalarials hydroxychloroquine and chloroquine are important tools for SLE management. Evidence suggests that continuation of these medications during pregnancy improves pregnancy outcome.49 While one early case series suggested that antimalarials were ototoxic and retinotoxic,50 subsequent studies have not shown increased teratogenicity. A 2006 survey of North American rheumatologists revealed that 69% of rheumatologists maintained their patients on hydroxychloroquine during pregnancy.51 Reassuringly, follow-ups of infants exposed to antimalarials during pregnancy have failed to demonstrate retinal toxicity in offspring.52 Large transplant registries including hundreds of pregnancy exposures have not documented increased teratogenicity of azathioprine and cyclosporine.53 Tacrolimus,

Fertility and pregnancy in systemic lupus erythematosus Chapter | 52

another immunosuppressive agent that may be used to manage lupus nephritis, is also considered compatible with pregnancy.54 Minimal levels of azathioprine and tacrolimus are transferred to breast milk; thus use of these medications in nursing mothers of full-term infants is considered low risk.55 Unfortunately, a number of congenital anomalies have been reported after in utero exposure to mycophenolate mofetil so this medication should be discontinued when pregnancy is anticipated and should not be used during breastfeeding.56 Methotrexate and leflunomide are both teratogenic and are contraindicated during pregnancy.57,58 Methotrexate and leflunomide should be avoided in lactating women. Recent data suggest that preconception and early gestation exposure to leflunomide resulted in few anomalies when patients were treated promptly with a cholestyramine washout.59 Nonetheless current recommendations are to either stop this medication 2 years prior to conception or to treat with a cholestyramine washout prior to conception to remove active metabolites. CYC is extremely teratogenic and is contraindicated during pregnancy with the exception of life-threatening circumstance;60 it should also be avoided in nursing mothers.

Biological agents There is limited information on the safety of biologics during lupus pregnancy. Package inserts for products recommend discontinuation prior to pregnancy ranging from a few months (belimumab, abatacept) to 1 year (rituximab). One large series of 153 pregnancies in which the mother was given rituximab did not demonstrate an increased rate of congenital anomalies.61 There has been been a case report of a successful pregnancy after the mother was treated with belimumab.62 However, given that IgG does not cross the placenta prior to 12 weeks of gestation, it is unlikely that administration of these medications in the period immediately preceding pregnancy would cause significant exposure to the developing embryo. Therefore, we recommend the continuation of IgG-based biologics through conception and discontinuation during pregnancy.

Other medications There are limited data on the safety of IVIG during pregnancy, but no cases of congenital anomalies have been reported;63 it is compatible with pregnancy and lactation and may be a low-risk agent to consider for severe SLE flare or, rarely, for refractory OB-APS. Anticoagulation is used in women with APS and other thrombotic conditions. Heparin and low molecular weight heparin are compatible with pregnancy while warfarin is not. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers are contraindicated during pregnancy,

503

although calcium channel blockers and beta blockers may be used to control blood pressure.

Medication summary Patients should be kept on their antimalarials during pregnancy. Additionally, given that SLE patients are at greater risk for preeclampsia, they should be maintained on low-dose aspirin (81–100 mg) throughout pregnancy.64 Glucocorticoids may be used in low doses for stable disease or in higher doses for flares with the caveat that exposure during the first trimester may increase the risk of cleft lip and palate formation in the offspring. Patients on mycophenolate mofetil, methotrexate, and leflunomide should be taken off of these medications and placed on an immunosuppressive agent compatible with pregnancy such as azathioprine, tacrolimus, or cyclosporine several months prior to conception. Importantly, disease should be stable on these medications for 6 months prior to attempting conception. While CYC is contraindicated during pregnancy, in life-threatening situations this medication has been used in the third trimester with successful pregnancy outcome. The biologics abatacept, belimumab, and rituximab should be discontinued as per the manufacturer's instructions; however, consideration of using these mediations in closer proximity to pregnancy is not unreasonable given that immunoglobulins do not cross the placenta in significant concentrations during the first trimester.

Conclusions Fertility and pregnancy for patients with SLE may be affected to varying degrees by both disease and treatmentrelated factors. Lupus patients with inactive disease who are without renal disease or exposure to CYC can expect fertility comparable to the age-matched population. Lupus itself is unlikely to affect long-term fertility to any significant degree. Pregnancy evaluation and counseling should include assessment of disease-related damage that might preclude pregnancy, such as PAH or severe renal insufficiency: these patients should not attempt pregnancy due to high risk of maternal morbidity or death. Patients without severe organ damage should be evaluated for current flare or recent disease activity in the preceding 6 months: if recent disease activity is present, they should be counseled to defer pregnancy until disease has been quiescent for at least 6 months on pregnancy-compatible medications, which include hydroxychloroquine, glucocorticoids, azathioprine, cyclosporine, and tacrolimus. For patients ready to conceive, other risk factors for maternal and fetal complications should be identified including history of renal disease, hypertension, thrombocytopenia, aPL status, and anti-SS-A/Ro and anti-SS-B/La

504 PART | IV  Clinical aspects of the disease

antibodies. Low-dose aspirin is suggested for all SLE patients, especially those with additional risk factors for preeclampsia, that is, those with history of renal disease, hypertension, or aPL. Anticoagulation therapy for patients with OB-APS should be administered according to current guidelines (Chapter 65). With careful evaluation, monitoring, and medical therapy, most SLE patients can have successful pregnancies without long-term adverse effects for mother or child.

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13. Balasch J, Cervera R. Reflections on the management of reproductive failure in the antiphospholipid syndrome--the clinician's perspective. Lupus 2002;11(8):467–77. 14. Bellver J, Pellicer A. Ovarian stimulation for ovulation induction and in vitro fertilization in patients with systemic lupus erythematosus and antiphospholipid syndrome. Fertil Steril 2009;92(6):1803–10. 15. Branch DW WL. Normal pregnancy, pregnancy complications and obstetric management. In: Sammaritano LR BB, editor. Contraception and pregnancy in patients wit rheumatic disease. New York, New York: Springer; 2014. 16. Veenstra van Nieuwenhoven AL, Heineman MJ, Faas MM. The immunology of successful pregnancy. Hum Reprod Update 2003;9(4): 347–57. 17. Lockshin MD. Pregnancy does not cause systemic lupus erythematosus to worsen. Arthritis Rheum 1989;32(6):665–70. 18. Petri M, Howard D, Repke J. Frequency of lupus flare in pregnancy. The Hopkins lupus pregnancy center experience. Arthritis Rheum 1991;34(12):1538–45. 19. Cavallasca JA, Laborde HA, Ruda-Vega H, Nasswetter GG. Maternal and fetal outcomes of 72 pregnancies in Argentine patients with systemic lupus erythematosus (SLE). Clin Rheumatol 2008;27(1):41–6. 20. Buyon JP, Kim MY, Guerra MM, Laskin CA, Petri M, Lockshin MD, et al. Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann Intern Med 2015;163(3):153–63. 21. Tedeschi SK, Massarotti E, Guan H, Fine A, Bermas BL, Costenbader KH. Specific systemic lupus erythematosus disease manifestations in the six months prior to conception are associated with similar disease manifestations during pregnancy. Lupus 2015;24(12):1283–92. 22. Clowse MEB, Magder LS, Witter F, Petri M. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum 2005;52(2): 514–21. 23. Clowse MEB. Lupus activity in pregnancy. Rheum Dis Clin North Am 2007;33(2):237–52. 24. Saavedra MA, Sánchez A, Morales S, Navarro-Zarza JE, Ángeles U, Jara LJ. Primigravida is associated with flare in women with systemic lupus erythematosus. Lupus 2015;24(2):180–5. 25. Saavedra MA, Cruz-Reyes C, Vera-Lastra O, Romero GT, Cruz-Cruz P, Arias-Flores R, et al. Impact of previous lupus nephritis on maternal and fetal outcomes during pregnancy. Clin Rheumatol 2012;31(5):813–9. 26. Borella E, Lojacono A, Gatto M, Andreoli L, Taglietti M, Iaccarino L, et al. Predictors of maternal and fetal complications in SLE patients: a prospective study. Immunol Res 2014;60(2–3):170–6. 27. Hou S. Pregnancy in chronic renal insufficiency and end-stage renal disease. Am J Kidney Dis 1999;33(2):235–52. 28. Smyth A, Oliveira GHM, Lahr BD, Bailey KR, Norby SM, Garovic VD. A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol 2010;5(11):2060–8. 29. Clowse MEB, Jamison M, Myers E, James AH. A national study of the complications of lupus in pregnancy. Am J Obstet Gynecol 2008;199(2) 127.e1–e6. 30. Hsu C-H, Gomberg-Maitland M, Glassner C, Chen J-H. The management of pregnancy and pregnancy-related medical conditions in pulmonary arterial hypertension patients. Int J Clin Pract Suppl 2011;(172):6–14.

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31. Chakravarty EF, Nelson L, Krishnan E. Obstetric hospitalizations in the United States for women with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 2006;54(3):899–907. 32. Clark CA, Spitzer KA, Laskin CA. Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period. J Rheumatol 2005;32(9):1709–12. 33. Buyon JP, Kim MY, Guerra MM, Laskin CA, Petri M, Lockshin MD, et al. Predictors of pregnancy outcomes in patients with lupus. Ann Intern Med 2015;163(3):153. 34. Wilcox AJ, Weinberg CR, O’Connor JF, Baird DD, Schlatterer JP, Canfield RE, et al. Incidence of early loss of pregnancy. N Engl J Med 1988;319(4):189–94. 35. Yasmeen S, Wilkins EE, Field NT, Sheikh RA, Gilbert WM. Pregnancy outcomes in women with systemic lupus erythematosus. J Matern Fetal Med 2001;10(2):91–6. 36. Chakravarty EF, Colón I, Langen ES, Nix DA, El-Sayed YY, Genovese MC, et al. Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J Obstet Gynecol 2005;192(6):1897–904. 37. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4(2):295–306. 38. Lockshin MD, Kim M, Laskin CA, Guerra M, Branch DW, Merrill J, et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum 2012;64(7):2311–8. 39. Cortés-Hernández J, Ordi-Ros J, Paredes F, Casellas M, Castillo F, Vilardell-Tarres M. Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies. Rheumatology (Oxford) 2002 Jun;41(6):643–50. 40. Johnson MJ, Petri M, Witter FR, Repke JT. Evaluation of preterm delivery in a systemic lupus erythematosus pregnancy clinic. Obstet Gynecol 1995;86(3):396–9. 41. Shand AW, Algert CS, March L, Roberts CL. Second pregnancy outcomes for women with systemic lupus erythematosus. Ann Rheum Dis 2013;72(4):547–51. 42. van Gelder MMHJ, Roeleveld N, Nordeng H. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and the risk of selected birth defects: a prospective cohort study. PLoS One 2011;6(7):e22174. 43. Koren G, Florescu A, Costei AM, Boskovic R, Moretti ME. Nonsteroidal antiinflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis. Ann Pharmacother 2006;(5):824–9. 44. Pall M, Fridén BE, Brännström M. Induction of delayed follicular rupture in the human by the selective COX-2 inhibitor rofecoxib: a randomized double-blind study. Hum Reprod 2001;16(7):1323–8. 45. Nakhai-Pour HR, Broy P, Sheehy O, Bérard A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ 2011;183(15):1713–20. 46. Edwards DRV, Aldridge T, Baird DD, Funk MJ, Savitz DA, Hartmann KE. Periconceptional over-the-counter nonsteroidal anti-inflammatory drug exposure and risk for spontaneous abortion. Obstet Gynecol 2012;120(1):113–22.

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47. Blanford AT, Murphy BE. In vitro metabolism of prednisolone, dexamethasone, betamethasone, and cortisol by the human placenta. Am J Obstet Gynecol 1977;127(3):264–7. 48. Ost L, Wettrell G, Björkhem I, Rane A. Prednisolone excretion in human milk. J Pediatr 1985;106(6):1008–11. 49. Clowse MEB, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum 2006;54(11):3640–7. 50. Hart CW, Naunton RF. The ototoxicity of chloroquine phosphate. Arch Otolaryngol 1964;80:407–12. 51. Al-Herz A, Schulzer M, Esdaile JM. Survey of antimalarial use in lupus pregnancy and lactation. J Rheumatol 2002 Apr;29(4):700–6. 52. Osadchy A, Ratnapalan T, Koren G. Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature. J Rheumatol 2011 Dec;38(12):2504–8. 53. Radomski JS, Ahlswede BA, Jarrell BE, Mannion J, Cater J, Moritz MJ, et al. Outcomes of 500 pregnancies in 335 female kidney, liver, and heart transplant recipients. Transplant Proc 1995 Feb;27(1): 1089–90. 54. Kainz A, Harabacz I, Cowlrick IS, Gadgil SD, Hagiwara D. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation 2000;70(12):1718–21. 55. Osadchy A, Koren G. Cyclosporine and lactation: when the mother is willing to breastfeed. Ther Drug Monit 2011;33(2):147–8. 56. Perez-Aytes A, Ledo A, Boso V, Sáenz P, Roma E, Poveda JL, et al. In utero exposure to mycophenolate mofetil: a characteristic phenotype? Am J Med Genet A 2008;146A(1):1–7. 57. Feldkamp M, Carey JC. Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy. Teratology 1993;47(6):533–9. 58. Brent RL. Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child. Teratology 2001;63(2): 106–12. 59. Cassina M, Johnson DL, Robinson LK, Braddock SR, Xu R, Jimenez JL, et al. Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis Rheum 2012;64(7):2085–94. 60. Fields CL, Ossorio MA, Roy TM, Bunke CM. Wegener's granulomatosis complicated by pregnancy. a case report. J Reprod Med 1991;36(6):463–6. 61. Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab. Blood 2011 Feb 3;117(5):1499–506. 62. Emmi G, Silvestri E, Squatrito D, Mecacci F, Ciampalini A, Emmi L, et al. Favorable pregnancy outcome in a patient with systemic lupus erythematosus treated with belimumab: a confirmation report. Semin Arthritis Rheum 2016;45(6):e26–7. 63. Parke A. The role of IVIG in the management of patients with antiphospholipid antibodies and recurrent pregnancy losses. Clin Rev Allergy 1992;10(1-2):105-18. 64. Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017;377(7): 613–22.

Chapter 53

Neonatal lupus: Clinical spectrum, biomarkers, pathogenesis, and approach to treatment Jill P. Buyona, Amit Saxenaa, Peter M. Izmirlya, Bettina Cuneob and Benjamin Wainwrighta a

Division of Rheumatology, New York University School of Medicine, New York City, NY, United States; Department of Pediatrics and Obstetrics, University of Colorado School of Medicine, Aurora, CO, United States

b

Introduction Fetal exposure to maternal autoantibodies transported across the human placenta via FcγRn can result in a spectrum of organ injury: transient if the tissue has regenerative capacity and permanent if this capacity is absent or limited. An important example of passively acquired autoimmunity in a fetus and neonate is that of neonatal lupus (NL) given the concordance between circulating maternal antibody in the fetus and disease manifestations. NL is often referred to as a syndrome since it can comprise one or more manifestations inclusive of cardiac, cutaneous, liver, and hematologic abnormalities. By definition, the maternal autoantibodies associated with NL are directed to antigen targets within the SSA/Ro–SSB/La ribonucleoprotein complex (60 kDa Ro, 52 kDa Ro, 48 kDa La) (reviewed in Ref.1). NL was coined based on the resemblance of the neonatal rash to the cutaneous lesions seen in SLE.2,3 Throughout this chapter, cardiac NL refers to the varied spectrum of cardiac disease, inclusive of complete heart block (CHB), cardiomyopathy, and endocardial fibroelastosis (EFE). The transient manifestations of the syndrome mimic the disease characteristics observed in adolescents or adults (rash and cytopenias). However, the permanent manifestation (heart block), with the exception of one published maternal case, is not observed in the adult despite the presence of identical antibodies in the maternal circulation.4 The term NL is misleading, as the neonate does not have SLE and often neither does the mother. In many cases, mothers are clinically asymptomatic and only identified to have serologic abnormalities when gestational surveillance reveals fetal bradycardia.4,5 Other maternal diseases include Systemic Lupus Erythematosus. http://dx.doi.org/10.1016/B978-0-12-814551-7.00053-2 Copyright © 2020 Elsevier Inc. All rights reserved.

an undifferentiated autoimmune syndrome or Sjogren’s syndrome.6 Despite the rarity of NL, the syndrome continues to be investigated with advances from the bench and bedside, which have been incorporated in this revised chapter.

Risk of cardiac NL and population prevalence The risk of having a child with cardiac NL is approximately 2% for an antiSSA/Ro-positive woman who has either never been pregnant or has previously had only healthy offspring.7–10 If an antiSSA/Ro-positive mother has a previous child affected with cardiac NL or cutaneous NL, the risk of recurrence is 18%11–16 and 13%,17 respectively. In general, women with low titers of antiSSA/Ro antibodies are at less risk than those with high titer antibodies18; however, there is considerable overlap in antibody levels between affected and unaffected cases and most women have high titers that remain stable over time. The risk of developing cutaneous manifestations of NL is 7%–16%,8,10 and the recurrence rate of cutaneous NL is estimated to be between 23% and 29%.17 The population prevalence of cardiac NL in Finland was reported at 1:17,000 live births19 with the highest annual estimates at 1:6,500. However, this may be an underestimation since only children with pacemakers were included and fetal deaths were not captured. In children born with cardiac NL in the absence of documented structural abnormalities, antiRo antibodies are found in over 85%.20 The prevalence of antiSSA/Ro antibodies had been initially reported at 0.20%–0.72% in female blood donors,21 0.87% in pregnant women,22 and more recently at 0.86% in 507

508 PART | IV  Clinical aspects of the disease

healthy females in the general population.23 The prevalence reported in the latter study may be even higher since only those positive for antinuclear antibodies (which may not always detect antiSSA/Ro) were then tested for antiSSA/ Ro antibodies. For patients with SLE the prevalence of this antibody reactivity is estimated at 40%24 and in those with Sjogren’s syndrome between 60% and 100%.24 In aggregate, if the true prevalence of antiSSA/Ro approaches 0.9% and cardiac NL occurs in 2% and recurrence in 18%, this could yield approximately 600–700 cases per year based on the 2017 National Vital Statistics of 3,855,500 births. Thus thousands of women in the United States may be faced with the risk of cardiac NL in their offspring, yet prenatal testing does not include an evaluation of antiSSA/Ro antibodies.

Transient clinical manifestations of NL: cutaneous, hepatic, hematologic, and neurologic In contrast to the in utero detection of cardiac NL, cutaneous disease most often appears after birth, with a mean time of detection at 6 weeks and mean duration of 17 weeks.25 Albeit the specificity of the maternal autoantibodies may be identical, the discordant timing of the cardiac and cutaneous disease supports distinct initiators or amplifiers of injury. The strong association of cutaneous lesions with UV exposure suggests that apoptosis of the keratinocytes and surface translocation of SSA/Ro may result in immune complex formation and tissue injury. All mothers with antiSSA/Ro antibodies should be counseled regarding UV protection of their infants as both a preventative and therapeutic measure. The rash is characterized by erythematous annular lesions or arcuate macules with slight central atrophy and raised active margins, which are located primarily on the scalp and face with a characteristic predilection for the upper eyelids. A raccoon-like appearance should immediately raise suspicion for NL. A review of the corporeal distribution of rash among 57 infants with cutaneous NL enrolled in the Research Registry for Neonatal Lupus (RRNL) revealed that 100% had facial involvement. Other affected areas included the scalp, trunk, extremities, neck, intertriginous areas, and rarely the palms or soles, in descending order.25 The NL rash resembles subacute cutaneous lupus erythematosus, with basal cell damage in the epidermis and a superficial monocyte cell infiltrate in the upper dermis.26 Immunofluorescence staining of skin biopsies reveals IgG deposition within the epidermis.26 Of relevance to the pathogenesis of tissue injury mediated by antiSSA/Ro antibodies, histiocytes consistent with M2 macrophages have been identified in the skin lesion of a neonate with cutaneous NL.27 Although purely speculative, this observation echoes the macrophage infiltrations noted in cardiac NL, suggesting a potential link between these

two manifestations: one induced by UV light and the other by apoptosis (see the following), both exposing intracellular antigen and inciting an inflammatory infiltrate in response to immune complexes. The rash is usually self-limiting and almost always resolves by approximately 8 months of age, coincident with the clearance of maternal antibodies from the child’s circulation.26 Residual skin abnormalities are uncommon but can include atrophy, scarring, pitting, hypopigmentation, or hyperpigmentation, and telangiectasias.25,26 On rare occasion, neither antiSSA/Ro nor SSB/La is detected in the maternal sera of a child with classic NL lesions, but rather antibodies to another ribonucleoprotein, U1-RNP, are present.28 Thus the evaluation of this latter reactivity should be considered when facing the differential diagnosis of NL in a child with characteristic rash and maternal disease is unsuspected. In general the self-limiting nature of the rash precludes therapy. Topical steroids (nonfluorinated) have been used. However, data from the RRNL revealed no significant differences in outcome with or without treatment.25 Systemic therapies are not recommended. Neonatal liver disease is associated with maternal antiSSA/Ro but its true prevalence is unknown since routine testing at birth does not include a liver enzyme profile.29 In one prospective study, 26% of children born to mothers with antiSSA/Ro had elevated liver enzymes.8 Laxer described NL associated with significant hepatic involvement in four infants, three living and one who died postnatally.30 The clinical picture in these neonates was cholestatic. Pathologic changes included giant cell transformation, ductal obstruction, and extramedullary hematopoiesis.30 Lee and coworkers investigated the incidence of hepatobiliary manifestations among 219 NL patients in the RRNL and noted that recognized hepatobiliary disease occurred in 19 (9%) of 219 infants, usually in conjunction with either cardiac or cutaneous involvement.29 Three clinical variants were observed: (1) severe liver failure present during gestation or in the neonatal period (least common); (2) conjugated hyperbilirubinemia with mild or no elevations of aminotransferases occurring in the first few weeks of life; and (3) mild elevations of aminotransferases occurring at approximately 2–3 months of life. The prognosis for the children in the last two categories was excellent.29 Hematologic manifestations of NL include thrombocytopenia, neutropenia, anemia,8 and, very rarely, aplastic anemia.31 Thrombocytopenia was present in 10% of the neonates referred to Lee and coworkers.26 While NL thrombocytopenia is presumed to be autoimmune in nature, its exact pathogenesis remains unclear since it is uncertain whether antiplatelet-specific antibodies or antiSSA/Ro-SSB/La antibodies target the surface of fetal platelets. With regard to the pathogenesis of neutropenia, in vitro exposure of intact neutrophils to antiSSA/Ro-positive maternal and/or infant serum from affected families results in immunoglobulin

Neonatal lupus: Clinical spectrum, biomarkers, pathogenesis, and approach to treatment Chapter | 53

deposition, suggesting a possible immune-mediated basis for NL neutropenia.32 Indeed, the neutrophil/immunoglobulin interactions were neutralized by preincubating the sera with 60 kDa Ro antigen that bound the autoantibody, suggesting that anti60 kDa SSA/Ro directly drives the pathogenesis of neutropenia.32 In one prospective study, 25 of 107 infants born to mothers with antiSSA/Ro or antiSSB/ La antibodies had neutropenia but no cases of neonatal sepsis occurred.8 Neurologic dysfunction has been reported in offspring of mothers with antiSSA/Ro antibodies. In a Canadian cohort of 87 infants exposed to maternal antiSSA/Ro and/ or antiSSB/La antibodies,33 8% (5/47 with and 2/40 without another manifestation of NL) had hydrocephalus, all but one resolving spontaneously. Maternal immunological dysfunction has been associated with reports of developmental language delay, learning difficulties, and left handedness.34 In a retrospective study based on detailed questionnaires, telephone interviews, and reviews of medical records of children with NL in the RRNL, their unaffected siblings, and healthy friend controls, it was noted that behavioral problems, either isolated or associated with attention disorder, were present in all groups with no statistical difference.35 The prevalence of depression, anxiety, developmental delays, learning disability, hearing and speech problems, and use of stimulants were also not significantly different between groups. The authors suggested that parental reporting of neuropsychiatric abnormalities was high in antibody-exposed children; however, it did not meet statistical significance when compared to the controls. More recently, in a study from Sweden, impaired neurodevelopment was reported in 16% of antiRo-exposed children [60 siblings with and 54 without CHB (18/114)]. Reported problems included speech (9%), motor (8%) and learning (8%) impairment, attention deficit (5%), and behavioral impairment (4%).36 Impairment in motor skill development was more common in boys (P 0.5 gram/24 hours.

2

Pyuria

>5 white blood cells/high power field. Exclude infection.

2

Rash

Inflammatory type rash.

2

Alopecia

Abnormal, patchy or diffuse loss of hair.

2

Mucosal ulcers

Oral or nasal ulcerations.

2

Pleurisy

Pleuritic chest pain with pleural rub or effusion, or pleural thickening.

2

Pericarditis

Pericardial pain with at least 1 of the following: rub, effusion, or electrocardiogram or echocardiogram confirmation.

2

Low complement

Decrease in CH50, C3, or C4 below the lower limit of normal for testing laboratory.

2

Increased DNA binding

Increased DNA binding by Farr assay above normal range for testing laboratory.

1

Fever

>38°C. Exclude infectious cause.

1

Thrombocytopenia