Immune-Mediated Myopathies and Neuropathies: Current Trends and Future Prospects 9811984204, 9789811984204

Table of contents :
Acknowledgments
Contents
About the Author
Part I: Immune-Mediated Myopathies
1: Introduction to Immune-Mediated Myopathies
1.1 Normal Skeletal Muscle
1.2 Immunometabolism of Skeletal Muscle
1.3 Immune Cells and Inflammatory Myopathies
1.4 Interferons in Inflammatory Myopathies
1.5 Conclusion
References
2: Diagnostic Evaluation of Immune-Mediated Myopathies
2.1 Introduction
2.2 Clinical Features
2.3 Serum Muscle Enzymes
2.4 Electrodiagnostic Studies
2.4.1 Nerve Conduction Studies
2.4.2 Electromyography
2.5 Muscle Imaging
2.5.1 Muscle MRI and Muscle Biopsy for IIM Diagnosis
2.6 Autoantibodies in Myositis
2.7 Muscle Biopsy
2.8 Conclusion
References
3: Classification of Immune-Mediated Myopathies
3.1 Introduction
3.2 Dermatomyositis
3.3 Sporadic Inclusion Body Myositis
3.4 Immune-Mediated Necrotizing Myopathy
3.5 Antisynthetase Syndrome
3.6 Overlap Myositis
3.7 Antimitochondrial M2-Associated Myopathy
3.8 Anti-Program Cell Death 1/PD-1 Ligand Inhibitor-Associated Myositis
3.9 Polymyositis
3.10 Conclusion
References
4: Idiopathic Inflammatory Myopathies
4.1 Introduction
4.2 Dermatomyositis
4.2.1 Introduction
4.2.2 Pathological Criteria for DM
4.2.3 Pathophysiology of DM
4.2.4 Juvenile Manifestations of DM and Inherited Interferonopathies
4.2.5 Treatment in DM
4.2.6 Cancer and DM
4.2.7 Conclusion
4.3 Sporadic Inclusion Body Myositis
4.3.1 Introduction
4.3.2 Nomenclature
4.3.3 Epidemiology
4.3.4 Clinical Features of sIBM
4.3.5 Anti-cN1A Autoantibody
4.3.6 Microscopic Pathology
4.3.7 Diagnostic Criteria
4.3.8 Associated Disorders and Comorbidities
4.3.9 Progression
4.3.10 sIBM Therapeutics
4.3.11 Pathogenesis of sIBM
4.3.12 Conclusion
4.4 Polymyositis
4.5 Conclusion
References
5: Specific Forms of Immune-Mediated Necrotizing Myopathies
5.1 Introduction
5.2 Diagnostic Criteria for IMNM
5.2.1 General Features of IMNM
5.2.2 Anti-SRP Autoantibodies
5.2.3 Anti-HMGCR Autoantibodies
5.3 Epidemiology
5.3.1 Prevalence, Incidence, and Risk Factors
5.3.2 Anti-SRP-Positive IMNM
5.3.3 Anti-HMGR-Positive IMNM
5.3.4 Seronegative IMNM
5.4 Clinical Features
5.4.1 Muscular Phenotype
5.4.1.1 Seropositive IMNM
5.4.1.2 Seronegative IMNM
5.4.2 Extramuscular Phenotype
5.4.2.1 Anti-SRP-Positive IMNM
5.4.2.2 Anti-HMGCR-Positive IMNM
5.4.2.3 Seronegative IMNM
5.5 Microscopic Pathology
5.5.1 General Pathology of IMNM
5.5.2 Immunohistochemistry of IMNM
5.6 Disease Course and Prognosis
5.6.1 Seropositive IMNM
5.6.2 Seronegative IMNM
5.7 Pathogenesis of Seropositive IMNM
5.7.1 Targets of Autoantibodies
5.7.2 Effects of Autoantibodies In Vitro
5.8 Treatment Recommendations for IMNM
5.9 Conclusions
5.10 Antisynthetase Syndrome
5.10.1 Introduction
5.10.2 Epidemiology
5.10.3 Pathogenesis
5.10.4 Diagnosis
5.10.5 Clinical Symptoms
5.10.6 Myositis
5.10.7 Extramuscular Manifestations
5.10.8 Outcome and Prognosis
5.10.9 Overview of Treatment Possibilities
5.10.10 Conclusion
5.11 IIMs that Mimic IMNM
References
6: Overlap Myositis
References
7: Vasculitic Myopathy
7.1 Introduction
7.2 Large Vessel Vasculitis
7.3 Medium Vessel Vasculitis
7.4 Small-Vessel Vasculitis
7.4.1 ANCA-Associated/Pauci-Immune Vasculitis
7.4.2 Immune-Complex Mediated Vasculitis
7.4.3 Anti-glomerular Basement Membrane Disease
7.4.4 Cryoglobulinemic Vasculitis
7.4.5 IgA Vasculitis (Henoch–Schönlein Purpura)
7.4.6 Hypocomplementemic Urticarial Vasculitis (Anti-C1q Vasculitis)
7.4.7 Variable Vessel Vasculitis
7.4.8 Single-Organ Vasculitis
7.5 Skeletal Muscle Vasculitis
7.5.1 Takayasu Arteritis
7.5.2 Giant Cell Arteritis
7.5.3 Polyarteritis Nodosa
7.5.4 Kawasaki Disease
7.5.5 Granulomatosis with Polyangiitis
7.5.6 Microscopic Polyangiitis
7.5.7 Eosinophilic Granulomatosis with Polyangiitis
7.5.8 Cryoglobulinemic Vasculitis
7.5.9 IgA Vasculitis
7.5.10 Anti-C1q Vasculitis
7.5.11 Cogan’s Syndrome
7.5.12 Behçet’s Disease
7.5.13 Single-Organ Vasculitis
7.5.14 Vasculitis Associated with Systemic Disease
7.6 Conclusion
References
8: Sarcoid Myopathy and Other Immune-Mediated Granulomatous Myopathies
8.1 Introduction
8.2 Sarcoid Myopathy
8.2.1 Introduction
8.2.2 Clinical Features
8.2.3 Non-invasive Investigations
8.2.4 Muscle Biopsy
8.2.5 Management and Prognosis
8.3 Idiopathic Granulomatous Myositis
8.4 Giant Cell Myositis
8.5 Conclusion
References
9: Paraproteinemia Associated Myopathy
9.1 Introduction
9.2 Amyloid Myopathy
9.3 Sporadic Late-Onset Nemaline Myopathy (SLONM)
9.4 Conclusion
References
10: AntiAMA-M2 Myopathy
10.1 Introduction
10.2 Pathogenesis
10.3 Clinical and Laboratory Findings
10.4 Muscle Biopsy
10.5 Conclusion
References
11: Paraneoplastic Myopathy
11.1 Introduction
11.2 Dermatomyositis (DM)
11.3 Sporadic Inclusion Body Myositis (sIBM)
11.4 Immune-Mediated Necrotizing Myopathy (IMNM)
11.5 Conclusions
References
12: Mimics of Immune-Mediated Myopathy
12.1 Introduction
12.2 Muscular Dystrophies
12.2.1 Facioscapulohumeral Muscular Dystrophy
12.2.2 Dysferlinopathy
12.2.3 Calpainopathy
12.2.4 Role of MHC Staining
12.3 Metabolic Myopathies
12.3.1 Acid Maltase Deficiency (Pompe Disease)
12.3.2 McArdle’s Disease
12.3.3 Mitochondrial Myopathies
12.4 Endocrine Myopathies
12.4.1 Thyroid Myopathies
12.4.2 Other Endocrine Myopathies
12.5 Nervous System Disease
12.6 Focal Disease
12.7 Conclusions
References
13: Current Concepts and Future Prospects in Immune-Mediated Myopathies
13.1 Introduction
13.2 Interferons in Muscle Disease
13.2.1 IFN-I
13.2.2 IFN-II
13.2.3 IFN-III
13.2.4 Genetic Interferonopathies Share Common Features with DM
13.2.5 Skin Manifestations
13.2.6 Muscle Manifestations
13.2.7 IFN Pathway and DM-Specific Autoantibodies
13.2.8 IFN Pathway Is Activated in DM
13.2.8.1 Muscle Tissue
13.2.8.2 Skin Tissue
13.2.8.3 Blood
13.2.9 IFN Production in DM
13.2.9.1 Immune Cells and IFN Production
13.2.9.2 Muscle Cells
13.2.9.3 Keratinocytes
13.2.10 IFNs Induce Muscle Damage
13.2.11 Interferon Pathway Activation in ASS
13.2.11.1 IFN-II Pathway in Muscle of ASS
13.2.11.2 IFN-II Pathway in Lungs of ASS Patients
13.2.11.3 IFN Pathways in the Blood of ASS Patients
13.2.12 Interferon Pathway Activation in sIBM
13.2.12.1 IFN-II Pathway in Muscle Tissue of sIBM
13.2.12.2 IFN-II Pathway in the Blood of sIBM
13.2.12.3 IFN-II Pathway and Muscle Degeneration
13.2.13 IFN and IMNM
13.2.14 Conclusion
13.3 Myositis Associated with Graft-Versus-Host Disease
13.3.1 Introduction
13.3.2 Pathophysiology of GVHD Myositis
13.3.3 Incidence and Onset of GVHD Myositis
13.3.4 Clinical Features
13.3.5 Muscle Enzymes and Autoantibodies
13.3.6 Imaging
13.3.7 Pathology
13.3.8 Association with GVHD
13.3.9 GVHD vs De Novo Myositis
13.3.10 Treatment
13.3.11 Outcome
13.3.12 Conclusion
13.4 SARS-CoV-2 Myopathy
13.4.1 Muscle Biopsy
13.4.2 Conclusion
13.5 Immune Checkpoint Inhibitors Associated Myopathy
13.5.1 Introduction
13.5.2 Epidemiology
13.5.3 Treatment Options for ICI-Induced Musculoskeletal Manifestations
13.5.4 Immunotherapy Type and Musculoskeletal Manifestations
13.5.5 Conclusion
References
Part II: Immune-Mediated Neuropathies
14: Introduction to Immune-Mediated Neuropathies: A Brief Overview of the Nervous System
14.1 Neurons
14.2 Synapse
14.3 Types of Neurons
14.3.1 Multipolar
14.3.2 Bipolar
14.3.3 Unipolar
14.4 Peripheral Nerve
14.5 Immune-Mediated Neuropathies
References
15: Diagnostic Evaluation of Immune-Mediated Neuropathies
15.1 Introduction
15.2 Initial Steps
15.3 Clinical History
15.4 Neurological Examination
15.4.1 Type of Nerve Fiber Involvement
15.4.2 Distribution of Symptoms
15.5 Electrodiagnostic Studies
15.6 Laboratory Testing
15.6.1 Examination of the Cerebrospinal Fluid
15.6.2 Genetic Testing
15.6.3 Nerve Biopsy
15.6.4 Peripheral Nerve Imaging
15.6.5 Other Examinations
15.7 Conclusion
References
16: Classification of Immune-Mediated Neuropathies
16.1 Classification
17: Immune-Mediated Demyelinating Neuropathies
17.1 Introduction
17.2 Guillain-Barré Syndrome
17.2.1 Pathogenesis
17.2.2 Clinical Features
17.2.3 Electrophysiological Findings
17.2.4 Laboratory Investigations
17.2.5 Role of Nerve Biopsy in GBS
17.2.6 Treatment
17.2.7 Paraneoplastic GBS
17.3 Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
17.3.1 Introduction
17.3.2 Clinical Features of Typical CIDP
17.3.3 Electrodiagnostic Features and Ancillary Testing
17.4 Patterns Suggestive of Atypical CIDP or Disease Mimickers
17.4.1 Rapid Clinical Progression by Definition
17.4.2 Length-Dependent Sensory-Greater-Than-Motor, Axonal-Predominant Peripheral Neuropathy
17.4.3 Non-Length-Dependent Sensory Ganglionopathy/Neuronopathy
17.4.4 Upper-Limb-Predominant Neuropathy
17.4.5 Sensory and Motor Demyelinating Neuropathy
17.4.6 Sensory and Motor Axonal Polyradiculoneuropathy
17.4.7 CIDP with a Paraprotein
17.4.8 Paraneoplastic CIDP
17.5 Conclusions
References
18: Immune-Mediated Axonal Neuropathies
18.1 Introduction
18.2 Vasculitic Neuropathy
18.2.1 Introduction
18.2.2 Classification
18.2.3 Clinical Features
18.2.4 Nonsystemic Vasculitic Neuropathy with Proximal Involvement (Nondiabetic Lumbosacral Radiculoplexus Neuropathy)
18.2.5 Subtypes
18.2.6 Imaging
18.2.7 Conclusion
18.3 Connective Tissue Disorders
18.4 Sarcoidosis
18.4.1 Neurosarcoidosis Consortium Consensus Group Definition and Consensus Diagnostic Criteria for Neurosarcoidosis
18.5 Immune-Mediated Gastrointestinal Disorders
18.5.1 Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative Colitis
18.5.2 Celiac Disease
18.6 Paraprotein-Associated Neuropathy
18.6.1 Epidemiology
18.6.2 Pathogenesis
18.6.3 IgM Paraproteinaemic Disorders
18.6.4 IgG or IgA Paraproteinaemic Disorders
18.6.5 IgM, IgG, or IgA Paraproteinaemic Disorders
18.6.6 Investigations
18.6.7 Nerve Biopsy
18.6.7.1 Endoneural Immunoglobulin Deposits
18.6.8 Conclusion
18.7 Paraneoplastic Disease
18.7.1 Types of Neuropathy
18.7.2 Diagnosis
18.7.3 Conclusion
18.8 Axonal GBS
18.9 Idiopathic Perineuritis
References
19: Mimics of Immune-Mediated Neuropathy
19.1 Introduction
19.2 Diagnosis of Peripheral Neuropathies
19.3 Acquired Neuropathies
19.3.1 Metabolic Neuropathies
19.3.1.1 Endocrine
19.3.1.2 Vitamin Deficiencies
19.3.2 Toxic Neuropathies Metals
19.3.3 Drugs
19.3.4 Chemicals and Plants
19.3.5 Neurolymphomatosis
19.3.6 Hansen’s Neuritis
19.3.7 Cholesterol Emboli Neuropathy
19.4 Conclusions
References
20: Current Concepts and Future Prospects in Immune-Mediated Neuropathies
20.1 Immune Checkpoint Inhibitors
20.1.1 Introduction
20.1.2 Approach to Differential Diagnosis
20.1.2.1 Clinical Features
20.1.3 Conclusions
20.2 Coronavirus Disease 19 (COVID-19)/Coronavirus 2 (SARS-CoV-2) Associated Peripheral Neuropathy
20.2.1 Introduction
20.2.2 Peripheral Nervous System Manifestations and Complications
20.3 Humoral Immune Endoneurial Microvasculopathy
20.3.1 Introduction
20.3.2 Conclusion
References

Citation preview

Immune-Mediated Myopathies and Neuropathies Current Trends and Future Prospects Balan Louis Gaspar

123

Immune-Mediated Myopathies and Neuropathies

Balan Louis Gaspar

Immune-Mediated Myopathies and Neuropathies Current Trends and Future Prospects

Balan Louis Gaspar NextGenPath Diagnostics Coimbatore, Tamil Nadu, India

ISBN 978-981-19-8420-4    ISBN 978-981-19-8421-1 (eBook) https://doi.org/10.1007/978-981-19-8421-1 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Acknowledgments

I would like to thank all the clinicians who have trusted and allowed me to interpret the muscle and nerve biopsies of their patients. My family has been with me throughout this work, and words will not be sufficient to thank them. Last but not least, I would also like to thank the patients for providing me the opportunity to interpret their biopsies and to carry out this work. Balan Louis Gaspar

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Contents

Part I Immune-Mediated Myopathies 1

I ntroduction to Immune-Mediated Myopathies��������������������������������������   3 1.1 Normal Skeletal Muscle����������������������������������������������������������������������   3 1.2 Immunometabolism of Skeletal Muscle ��������������������������������������������   3 1.3 Immune Cells and Inflammatory Myopathies������������������������������������   5 1.4 Interferons in Inflammatory Myopathies��������������������������������������������   6 1.5 Conclusion������������������������������������������������������������������������������������������   6 References����������������������������������������������������������������������������������������������������   7

2

 iagnostic Evaluation of Immune-­Mediated Myopathies����������������������   9 D 2.1 Introduction����������������������������������������������������������������������������������������   9 2.2 Clinical Features ��������������������������������������������������������������������������������   9 2.3 Serum Muscle Enzymes����������������������������������������������������������������������  10 2.4 Electrodiagnostic Studies��������������������������������������������������������������������  10 2.4.1 Nerve Conduction Studies������������������������������������������������������  11 2.4.2 Electromyography������������������������������������������������������������������  11 2.5 Muscle Imaging����������������������������������������������������������������������������������  15 2.5.1 Muscle MRI and Muscle Biopsy for IIM Diagnosis��������������  15 2.6 Autoantibodies in Myositis ����������������������������������������������������������������  16 2.7 Muscle Biopsy������������������������������������������������������������������������������������  17 2.8 Conclusion������������������������������������������������������������������������������������������  19 References����������������������������������������������������������������������������������������������������  19

3

 lassification of Immune-Mediated Myopathies������������������������������������  21 C 3.1 Introduction����������������������������������������������������������������������������������������  21 3.2 Dermatomyositis ��������������������������������������������������������������������������������  21 3.3 Sporadic Inclusion Body Myositis������������������������������������������������������  27 3.4 Immune-Mediated Necrotizing Myopathy ����������������������������������������  28 3.5 Antisynthetase Syndrome ������������������������������������������������������������������  29 3.6 Overlap Myositis��������������������������������������������������������������������������������  30 3.7 Antimitochondrial M2-Associated Myopathy������������������������������������  31 3.8 Anti-Program Cell Death 1/PD-1 Ligand Inhibitor-Associated Myositis����������������������������������������������������������������������������������������������  31

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3.9 Polymyositis����������������������������������������������������������������������������������������  32 3.10 Conclusion������������������������������������������������������������������������������������������  32 References����������������������������������������������������������������������������������������������������  32 4

I diopathic Inflammatory Myopathies������������������������������������������������������  37 4.1 Introduction����������������������������������������������������������������������������������������  37 4.2 Dermatomyositis ��������������������������������������������������������������������������������  37 4.2.1 Introduction����������������������������������������������������������������������������  37 4.2.2 Pathological Criteria for DM��������������������������������������������������  42 4.2.3 Pathophysiology of DM����������������������������������������������������������  45 4.2.4 Juvenile Manifestations of DM and Inherited Interferonopathies ������������������������������������������������������������������  50 4.2.5 Treatment in DM��������������������������������������������������������������������  52 4.2.6 Cancer and DM ����������������������������������������������������������������������  52 4.2.7 Conclusion������������������������������������������������������������������������������  53 4.3 Sporadic Inclusion Body Myositis������������������������������������������������������  54 4.3.1 Introduction����������������������������������������������������������������������������  54 4.3.2 Nomenclature��������������������������������������������������������������������������  55 4.3.3 Epidemiology��������������������������������������������������������������������������  55 4.3.4 Clinical Features of sIBM������������������������������������������������������  56 4.3.5 Anti-cN1A Autoantibody��������������������������������������������������������  57 4.3.6 Microscopic Pathology ����������������������������������������������������������  58 4.3.7 Diagnostic Criteria������������������������������������������������������������������  58 4.3.8 Associated Disorders and Comorbidities��������������������������������  58 4.3.9 Progression������������������������������������������������������������������������������  61 4.3.10 sIBM Therapeutics������������������������������������������������������������������  61 4.3.11 Pathogenesis of sIBM ������������������������������������������������������������  61 4.3.12 Conclusion������������������������������������������������������������������������������  63 4.4 Polymyositis����������������������������������������������������������������������������������������  64 4.5 Conclusion������������������������������������������������������������������������������������������  65 References����������������������������������������������������������������������������������������������������  65

5

 pecific Forms of Immune-Mediated Necrotizing Myopathies ������������  73 S 5.1 Introduction����������������������������������������������������������������������������������������  73 5.2 Diagnostic Criteria for IMNM������������������������������������������������������������  74 5.2.1 General Features of IMNM����������������������������������������������������  74 5.2.2 Anti-SRP Autoantibodies��������������������������������������������������������  75 5.2.3 Anti-HMGCR Autoantibodies������������������������������������������������  75 5.3 Epidemiology��������������������������������������������������������������������������������������  76 5.3.1 Prevalence, Incidence, and Risk Factors��������������������������������  76 5.3.2 Anti-SRP-Positive IMNM������������������������������������������������������  76 5.3.3 Anti-HMGR-Positive IMNM��������������������������������������������������  76 5.3.4 Seronegative IMNM���������������������������������������������������������������  77 5.4 Clinical Features ��������������������������������������������������������������������������������  77 5.4.1 Muscular Phenotype���������������������������������������������������������������  77 5.4.2 Extramuscular Phenotype ������������������������������������������������������  78

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5.5 Microscopic Pathology ����������������������������������������������������������������������  79 5.5.1 General Pathology of IMNM��������������������������������������������������  79 5.5.2 Immunohistochemistry of IMNM������������������������������������������  79 5.6 Disease Course and Prognosis������������������������������������������������������������  81 5.6.1 Seropositive IMNM����������������������������������������������������������������  81 5.6.2 Seronegative IMNM���������������������������������������������������������������  82 5.7 Pathogenesis of Seropositive IMNM��������������������������������������������������  82 5.7.1 Targets of Autoantibodies ������������������������������������������������������  83 5.7.2 Effects of Autoantibodies In Vitro������������������������������������������  84 5.8 Treatment Recommendations for IMNM ������������������������������������������  84 5.9 Conclusions����������������������������������������������������������������������������������������  86 5.10 Antisynthetase Syndrome ������������������������������������������������������������������  87 5.10.1 Introduction����������������������������������������������������������������������������  87 5.10.2 Epidemiology��������������������������������������������������������������������������  87 5.10.3 Pathogenesis����������������������������������������������������������������������������  88 5.10.4 Diagnosis��������������������������������������������������������������������������������  90 5.10.5 Clinical Symptoms������������������������������������������������������������������  91 5.10.6 Myositis����������������������������������������������������������������������������������  91 5.10.7 Extramuscular Manifestations������������������������������������������������  92 5.10.8 Outcome and Prognosis����������������������������������������������������������  92 5.10.9 Overview of Treatment Possibilities ��������������������������������������  93 5.10.10 Conclusion����������������������������������������������������������������������������  94 5.11 IIMs that Mimic IMNM����������������������������������������������������������������������  94 References����������������������������������������������������������������������������������������������������  94 6

Overlap Myositis���������������������������������������������������������������������������������������� 101 References���������������������������������������������������������������������������������������������������� 102

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Vasculitic Myopathy���������������������������������������������������������������������������������� 103 7.1 Introduction���������������������������������������������������������������������������������������� 103 7.2 Large Vessel Vasculitis������������������������������������������������������������������������ 105 7.3 Medium Vessel Vasculitis�������������������������������������������������������������������� 105 7.4 Small-Vessel Vasculitis ���������������������������������������������������������������������� 105 7.4.1 ANCA-Associated/Pauci-Immune Vasculitis ������������������������ 106 7.4.2 Immune-Complex Mediated Vasculitis���������������������������������� 106 7.4.3 Anti-glomerular Basement Membrane Disease������������������������������������������������������������������������������������ 107 7.4.4 Cryoglobulinemic Vasculitis �������������������������������������������������� 107 7.4.5 IgA Vasculitis (Henoch–Schönlein Purpura)�������������������������� 107 7.4.6 Hypocomplementemic Urticarial Vasculitis (Anti-C1q Vasculitis)�������������������������������������������������������������� 108 7.4.7 Variable Vessel Vasculitis�������������������������������������������������������� 108 7.4.8 Single-Organ Vasculitis���������������������������������������������������������� 108 7.5 Skeletal Muscle Vasculitis������������������������������������������������������������������ 109 7.5.1 Takayasu Arteritis ������������������������������������������������������������������ 110 7.5.2 Giant Cell Arteritis������������������������������������������������������������������ 110

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7.5.3 Polyarteritis Nodosa���������������������������������������������������������������� 111 7.5.4 Kawasaki Disease ������������������������������������������������������������������ 112 7.5.5 Granulomatosis with Polyangiitis ������������������������������������������ 114 7.5.6 Microscopic Polyangiitis�������������������������������������������������������� 115 7.5.7 Eosinophilic Granulomatosis with Polyangiitis���������������������� 116 7.5.8 Cryoglobulinemic Vasculitis �������������������������������������������������� 116 7.5.9 IgA Vasculitis�������������������������������������������������������������������������� 117 7.5.10 Anti-C1q Vasculitis ���������������������������������������������������������������� 117 7.5.11 Cogan’s Syndrome������������������������������������������������������������������ 117 7.5.12 Behçet’s Disease �������������������������������������������������������������������� 118 7.5.13 Single-Organ Vasculitis���������������������������������������������������������� 118 7.5.14 Vasculitis Associated with Systemic Disease ������������������������ 119 7.6 Conclusion������������������������������������������������������������������������������������������ 119 References���������������������������������������������������������������������������������������������������� 120 8

Sarcoid Myopathy and Other Immune-­Mediated Granulomatous Myopathies���������������������������������������������������������������������� 125 8.1 Introduction���������������������������������������������������������������������������������������� 125 8.2 Sarcoid Myopathy������������������������������������������������������������������������������ 125 8.2.1 Introduction���������������������������������������������������������������������������� 125 8.2.2 Clinical Features �������������������������������������������������������������������� 126 8.2.3 Non-invasive Investigations���������������������������������������������������� 126 8.2.4 Muscle Biopsy������������������������������������������������������������������������ 127 8.2.5 Management and Prognosis���������������������������������������������������� 128 8.3 Idiopathic Granulomatous Myositis���������������������������������������������������� 129 8.4 Giant Cell Myositis ���������������������������������������������������������������������������� 129 8.5 Conclusion������������������������������������������������������������������������������������������ 130 References���������������������������������������������������������������������������������������������������� 130

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Paraproteinemia Associated Myopathy �������������������������������������������������� 131 9.1 Introduction���������������������������������������������������������������������������������������� 131 9.2 Amyloid Myopathy���������������������������������������������������������������������������� 131 9.3 Sporadic Late-Onset Nemaline Myopathy (SLONM)������������������������ 133 9.4 Conclusion������������������������������������������������������������������������������������������ 134 References���������������������������������������������������������������������������������������������������� 134

10 AntiAMA-M2 Myopathy�������������������������������������������������������������������������� 137 10.1 Introduction�������������������������������������������������������������������������������������� 137 10.2 Pathogenesis�������������������������������������������������������������������������������������� 137 10.3 Clinical and Laboratory Findings ���������������������������������������������������� 138 10.4 Muscle Biopsy���������������������������������������������������������������������������������� 139 10.5 Conclusion���������������������������������������������������������������������������������������� 139 References���������������������������������������������������������������������������������������������������� 139 11 Paraneoplastic Myopathy�������������������������������������������������������������������������� 141 11.1 Introduction�������������������������������������������������������������������������������������� 141 11.2 Dermatomyositis (DM)�������������������������������������������������������������������� 142

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11.3 Sporadic Inclusion Body Myositis (sIBM) �������������������������������������� 144 11.4 Immune-Mediated Necrotizing Myopathy (IMNM)������������������������ 144 11.5 Conclusions�������������������������������������������������������������������������������������� 145 References���������������������������������������������������������������������������������������������������� 145 12 M  imics of Immune-Mediated Myopathy ������������������������������������������������ 149 12.1 Introduction�������������������������������������������������������������������������������������� 149 12.2 Muscular Dystrophies ���������������������������������������������������������������������� 149 12.2.1 Facioscapulohumeral Muscular Dystrophy������������������������ 150 12.2.2 Dysferlinopathy������������������������������������������������������������������ 150 12.2.3 Calpainopathy �������������������������������������������������������������������� 152 12.2.4 Role of MHC Staining�������������������������������������������������������� 152 12.3 Metabolic Myopathies���������������������������������������������������������������������� 153 12.3.1 Acid Maltase Deficiency (Pompe Disease)������������������������ 153 12.3.2 McArdle’s Disease�������������������������������������������������������������� 154 12.3.3 Mitochondrial Myopathies�������������������������������������������������� 155 12.4 Endocrine Myopathies���������������������������������������������������������������������� 156 12.4.1 Thyroid Myopathies������������������������������������������������������������ 156 12.4.2 Other Endocrine Myopathies���������������������������������������������� 156 12.5 Nervous System Disease������������������������������������������������������������������ 157 12.6 Focal Disease������������������������������������������������������������������������������������ 158 12.7 Conclusions�������������������������������������������������������������������������������������� 158 References���������������������������������������������������������������������������������������������������� 159 13 C  urrent Concepts and Future Prospects in Immune-Mediated Myopathies�������������������������������������������������������������������������������������������������� 161 13.1 Introduction�������������������������������������������������������������������������������������� 161 13.2 Interferons in Muscle Disease���������������������������������������������������������� 162 13.2.1 IFN-I ���������������������������������������������������������������������������������� 162 13.2.2 IFN-II���������������������������������������������������������������������������������� 163 13.2.3 IFN-III�������������������������������������������������������������������������������� 163 13.2.4 Genetic Interferonopathies Share Common Features with DM �������������������������������������������������������������� 163 13.2.5 Skin Manifestations������������������������������������������������������������ 164 13.2.6 Muscle Manifestations�������������������������������������������������������� 164 13.2.7 IFN Pathway and DM-Specific Autoantibodies������������������ 165 13.2.8 IFN Pathway Is Activated in DM���������������������������������������� 165 13.2.9 IFN Production in DM�������������������������������������������������������� 166 13.2.10 IFNs Induce Muscle Damage��������������������������������������������� 167 13.2.11 Interferon Pathway Activation in ASS�������������������������������� 167 13.2.12 Interferon Pathway Activation in sIBM������������������������������ 168 13.2.13 IFN and IMNM ������������������������������������������������������������������ 170 13.2.14 Conclusion�������������������������������������������������������������������������� 170 13.3 Myositis Associated with Graft-Versus-Host Disease���������������������� 171 13.3.1 Introduction������������������������������������������������������������������������ 171 13.3.2 Pathophysiology of GVHD Myositis���������������������������������� 172

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1 3.3.3 Incidence and Onset of GVHD Myositis���������������������������� 173 13.3.4 Clinical Features ���������������������������������������������������������������� 173 13.3.5 Muscle Enzymes and Autoantibodies �������������������������������� 173 13.3.6 Imaging ������������������������������������������������������������������������������ 174 13.3.7 Pathology���������������������������������������������������������������������������� 174 13.3.8 Association with GVHD ���������������������������������������������������� 175 13.3.9 GVHD vs De Novo Myositis���������������������������������������������� 175 13.3.10 Treatment���������������������������������������������������������������������������� 175 13.3.11 Outcome������������������������������������������������������������������������������ 176 13.3.12 Conclusion�������������������������������������������������������������������������� 177 13.4 SARS-CoV-2 Myopathy ������������������������������������������������������������������ 177 13.4.1 Muscle Biopsy�������������������������������������������������������������������� 179 13.4.2 Conclusion�������������������������������������������������������������������������� 179 13.5 Immune Checkpoint Inhibitors Associated Myopathy �������������������� 179 13.5.1 Introduction������������������������������������������������������������������������ 179 13.5.2 Epidemiology���������������������������������������������������������������������� 180 13.5.3 Treatment Options for ICI-Induced Musculoskeletal Manifestations�������������������������������������������������������������������� 181 13.5.4 Immunotherapy Type and Musculoskeletal Manifestations�������������������������������������������������������������������� 181 13.5.5 Conclusion�������������������������������������������������������������������������� 181 References���������������������������������������������������������������������������������������������������� 181 Part II Immune-Mediated Neuropathies 14 I ntroduction to Immune-Mediated Neuropathies: A Brief Overview of the Nervous System������������������������������������������������ 193 14.1 Neurons �������������������������������������������������������������������������������������������� 194 14.2 Synapse �������������������������������������������������������������������������������������������� 195 14.3 Types of Neurons������������������������������������������������������������������������������ 195 14.3.1 Multipolar �������������������������������������������������������������������������� 195 14.3.2 Bipolar�������������������������������������������������������������������������������� 196 14.3.3 Unipolar������������������������������������������������������������������������������ 196 14.4 Peripheral Nerve ������������������������������������������������������������������������������ 196 14.5 Immune-Mediated Neuropathies������������������������������������������������������ 196 References���������������������������������������������������������������������������������������������������� 197 15 D  iagnostic Evaluation of Immune-­Mediated Neuropathies������������������ 199 15.1 Introduction�������������������������������������������������������������������������������������� 199 15.2 Initial Steps �������������������������������������������������������������������������������������� 200 15.3 Clinical History�������������������������������������������������������������������������������� 200 15.4 Neurological Examination���������������������������������������������������������������� 201 15.4.1 Type of Nerve Fiber Involvement �������������������������������������� 201 15.4.2 Distribution of Symptoms�������������������������������������������������� 202 15.5 Electrodiagnostic Studies������������������������������������������������������������������ 202 15.6 Laboratory Testing���������������������������������������������������������������������������� 203

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1 5.6.1 Examination of the Cerebrospinal Fluid ���������������������������� 204 15.6.2 Genetic Testing ������������������������������������������������������������������ 204 15.6.3 Nerve Biopsy���������������������������������������������������������������������� 205 15.6.4 Peripheral Nerve Imaging �������������������������������������������������� 205 15.6.5 Other Examinations������������������������������������������������������������ 205 15.7 Conclusion���������������������������������������������������������������������������������������� 206 References���������������������������������������������������������������������������������������������������� 206 16 C  lassification of Immune-Mediated Neuropathies �������������������������������� 207 16.1 Classification������������������������������������������������������������������������������������ 208 17 I mmune-Mediated Demyelinating Neuropathies������������������������������������ 209 17.1 Introduction�������������������������������������������������������������������������������������� 209 17.2 Guillain-Barré Syndrome������������������������������������������������������������������ 209 17.2.1 Pathogenesis������������������������������������������������������������������������ 210 17.2.2 Clinical Features ���������������������������������������������������������������� 212 17.2.3 Electrophysiological Findings�������������������������������������������� 213 17.2.4 Laboratory Investigations��������������������������������������������������� 213 17.2.5 Role of Nerve Biopsy in GBS�������������������������������������������� 214 17.2.6 Treatment���������������������������������������������������������������������������� 214 17.2.7 Paraneoplastic GBS������������������������������������������������������������ 215 17.3 Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) ������������������������������������������������������ 215 17.3.1 Introduction������������������������������������������������������������������������ 215 17.3.2 Clinical Features of Typical CIDP�������������������������������������� 217 17.3.3 Electrodiagnostic Features and Ancillary Testing�������������� 217 17.4 Patterns Suggestive of Atypical CIDP or Disease Mimickers���������� 218 17.4.1 Rapid Clinical Progression by Definition �������������������������� 218 17.4.2 Length-Dependent Sensory-Greater-Than-Motor, Axonal-­­Predominant Peripheral Neuropathy���������������������� 219 17.4.3 Non-Length-Dependent Sensory Ganglionopathy/Neuronopathy������������������������������������������ 219 17.4.4 Upper-Limb-Predominant Neuropathy ������������������������������ 219 17.4.5 Sensory and Motor Demyelinating Neuropathy ���������������� 220 17.4.6 Sensory and Motor Axonal Polyradiculoneuropathy���������� 221 17.4.7 CIDP with a Paraprotein ���������������������������������������������������� 221 17.4.8 Paraneoplastic CIDP ���������������������������������������������������������� 221 17.5 Conclusions�������������������������������������������������������������������������������������� 222 References���������������������������������������������������������������������������������������������������� 222 18 Immune-Mediated Axonal Neuropathies������������������������������������������������ 227 18.1 Introduction�������������������������������������������������������������������������������������� 227 18.2 Vasculitic Neuropathy���������������������������������������������������������������������� 228 18.2.1 Introduction������������������������������������������������������������������������ 228 18.2.2 Classification���������������������������������������������������������������������� 229 18.2.3 Clinical Features ���������������������������������������������������������������� 230

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18.2.4 Nonsystemic Vasculitic Neuropathy with Proximal Involvement (Nondiabetic Lumbosacral Radiculoplexus Neuropathy)���������������������������������������������� 235 18.2.5 Subtypes������������������������������������������������������������������������������ 236 18.2.6 Imaging ������������������������������������������������������������������������������ 239 18.2.7 Conclusion�������������������������������������������������������������������������� 239 18.3 Connective Tissue Disorders������������������������������������������������������������ 240 18.4 Sarcoidosis���������������������������������������������������������������������������������������� 240 18.4.1 Neurosarcoidosis Consortium Consensus Group Definition and Consensus Diagnostic Criteria for Neurosarcoidosis ���������������������������������������������������������� 241 18.5 Immune-Mediated Gastrointestinal Disorders���������������������������������� 242 18.5.1 Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative Colitis���������������������������������������������������������� 243 18.5.2 Celiac Disease�������������������������������������������������������������������� 243 18.6 Paraprotein-Associated Neuropathy ������������������������������������������������ 244 18.6.1 Epidemiology���������������������������������������������������������������������� 245 18.6.2 Pathogenesis������������������������������������������������������������������������ 245 18.6.3 IgM Paraproteinaemic Disorders���������������������������������������� 245 18.6.4 IgG or IgA Paraproteinaemic Disorders ���������������������������� 248 18.6.5 IgM, IgG, or IgA Paraproteinaemic Disorders ������������������ 249 18.6.6 Investigations���������������������������������������������������������������������� 251 18.6.7 Nerve Biopsy���������������������������������������������������������������������� 252 18.6.8 Conclusion�������������������������������������������������������������������������� 254 18.7 Paraneoplastic Disease���������������������������������������������������������������������� 256 18.7.1 Types of Neuropathy���������������������������������������������������������� 257 18.7.2 Diagnosis���������������������������������������������������������������������������� 258 18.7.3 Conclusion�������������������������������������������������������������������������� 259 18.8 Axonal GBS�������������������������������������������������������������������������������������� 259 18.9 Idiopathic Perineuritis���������������������������������������������������������������������� 261 References���������������������������������������������������������������������������������������������������� 261 19 M  imics of Immune-Mediated Neuropathy���������������������������������������������� 269 19.1 Introduction�������������������������������������������������������������������������������������� 269 19.2 Diagnosis of Peripheral Neuropathies���������������������������������������������� 269 19.3 Acquired Neuropathies �������������������������������������������������������������������� 270 19.3.1 Metabolic Neuropathies������������������������������������������������������ 270 19.3.2 Toxic Neuropathies Metals ������������������������������������������������ 272 19.3.3 Drugs���������������������������������������������������������������������������������� 273 19.3.4 Chemicals and Plants���������������������������������������������������������� 274 19.3.5 Neurolymphomatosis���������������������������������������������������������� 275 19.3.6 Hansen’s Neuritis���������������������������������������������������������������� 276 19.3.7 Cholesterol Emboli Neuropathy ���������������������������������������� 277 19.4 Conclusions�������������������������������������������������������������������������������������� 278 References���������������������������������������������������������������������������������������������������� 278

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20 C  urrent Concepts and Future Prospects in Immune-Mediated Neuropathies���������������������������������������������������������������������������������������������� 281 20.1 Immune Checkpoint Inhibitors �������������������������������������������������������� 281 20.1.1 Introduction������������������������������������������������������������������������ 281 20.1.2 Approach to Differential Diagnosis������������������������������������ 282 20.1.3 Conclusions������������������������������������������������������������������������ 283 20.2 Coronavirus Disease 19 (COVID-19)/Coronavirus 2 (SARS-CoV-2) Associated Peripheral Neuropathy�������������������������� 283 20.2.1 Introduction������������������������������������������������������������������������ 283 20.2.2 Peripheral Nervous System Manifestations and Complications �������������������������������������������������������������������� 284 20.3 Humoral Immune Endoneurial Microvasculopathy�������������������������� 284 20.3.1 Introduction������������������������������������������������������������������������ 284 20.3.2 Conclusion�������������������������������������������������������������������������� 287 References���������������������������������������������������������������������������������������������������� 288

About the Author

Balan  Louis  Gaspar  is the Founder and Director of NextGenPath Diagnostics which provides state-of-the-art histopathology services in India. He is the first in the country to super-specialize in the field of histopathology (DM Histopathology) from the prestigious Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh. Of note, he had established the neuromuscular lab during his 3-year DM residency. He was awarded the prestigious “Prof. Subhash Kumari Gupta Memorial Gold Medal” in his postgraduation (MD Pathology) from the same institute. Apart from his sound knowledge in the field of diagnostic histopathology, he has profound experience in ancillary techniques such as immunohistochemistry, immunofluorescence, electron microscopy, conventional and advanced molecular techniques such as fluorescence in situ hybridization (FISH), Sanger sequencing, and next-generation sequencing (NGS). He has more than 40 scientific papers in peer-reviewed indexed national and international journals to his credit. His recent textbook Myopathology: A Practical Clinico-pathological Approach to Skeletal Muscle Biopsies Springer Publications, 2019, has been well received in the academic and research community. He is one of the few in the country to have expertise in muscle and nerve biopsy interpretation. He has been a guest faculty in national and international conferences and an active member of several scientific societies.

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Part I Immune-Mediated Myopathies

1

Introduction to Immune-Mediated Myopathies

1.1 Normal Skeletal Muscle Skeletal muscle is a specialized structure in the body with specific functions and is made up of myocytes and extracellular components. The extracellular component comprises the extracellular matrix (ECM), resident cells, and neurovascular bundle. The interaction between cytoskeletal proteins of the myocytes and extracellular matrix components plays a major role in normal muscle contraction. Anatomically, the ECM can be distinguished into epimysium, perimysium, and endomysium. Collagen type I is the major content of perimysial connective tissue. Type III collagen has uniform distribution in endomysium and epimysium. Type IV collagen forms the basement membrane of myocytes. Proteoglycans constitute the second most abundant ECM protein in the skeletal muscle and serve as major regulators of local homeostasis. The ECM is also the residing site for fibroblasts, adipocytes, and satellite cells. Last, but not least neurovascular bundle, a complicated structure made up of arterioles, capillaries, venules, lymphatics, and autonomic nerves are responsible for the control of muscle perfusion.

1.2 Immunometabolism of Skeletal Muscle The concept of linking metabolism and immunity has gained importance in the recent past. Inflammation plays a central role in various metabolic diseases and conversely, the metabolic derangements in the cells of the immune system can result in immune dysregulation [1]. Warburg described metabolic changes and aerobic glycolysis in cancer cells early in the twentieth century that are now known to be driven by activated oncogenic signaling pathways [2, 3]. Those same signaling pathways are activated to promote aerobic glycolysis in stimulated immune cells and play key roles to reprogram metabolism from catabolic oxidative pathways to anabolic pathways [4–6]. First demonstrated by Vats et  al. that macrophage metabolism can © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. L. Gaspar, Immune-Mediated Myopathies and Neuropathies, https://doi.org/10.1007/978-981-19-8421-1_1

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4

1  Introduction to Immune-Mediated Myopathies

influence the production of inflammatory cytokines as alternatively activated macrophages rely on a different metabolic program than classically activated macrophages, this principle has since been shown in T cells, myeloid-derived suppressor cells (MDSCs), and dendritic cells (DCs). The cytokines and signaling pathways that guide distinct immune responses also promote these specific programs that support bioenergetics and biosynthesis [7–10]. The intersection of metabolism and immunity at the systemic and cellular levels now forms the rapidly evolving field of immunometabolism. Another innate mechanism of immunometabolic regulation is through the complement system. The complement system is a pattern recognition receptor (PRR) system that has newly identified roles to regulate basic T cell metabolism and physiology [11]. In addition to secreted complement that arises from the liver, West et al. review recent findings showing that T cells produce small amounts of intracellular forms of complement [12]. C3 and C5 in this setting are each cleaved to C3a and C3b and C5a and C5b by intracellular proteases. A subsequent set of intracellular receptors then recognize these ligands that promote glycolysis and lipid oxidation. Indeed, West et al. speculate that complement arose in single-celled organisms as a metabolic and stress-sensing mechanism that subsequently evolved to recognize and help eliminate pathogens. This intracellular system may be essential for cell viability, as individuals with complement deficiency syndromes nevertheless have been shown to retain expression of intracellular complement components. In addition to direct actions of complement, the complement regulatory cofactor CD46 is a human-specific complement receptor that can promote T cell glycolysis in response to engagement with extracellular complement. While the CD46 proximal signals are not certain, the Notch and PI3K pathways are likely candidates to then promote T cell glycolysis and inflammation. Importantly, individuals deficient in CD46 have T cell immunodeficiencies. Overall, complement has been previously recognized to promote defense from invading pathogens, but current data support an additional role to maintain cell survival and tissue homeostasis. One tissue that has been a focus of immunological research is adipose tissue. A wide range of changes in the adipose tissue-resident immune cell populations occurs with obesity, which can vary by the depot. Macrophages, in particular, change in content and phenotype from lean to obese to weight-cycled states and influence the development of insulin resistance, diabetes, cardiovascular disease, and cancer. Since back-to-back reports of adipose tissue infiltration by macrophages in 2003, the field has shown the importance of essentially every immune cell in adipose tissue with unique depot-specific differences [13–15]. Caslin et al. review the contribution of the predominant immune cell in fat tissue and adipose tissue macrophages (ATM) where extrinsic effects on local and systemic immunometabolism, as well as intrinsic immunometabolism and effects on phenotype, are discussed [16]. From the first report of differences in ATM characteristics between lean and obese, the evolution of the ATM phenotype has varied. In short, in vitro differentiation studies to generate proinflammatory M1-like macrophages vs. anti-inflammatory immunomodulatory M2-like macrophages failed to hold in  vivo [17]. Advances in flow cytometry, proteomics, metabolomics, and single-­cell sequencing of macrophages have shown varied phenotypes that blend both classical M1-like and alternative M2-like markers depending on the age of mice, duration of the diet, and extent of obesity or weight loss. The interaction of

1.3  Immune Cells and Inflammatory Myopathies

5

ATM with oxidized lipids and other metabolites secreted from adipocytes or varied stromal cells in adipose impacts inflammation and insulin resistance [18]. Thus, it is increasingly important to assess the metabolic and cellular interactions in the adipose tissue. Skeletal muscle serves as the major site for insulin-stimulated glucose disposal and subsequently, glucose homeostasis. The association of metabolic and cardiovascular diseases with exercise and muscle metabolism is widely acknowledged. Several of these diseases also exhibit chronic tissue inflammation with obesity, as an underlying etiology. Recent research has begun to unravel the complexity of this cross-talk (both inter- and intra-organ) between inflammation and metabolism, spawning a body of active and rapidly expanding research called “immunometabolism” [19]. In the following section, we highlight several important factors that have been identified as contributing to immunometabolism within skeletal muscle. We do not focus on a whole-body view (intra-organ) signaling that drives communication between immune and metabolic factors [20–22]. Skeletal muscle, in states such as exercise, injury, inactivity, or disease, is replete with infiltrating immune cells, and circulating immune factors (cytokines and adipokines derived from muscle fat depots—intermyocellular and perimuscular adipose tissue [23, 24]. Additionally, it is also now established that the skeletal muscle is an endocrine organ secreting cytokines and other peptides (such as IL-6, IL-8, IL-15, IGF1, FGF21, FSTL1, irisin, all termed “myokines”), whose levels are regulated by muscle contractile activity and subsequently exercise [25–28]. Interestingly, several of these are known to be secreted by adipocytes and are often referred to in the literature as adipomyokines [29]. For instance, irisin, a recently discovered and much-­debated exercise (PGC-1α) induced myokine is suggested to be a metabolic regulator in muscle [30]. These cytokines/myokines exert auto-, para-, and/or endocrine effects in a context-specific manner enabling the muscle to maintain the metabolic homeostasis of lipids and proteins, in health and exercise. A shift in balance from an immunometabolic adaptive profile, observed in healthy muscle tissue, to a maladaptive state as observed in chronic metabolic disorders, occurs through deficient cross-talk between immune and metabolic signaling factors such as the inflammasome, insulin receptors, TNFα, and other cytokines.

1.3 Immune Cells and Inflammatory Myopathies Although the detailed pathogenesis of idiopathic inflammatory myopathies (IIMs) remains unclear, immune mechanisms have long been recognized as of key importance. Immune cells contribute to many inflammatory processes via intercellular interactions and secretion of inflammatory factors, and many studies have demonstrated the participation of a variety of immune cells, such as T cells and B cells, in the development of IIMs. Accumulating advances in pathogenesis elucidation have prompted a better understanding of IIMs. Immune cells in the peripheral blood and inflamed tissues of IIM patients show significant numerical or phenotypic changes leading to pathogenetic immune imbalance. The encouraging therapeutic effects of biological agents targeting immune cells and related pathways also emphasize a key role in the immune response in the pathogenesis of IIMs [31].

6

1  Introduction to Immune-Mediated Myopathies

Over the past decade, researchers have mainly focused on immune mechanisms in the development of IIMs due to the evidence regarding quantitative as well as qualitative abnormalities of immune cells in tissues and the circulation for almost all types of IIMs. Lymphocytes are an important class of immune cells that are subdivided into T cells, B cells, and natural killer (NK) cells. T cells and B cells are major components of adaptive immunity, recognizing specific antigens and generating specific cell-mediated or antibody-mediated responses. NK cells participate in innate immunity and function by releasing immunomodulatory cytokines or cytotoxic granules following their activation. Other innate immune cells mainly include dendritic cells and macrophages, which initiate and support local immune responses by processing and presenting antigens. In addition, mesenchymal stem cells and low-density granulocytes exhibit unique immunologic functions.

1.4 Interferons in Inflammatory Myopathies Recently, interferon (IFN) pathways have been identified as key players implicated in the pathophysiology of myositis. In dermatomyositis (DM), the key role of IFN, especially type I IFN, has been supported by the identification of an IFN signature in the muscle, blood, and skin of DM patients [32]. In addition, DM-specific antibodies target antigens involved in the IFN signaling pathways. The pathogenicity of type I IFN has been demonstrated by the identification of mutations in the IFN pathways leading to genetic diseases, the monogenic interferonopathies. This constitutive activation of IFN signaling pathways induces systemic manifestations such as interstitial lung disease, myositis, and skin rashes. Since DM patients share similar features in the context of an acquired activation of the IFN signaling pathways, we may extend underlying concepts of monogenic diseases to acquired interferonopathy such as DM. Conversely, in antisynthetase syndrome (ASyS), available data suggest a role of type II IFN in blood, muscle, and lung. Indeed, transcriptomic analyses have highlighted a type II IFN gene expression in ASyS muscle tissue. In sporadic inclusion body myositis (sIBM), type II IFN appears to be an important cytokine involved in muscle inflammation mechanisms and potentially linked to degenerative features. For immune-mediated necrotizing myopathy (IMNM), currently published data are scarce, suggesting a minor implication of type II IFN. The role of involvement of different IFN subtypes and their specific molecular mechanisms in each myositis subset will be discussed later.

1.5 Conclusion Skeletal muscle is an immunologically privileged site. Any disturbance in the systemic and local immunological homeostasis can result in muscle inflammation. Knowledge of normal immunological homeostasis can help understand the pathophysiology of IIMs.

References

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References 1. Makowski L, Chaib M, Rathmell JC. Immunometabolism: from basic mechanisms to translation. Immunol Rev. 2020;295:5–14. 2. Warburg O. On the origin of cancer cells. Science. 1956;123:309–14. 3. Kim J, DeBerardinis RJ. Mechanisms and implications of metabolic heterogeneity in cancer. Cell Metab. 2019;30:434–46. 4. Rathmell JC, Vander Heiden MG, Harris MH, Frauwirth KA, Thompson CB. In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol Cell. 2000;6:683–92. 5. Frauwirth KA, Riley JL, Harris MH, et  al. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16:769–77. 6. Wang R, Dillon CP, Shi LZ, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35:871–82. 7. Vats D, Mukundan L, Odegaard JI, et  al. Oxidative metabolism and PGC-1beta attenuate macrophage-­mediated inflammation. Cell Metab. 2006;4:13–24. 8. Michalek RD, Gerriets VA, Jacobs SR, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. 2011;186:3299–303. 9. Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5:3–8. 10. Krawczyk CM, Holowka T, Sun J, et  al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood. 2010;115:4742–9. 11. Kolev M, Dimeloe S, Le Friec G, et al. Complement regulates nutrient influx and metabolic reprogramming during Th1 cell responses. Immunity. 2015;42:1033–47. 12. West EE, Kunz N, Kemper C. Complement and human T cell metabolism: location, location, location. Immunol Rev. 2020;295:68–81. 13. Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30. 14. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808. 15. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003;112:1785–8. 16. Caslin HL, Bhanot M, Bolus WR, Hasty AH. Adipose tissue macrophages: unique polarization and bioenergetics in obesity. Immunol Rev. 2020;295:101–13. 17. Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes. 2007;56:16–23. 18. Flaherty SE 3rd, Grijalva A, Xu X, Ables E, Nomani A, Ferrante AW Jr. A lipase-independent pathway of lipid release and immune modulation by adipocytes. Science. 2019;363:989–93. 19. Hotamisligil GS.  Foundations of immunometabolism and implications for metabolic health and disease. Immunity. 2017;47:406–20. 20. Hamrick MW.  A role for myokines in muscle-bone interactions. Exerc Sport Sci Rev. 2011;39:43–7. 21. Hamrick MW. The skeletal muscle secretome: an emerging player in muscle-bone crosstalk. Bonekey Rep. 2012;1:60. 22. Lee YS, Wollam J, Olefsky JM.  An integrated view of immunometabolism. Cell. 2018;172:22–40. 23. Khan IM, Perrard XY, Brunner G, et al. Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance. Int J Obes. 2015;39:1607–18. 24. Pillon NJ, Krook A. Innate immune receptors in skeletal muscle metabolism. Exp Cell Res. 2017;360:47–54.

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25. So B, Kim HJ, Kim J, Song W. Exercise-induced myokines in health and metabolic diseases. Integr Med Res. 2014;3:172–9. 26. Febbraio MA, Pedersen BK. Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev. 2005;33:114–9. 27. Pedersen BK. Muscles and their myokines. J Exp Biol. 2011;214:337–46. 28. Schnyder S, Handschin C. Skeletal muscle as an endocrine organ: PGC-1alpha, myokines and exercise. Bone. 2015;80:115–25. 29. Raschke S, Eckel J. Adipo-myokines: two sides of the same coin—mediators of inflammation and mediators of exercise. Mediat Inflamm. 2013;2013:320724. 30. Mukund K, Subramaniam S. Skeletal muscle: a review of molecular structure and function, in health and disease. Wiley Interdiscip Rev Syst Biol Med. 2020;12:e1462. 31. Zhao L, Wang Q, Zhou B, Zhang L, Zhu H. The role of immune cells in the pathogenesis of idiopathic inflammatory myopathies. Aging Dis. 2021;12:247–60. 32. Bolko L, Jiang W, Tawara N, et  al. The role of interferons type I, II and III in myositis: a review. Brain Pathol. 2021;31:e12955.

2

Diagnostic Evaluation of Immune-­Mediated Myopathies

2.1 Introduction The inflammatory myopathies (IM) constitute a heterogeneous group of acquired myopathies that have in common the presence of endomysial inflammation and/or express markers of inflammatory myopathy. Based on steadily evolved clinical, histological, and immunopathological features and some autoantibody associations, they can be classified. Each inflammatory myopathy subset has distinct immunopathogenesis, prognosis, and response to immunotherapies, necessitating the need to correctly identify each subtype from the outset to avoid disease mimics and proceed to early therapy initiation. The diagnosis of IM is based on the combination of clinical history including the pattern of muscle involvement and tempo of disease progression (as described above), combined with the determination of serum muscle enzymes, muscle biopsy findings, and at times autoantibodies. Ancillary information is provided by electromyography, which can be useful to exclude neurogenic conditions or assess disease activity. Muscle MRI with contrast can reveal edema and inflammation in muscle and fascia and is mainly useful to define and assess the distribution of atrophic muscles.

2.2 Clinical Features Patients with all IM forms experience slow, subacute, and rarely acute onset of difficulty performing tasks requiring the use of proximal muscles, such as climbing steps or getting up from a chair; patients with sporadic inclusion body myositis (sIBM), however, may present first with weakness in the distal muscles of hands and feet and difficulties with buttoning, typing, or raising toes and feet. Neck-extensor and pharyngeal muscles can be affected in all subsets resulting in difficulty holding up the head (head drop) and dysphagia. In advanced cases, respiratory muscles can be affected. Myalgia and muscle tenderness may also occur, most often in © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. L. Gaspar, Immune-Mediated Myopathies and Neuropathies, https://doi.org/10.1007/978-981-19-8421-1_2

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anti-synthetase syndrome (ASS); if myalgia is prominent, coexistent fasciitis should be considered. Extramuscular manifestations may occur in all IM, but rarely in sIBM, and include arthralgia, Raynaud’s phenomenon, and pulmonary complications due to interstitial lung disease as seen in ASS or amyopathic dermatomyositis (DM) with anti-melanoma differentiation-associated protein-5 [MDA-5] antibodies [1].

2.3 Serum Muscle Enzymes Creatine kinase (CK) is elevated in all subtypes with active disease but can be normal when the disease has become chronic. Very high levels point to immune-mediated necrotizing myopathy (IMNM), while normal levels from the outset can be seen in DM and ASS reflecting predominant pathology in the interstitial tissues. Aldolase may be also elevated especially if the fascia is involved [1].

2.4 Electrodiagnostic Studies Electrodiagnostic (EDX) studies, in this respect, are an extension of the physical examination and may help establish the diagnosis of myopathy [2]. EDX studies, however, are not always needed to diagnose a myopathy. This is particularly true in the pediatric and, occasionally, the adult population. Often, patients with inherited myopathies present with characteristic phenotypes, and, possibly, a positive family history. In these cases, it is reasonable to proceed directly to genetic testing. In addition, at times, the diagnosis ultimately requires a muscle biopsy, regardless of the EDX study results. Therefore, if clinical suspicion for myopathy is high, generally corroborated by elevated CK levels, it is often reasonable to skip or limit the extent of the EDX studies. Finally, EDX studies may be normal in selected muscle diseases (certain endocrine, metabolic, congenital, and mitochondrial myopathies). Thus, in the appropriate clinical context, normal EDX studies do not necessarily rule out the presence of myopathy. EDX studies are most useful to diagnose a myopathy when further data are needed to exclude alternative diagnoses, confirm the presence of muscle disease, and narrow down the differential. First of all, the results of nerve conduction studies (NCSs) and electromyography (EMG) are used to exclude neuromuscular conditions that may mimic a myopathy (such as motor neuron disease and neuromuscular junction disorders or, occasionally, motor neuropathies). Second, EMG is often able to confirm the diagnosis of a muscle disorder, when motor units with characteristic morphology and recruitment pattern are identified. In such cases, EMG may also add diagnostic information relating to the location, type, and severity of the underlying process. For example, the presence of abnormal spontaneous activity may help narrow down the differential among different myopathic processes. Finally, EMG may be useful in identifying target muscles for biopsy. This is particularly helpful when the only clinically weak muscles are not easily accessible for biopsy

2.4 Electrodiagnostic Studies

11

(such as the gluteal muscles, the hip flexors, or the paraspinals). The yield of a muscle biopsy increases when a weak (Medical Research Council grade 4 of 5), but not end-stage, muscle is biopsied. EMG analysis allows the evaluation of multiple sites and the identification of affected muscles that are not weak on neurologic examination.

2.4.1 Nerve Conduction Studies The authors usually perform routine NCSs first, expecting sensory NCSs to be normal in myopathies unless there is a coexistent neuropathy. Motor NCSs are also generally normal because routine motor NCSs assess distal muscles that are preserved in most myopathic processes. Exceptions in this respect are distal myopathies (which preferentially affect distal muscles), the myopathy of intensive care (which is often generalized and may be associated with polyneuropathy), or severe cases of myopathies that start proximally but then extend to involve distal muscles in the end-stage. If motor NCSs are affected, CMAP amplitudes are expected to be reduced, with preserved distal latencies and conduction velocities, reflecting muscle damage in the face of normal nerve function. The motor NCSs of a myopathy affecting distal muscles may be similar to the ones seen in motor neuron disorders and presynaptic neuromuscular junction transmission disorders. The former is differentiated from myopathy based on the clinical history and needle EMG findings. The latter is ruled out with additional studies.

2.4.2 Electromyography Needle EMG examination is the most informative part of the EDX study in myopathic disorders [3, 4]. It can confirm the presence of a myopathy, narrow down the differential, and identify an appropriate biopsy site. The number and location of muscles studied depend on the pattern of weakness. At a minimum, studying one proximal and one distal muscle from one upper extremity and one lower extremity as well as the thoracic paraspinals is recommended. Commonly assessed muscles include the deltoid, biceps, triceps, pronator teres, extensor digitorum communis, first dorsal interosseous, gluteal muscles, iliopsoas, vasti, tibialis anterior, and gastrocnemius. Additional muscles may be selected depending on a patient’s pattern of weakness and clinical suspicion. For example, finger flexors are often evaluated in suspected sIBM because they tend to be preferentially affected in this condition. Because most myopathies generally involve proximal muscles first, the diagnostic yield increases when more proximal muscles are sampled. The paraspinals are the most proximal muscles that can be examined and may be the only ones with abnormalities in selected myopathies, such as Pompe disease. Instead cervical or lumbosacral thoracic paraspinals are examined because they are less likely to be affected by unrelated processes, such as nerve root impingement secondary to degenerative spine disease.

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2  Diagnostic Evaluation of Immune-­Mediated Myopathies

The yield of needle EMG increases if clinically weak muscles are studied. EMG is more sensitive than clinical examination and may reveal abnormalities in muscles that, clinically, were believed spared. This is particularly helpful when a decision needs to be made about which muscle to biopsy. Commonly biopsied muscles include the deltoid, biceps, and vasti, and, occasionally, the extensor digitorum communis and tibialis anterior. The gastrocnemius is also easily accessible, but muscle biopsy results may be confounded by the presence of unrelated chronic neurogenic changes secondary to preganglionic neuropathy, which are commonly encountered in asymptomatic individuals. In some patients, the only clinically weak muscles are not readily accessible for biopsy, such as the hip girdle muscles. In these circumstances, the value of the EMG is to identify suitable targets for biopsy. It is best not to biopsy a muscle where needle EMG has been recently performed in order not to mistake inflammatory changes secondary to needle insertion for true pathologic findings. If both sides are affected equally, needle EMG on the dominant side is usually preferred. Muscle biopsy then is performed on the non-dominant side, which is generally more comfortable for the patient, especially if an upper extremity is biopsied. The analysis of spontaneous activity helps narrow down the differential diagnosis. Muscle membrane irritability, in the form of increased insertional activity, fibrillation potentials, and positive sharp waves (PSWs), is characteristic of certain myopathies but not others (inflammatory and toxic/necrotic processes, muscular dystrophies, and selected congenital and metabolic disorders). Although fibrillation potentials and PSWs are often colloquially referred to as denervating potentials, this term needs to be avoided. Denervation implies the presence of an underlying neurogenic pathophysiologic mechanism. Fibrillation potentials and PSWs may, however, also be present in myopathic disorders when the muscle membrane is irritable due to the presence of inflammation or necrosis. Thus, these myopathies are reported as myopathy with muscle membrane irritability or membrane instability and include inflammatory and toxic/necrotic processes, muscular dystrophies, and selected congenital and metabolic disorders. Occasionally, in chronic myopathies, complex repetitive discharges (CRDs) may be seen. This type of abnormal spontaneous activity is nonspecific and simply speaks to the chronic nature of the underlying process. Alternatively, myotonic discharges yield additional diagnostic information. Myotonic discharges, similarly to fibrillations, PSWs and CRDs, are generated at the muscle fiber level. Although their morphology is similar to fibrillations and PSWs, they characteristically wax and wane in both frequency and amplitude. They are typically seen in myotonic disorders, such as myotonic dystrophy type 1 and 2 (DM1 and DM2), myotonia congenita, potassium-­ aggravated myotonias, and potassium-sensitive periodic paralysis. In addition, electrical myotonia may be occasionally encountered in selected myopathies that do not present with clinical myotonia, including inflammatory myopathies, metabolic myopathies (e.g. Pompe disease), and toxic myopathies. Finally, there are some circumstances when the normal insertional activity generated by needle insertion is decreased. This may occur in chronic end-stage myopathies, when electrically active muscle fibers are replaced by fat or connective tissue, typically in muscular dystrophies or, occasionally, in long-standing

2.4 Electrodiagnostic Studies

13

inflammatory myopathies. The electromyographer may also feel increased resistance to needle advancement due to the fibrotic nature of the remaining muscle. Decreased insertional activity may also be seen in patients with certain glycogen storage disorders, such as McArdle disease, experiencing a contracture in that muscle, or during an episode of severe weakness from periodic paralysis. Analysis of motor unit action potential (MUAP) morphology and recruitment pattern is the key element of needle EMG that helps establish the diagnosis of myopathy. In myopathic processes, there is dropout or dysfunction of individual muscle fibers. Thus, the size of the motor unit decreases. The number of available motor units does not change because the pathologic process occurs distal to the motor axons. This results in the emergence of short, small, polyphasic MUAPs. Sometimes, this combination of findings is referred to as a myopathic unit. This term is discouraged because similar MUAPs may be occasionally found in neurogenic and neuromuscular junction disorders and, therefore, do not always imply a primary muscle disease. Most notably, they may be seen in early reinnervation after severe denervation (nascent motor units) when each motor unit is composed of only a few fibers that have successfully reinnervated. More rarely, they may be seen in neuromuscular junction disorders when there is a significant block resulting in functional dropout of individual muscle fibers within each motor unit. When analyzing MUAP morphology, 3 parameters are evaluated: duration, amplitude, and the number of phases. In myopathies, MUAP duration and amplitude both decrease, whereas the number of phases increases; hence, MUAPs are brief, small, and polyphasic. The most important of these parameters is MUAP duration. The decrease in MUAP duration most closely reflects the decrease in the total number of muscle fibers per motor unit, including those that are located at a distance from the recording electrode. Acoustically, this corresponds to a crisp, high-pitch sound. To diagnose a myopathy, however, many MUAPs should be analyzed per muscle and the results compared with what is normally expected for that particular muscle. There is a range of MUAP duration, influenced by age (MUAP duration increases with age) and muscle studied (e.g. some small facial muscles normally have much smaller MUAPs than big limb muscles). Mean MUAP duration is reduced in myopathies, although some of the MUAPs may still be normal. Occasionally, the results of qualitative needle EMG are indeterminate. This may occur when there are only subtle MUAP changes. In such cases, if there is a high clinical suspicion of an underlying myopathy, quantitative MUAP analysis may be performed to increase the diagnostic yield. This is accomplished using standard EMG equipment. Quantitative data regarding the duration of at least 20 MUAPs are collected. Results are then compared with established age-matched, muscle-specific normative values [5]. In a myopathy, these short, small, polyphasic, high-pitch MUAPs display a characteristic early recruitment pattern. Because each motor unit is smaller than normal, it can generate only a small amount of force. Therefore, to produce even a small amount of power, individuals need to recruit many MUAPs that fill the screen early on during muscle contraction. Only the electromyographer performing the study can adequately identify recruitment as early because how much force is being

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2  Diagnostic Evaluation of Immune-­Mediated Myopathies

generated to make such an assessment needs to be known. Importantly, in myopathies, a full interference pattern is seen even in very weak muscles, with many units firing at the same time but producing little power. This is in contrast to weakness secondary to neurogenic processes or central processes. In the former, the interference pattern is not full due to the loss of available motor units. The remaining motor units fire rapidly as a compensatory mechanism creating the pattern of reduced recruitment with rapid firing. In the latter, recruitment is normal, but the interference pattern is not full due to lack of activation, resulting slow firing rate. The only exception to the pattern of short, small, polyphasic MUAPs with early recruitment (described previously) is cases of end-stage muscle that may occasionally be seen in severe chronic myopathies. If all the muscle fibers of an individual motor unit are lost, there is a reduction in the number of available motor units resulting in reduced recruitment. Some reinnervation and motor unit remodeling may also occur over time and a mixed population of short- and long-duration MUAPs may occasionally be seen in severe chronic myopathies, such as sIBM, long-standing polymyositis and dermatomyositis, and end-stage muscular dystrophies. Finally, as discussed previously, short, small, polyphasic MUAPs may also be seen in nascent motor units. In these cases, recruitment of such units is reduced, reflecting the reduced number of motor units available due to the underlying neurogenic process. Polymyositis and dermatomyositis are idiopathic inflammatory myopathies that are characterized on needle EMG by the presence of prominent muscle membrane irritability (fibrillations, PSWs, and even myotonic discharges), especially in proximal muscles. MUAPs are small, short, and polyphasic and recruit early. These abnormal features do not distinguish inflammatory myopathies from other myopathies with muscle membrane instability. In long-standing diseases, a mixed population of small and long-duration MUAPs may be seen. The degree of abnormal muscle membrane irritability is believed to reflect the ongoing disease activity. Many patients with inflammatory myopathies are treated with high-dose steroids. Some may develop new weakness after a period of symptom improvement on steroids. In these cases, it needs to be determined whether the new weakness is secondary to an increase in disease activity or is attributable to type 2 muscle fiber atrophy, which may occur from disuse or chronic steroid administration. Abnormal spontaneous activity is expected in active myositis, although it is not associated with isolated type 2 muscle fiber atrophy. sIBM is an idiopathic inflammatory myopathy that presents generally after the age of 50 years with slowly progressive weakness. The clinical hallmark of sIBM is early involvement of the quadriceps, wrist and finger flexors, and ankle dorsiflexors. The clinical diagnosis is often elusive and many patients have been misdiagnosed with other inflammatory myopathies. Unfortunately, patients with sIBM do not typically respond to immunosuppressive therapies. EDX studies are nonspecific and may provide additional diagnostic confusion. Fibrillations and PSWs are common and, early in the course, are associated with small, short, polyphasic MUAPs. Due to the insidious nature of the myopathic process, however, many patients also exhibit large, long MUAPs, reflecting the chronicity of the disease. Although the morphology of these units may resemble those seen in a chronic neurogenic process, the

2.5 Muscle Imaging

15

recruitment pattern in sIBM is early pointing toward a myogenic basis. In addition, approximately a third of the patients also demonstrate mild axonal sensory polyneuropathy in nerve conduction studies.

2.5 Muscle Imaging MRI is a non-invasive and safe technique for muscle exploration. It allows both muscle morphological analysis (e.g. muscle atrophy) and muscle tissue characterization (e.g. fat replacement or edema). The fascia and the skin, also affected in IIM, may also be imaged with MRI [6]. Normal muscle shows intermediate intensity on T1-weighted sequences and low signal (lower than water or fat) on T2-weighted sequences. For optimal topographic analysis, the transverse plane (also known as the axial or horizontal plane) is the best orientation. In routine, specific sequences are needed to detect intramuscular edema, signs of muscle inflammation, or muscle fiber necrosis. T2 sequences show edema as hypersignals more or less homogeneous without mass effect involving muscles and/or fasciae. The best sequences for edema are Short Tau Inversion-Recuperation (STIR) or Dixon sequences. T2 fat suppression sequences are less used in muscular MRIs since the fat saturation is indeed less homogeneous in the usually large fields of view. T1-weighted images are used to reveal muscle fatty degeneration and atrophy. Atrophy is defined by a loss of muscular volume. Indirect signs can be useful in doubts and when no anteriority is available: thickening of fat tissue located between the muscles, loosening of the muscular aponeuroses and tendons. Fatty degeneration is defined by T1 hypersignal changes in the muscular tissue. T1 sequence with gadolinium injection also permits the detection of edema. This sequence does not have better sensitivity than the STIR sequences for inflammation detection. For muscle MRI in the case of IIM, sequences with gadolinium injection are not recommended. However, they can be useful to detect fasciitis or to help characterize focal myositis.

2.5.1 Muscle MRI and Muscle Biopsy for IIM Diagnosis MRI sensitivity is good but not perfect: pathological analysis can exhibit inflammatory infiltrates in muscle areas without any hyperintense signal on MRI demonstrating that muscle biopsy remains the most sensitive technique. Besides, muscle biopsy is crucial for IIM classification as only myopathological findings are specific to the IIM subsets. On the contrary, when a muscle biopsy is required for IIM diagnosis, it may show false-negative results in up to 10%–20% of cases, probably because of sampling errors, nonspecific changes, or the predominance of fat tissue within samples (muscle degeneration). To improve the sensitivity of the biopsy some authors have suggested that the biopsy could be guided by MRI. The usefulness of muscle MRI has been excessively

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2  Diagnostic Evaluation of Immune-­Mediated Myopathies

overestimated because the findings are not diagnostic for an IM and, contrary to suggestions that it can help select the specific muscle to biopsy, it does not provide more than a careful neurological examination because the surgeon can still obtain tissue from a very atrophic muscle fascicle since the biopsy is not MRI- or CT-guided and within the seemingly viable muscle tissue there are long atrophic fascicles.

2.6 Autoantibodies in Myositis The discovery of novel autoantigen systems related to idiopathic inflammatory myopathies (collectively referred to as myositis) in adults and children has had major implications for the diagnosis and management of this group of diseases across a wide range of medical specialties [7]. Traditionally, autoantibodies found in patients with myositis are described as being myositis-specific autoantibodies (MSAs) or myositis-associated autoantibodies (MAAs), depending on their prevalence in other, related conditions. However, certain MSAs are more closely associated with extramuscular manifestations, such as skin and lung disease, than with myositis itself. It is very rare for more than one MSA to coexist in the same individual, underpinning the potential to use MSAs to precisely define genetic and disease endotypes. Each MSA is associated with a distinctive pattern of disease or phenotype, which has implications for diagnosis and a more personalized approach to therapy. Knowledge of the function and localization of the autoantigenic targets for MSAs has provided key insights into the potential immunopathogenic mechanisms of myositis. In particular, evidence suggests that the alteration of expression of a myositis-related autoantigen by certain environmental influences or oncogenesis could be a pivotal event linking autoantibody generation to the development of disease. Conventionally, autoantibodies found in patients with myositis have been termed either myositis-specific autoantibodies (MSAs) or myositis-associated autoantibodies (MAAs), with the latter term referring to those autoantibodies that are also found in other conditions in which myositis can occur, including systemic sclerosis (SSc) and systemic lupus erythematosus. Although we follow the same convention, we suggest that an alternative terminology might be more appropriate for future use. Given the heterogeneity of disease that is encountered in association with these autoantibodies, “myositis-spectrum disease autoantibodies” might be a preferable term, with MAA retained for those autoantibody specificities commonly also found in other, related autoimmune conditions; alternatively, MSA and MAA could be combined into a single entity such as myositis-related autoantibodies. An intriguing aspect of MSAs is that the detection of more than one such autoantibody in the same individual patient is extremely rare, although MAAs can sometimes coexist [6]. As such, MSAs are ideal biomarkers, not only for identifying homogeneous subsets of myositis but also for exploring more precisely the potential environmental and genetic factors contributing to the disease. Furthermore, knowledge of the function and localization of the autoantigenic targets for MSAs has provided key insights into the potential immunopathogenic mechanisms underlying myositis.

2.7 Muscle Biopsy

17

Indirect immunofluorescence (IIF) using human epithelial type 2 (HEp-2) cells as the substrate is the standard screening test for the presence of an antinuclear antibody (ANA) and is a useful, although imperfect, screen for the detection of MSAs. IIF reveals the intracellular location of the autoantigens recognized by MSAs, and some autoantigens are associated with characteristic staining patterns that provide an important clue to the presence of particular MSAs and MAAs. Most MSAs will yield a positive ANA test but the staining pattern on IIF is not distinctive enough to confirm the antibody specificity. Furthermore, certain MSAs (especially anti-ARS autoantibodies) can yield a negative or only weakly positive ANA test, yet a cytoplasmic speckle staining pattern should be present but is often not assessed or the pattern not reported. Therefore, further assays are necessary to identify the type of MSA following a positive ANA and anticytoplasmic antibody screen, and even following a negative screen if there is a high index of suspicion. Several single and multiplex commercial assays are available for detecting the majority, but not the full repertoire, of MSAs. These assays include (but are not limited to) enzyme-linked immunosorbent assay, addressable laser bead immunoassay, and immunoblotting techniques (such as line blot and dot blot). Immunoprecipitation of the autoantigens extracted from cell lines by MSAs present in the serum, followed by polyacrylamide gel separation, is a highly useful technique for detecting all known MSAs as well as potentially identifying unknown or novel specificities but is not routinely available. The available assays show variable results in terms of performance and at present, there is a lack of a standardized approach to MSA testing. Until more work has been undertaken to compare the performance of the newer assays, it is advisable to check that a positive MSA result is consistent with findings from the ANA IIF screen and with the clinical pattern of disease, and if not consistently seek corroboration of the result using a separate assay system. An MSA or MAA can be found in the majority of patients with either juvenile-­ onset or adult-onset myositis, and further MSAs will probably be identified in addition to those already known. The knowledge and interpretation of the presence of an MSA in a given clinical context may become increasingly important for many specialist areas, especially as reliable assays for the full repertoire of autoantibodies become more widely available. Further studies of the diagnostic accuracy and utility of these assays are needed and will help inform future classification criteria. Moreover, it is also becoming increasingly apparent that serologically defined subgroups of myositis provide valuable insights into genetic susceptibility factors as well as oncogenic and environmental triggers of the disease.

2.7 Muscle Biopsy Inflammatory myopathies (IM) frequently require muscle biopsy as an essential diagnostic procedure to document inflammation as a general myopathological process or to reveal certain IM-specific additional features, such as lymphocytes within intact muscle fibers in polymyositis (PM) and inclusion body myositis (sIBM), conspicuous PAS-positive macrophages in macrophagic myofasciitis, rimmed or

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2  Diagnostic Evaluation of Immune-­Mediated Myopathies

autophagic vacuoles with tubulofilamentous inclusions and/or intracellular amyloid in sIBM, a perifascicular pattern of lesions or undulating tubules in dermatomyositis (DM). IM as a generic group of diseases encompasses the entire age spectrum, although with a different emphasis on different IM at different ages, e.g. juvenile DM or late-onset IBM.  Being grossly divided into infectious and noninfectious (immune-related) conditions, IM does occur worldwide, although infectious forms are more frequently seen in the developing world as distinct entities. However, infectious IM may certainly be encountered in “developed” countries, probably most often in conjunction with trauma and surgical procedures, but then, muscle biopsy is usually not a diagnostic procedure. Hence, the entire spectrum of myopathological diagnostic parameters and markers for IM yields different patterns during and for the diagnostic workup of IM specimens. As is true for the overwhelming majority of neuromuscular disorders in general, autopsy studies of IM, employing modern diagnostic myopathological techniques, have been and still are rarely performed and, therefore, have provided little information on the diagnostic myopathological regimen, to distributional patterns of individual IM, and have hardly ever been available to corroborate biopsy-based findings. Patients who die of IM may be few because of treatability and curability, whereas patients who die with IM may be many because still, a sufficient number of IM are long-lasting chronic diseases. This autopsy-based potential of available muscle tissues has not yet successfully and gainfully been explored, which allows multiple, even abundant sampling of specimens from numerous different muscles to address the frequent diagnostic myopathological problem of focality in IM. Predicated on the essentiality in the diagnostic regimen of IM of the muscle biopsy, only the armamentarium of modern techniques employed in myopathology may allow a thorough and, perhaps, complete myopathological investigation of the biopsied muscle. Different techniques, e.g. histology, enzyme histochemistry, electron microscopy, and immunohistochemistry have different diagnostic values in different forms of IM, but for each IM-suspected biopsied muscle tissue, adequate preparative conditions have to be provided for a panoply of investigations. This care for subsequent optimal diagnostic investigations of the biopsied muscle tissue commences with choosing the correct muscle for biopsy and continues in the operating room where, upon removal of the biopsied tissue, the proper techniques have immediately to be employed, i.e. freezing of muscle for light microscopic studies and adequate fixation of muscle for electron microscopy, and, perhaps, complementary light microscopic investigations. While the individual histological, enzyme histochemical, and electron microscopic methods have not been expanded over the past 20 years, the introduction of immunohistochemistry into myopathology has revolutionarily augmented our diagnostic armamentarium and our myopathological knowledge concerning IM.  Immunoglobulins, complement factors, cell adhesion molecules, cytokines, chemokines, metalloproteinases, and not the least, major histocompatibility complexes (MHC-) I and II, subtyping of lymphocytic infiltrates, and recently of macrophage subpopulations have yielded different results in different forms of IM and, thus, accorded different diagnostic connotations to individual IM.

References

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While noninflammatory neuromuscular diseases largely affect the muscle parenchyma, i.e. the myofibers, sometimes connective tissue, and rarely vessels, IM is marked by involvement of all skeletal muscle constituents, i.e. muscle fibers, vessels of different calibers, i.e. capillaries, arterioles, venules, connective tissue, and as an important additional component, by inflammatory infiltrates of heterogeneous nature. Each of these components may provide typical or atypical patterns of immunohistochemically expressed parameters in different IM. The abundance of applicable antibodies may demonstrate diagnostic overlap in different types of IM, sometimes showing the usefulness of semi-quantitative information, the application of “inflammatory scores,” or the proportion or ratio of, e.g. T4 to T8 lymphocytes in different IM to better assess the diagnostic value of individual immunohistochemical parameters in the complex myopathology of IM on the diagnostic path to identify the individual IM.  Hence, in immunomyopathology of IM, not the only expression of antigens and their demonstration by respective antibodies and immunohistochemical patterns in different IM are of importance, but also immunohistochemical profiles of all the individual muscle tissue constituents among the many different IM. When diagnosing IM by myopathology, three general aspects are of concern: IM with inflammatory infiltrates, IM without inflammatory infiltrates, and non-IM though with inflammatory infiltrates, such as certain muscular dystrophies.

2.8 Conclusion In IM, the combination of clinical features, non-invasive investigations and muscle pathology aid in the final diagnosis. The advances in the application of immunohistochemical (IHC) marker molecules over the past few decades are notable and can be widely used since these markers are part of the routine workup of neuro-/myopathological standard repertoire of most specialized diagnostic units worldwide. Assessment of biopsied skeletal muscle employing IHC is useful not only for diagnostic practice but also for a better understanding of pathophysiological mechanisms.

References 1. Dalakas MC. Inflammatory muscle diseases. N Engl J Med. 2015;372:1734–47. 2. Paganoni S, Amato A. Electrodiagnostic evaluation of myopathies. Phys Med Rehabil Clin N Am. 2013;24:193–207. 3. Petajan JH.  AAEM minimonograph #3: motor unit recruitment. Muscle Nerve. 1991;14:489–502. 4. Daube JR.  AAEM minimonograph #11: needle examination in clinical electromyography. Muscle Nerve. 1991;14:685–700. 5. Nandedkar SD, Stålberg EV. Quantitative measurements and analysis in electrodiagnostic studies: present and future. Future Neurol. 2008;3:745–64. 6. Malartre S, Bachasson D, Mercy G, et al. MRI and muscle imaging for idiopathic inflammatory myopathies. Brain Pathol. 2021;31:e12954. 7. McHugh NJ, Tansley SL. Autoantibodies in myositis. Nat Rev Rheumatol. 2018;14:290–302.

3

Classification of Immune-Mediated Myopathies

3.1

Introduction

Idiopathic inflammatory myopathies (IIM), also known as autoimmune myositis, are a rare group of auto-immune-associated muscle disorders with a heterogenous yet highly specific spectrum of muscular and extra-muscular involvement. Historically, IIM were classified into three major subgroups including polymyositis, dermatomyositis (DM), and sporadic inclusion body myositis (sIBM) mainly by their clinical or pathological features or both in combination [1–10]. The discovery of myositis-­ specific antibodies (MSA) and mounting evidence of their association with relatively specific clinicopathological features together with transcriptomics findings have gradually changed the trend of IIM classification over the past four decades to clinicoseropathological criteria, which classifies IIM into four major subgroups (Table  3.1) DM, sIBM, immune-mediated necrotizing myopathy (IMNM), and recently proposed as a separate entity—antisynthetase syndrome (ASS), whereas the existence of polymyositis as a distinct entity has been questioned [11].

3.2 Dermatomyositis In the 1975 Bohan and Peter classification, myositis patients were clinically divided into dermatomyositis and polymyositis by the presence of typical skin rash, which included description compatible with heliotrope rash, periorbital edema, Gottron papules, Gottron sign, V-sign, and shawl sign only in dermatomyositis [1, 2]. Interestingly, its pathological criteria did not separate dermatomyositis from polymyositis as it allowed perifascicular atrophy (PFA) to be present in both entities. Some of the later classifications were also clinically oriented with criteria variations based on expert opinion. The clinicopathological classification for dermatomyositis was introduced by Dalakas in 1991 and later by the 119th European Neuromuscular Centre (ENMC) international workshop classification of idiopathic inflammatory © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. L. Gaspar, Immune-Mediated Myopathies and Neuropathies, https://doi.org/10.1007/978-981-19-8421-1_3

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JDM, DMSD, CAM, calcinosis, muscle ischemia, skin edema ADM, RP (fatal)-ILD in 1/3 of patients, mucocutaneous ulceration, palmar papules, nonscarring alopecia, panniculitis HLA-DRB1*01:01 HLA-DRB1*04:05 HLA-DRB1*12:02

Anti-NXP-2

Anti-MDA5

Prominent muscle involvement HLA-DRB1*07:01 HLA-DRB1*03:02

Non-PFA

PFA, PFN, perimysial connective tissue fragmentation, PF-ALP, B cells, and B cell clusters can be present Microinfarction

Clinical features and associated HLA haplotype(s) Histological features CAM ( myositis ILD > myositis Severe muscle involvement in early stage Risk cardiac involvement HLA-DRB1*08:03

CAM? HLA-DRB1*07:01 (juvenile) HLA-DRB1*11:01 (adult) CAM

Anti-PL-7 Anti-PL1-2 Anti-OJ

Anti-­ HMGCR

Seronegative IMNM

Anti-SRP

ILD Myositis > ILD HLA-B*08:01 HLA-DRB1*03:01

Anti-SAE Anti-Jo-1

Myofiber necrosis and regeneration, sparse inflammation (macrophages > lymphocytes)

PFA Myofiber necrosis and regeneration, PFN, perimysial connective tissue fragmentation, PF-ALP

Sarcolemma

Sarcolemma

− −/+

+

+

Sarcolemma

−

+

Capillaries Sarcolemma

Sarcolemma Sarcolemma Sarcolemma

−/+ + (PF)

+ (PF) + (PF) + (PF)

+ + +

+ +

(continued)

IMNM: p62 diffuse tiny dots

ASS: Various combination of: myositis, ILD, Raynaud phenomenon mechanic’s hands, joint involvement, fever

3.2 Dermatomyositis 23

Clinical features and associated HLA haplotype(s) Frequently asymmetrical weakness, knee extensors, finger flexors >45 years of age (younger in virus-associated IBM) HLA-DRB1*03:01 HLA*08:01 Histological features H&E: lymphocytic invasion in endomysium and nonnecrotic fibers mGT: rimmed vacuoles COX: COX-negative fibers Tubulofilaments in vacuoles and/or in nuclei

Pathological features Immunohistochemical features HLA-­ ABC HLA-DR C5b-9 + + +/−

Key features p62 discrete subsarcolemmal, perivacuolar area CD8 endomysial, nonnecrotic fibers invasion Highly differentiated T cells

− negative, + positive, ALP alkaline phosphatase, ASS antisynthetase syndrome, C5b-9 membrane attack complex, CADM clinically amyopathic dermatomyositis, CAM cancer-associated myositis, cN1A cytosolic 5’-nucleotidase 1A, COX cytochrome C oxidase, DMSD dermatomyositis sine dermatitis, H&E hematoxylin and eosin, HLA human leucocyte antigen, HMGCR 3-hydroxy-3-methylglutaryl-coenzyme A reductase, sIBM sporadic inclusion body myositis, IIM idiopathic inflammatory myopathy, ILD interstitial lung disease, IMNM immune-mediated necrotizing myopathy, JDM juvenile dermatomyositis, MDA5 melanoma differentiation-associated gene 5, Mi-2 nucleosome remodeling deacetylase complex, mGT modified Gomori trichrome, MxA myxovirus resistance protein A, NXP-2 nuclear matrix protein 2, PF perifascicular, PFA perifascicular atrophy, PFN perifascicular necrosis, PF-ALP perifascicular alkaline phosphatase, RP-ILD rapidly progressive interstitial lung disease, SAE small ubiquitin-like modifier-activating enzyme, SRP signal recognition particle, TIF1γ transcription intermediary factor 1γ

IIM Associated subgroup antibody sIBM AnticN1A?

Table 3.1 (continued)

24 3  Classification of Immune-Mediated Myopathies

3.2 Dermatomyositis

25

myopathies in 2003 (2003 ENMC-IIM) [3, 6]. The 2003 ENMC-IIM criteria for dermatomyositis included subacute or insidious onset symmetrical limb-girdle type muscle weakness and typical dermatomyositis skin rash and require PFA as the specific criterion for the diagnosis of “definite” dermatomyositis. The discovery of a prominent type 1 interferon (IFN1) signature and the recognition of dermatomyositis-­specific antibodies (DMSA) initiated the transformation of the current understanding of dermatomyositis classification [12]. Surrogate immunohistochemical markers for IFN1 signature including sarcoplasmic expression of myxovirus resistance protein A (MxA), interferon-stimulated gene 15 (ISG15), and retinoic acid-inducible gene I (RIG-I) are consistently present in dermatomyositis [13–17]. Among these surrogate markers, MxA is the most studied and is probably the most diagnostically useful marker on muscle histology [18]. To date, five DMSAs are identified: anticomplex nucleosome remodeling histone deacetylase (Mi-2), antitranscription intermediary factor 1γ (TIF1γ), antinuclear matrix protein 2 (NXP-2), anti-melanoma differentiation-associated gene 5 (MDA5), and anti-­ small ubiquitin-like modifier-activating enzyme (SAE). Amounting evidence suggests that each DMSA is associated with distinct clinicopathological features [11]. Clinically, anti-TIF1γ and anti-NXP-2 dermatomyositis are highly associated with malignancy; anti-TIF1γ with dysphagia; anti-Mi-2 with prominent muscle involvement but less evidence of association with malignancy; anti-NXP-2 with skin edema, muscle ischemia, and subcutaneous calcinosis; and anti-MDA5 with clinically amyopathic dermatomyositis, atypical skin lesions, rapidly progressive and eventually fatal interstitial lung disease (RP-ILD), and arthritis. A recent unsupervised data analysis in a Caucasian and African cohort identified three subgroups of MDA5-positive patients: RP-ILD cluster frequently associated with mechanic’s hands and poor prognosis; rheumatoid cluster associated with joint involvements with a less frequent skin lesion, less muscle involvement, less RP-ILD (this cluster has very good prognosis); and vasculopathic cluster associated with skin vasculopathy, skin ulcers, digital necrosis, calcinosis, and muscle weakness with an intermediate prognosis [19]. Anti-SAE seems to be differently associated with malignancy in different ethnic groups; the risk is increased in Chinese but not in a European cohort [20, 21]. Although anti-TIF1γ, anti-Mi-2 and anti-SAE are associated with typical dermatomyositis skin rash, anti-MDA5 is associated with mucocutaneous ulceration, palmar papules, nonscarring alopecia, and panniculitis [22]. Anti-NXP-2 is the least associated with a skin lesion [23]. Associations between human leukocyte antigen (HLA) regions and different DMSAs have been reported in some antibody subtypes in different ethnic groups. In anti-Mi-2 dermatomyositis, HLADRB1*07:01 has been reported in Korean populations and adult Caucasian populations and HLA-DRB*03:02  in the African American population. In anti-MDA5 dermatomyositis, HLA-DRB101:01/*04:05 has been reported in the Japanese population and HLADRB1*12:02 in the Korean population. In Caucasian population with anti-TIF1γ dermatomyositis, HLADQB1*02:01 has been reported in juvenile-onset disease and HLA-­ DQB*02:02 in adult-onset disease, suggestive of possible different pathogenesis in different age groups in anti-TIF1γ dermatomyositis. There was no significant

26

3  Classification of Immune-Mediated Myopathies

classical HLA or amino acid associations in the Caucasian population with antiNXP-2, anti-MDA5, or anti-SAE dermatomyositis [24–26]. Until the recent 239th ENMC international workshop classification of dermatomyositis in 2018 (2018 ENMC-DM), DMSA has never been officially incorporated into dermatomyositis classification [27]. This may be because of the relatively recent discovery of the majority of DMSA as compared with the discovery of anti-Mi-2. In 2018, the 239th ENMC workshop reached an international consensus for a modernized dermatomyositis classification—2018 ENMC-DM. According to the 2018 ENMC-DM, a dermatomyositis classification can be made when presence of clinical cutaneous exam findings of at least two of the following: Gottron sign, Gottron papules and/or heliotrope rash, and skin biopsy consistent with interface dermatitis; presence of at least one of clinical exam findings and dermatomyositis muscle features that is fulfilled with one of the following: presence of proximal muscle weakness and elevated muscle enzyme (creatine kinase, CK); presence of proximal muscle weakness and suggestive dermatomyositis muscle biopsy, that is, lymphocytic infiltration (often in perivascular area), pale staining of COX on perifascicular fibers, and/or positive neuronal cell adhesion molecule (NCAM) staining on perifascicular fibers; presence of elevated muscle enzyme and suggestive dermatomyositis muscle biopsy (as described above) or presence of definitive dermatomyositis muscle biopsy, that is, PFA and/or perifascicular MxA overexpression with rarity or absence of perifascicular necrosis; or presence of clinical exam findings (as previously described) and positivity of one of the following DMSA: anti-Mi-2, anti-MDA5, anti NXP-2, and anti-SAE. Notably, ulcerative skin lesions on the extensor surface of the metacarpophalangeal, proximal interphalangeal, and/or distal interphalangeal joints as could be present in anti-MDA5 dermatomyositis are considered equivalent to Gottron papules by the criteria. The diagnosis of clinically ADM is rendered if at least two clinical findings and skin biopsy finding criteria are fulfilled in the absence of muscle features. The 2018 ENMC-DM criteria are clinicoseropathologically oriented and include antibody-defined subgroups in the classification. Dermatomyositis patients with DMSA will be subclassified according to antibody subtype, whereas dermatomyositis patients without DMSA will be subclassified as seronegative dermatomyositis. Other antibody-defined IIM (i.e. IMNM and ASS) with or without dermatomyositis-like rash will not be classified as dermatomyositis by this classification. Although the 2018 ENMC-DM expands the criteria for definitive dermatomyositis muscle biopsy by including the presence of sarcoplasmic MxA expression, the criteria only limit to perifascicular pattern positivity. In a previous study, however, 43% of MxA positivity can be present beyond the perifascicular area [17]. Presence of any sarcoplasmic MxA positivity should be regarded as a muscle biopsy criterion for definitive dermatomyositis. Notably, the absence of overt PFA and the presence of necrotic fibers in the perifascicular region should not preclude the diagnosis of dermatomyositis. The 2018 ENMC-DM only allows the diagnosis of dermatomyositis in patients with clinical dermatomyositis skin lesions, the diagnosis of “dematomyositis sine dermatitis” (DMSD)-DM without skin manifestation cannot be made with this classification. Dermatomyositis is characterized by a prominent IFN1 signature and categorized by DMSA, thus, sarcoplasmic expression of

3.3  Sporadic Inclusion Body Myositis

27

IFN1 surrogate marker together with DMSA positivity even in the absence of dermatomyositis skin lesion should suffice to make the diagnosis of dermatomyositis [12, 28, 29]. The concept of DMSD is not well accepted and there are no definite criteria for the duration of the adermopathic period to qualify the diagnosis. As there are ongoing developments of dermatomyositis-specific therapy targeting IFN1 pathway, such as Janus kinase inhibitor, having DMSD categorized as an entity of dermatomyositis spectrum will guide access to future clinical trials and treatments that could be beneficial for these patients [30, 31]. Needless to say, serology and muscle biopsy play crucial roles to recognize this condition.

3.3 Sporadic Inclusion Body Myositis The first classification of sporadic inclusion body myositis (sIBM) classification by Griggs et al. in 1995 was principally pathology-based; it allowed sIBM to be diagnosed without any clinical or laboratory data required if the muscle biopsy already met all requirements for pathological criteria [32]. The clinicopathological classification of sIBM was later formulated during the 188th ENMC international workshop “ENMC IBM Research Diagnostic Criteria” (2011 ENMC-sIBM) and classified sIBM into three categories: clinicopathologically defined IBM (CPD-­ sIBM), clinically defined sIBM, and probable sIBM, allowing some diagnostic flexibilities as compared to classification by Griggs et  al. [8]. Clinically, the basic criteria for all three categories include slowly progressive muscle weakness more than 12 months in individuals over 45 years of age with CK level less than 15 times of upper normal limits. A combination of muscle weakness levels involving (a) knee extension muscle equal to or more than hip flexion muscle and (b) finger flexion muscle over shoulder abduction muscle is evaluated in each category as follows: (a) and/or (b) in CPD-sIBM; (a) and (b) in clinically defined sIBM; and (a) or (b) in probable sIBM. Pathological criteria for CPD-sIBM require the presence of all of the following: endomysial inflammatory cell infiltration, rimmed vacuoles, and presence of protein accumulation (by histochemical methods for amyloid or immunohistochemistry for p62, SMI-31, or TDP-43) or presence of 15–18 nm tubulofilaments by electron microscopy. Presence of at least one of the above pathological criteria or expression of MHC class I is required for clinically defined sIBM and probable sIBM. Both “definite” sIBM by Griggs et al. and CPD-sIBM 2011 ENMCsIBM criteria are highly specific (98–100%) but the sensitivity of these criteria is low: 11 and 29% for “definite” and “possible” sIBM by Griggs et al., respectively, and 15, 57, and 84% for CPD-sIBM, clinically defined sIBM, and probable sIBM by 2011 ENMC-sIBM, respectively. To invent higher performing criteria, Lloyd et al. used machine learning to construct data-derived sIBM classification and proposed criteria that require all of the following to be present: finger flexor or quadriceps weakness; endomysial inflammation; and either invasion of nonnecrotic muscle fibers or presence of rimmed vacuoles [7]. The criteria by Lloyd et al. have 90% sensitivity and 96% specificity. These criteria are user-friendly but some severe inflammatory myopathies or other myopathies with rimmed vacuoles may meet the

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3  Classification of Immune-Mediated Myopathies

criteria as well. Thus, additional pathological, immunohistochemical, or even genetic studies should be performed to rule out any possibility of “non-sIBM” vacuolar myopathy. Additional pathological/immunohistochemical findings characteristic of sIBM included: the presence of mitochondrial abnormality demonstrated by COX-­negative fibers or ragged red fibers, CD8-positive cell infiltration in endomysium and nonnecrotic fibers, presence of degenerative biomarkers, for example, discrete subsarcolemmal or perivacuolar p62 positivity, and HLA-DR positivity [33]. Markers associated with T cell cytotoxicity, differentiation/exhaustion/senescent signature are increased in sIBM in comparison with other IIM and other nonimmune muscle diseases [34, 35]. Anticytosolic-5′ nucleotidase 1A (cN1A, NT5C1A) is the only known antibody to be present but not exclusive to sIBM [36]. It is also present in a substantial portion of heterogeneous neuromuscular and non-neuromuscular conditions including but not limited to Sjögren’s syndrome, dermatomyositis, juvenile myositis, and healthy children, although at a lower frequency than sIBM [37]. Presence of anticN1A antibody has been suggested to be associated with more severe clinical phenotype in sIBM: more severe muscle weakness, bulbar, and respiratory involvement, and increased mortality risk, excess of COX-deficient fibers on muscle biopsy, and likelihood of having facial weakness and death because of respiratory cause in sIBM [38–40]. Thus, its utility as a prognostic marker in sIBM may be considered only in relevant clinicopathological context. Of note, HLADRB1*03:01 and HLA*08:01 are reported to be associated with sIBM [33, 36].

3.4 Immune-Mediated Necrotizing Myopathy The current classification of IMNM established by the 224th ENMC international workshop in 2016 (2016 ENMC-IMNM) is a revision of the clinicopathologic description of IMNM in 2003 ENMC-IIM with the integration of serological studies [41]. The 2016 ENMC-IMNM categorizes IMNM into three subgroups according to positive antibodies: antisignal recognition particle (SRP) IMNM, anti3-hydroxy3-methylgluaryl-coenzyme A reductase (HMGCR), and seronegative IMNM. IMNM can affect people of a wide age range [42–44]. In children, the disease can be slowly progressed and mimic muscular dystrophy; the youngest age of onset in IMNM is 10 months old in a patient with anti-HMGCR positivity [43, 45]. Among the three subgroups, anti-SRP IMNM is associated with more severe muscle involvement and may associate with increased risk of cardiac involvement and ILD [46]. Extramuscular involvement in anti-HMGCR IMNM is rare. Although anti-HMGCR autoantibodies were initially found in IMNM patients who were taking statins, a significant number of patients are statin naïve. Statin-naïve patients are younger and tend to have a poorer outcome than statin-exposed anti-HMGCR and anti-SRP IMNM patients [42]. Seronegative IMNM show frequent association with extra-muscular involvement and increased risk of malignancy; anti-HMGCR IMNM association with malignancy is controversial, whereas there is no association in anti-SRP IMNM [47]. Unlike the other major subgroups of IIM, IMNM does not show a strong correlation with either IFN1 or IFN2 signature pathway [28, 29]. HLA-DRB1*11:01 and HLADRB1*07:01

3.5  Antisynthetase Syndrome

29

reported being associated with adult and juvenile anti-HMGCR IMNM, respectively [48, 49]. There is no significant association with classical HLA alleles and anti-SRP IMNM in a large cohort of the Caucasian population [24]. In the Japanese population, HLA-DRB1*08:03 is associated with statin-associated IMNM and anti-SRP IMNM but not anti-HMGCR, which may implicate statin treatment on pathogenesis of IMNM through both HLA-­ DRB1*08:03 anti-SRP and HLA-DRB1*11:01 antiHMGCR pathway [48]. Pathologically, IMNM is characterized by scattered different necrotic and regenerating fibers. The majority of infiltrating inflammatory cells are macrophages; in most cases, only a small number of lymphocytes are present. On immunohistochemistry, in addition to mild HLA-ABC expression, C5b-9 is deposited on the sarcolemma, which suggests that myofiber necrosis is mediated by antibody-­ mediated classical complement activation. This hypothesis is supported by the presence of patients’ autoantibodies, IgG, and C1q depositions on the sarcolemma; C1q is the initiator of the classical pathway [50]. Furthermore, passive transfer of patients’ sera recapitulates IMNM in mice [51]. In a recent study, sarcolemmal p62 positivity with a pattern of diffuse tiny dots in IMNM was shown to be colocalized with key molecules in chaperon-assisted selective autophagy (CASA), for example, BAG3, HSP70, HSPB5 [52]. HLA-ABC expression was also present on the same fibers. In the same study, increased mRNA levels of endoplasmic reticulum (ER)-stress response genes, EDEM, and XBP1 are shown in IMNM. As SRP and HMGCR are present on ER, the authors of the study linked IMNM with CASA and proposed that a diffuse tiny dot-like p62 positive pattern might be useful to distinguish seronegative IMNM from other entities. However, its sensitivity and specificity in IMNM and potentially IMNM-mimic neuromuscular diseases should be further evaluated.

3.5 Antisynthetase Syndrome Antisynthetase syndrome (ASS) is a serologically based entity defined by the presence of one of the following autoantibodies directed against aminoacyl transfer RNA synthetase (antisynthetase): anti-Jo-1 (histidyl), anti-PL-7 (threonyl), anti-­ PL-­12 (alanyl), anti-EJ (glycyl), anti-OJ (isoleucyl), anti-KS (asparaginyl), antiHa (tyrosyl), and anti-Zo (phenylalanyl) clinically accompanied by various combination of myositis, interstitial lung disease (ILD), arthritis/arthralgia, mechanic’s hands, Raynaud phenomenon, and fever [53]. ASS is rarely associated with cancer and rarely present in children [53, 54]. Clinical findings and the clinical courses of ASS are various among reports. Anti-Jo-1 was reported to have a trend toward exclusive and more severe muscle involvement, whereas anti-PL-7 and anti-PL-12 were reported to have a trend toward exclusive and more severe lung involvement. However, a recent large retrospective study of 828 patients in the American and European Network of Antisynthetase Syndrome (AENEAS) collaborative cohort showed broad similarity of clinical findings and clinical course in these antibodies although muscle involvement was less common in anti-PL-12 [54]. Of note, anti-OJ detection can be technically challenging by line/blot immunoassays and ELISA as isoleucyl-tRNA synthetase is a component of multienzyme

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3  Classification of Immune-Mediated Myopathies

synthetase complex. As the structural complex confirmation is essential for anti-OJ recognition, the current preferred method to detect anti-OJ is immunoprecipitation [55]. As a result, the clinicopathologic description and prevalence of anti-OJ ASS described in the literature may not be reliable unless the immunoprecipitation method is used for antibody detection. In a recent study in the Caucasian population, anti-Jo-1 ASS was associated with HLA-B*08:01 and HLA-DRB1*03:01 [24]. Absence of significant HLA region association in other ASS subtypes in this study was likely because of the small sample size. Pathological description in ASS is limited to anti-Jo-1, anti-­OJ, and anti-PL-7 with the presence of perifascicular necrosis, perifascicular fragmentation, and perimysial alkaline phosphatase positivity, which may be at least partly because of scarce muscle involvement in some subtypes including anti-PL-12 [56, 57]. Although there was an attempt to categorize ASS as a clinicoserological subgroup by Love et al. back in 1991, ASS has never been officially categorized as a separate entity of IIM [58]. Without a serological test, ASS may well be misclassified either as polymyositis or, if skin lesion or PFA present, as dermatomyositis. This speculation is supported by the recent unsupervised multivariate analysis by Mariampillai et al. that a population of IIM reclassified as clinically and serologically representative of ASS is composed of patients historically diagnosed as polymyositis and rarely dermatomyositis by Bohan and Peter classification [59]. It is noteworthy that the ASS cluster is separate from other reclassified clusters of dermatomyositis, IMNM, and sIBM; the finding supports ASS as a separate entity. Transcriptomic studies suggested that, in ASS, activation of the type 2 interferon (IFN2) pathway is higher than that of IFN1 pathway resulting in higher expression of IFN2-inducible genes [28, 29]. The findings correlate well with the expression level of IFN2-inducible genes on muscle biopsy sample including expression of HLA-DR on myofibers. HLA-DR expression and its perifascicular predominance can be used as a surrogate marker for IFN2 activation in ASS. Finally, nuclear actin inclusions have been found exclusively in ASS muscle biopsies [60].

3.6 Overlap Myositis Overlap syndrome was mentioned in Bohan and Peter’s classification as a myositis in the course of connective tissue disorder and the independent criteria should be met for each disorder. The concept of overlap myositis was proposed by Troyanov et al. in 2005 as a clinicoserological classification defined by the presence of myositis and at least one clinical overlap feature with those present in connective tissue disease and/or an overlap antibody [61]. Many antibodies that were originally or later categorized as an antibody for overlap myositis including antisynthetase, anti-­SRP, anti-MDA5 are now reclassified to ASS, IMNM, and dermatomyositis, respectively. The remaining antibody in overlap myositis classification includes antisystemic sclerosis (SSc)-specific antibodies and antibodies associated with SSc in the overlap, which include but not limit to anti-Ku, antipolymyositis (polymyositis)/

3.8  Anti-Program Cell Death 1/PD-1 Ligand Inhibitor-Associated Myositis

31

scleroderma (Scl), and anti-U1-ribonucleoprotein (RNP) antibodies [62]. The antibodies list mentioned above has been reported in a wide spectrum of connective tissue/autoimmune diseases.

3.7 Antimitochondrial M2-Associated Myopathy Antimitochondrial M2 antibody (AMA), a signature for primary biliary cholangitis (PBC), can be present in various conditions mainly in the autoimmune disease spectrum including but not limited to SSc, Sjögren’s syndrome, and autoimmune hepatitis; it can also be present in non-autoimmune liver disease. AMA has been increasingly recognized to be associated with myositis with an incidence of 11.3% in a 212 Japanese cohort and 0.006% in an 1180 American cohort of inflammatory myopathy [63]. In these cohorts, 12.5 and 14.3% had to precede PBC. Myopathy with AMA positivity tended to be associated with chronic disease course, muscle atrophy, frequent cardiac involvement (especially arrhythmias), and pathologically necrotizing myopathy [63, 64].

3.8 Anti-Program Cell Death 1/PD-1 Ligand Inhibitor-Associated Myositis Cytotoxic T-lymphocyte-associate protein 4 (CTLA-4), program cell death 1 (PD-1), and PD-1 ligand (PDL1) are immune checkpoints with inhibitory function on T cell immune response. Activation of these pathways allows tumor cells to escape from the host immune system. Blockade of these pathways by immune checkpoint inhibitors (ICIs) in tumor immunotherapy, thus enhance T cell activity and may increase the immune response to self-antigen may lead to a large variety of immune-related adverse events (irAE). Anti-PD-1/PD-L1 inhibitor-associated myositis is not a typical IIM but a recently recognized emergence condition because of the high rate of patients needing intensive care treatment and a high rate of a fatal disease. Notably, myositis associated with anti-PD1/PD-L1 inhibitor monotherapy is more common than anti-CTLA4 and PD-1/PD-L1 inhibitor treatment in combination and much more common than anti-CTLA4 monotherapy. Theoretically, anti-­ PD-­ 1/PD-L1 inhibitor-associated myositis needs to be distinguished from paraneoplastic myopathy. Unlike paraneoplastic myositis which could occur any time during the clinical course, anti-PD-1/PDL-1-associated myositis has an acute or subacute onset within 1 month after initial ICIs exposure. In addition, anti-PD-1/ PD-L1-associated myositis usually accompanies by ocular involvement similar to myasthenia gravis-type features and myocarditis and associates with a higher mortality rate as compared with IIM.  Thorough clinical and laboratory assessments including neurophysiology, antibody workup, muscle enzymes, and muscle biopsy are essential for the recognition of the potentially fatal condition, characterization, and further explanation of its pathogenesis.

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3.9 Polymyositis Polymyositis (PM) is currently considered a wastebasket entity as there is no concrete evidence linking clinical features, autoantibody profile, and/or histological finding that has stood the test of time. Therefore, many experts have questioned its existence. Since PM is the most commonly used terminology in IIM, we have still retained this entity.

3.10 Conclusion IIM is suggestively classified into four major subgroups: dermatomyositis, ASS, IMNM, and sIBM.  Most of the classifications are clinicoseropathologically oriented and clinical and serological criteria play major parts. Transcriptomics and haplotype studies will probably tailor subclassification. Nevertheless, pathomorphological evaluation is indispensable for the classification of sIBM, categorization of seronegative IIM, and in-depth characterization of IIM with known antibodies. In addition, pathological findings may provide clues to improve our understanding of underlying pathomechanisms and their diagnostic and therapeutic implications.

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36. Benveniste O, Allenbach Y. Inclusion body myositis: accumulation of evidence for its autoimmune origin. Brain. 2019;142:2549–51. 37. Yeker RM, Pinal-Fernandez I, Kishi T, et al. Anti-NT5C1A autoantibodies are associated with more severe disease in patients with juvenile myositis. Ann Rheum Dis. 2018;77:714–9. 38. Amlani A, Choi MY, Tarnopolsky M, et  al. Anti-NT5c1A autoantibodies as biomarkers in inclusion body myositis. Front Immunol. 2019;10:745. 39. Lilleker JB, Rietveld A, Pye SR, et al. Cytosolic 5′-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis. Ann Rheum Dis. 2017;76:862–8. 40. Goyal NA, Cash TM, Alam U, et al. Seropositivity for NT5c1A antibody in sporadic inclusion body myositis predicts more severe motor, bulbar and respiratory involvement. J Neurol Neurosurg Psychiatry. 2016;87:373–8. 41. Allenbach Y, Mammen AL, Benveniste O, Stenzel W, Immune-Mediated Necrotizing Myopathies Working Group. 224th ENMC International Workshop: clinico-sero-­pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14–16 October 2016. Neuromuscul Disord. 2018;28:87–99. 42. Lim J, Rietveld A, De Bleecker JL, et al. Seronegative patients form a distinctive subgroup of immune-mediated necrotizing myopathy. Neurol Neuroimmunol Neuroinflamm. 2019;6:e513. 43. Liang WC, Uruha A, Suzuki S, et al. Pediatric necrotizing myopathy associated with anti-­3-­ hydroxy-3-methylglutaryl-coenzyme A reductase antibodies. Rheumatology (Oxford). 2017;56:287–93. 44. Suzuki S, Nishikawa A, Kuwana M, et al. Inflammatory myopathy with anti-signal recognition particle antibodies: case series of 100 patients. Orphanet J Rare Dis. 2015;10:61. 45. Suzuki S, Ohta M, Shimizu Y, Hayashi YK, Nishino I. Anti-signal recognition particle myopathy in the first decade of life. Pediatr Neurol. 2011;45:114–6. 46. Watanabe Y, Uruha A, Suzuki S, et al. Clinical features and prognosis in anti-SRP and anti-­ HMGCR necrotising myopathy. J Neurol Neurosurg Psychiatry. 2016;87:1038–44. 47. Anquetil C, Boyer O, Wesner N, Benveniste O, Allenbach Y. Myositis-specific autoantibodies, a cornerstone in immune-mediated necrotizing myopathy. Autoimmun Rev. 2019;18:223–30. 48. Ohnuki Y, Suzuki S, Shiina T, et  al. HLA-DRB1 alleles in immune-mediated necrotizing myopathy. Neurology. 2016;87:1954–5. 49. Kishi T, Rider LG, Pak K, et al. Association of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies with DRB1*07:01 and severe myositis in juvenile myositis patients. Arthritis Care Res (Hoboken). 2017;69:1088–94. 50. Allenbach Y, Arouche-Delaperche L, Preusse C, et  al. Necrosis in anti-SRP(+) and anti-HMGCR(+)myopathies: role of autoantibodies and complement. Neurology. 2018;90:e507–e17. 51. Bergua C, Chiavelli H, Allenbach Y, et al. In vivo pathogenicity of IgG from patients with anti-­ SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy. Ann Rheum Dis. 2019;78:131–9. 52. Fischer N, Preusse C, Radke J, et  al. Sequestosome-1 (p62) expression reveals chaperone-­ assisted selective autophagy in immune-mediated necrotizing myopathies. Brain Pathol. 2020;30:261–71. 53. Pinal-Fernandez I, Casal-Dominguez M, Huapaya JA, et  al. A longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies. Rheumatology (Oxford). 2017;56:999–1007. 54. Cavagna L, Trallero-Araguas E, Meloni F, et al. Influence of antisynthetase antibodies specificities on antisynthetase syndrome clinical spectrum time course. J Clin Med. 2019;8:2013. 55. Vulsteke JB, Satoh M, Malyavantham K, Bossuyt X, De Langhe E, Mahler M. Anti-OJ autoantibodies: rare or underdetected? Autoimmun Rev. 2019;18:658–64. 56. Mescam-Mancini L, Allenbach Y, Hervier B, et al. Anti-Jo-1 antibody-positive patients show a characteristic necrotizing perifascicular myositis. Brain. 2015;138:2485–92. 57. Uruha A, Suzuki S, Suzuki N, Nishino I. Perifascicular necrosis in anti-synthetase syndrome beyond anti-Jo-1. Brain. 2016;139:e50.

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58. Love LA, Leff RL, Fraser DD, et al. A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups. Medicine (Baltimore). 1991;70:360–74. 59. Mariampillai K, Granger B, Amelin D, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol. 2018;75:1528–37. 60. Stenzel W, Preusse C, Allenbach Y, et  al. Nuclear actin aggregation is a hallmark of anti-­ synthetase syndrome-induced dysimmune myopathy. Neurology. 2015;84:1346–54. 61. Troyanov Y, Targoff IN, Tremblay JL, Goulet JR, Raymond Y, Senecal JL. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine (Baltimore). 2005;84:231–49. 62. Fredi M, Cavazzana I, Franceschini F. The clinico-serological spectrum of overlap myositis. Curr Opin Rheumatol. 2018;30:637–43. 63. Albayda J, Khan A, Casciola-Rosen L, Corse AM, Paik JJ, Christopher-Stine L. Inflammatory myopathy associated with anti-mitochondrial antibodies: a distinct phenotype with cardiac involvement. Semin Arthritis Rheum. 2018;47:552–6. 64. Maeda MH, Tsuji S, Shimizu J. Inflammatory myopathies associated with anti-mitochondrial antibodies. Brain. 2012;135:1767–77.

4

Idiopathic Inflammatory Myopathies

4.1 Introduction Idiopathic inflammatory myopathies (IIM) are composed of heterogeneous subgroups of neuromuscular disorders generally known as myositis. They are collectively characterized by various degrees of muscle weakness and inflammation associated with a different spectrum of extra-muscular manifestations. Until recently, IIM had been widely classified into three major subgroups including polymyositis and dermatomyositis using the 1975 Bohan and Peter classification and inclusion body myositis (sIBM) using the 1995 Griggs et al. classification [1–3]. In 2003, the European Neuromuscular Centre (ENMC) international workshop (2003 ENMC– IIM) revised dermatomyositis and polymyositis classification and proposed two additional categories, immune-mediated necrotizing myopathy (IMNM) and nonspecific myositis to further subclassify IIM according to possible different pathogenesis [4]. Various classification systems based on experts’ opinions were also proposed. These historical classifications, however, contain overlapping clinical and pathological criteria. Inevitably, diagnostic discrepancies and heterogenous treatment outcomes within the same IIM subgroups occur as a result of limitations of classifications and divergent diagnostic approaches, mainly between clinically oriented and pathologically oriented physicians. In the last decade, new IIM classification systems based on extensive clinical data collection, new pathological development, and discovery of myositis-specific autoantibodies (MSA) have been proposed.

4.2 Dermatomyositis 4.2.1 Introduction Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) that is characterized by distinct skin lesions and a clinically heterogeneous constellation of © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. L. Gaspar, Immune-Mediated Myopathies and Neuropathies, https://doi.org/10.1007/978-981-19-8421-1_4

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systemic manifestations. In the absence of characteristic dermatologic findings or myopathy, DM can be difficult to diagnose. In addition, historical approaches to the diagnosis of DM have embraced the use of “overlap” syndromes to account for clinical heterogeneity, making diagnosis even more difficult. Here, the emphasis will be placed on the unique clinical manifestations associated with the presence of myositis-specific antibodies (MSAs). The epidemiology of DM is difficult to determine because a variety of classification systems have historically been used to diagnose the condition. Epidemiologic studies report incidence rates for the IIMs of 2.47–7.8 per 100,000 person-years and prevalence rates of 9.54–32.74 per 100,000 individuals [4, 5]. DM-specific prevalence has been estimated at 1–6 per 100,000 adults in the USA. DM is the most common of the IIMs with a recent analysis of 3067 patients in the EuroMyositis registry identifying DM in 31% of patients [6]. DM affects both genders with a female:male ratio of 2:1. All ethnic groups are affected, but it is more common in African Americans [7]. Population-based data suggest that clinically amyopathic DM (CADM) occurs in ~20% of adults with DM [8]. The average age of diagnosis of DM is bimodal, with juvenile DM (JDM) most commonly diagnosed between 4 and 14 years of age and adult DM diagnosed between 40 and 60 years of age [9]. JDM is the most common inflammatory myopathy of childhood but remains rare, with an estimated incidence of 3.2 cases per million children per year. Rates of clinically amyopathic JDM are not well established [10]. In a recent series of patients with clinically amyopathic JDM, 25% eventually developed muscle involvement [11]. Over the last few decades, several DM-specific autoantibodies have been discovered and each of these has been associated with a unique clinical phenotype. The clinical features of patients with autoantibodies recognizing nuclear matrix protein (NXP) are as follows. Initially named “anti-MJ,” these autoantibodies were first recognized to exist in ∼18% of juvenile DM patients. After the protein target was identified as NXP2, it was shown that these autoantibodies are associated with calcinosis in children with DM.  Approximately 17% of adult DM patients have anti-­NXP2 autoantibodies and initial reports suggested a possible association with cancer. The association between cancer and anti-NXP2 autoantibodies was confirmed in subsequent studies that also demonstrated an increased prevalence of subcutaneous edema, calcinosis, distal weakness, dysphagia, and myalgia compared to adult DM patients without these autoantibodies. Another study showed that anti-­NXP2-­positive juvenile DM patients are weaker and less likely to enter remission than other children with DM [12]. An analysis of muscle biopsies from patients with different DM-specific autoantibodies revealed that lymphocytes surround and invade myofibers in 28% of muscle biopsies from DM patients with other autoantibodies [13]. However, this pathologic finding was never observed in DM patients with anti-NXP2 autoantibodies. Despite these histological differences in muscle biopsy features, preliminary data from gene expression profiling studies show that anti-NXP2 muscle tissue has a prominent type I interferon signature that is indistinguishable from patients with other DM-specific autoantibodies [14]. The clinical features of DM patients with

4.2 Dermatomyositis

39

autoantibodies recognizing transcription intermediary factor 1γ ((TIF-1γ) are as follows. Also called TRIM33, TIF-1γ is a multifunctional protein with complex effects on several cellular pathways, including immunoregulation and carcinogenesis [15]. In a Chinese cohort of DM patients, the prevalence of anti-TIF-1γ autoantibodies was 19.2%; no anti-TIF-1γ autoantibodies were found in other types of IIM [16]. Two types of skin rash were observed in patients with anti-TIF-1γ: one is a facial dermatosis which usually comes with long-­time disease course; the second type is characterized by a skin rash around the hairline. Muscle weakness is common in anti-TIF-1γ positive DM. Muscle biopsy had typical perifascicular atrophy (50%) and other DM-associated pathological features, nonspecific changes (~30%), and a small portion had normal muscle pathology (~12%). Patients with anti-TIF-1γ autoantibodies less infrequently developed interstitial lung disease (ILD) compared with anti-TIF-1γ negative DM patients; of note, the latter group included antisynthetase patients with DM-like rashes. Also, ILD in anti-TIF-1γ positive DM was usually relatively mild and that rapidly progressive (RP)-ILD was rare. Dysphagia occurred in 43% of patients with anti-­TIF-­1γ autoantibodies. A striking clinical feature of patients with anti-TIF-1γ is an association with cancer (55%). Moreover, among those with cancer-associated-­myositis, 64% were positive for anti-TIF-1γ autoantibodies. These results are consistent with a meta-analysis conducted by Prof. Albert Selva-O’Callaghan from Spain [17]. In a further comparison of the clinical features between anti-TIF-1γ positive patients with and without cancer, the age of the disease onset in the group with cancer was significantly older than that of patients without cancer. Although there was a trend for an increased prevalence of dysphagia in patients with cancer, this was not statistically significant. Moreover, other symptoms, including muscle weakness, arthritis, and ILD, were not significantly different between these two groups. Of importance, the survival rate was much lower in patients with cancer than in patients without cancer. The autoantibodies recognizing Mi2 were the first DM-specific serologic marker [18, 19]. The prevalence of anti-Mi2 autoantibodies ranges from 2% to 45% in adult DM patients and from 4% to 10% in juvenile DM patients [20]. These autoantibodies have been associated with the “classic” form of DM, with hallmark cutaneous lesions as well as cuticular overgrowth and periungual hemorrhage, mild muscle disease, a low risk of ILD, and a good prognosis with a low risk of cancer [21, 22]. Previous case series have reported a low prevalence of extra-muscular features, including Raynaud phenomenon, ILD, and arthritis [23, 24]. In the French cohort, however, a third of patients presented with ILD, albeit mostly mild. Arthritis and Raynaud phenomenon were observed in only 10% of anti-Mi2-positive DM patients. Pathological descriptions of anti-Mi2positive DM have reported an increased prevalence of primary inflammation (i.e. focal lymphocytic invasion of myofibers) and, in children, relatively severe pathological findings based on a validated juvenile DM biopsy scoring system [25, 26]. A systematic review of muscle biopsies from the French patients revealed that anti-Mi2-positive DM patients (n = 14) had increased numbers of diffuse CD68 + dominant inflammatory infiltrates, more necrotic and regenerative fibers, and increased sarcolemmal C5b-9 deposition on nonnecrotic fibers compared to

40

4  Idiopathic Inflammatory Myopathies

anti-Mi2-negative DM controls (n = 32). Traditionally, anti-Mi2 antibodies have been associated with a good prognosis and low risk of malignancy. Indeed, the presence of these autoantibodies was even suggested to be an exclusion criterion for paraneoplastic myositis [27]. However, in the French cohort, cancer was found in 22% of anti-Mi2 DM patients within 3 years of diagnosis, with a standardized incidence ratio (SIR) of 5.1 [3.0–8.6] (p 6 months 2. Age of onset >30 years 3. Pattern of weakness  a. Finger flexor weakness  b. Wrist flexor and wrist extensor weakness  c. Quadriceps weakness

Definite All the biopsy features must be present

Laboratory 1. Serum CK < 12× normal 2. Muscle biopsy  a. Mononuclear inflammatory infiltration of nonnecrotic fibers  b. Vacuolated muscle fibers  c. Either intracellular amyloid deposits or 15–18 nm tubulofilaments by electromyography 3. Electromyography  a. Follow-on inflammatory myopathy  b. Long duration motor unit action potential maybe Probable sIBM All the biopsy features are not present

ENMC criteria 2011 (Hilton-Jones) [43] Category Clinical and laboratory features Pathological features Clinicopathologically Duration > 12 months All of the following: defined Age at onset > 45 years Endomysial inflammatory Knee extension weakness ≥ hip infiltrate flexion Rimmed vacuoles Weakness and/or finger flexion Protein accumulation or 15weakness > shoulder abduction to 18-nm filaments weakness Serum CK no greater than 15 × ULN Clinically defined Duration > 12 months One or more, but not all, of: Age at onset > 45 years Endomysial inflammatory Knee extension weakness ≥ hip infiltrate flexion weakness and finger flexion Upregulation of MHC class I weakness > shoulder abduction Rimmed vacuoles weakness Protein accumulation or 15 Serum CK no greater than 15 × ULN to 18 nm filaments Probable Duration > 12 months One or more, but not all, of: Age at onset > 45 years Endomysial inflammatory Knee extension weakness ≥ hip infiltrate flexion weakness or finger flexion Upregulation of MHC class I weakness > shoulder abduction Rimmed vacuoles weakness Protein accumulation or 15 Serum CK no greater than 15 × ULN to 18 nm filaments CK creatine kinase, ENMC European Neuromuscular Center, MHC major histocompatibility complex, ULN upper limit of normal

with sIBM (58% in one series) meet the diagnostic criteria for large granular lymphocytosis, and a small number have overt large granular lymphocytic  leukemia with cytopenias. sIBM might develop from HIV162–165 and HTLV-1 infection, resulting in a typical disease course except for a younger age of onset. HIV-­ associated myositis has been categorized as either polymyositis or sIBM [144, 145]. Patients with HIV-associated myositis might show improved strength of proximal muscles as a result of treatment, but in a study of 11 patients with HIV-associated myositis, all subsequently developed treatment-refractory sIBM [146, 147]. The

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prevalence of some comorbidities, such as cardiovascular disease and diabetes mellitus, in sIBM seemed to be high in several population-based cohort and case series studies that lacked comparator groups (for example, 65% of patients had hypertension and 24% had diabetes mellitus in one study population of patients with sIBM) [148, 149]. A matched case–control Medicare database study reported a higher prevalence of comorbidities in patients with sIBM than in matched patients without sIBM, with increased rates of hypertension (66% versus 22%), hyperlipidaemia (47% versus 18%), diabetes mellitus (34% versus 10%), myocardial infarction (13% versus 2%), congestive heart failure (17% versus 5%), pneumonia (11% versus 2%, aspiration pneumonia, 6% versus 0.3%), and anemia (32% versus 7%). These sIBM comorbidities do not seem to be a consequence of complications of immunosuppressant therapy, such as corticosteroids, and are probably instead related to the systemic inflammatory environment resulting from autoimmunity, as in other forms of inflammatory myopathy and other autoimmune diseases [95, 139].

4.3.9 Progression sIBM is a progressive disease, with a mean or median loss of device-free ambulation from symptom onset estimated at 7.5 to 10 years for a cane and 13–15 years for a wheelchair hand impairment and dysphagia progression are less well quantified. Published longitudinal data regarding sIBM progression are insufficient, and non-­ uniform methods have been used to measure it. Furthermore, published annualized rates of progression of 4–28% per year are specific to the outcome measure used, such as quantitative muscle testing, and assume linearity over time. Some patients experience very little or no disease progression over periods ranging from 4 to 12 years. Although sIBM has been characterized as not fatal because statistical analyses of sIBM populations have not detected a reduction in life expectancy, it is a cause of premature mortality in some patients, most directly from aspiration pneumonia.

4.3.10 sIBM Therapeutics The standard of care for most patients with sIBM involves strictly nonpharmacological management, including emotional support, physical therapy, education on fall precautions and exercise, and dysphagia evaluation. Dysphagia can be treated transiently with pharyngoesophageal dilatation or cricopharyngeal myotomy. Few physicians routinely prescribe immunosuppressant therapies, with the belief that such therapies result in transient responses at best.

4.3.11 Pathogenesis of sIBM No feature of sIBM has generated more debate and speculation than the nature of its pathogenesis. sIBM is often viewed as both a degenerative and autoimmune disease. Various sIBM muscle histochemical abnormalities have collectively been

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called degenerative. However, referring to sIBM as a degenerative disease does not provide information on the mechanisms by which the muscle is injured. The degenerative features of sIBM include rimmed vacuoles and the related myonuclear degeneration, mitochondrial pathology, and myofiber cytoplasmic protein aggregates [150–152]. The concept of protein aggregation has dominated mechanistic thought since the early 1990s, with interest initially focused on four muscle biomarkers (amyloid detected by Congo red, ubiquitin, β-amyloid, and tau) [153–155]. The number of distinct molecules reported as aggregated grew to >80 by 2010 [156]. A theory of β-amyloid accumulation and myotoxicity has dominated and continues to be featured in conceptual models of sIBM [157–159]. In hindsight, a published belief in this theory now seems to be out of proportion to the data supporting it. Indeed, citation distortions in its citation network might have contributed to overvaluing the role of β-amyloid deposition in sIBM pathogenesis. The supporting data were based on methods (immunohistochemistry) and reagents (anti-β-amyloid antibodies) that do not distinguish β-amyloid from its precursor protein, the latter reported as nonspecifically expressed in regenerating myofibers in all muscle diseases [160]. Similar interest in tau protein deposits (using SMI-31 immunoreactivity) also occurred and has similar limitations. Focus on these biomarkers proceeded for decades despite studies demonstrating their rarity or non-existence in sIBM muscle (for example, the presence of Congo red amyloid in 0.4% of myofibers, ubiquitin in 0.7% of myofibers, and β-amyloid in 0% of myofibers. The second generation of muscle histochemical degenerative biomarkers (p62, LC3, and TDP43) has evolved around the unfolded protein response and endoplasmic reticulum (ER) stress, altered autophagy, and mislocalized myonuclear heterogeneous nuclear ribonucleoproteins (hnRNPs) [95, 139]. Some of these studies have combined immunohistochemical results with western blots (TDP43 and p62). Furthermore, results have been reproduced by multiple independent laboratories, with quantitative data showing superior biomarker performance compared with Congo red, ubiquitin, β-amyloid, or SMI-31 immunoreactivity. T cells, myeloid dendritic cells, macrophages, and plasma cells all invade sIBM muscle, but it is the infiltration of muscle by T cells that is the most obvious histological feature of sIBM muscle. The invasion of myofibers by cytotoxic T cells is easily visible by microscopy. sIBM might be the only muscle disease involving cytotoxic T cell-mediated myofiber injury; although polymyositis has been said to share this feature, considerable skepticism exists regarding this view, in part because of the historical misdiagnosis of sIBM as polymyositis or the evolution of patients with partially responsive polymyositis into treatment-refractory sIBM over time. In sIBM, there is an estimated fivefold greater preponderance of endomysial CD8+ T cells than CD4+ T cells in muscle. Numerous studies have reported in sIBM, CD4+ and CD8+ T cells are driven into highly differentiated effector cells in muscle and blood. Highly differentiated CD8+ T cells express high levels of cytotoxic molecules (such as perforin and granzymes) and overlap phenotypically and functionally with natural killer cells. CD8+ T cell loss of CD5 expression and evolution into natural-killer-like T cells that express CD16 or CD56 are common in sIBM blood and suggest that, in sIBM muscle, T cell cytotoxic injury to myofibers occurs

References

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independently of antigen recognition through CD3 or costimulation through CD28. These T cell phenotypic changes are also seen in T cell LGLL (T-LGLL), a treatment-­refractory expansion of clonal highly differentiated effector CD8+ T cells. An autoantibody in sIBM was recognized only in 2011. This delay was probably related to the early observations that, in sIBM muscle, only sparse numbers of CD20+ endomysial B cells (0.5%) were present, compared with the large numbers of T cells (75%), combined with the popularity of the degenerative model of sIBM. The application of newly invented gene expression microarray profiling to sIBM muscle in 2002 provided an opportunity for non-hypothesis-driven research— to examine sIBM muscle globally without bias. These studies unexpectedly demonstrated robust production of immunoglobulin transcripts, which could only be coming from intramuscular plasma cells. The paucity of CD20+ B cells in sIBM muscle seems to be the result of an intense autoimmune environment causing antigen-­driven transformation of CD20+ B cells into CD19+ plasmablasts and clonal CD138+ plasma cells. Recognition of this pathway facilitated the identification of circulating blood autoantibodies and the target antigen of these autoantibodies, cN1A (NT5C1A). Strong genetic linkage of sIBM has been established exclusively to immune gene variants, specifically to HLA-DRB1*03:01 and HLA-B*08:01, both of which are part of the common autoimmune disease ancestral MHC haplotype and to the chemokine receptor CCR5 gene. A variant in TOMM40, encoding a mitochondrial protein, has been found to influence the age of onset and perhaps disease risk. sIBM muscle is highly enriched with many secreted immune chemokines and cytokines that are difficult to measure at the protein level but whose transcripts can be detected through microarray experiments. The marked elevation of levels of CXCL9 and CCL5 in the muscle strongly suggests upstream T cell activation and IFNγ production. The expression of genes encoding members of the IFNγ signaling cascade (the IFNγ signature) is higher in myofibers invaded by CD8+ T cells than in non-invaded myofibers.

4.3.12 Conclusion Tremendous progress has been made in the clinical and pathogenic understanding of sIBM over the past decade. Major advances in biomarker identification, including the notable whole-genome linkage to an HLA autoimmune haplotype, and the identification of a specific autoantibody and T cell phenotypical abnormalities, have advanced sIBM diagnosis and pathogenic understanding. sIBM is unique among muscle diseases owing to its molecular signature involving highly differentiated cytotoxic T cells that have escaped immune regulation. Although viewed as treatment-­refractory, only very limited therapeutic approaches have been carefully studied to date, and none of these has been rationally directed toward targeting this population of T cells; some treatments (such as corticosteroids and alemtuzumab) have had predictably counterproductive liabilities. A complete understanding of the pathogenesis of sIBM, like most acquired diseases in humans, awaits successful therapeutic responses from mechanistically targeted therapies.

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4.4 Polymyositis Polymyositis (PM) is currently considered a wastebasket entity as there is no convincing evidence linking clinical features, autoantibody profile, and/or histological finding that has stood the test of time. Therefore, many experts have questioned its existence. Since PM is the most commonly used terminology in IIM, its terminolog is still retained here. The concept of PM defined by endomysial inflammation involving nonnecrotic fibers in the absence of rimmed vacuoles was challenged by various studies. Many of the patients who were diagnosed as PM were shown to be sIBM on subsequent biopsies because rimmed vacuoles were absent in the initial biopsy (Table 4.3). Table 4.3  Features differentiating sporadic inclusion body myositis (sIBM) from polymyositis/ dermatomyositis (PM/DM) No 1 2 3 4 5 6

Parameters Age Sex Onset Progression Symmetry Affected muscles

7

Dysphagia

8 9

10 × ULN usually Positive in 60%

Anticytosolic 5′nucleotidase 1 antibody

12 13

Electromyography Muscle biopsy

14

Magnetic resonance imaging

15

Amyloid on PET scan Response to steroids Response to IVIG Other immunosuppression Complications

Mixed myopathic and neuropathic Varying size of muscle fibers, endomysial infiltrates, fiber invasion, rimmed vacuoles, TDP43, p62 inclusion, COX-SDH + fibers Edema, atrophy, and fat replacement of affected muscle groups; T1 weighted image and STIR hyperintensity; patchy involvement High SUV in IBM

Myositis associated and myositis-specific autoantibodies Myopathic Endomysial infiltrate, fiber necrosis, MHC1 expression in PM Perifascicular atrophy and microangiopathy in DM Diffuse involvement; foggy appearance on STIR

10

16 17 18 19

sIBM >50 years; uncommon before 50 Male > female Insidious Gradual Asymmetric Knee extension > hip flexion Finger flexion > shoulder abduction Can occur at onset

PM/DM Common before 50 Female > male Acute or subacute Rapid Symmetric Proximal > distal

Less uptake

Steroid resistant disease Minimal No role

Improves the weakness Moderate to good Indicated

Aspiration pneumonia

Myocarditis, interstitial lung disease, and malignancy

References

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Robust autoantibody screening supplemented by state-of-the-art molecular and morphological techniques has categorized previously diagnosed PM into clearly defined clinicopathological entities. Before labeling a patient as PM an underlying genetic condition with nonspecific inflammation needs to be excluded. Of note, LGMDs, especially dysferlinopathy, anoctaminopathy, facioscapulohumeral muscular dystrophy, and laminopathies are potential diagnostic pitfalls. Hence, the diagnosis of PM should be made only in patients who present with a subacute proximal symmetric myopathy in the absence of any skin findings after having ruled out inherited, toxic, and infectious etiologies fulfilling the ENMC morphological criteria for PM such as endomysial T cell infiltrate surrounding and/or invading nonnecrotic muscle fibers or ubiquitous MHC class I expression in the absence of basophilic rimmed inclusions. Overall, it appears that the term “polymyositis” is likely to be abandoned in the future.

4.5 Conclusion The spectrum of inflammatory myopathy is much broader than it seems. Furthermore, new clinicopathologically defined subgroups are more likely to emerge in the future, and the umbrella term inflammatory myopathies may be altered or discontinued.

References 1. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292:344–7. 2. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975;292:403–7. 3. Griggs RC, Askanas V, DiMauro S, et  al. Inclusion body myositis and myopathies. Ann Neurol. 1995;38:705–13. 4. Hoogendijk JE, Amato AA, Lecky BR, et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10–12 October 2003, Naarden, The Netherlands. Neuromuscul Disord. 2004;14:337–45. 5. Lundberg IE, Tjarnlund A, Bottai M, et  al. 2017 European league against rheumatism/ American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis. 2017;76:1955–64. 6. Allenbach Y, Mammen AL, Benveniste O, Stenzel W, Immune-Mediated Necrotizing Myopathies Working Group. 224th ENMC International Workshop: clinico-sero-­pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14–16 October 2016. Neuromuscul Disord. 2018;28:87–99. 7. Ceribelli A, Fredi M, Taraborelli M, et  al. Anti-MJ/NXP-2 autoantibody specificity in a cohort of adult Italian patients with polymyositis/dermatomyositis. Arthritis Res Ther. 2012;14:R97. 8. Gunawardena H, Wedderburn LR, Chinoy H, et al. Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis Rheum. 2009;60:1807–14. 9. Fiorentino DF, Chung LS, Christopher-Stine L, et al. Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1gamma. Arthritis Rheum. 2013;65:2954–62. 10. Albayda J, Pinal-Fernandez I, Huang W, et al. Antinuclear matrix protein 2 autoantibodies and edema, muscle disease, and malignancy risk in dermatomyositis patients. Arthritis Care Res (Hoboken). 2017;69:1771–6.

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137. Pestronk A. Acquired immune and inflammatory myopathies: pathologic classification. Curr Opin Rheumatol. 2011;23:595–604. 138. van der Meulen MF, Hoogendijk JE, Moons KG, Veldman H, Badrising UA, Wokke JH. Rimmed vacuoles and the added value of SMI-31 staining in diagnosing sporadic inclusion body myositis. Neuromuscul Disord. 2001;11:447–51. 139. Benveniste O, Allenbach Y. Inclusion body myositis: accumulation of evidence for its autoimmune origin. Brain. 2019;142:2549–51. 140. Lloyd TE, Mammen AL, Amato AA, Weiss MD, Needham M, Greenberg SA. Evaluation and construction of diagnostic criteria for inclusion body myositis. Neurology. 2014;83:426–33. 141. Kanellopoulos P, Baltoyiannis C, Tzioufas AG. Primary Sjogren’s syndrome associated with inclusion body myositis. Rheumatology (Oxford). 2002;41:440–4. 142. Misterska-Skora M, Sebastian A, Dziegiel P, Sebastian M, Wiland P. Inclusion body myositis associated with Sjogren’s syndrome. Rheumatol Int. 2013;33:3083–6. 143. Colafrancesco S, Priori R, Gattamelata A, et al. Myositis in primary Sjogren’s syndrome: data from a multicentre cohort. Clin Exp Rheumatol. 2015;33:457–64. 144. Cupler EJ, Leon-Monzon M, Miller J, Semino-Mora C, Anderson TL, Dalakas MC. Inclusion body myositis in HIV-1 and HTLV-1 infected patients. Brain. 1996;119(Pt 6):1887–93. 145. Matsuura E, Umehara F, Nose H, et  al. Inclusion body myositis associated with human T-lymphotropic virus-type I infection: eleven patients from an endemic area in Japan. J Neuropathol Exp Neurol. 2008;67:41–9. 146. Lloyd TE, Pinal-Fernandez I, Michelle EH, et al. Overlapping features of polymyositis and inclusion body myositis in HIV-infected patients. Neurology. 2017;88:1454–60. 147. Hiniker A, Daniels BH, Margeta M. T-cell-mediated inflammatory myopathies in HIV-positive individuals: a histologic study of 19 cases. J Neuropathol Exp Neurol. 2016;75:239–45. 148. Cox FM, Delgado V, Verschuuren JJ, et al. The heart in sporadic inclusion body myositis: a study in 51 patients. J Neurol. 2010;257:447–51. 149. Limaye VS, Lester S, Blumbergs P, Roberts-Thomson PJ. Idiopathic inflammatory myositis is associated with a high incidence of hypertension and diabetes mellitus. Int J Rheum Dis. 2010;13:132–7. 150. Chou SM.  Myxovirus-like structures and accompanying nuclear changes in chronic polymyositis. Arch Pathol. 1968;86:649–58. 151. Rifai Z, Welle S, Kamp C, Thornton CA. Ragged red fibers in normal aging and inflammatory myopathy. Ann Neurol. 1995;37:24–9. 152. Oldfors A, Moslemi AR, Jonasson L, Ohlsson M, Kollberg G, Lindberg C. Mitochondrial abnormalities in inclusion-body myositis. Neurology. 2006;66:S49–55. 153. Askanas V, Serdaroglu P, Engel WK, Alvarez RB. Immunolocalization of ubiquitin in muscle biopsies of patients with inclusion body myositis and oculopharyngeal muscular dystrophy. Neurosci Lett. 1991;130:73–6. 154. Askanas V, Engel WK, Alvarez RB. Light and electron microscopic localization of beta-­amyloid protein in muscle biopsies of patients with inclusion-body myositis. Am J Pathol. 1992;141:31–6. 155. Askanas V, Engel WK, Bilak M, Alvarez RB, Selkoe DJ. Twisted tubulofilaments of inclusion body myositis muscle resemble paired helical filaments of Alzheimer brain and contain hyperphosphorylated tau. Am J Pathol. 1994;144:177–87. 156. Greenberg SA.  Theories of the pathogenesis of inclusion body myositis. Curr Rheumatol Rep. 2010;12:221–8. 157. Askanas V, Engel WK. Proposed pathogenetic cascade of inclusion-body myositis: importance of amyloid-beta, misfolded proteins, predisposing genes, and aging. Curr Opin Rheumatol. 2003;15:737–44. 158. Askanas V, Engel WK. Inclusion-body myositis: a myodegenerative conformational disorder associated with Abeta, protein misfolding, and proteasome inhibition. Neurology. 2006;66:S39–48. 159. Askanas V, Engel WK, Nogalska A. Sporadic inclusion-body myositis: a degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy. Biochim Biophys Acta. 2015;1852:633–43. 160. Sarkozi E, Askanas V, Johnson SA, McFerrin J, Engel WK. Expression of beta-amyloid precursor protein gene is developmentally regulated in human muscle fibers in vivo and in vitro. Exp Neurol. 1994;128:27–33.

5

Specific Forms of Immune-Mediated Necrotizing Myopathies

5.1

Introduction

Necrotizing myopathy with an “immune background” was suggested in the literature in the late 1960s and discussion immediately followed as to whether subentities needed to be differentiated [1]. Of note, and although necrotizing myopathies have been described since, the mid-1970s Peter and Bohan did not include them as a separate entity in their dichotomic differentiation between dermatomyositis (DM) and polymyositis (PM), which was based on the presence of skin symptoms [2]. The first description of anti-signal recognition particle (SRP) autoantibodies, which were identified to target a protein complex initiating protein translocation, was published in 1985 [3]. A few months later, the first patient with PM and autoantibodies against SRP 54 kDa protein (SRP54) was described and, as expected given the location of the SRP complex at the surface of the endoplasmic reticulum (ER), a cytoplasmic pattern of anti-SRP was observed on human epithelial type 2 (HEP2) cells by indirect immunofluorescence [4]. Finally, details of the first series of 13 patients with “anti-SRP PM” was published in 1990, revealing that these patients have a relatively homogeneous clinical phenotype and that the prevalence was 4% of patients with idiopathic inflammatory myopathies (IIM) [5]. In 2002, the first description of pathological findings in a larger series of patients with anti-SRP PM showed that necrotic muscle fibers were often present, whereas the presence of mononuclear inflammatory cells was uncommon [6]. A year later, the subgroup of “Immune-mediated necrotizing myopathy (IMNM)” emerged as a separate entity among IIMs based on pathological criteria, during the 119th international workshop of the European Neuromuscular Centre (ENMC) [7]. In 2010, a novel autoantibody against ~200 and 100-kDa proteins (initially called anti-200kd/100kd) was first recognized in a series of 38 patients with IMNM who had been pathologically characterized, and 1 year later the target was identified as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) [8, 9]. The same authors showed that patients with IMNM and anti-HMGCR autoantibodies have a fairly homogeneous clinical phenotype and strikingly, 63% of patients had been © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. L. Gaspar, Immune-Mediated Myopathies and Neuropathies, https://doi.org/10.1007/978-981-19-8421-1_5

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exposed to statins. Knowing that the target of statins is HMGCR and that HMGCR exists as a 97 kDa monomer and as a dimer, they proved that the target of these autoantibodies against ~100 and 200 kDa proteins was indeed HMGCR. The presence of anti-HMGCR antibodies in patients with IMNM was subsequently confirmed in 2014 using a different immunoassay and samples from an independent cohort of patients with IMNM who were negative for anti-SRP [10, 11]. Unsupervised machine learning statistical analyses have also been used to show that anti-SRP-positive IMNM and anti-HMGCR-positive IMNM are separate entities [12]. Results demonstrated that IIM can be subdivided into four categories based on clinical signs, myopathology, and the presence of myositis specific antibodies (MSA). These subgroups are DM, antisynthetase syndrome  (ASS), sporadic inclusion body myositis (sIBM), and IMNM.  These four subgroups of IIM were also identified by studying unique gene expression profiles in muscle biopsies [13]. Among MSA, anti-SRP and antiHMGCR autoantibodies are paramount for the identification and definition of IMNM as a disease entity. Together these data and other studies support the use of anti-SRP and anti-HMGCR autoantibodies in the diagnosis and classification of IMNM [14]. Of note, patients with IMNM were not distinguished from patients with PM in the subclassification tree established in the 2017 EULAR–ACR classification of adult and juvenile IIM and their major subgroups [15]. It was not possible to make this distinction because only a few patients with IMNM were included in the study, as this subgroup was not yet well characterized and no MSA (with the notable exception of anti-Jo1) were part of the classification.

5.2 Diagnostic Criteria for IMNM 5.2.1 General Features of IMNM The first definition of IMNM was based on clinicopathological criteria [16]. The key pathological criteria for this classification, established by a group of specialists back in 2003 were the presence of many necrotic muscle fibers as the predominant abnormal histological feature. Inflammatory cells are sparse or only slightly perivascular; perimysial infiltrate is not evident. Membrane attack complex (MAC) deposition on small blood vessels or pipestem capillaries on EM may be seen, but tubuloreticular inclusions in endothelial cells are uncommon or not evident. The exclusion criteria were multiple, including an endomysial T cell infiltrate surrounding or invading nonnecrotic muscle fibers; perifascicular atrophy; MAC deposition on small blood vessels or reduced capillary density; rimmed vacuoles, ragged red fibers, cytochrome c oxidase-negative fibers; and MAC deposition on the sarcolemma of nonnecrotic fibers. In due course, it was demonstrated that anti-SRP and anti-HMGCR autoantibodies were specific for IMNM and further pathological analysis demonstrated that, in IMNM, sarcolemmal complement deposition occurs frequently and that marked muscular inflammation (as indicated by MHC-I expression and/or endomysial inflammatory infiltrates) may be observed in severe cases [17]. These observations led to a refined definition of IMNM that uses

5.2  Diagnostic Criteria for IMNM

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clinicoserological and pathological criteria [18]. Specifically, patients with elevated serum creatine kinase levels (a marker of muscle damage), proximal muscle weakness predominantly in the lower extremities, and anti-HMGCR or anti-SRP autoantibodies can be classed as having anti-HMGCR or anti-SRP myopathy. In these patients, a muscle biopsy may not be required to diagnose IMNM. However, patients without MSA and those for which autoantibody testing was unavailable or the results of such testing were unclear, as well as patients with atypical or non-specific clinical symptoms, require a muscle biopsy to confirm that they have enough features of IMNM to be diagnosed with it. Of note, drug- and toxin-induced myopathy should be excluded to confirm seronegative IMNM by biopsy.

5.2.2 Anti-SRP Autoantibodies The SRP complex was isolated in 1980 as a complex with a sedimentation coefficient of 11S consisting of six distinct polypeptide chains of 72, 68, 54, 19, 14, and 9 kDa [19]. The same authors then showed that this complex also contains a 7SL RNA molecule that is required for the structure and function of signal recognition protein and renamed this complex SRP [20]. SRP is essential for the translocation of nascent polypeptides into the ER. The 54 kDa polypeptide of the SRP complex binds both the 7SL RNA molecule and the signal sequence-bound polypeptide emerging from the ribosome to the SRP receptor, which is located on the ER membrane [21]. Anti-SRP autoantibodies almost always target at least the 54 kDa subunit of the SRP in serum in patients with IMNM.  It was demonstrated that autoantibodies bind to the SRP54 N-terminal or G central region [22]. Anti-SRP autoantibodies are present as immunoglobulin G1 (IgG1) subtype in 81% of patients and as IgG4 antibodies in 29% of patients (note that some patients have both IgG1 and IgG4 antibodies) [23]. In vitro, anti-SRP autoantibodies inhibited the function of the SRP complex. Of note, mutations in SRP54 may cause bone marrow failure with neutropenia and exocrine pancreatic insufficiency [24].

5.2.3 Anti-HMGCR Autoantibodies HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, an essential step in cholesterol biosynthesis [25]. Statins are HMGCR inhibitors that lower serum cholesterol levels and markedly reduce the overall cardiovascular events. HMGCR is also a glycoprotein, the cytoplasmic catalytic domain of which is anchored to an ER membrane-embedded domain [26]. Anti-HMGCR antibodies recognize the intracellular C-terminal part of the enzyme and, to date, no mutations have been described in the gene encoding HMGCR, presumably as this would be lethal. Indeed, liver-specific HMGCR knockout mice die before 6 weeks of age from severe hepatic steatosis, hypercholesterolemia, and hypoglycemia [27]. Skeletal musclespecific HMGCR knockout mice exhibit rhabdomyolysis [28]. Of note, genetic variants of HMGCR are associated with different levels of low-density lipoproteins

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and cardiovascular risks [29]. In addition, up to 20% of patients exposed to statins experienced muscle symptoms, but the large majority of these symptoms were due to statin-induced direct toxicity, as these patients did not develop anti-­HMGCR autoantibodies [30, 31]. Indeed, the presence of anti-HMGCR autoantibodies in this population allowed to discriminate between patients with immune-mediated events and those with adverse toxic events [32].

5.3 Epidemiology 5.3.1 Prevalence, Incidence, and Risk Factors As IMNM is still frequently misdiagnosed as polymyositis, it is difficult to establish the proportion of patients with IIM who have IMNM. A review of 46 articles published between 1966 and 2013 indicated that the global incidence of IIM ranges from 1.16 to 19 per 1 million person-years and their global prevalence ranges from 2.4 to 33.8 per 100,000 inhabitants [33].

5.3.2 Anti-SRP-Positive IMNM In patients with IIM, the prevalence of anti-SRP positivity ranges from 5 to 15% [34, 35]. Anti-SRP-positive IMNM is commonly diagnosed in patients in their 40s or 50s but may also occur in childhood [16]. Anti-SRP-positive IMNM represents 4% of patients with juvenile IIM and, as is the case for other IIMs, anti-SRP-­positive IMNM affects females more frequently than males [36, 37]. Risk factors for antiSRP-­positive IMNM are less well characterized than those for anti-HMGCR-­ positive IMNM. In white people, no specific HLA haplotype has been associated with anti-SRP-positive IMNM, whereas DRB1*08:03 and DRB1*14:03 alleles have been associated with this disease in Japanese and Korean populations, respectively [38–40].

5.3.3 Anti-HMGR-Positive IMNM The prevalence of anti-HMGCR-positive IMNM ranges from 6 to 10% of IIM and anti-HMGCR-positive IMNM occurs more frequently in women after 40 years of age. Anti-HMGCR-positive IMNM can also occur in childhood and represents 1% of patients with juvenile IIM [16]. In patients positive for anti-HMGCR antibodies, the target of these autoantibodies is also the target of statins; thus, it has been hypothesized that statins may be a trigger of the disease. The percentage of statin exposure in these patients ranges from 15 to 65% depending on their geographic origin (and probably also their ethnicity, with statin exposure low, moderate, and high in Asia, Europe, and the USA, respectively) and age (90% of patients with antiHMGCR-positive IMNM who are over 50 years of age have been exposed to statins)

5.4  Clinical Features

77

[16]. As for other autoimmune conditions, the genetic background may play a role in anti-HMGCR-positive IMNM susceptibility. In adults, the presence of the MHC class II allele DRB1*11:01 confers a strong immunogenetic predisposition to antiHMGCR-positive IMNM, whereas this risk is associated with DRB1*07:01  in infants39 [41, 42].

5.3.4 Seronegative IMNM As seronegative IMNM was individualized in 2011, after the discovery of anti-­ HMGCR, it is difficult to estimate its prevalence and incidence, although it represents 10–12% of cases of IMNM. The age of onset and sex ratio of seronegative IMNM are similar to those for seropositive IMNM.  The main risk factor or co-­ morbidity associated with seronegative IMNM is cancer [43].

5.4 Clinical Features 5.4.1 Muscular Phenotype The main clinical symptoms observed in patients with IMNM are directly linked to muscle involvement.

5.4.1.1 Seropositive IMNM As described previously, the anti-SRP autoantibody was initially identified in a group of patients with polymyositis. When IMNM was considered to be a separate entity from polymyositis based on pathological criteria, the anti-HMGCR autoantibody was discovered. Thus, both anti-SRP and anti-HGMCR positive IMNM were first considered to be conditions with an acute–sub-acute onset similar to other subtypes of IIM.  More than two-thirds of patients with seropositive IMNM have an acute (within a few weeks) or sub-acute (in 12 months) [47]. In patients with slow disease progression, especially in young patients, scapular winging may be observed [44]. In individual cases, and especially if the course of the disease is slowly progressive, the distinction between limb-girdle muscular dystrophy and IMNM may be difficult. In young patients who present with slowly progressive muscle weakness and high levels of serum creatine kinase without extramuscular manifestations and are thought to have limb-girdle muscular dystrophy, testing for anti-SRP and anti-HMGCR autoantibodies should be considered before the results of genetic testing are received so that efficacious treatments are not delayed. Serum creatine kinase levels are typically high in both seropositive IMNMs (6000–8000  IU/l, which is >30-fold over the upper limit of normal) [16]. Normal serum creatine kinase levels in patients with normal muscle mass largely rule out the diagnosis of untreated IMNM. The mean serum creatine kinase level is higher in IMNM than in other IIM groups and the serum creatine kinase level correlates with the percentage of necrotic muscle fibers. As the serum creatine kinase level correlates with muscle mass, the increase in serum creatine kinase level may become lower over time, notably in patients with long disease duration and severe muscle atrophy that is verified by a low creatinine level.

5.4.1.2 Seronegative IMNM Descriptions of seronegative IMNM are limited, but the phenotype of patients with this disease seems similar to that of patients with seropositive IMNM. Until now, the slowly progressive course seems to be a characteristic of a subgroup of patients with seropositive IMNM.

5.4.2 Extramuscular Phenotype IMNM can be considered a muscle-predominant autoimmune disease as it is associated with little if any extramuscular immune-mediated damage [47].

5.4.2.1 Anti-SRP-Positive IMNM Interstitial lung disease is frequently associated with anti-SRP seropositivity and is present in 23–38% of patients on computed tomography (CT) [48]. However, its presence has no relevant clinical implications, as the large majority of patients with interstitial lung disease do not complain of dyspnea, and pulmonary functional tests remain normal. In addition, myocarditis is frequently observed in patients with anti-­ SRP-­positive IMNM. Studies suggest that cardiac signs, including chest pain, palpitations, and congestive heart failure, as well as electrocardiographic and echocardiographic changes or changes observed by magnetic resonance imaging (MRI), occur in 2–40% of these patients. Cardiac involvement was particularly

5.5  Microscopic Pathology

79

clear in two patients with signs of myocarditis concurrent with an anti-SRP-positive IMNM diagnosis (specifically, increased cardiac muscle enzyme and cardiac MRI and/or the presence of inflammatory infiltrates on cardiac muscle biopsy), exclusion of other heart diseases (including ischemia with coronarography), and a favorable response to immunotherapy [49, 50].

5.4.2.2 Anti-HMGCR-Positive IMNM For patients with anti-HMGCR-positive IMNM, no extramuscular manifestations, including cardiac involvement, have been considered to be part of the disease spectrum so far. Only a single case of acute systemic heart failure that improved with immunosuppressants has been reported in a patient with anti-HMGCR-positive IMNM, consistent with the rarity of this association [51]. 5.4.2.3 Seronegative IMNM Patients with seronegative IMNM usually do not display extramuscular symptoms but seronegative IMNM is a subclass of IMNM by “default” and its characteristics have not been well studied. Of note, some systemic autoimmune diseases may have muscle involvement, characterized by both muscle fiber necrosis and marked inflammation that does not fall under the definition of IMNM.

5.5 Microscopic Pathology 5.5.1 General Pathology of IMNM Based on ENMC criteria, patients with anti-SRP or anti-HMGCR autoantibodies do not necessarily require muscle biopsy to diagnose IMNM, although patients with seronegative IMNM always do [14]. The presence of necrotic myofibers is characteristic of necrotizing myopathies, but further myopathological features are required for the morphological diagnosis of IMNM. Necrotic myofibers exhibit the characteristics of different stages of necrotic and regenerating myofibers (that is, hyalinized, granular, myophagocytic, lytic, and regenerative). Quantitatively, necrotic myofibers represent between 1 and 20% of all fibers and they are randomly distributed throughout the muscle fascicles (Fig. 5.1a) [16]. The sarcoplasm is coarsely stained by NADH-tetrazolium reductase in many fibers (Fig. 5.1b), but mitochondrial abnormalities are consistently absent, as indicated by the absence of cytochrome c oxidase-negative succinate dehydrogenase-positive fibers, ragged brown fibers, or ragged blue fibers above those expected to occur as a result of the physiological aging of skeletal muscle.

5.5.2 Immunohistochemistry of IMNM Lymphocytic infiltrates are always present in muscle biopsies from patients with IMNM and these can be mild or more pronounced. The presence of MHC class I on the sarcolemma (Fig. 5.1c), whereas MHC class II is consistently absent from the

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5  Specific Forms of Immune-Mediated Necrotizing Myopathies

a

b

c

d

Fig. 5.1 (a) H&E stain shows numerous necrotic fibers and concomitant regenerating fibers in a case of IMNM. (b) NADH-TR stain shows coarse staining of the sarcoplasm in a case of IMNM. (c) MHC-I stain shows diffuse sarcolemmal upregulation in a case of IMNM. (d) MAC (C5b-9) stain shows sarcoplasmic staining of necrotic fibers and sarcolemmal staining of nonnecrotic fibers in a case of IMNM

sarcolemma. MHC class II staining is observed on the sarcolemma of myofibers in patients with non-specific myositis or an overlap myositis syndrome, but those should not be classified as IMNM [52, 53]. Different types of macrophages accumulating in patterns of myophagocytosis and more widely distributed in the endomysium are characteristic of patients with IMNM, with the presence of specific T lymphocytes, B cells, and plasma cells being the exception [54]. Of note, in about 20–30% of biopsies from patients with IMNM, when there is a high proportion of necrotic myofibers, the signs of T cell infiltration are similar to those in other IIM. Higher numbers of T cells or a diffuse MHC class I sarcolemmal expression pattern quantitatively similar to those observed in DM and ASS have been reported in biopsies from patients with IMNM. These signs underscore the activation of non-­ specific immunological pathomechanisms in patients with IMNM.  Along these lines, in patients with IMNM, deposits of C5b–9 (the membrane attack complex (MAC)) on the sarcolemma are observed on a variable number of myofibers. This feature can be seen on single fibers, on groups or rows of myofibers, and sometimes even in whole fascicles. In patients with necrotizing myopathy harboring the typical features mentioned above, complement deposition is a sign of IMNM, but it does not distinguish between patients with anti-SRP-positive IMNM and those with anti-­ HMGCR-­positive IMNM or seronegative IMNM [55]. Complement deposition is not a unique feature of IMNM or any IIM as it may also occur (with different

5.6  Disease Course and Prognosis

81

qualitative characteristics) in hereditary diseases of skeletal muscle. An interesting diagnostic hallmark of IMNM is the constant presence of several myofibers with fine granular and homogeneous staining of the autophagy marker p62 in the sarcoplasm [56, 57]. Of note, there is no coarse, squiggly, or “plaque-like” p62 positivity and no association of p62 with large, rimmed vacuoles, features that are characteristic of sIBM.  The proportions of myofibers containing p62 and LC3b (also an autophagy marker) were higher in IMNM than in other IIM, but this feature is not specific to IMNM. When muscle biopsy is performed after a long disease duration, a considerable number of atrophic myofibers, irrespective of regenerative processes, and signs of fibrosis and fatty tissue replacement may be observed. Also, the longterm effect of certain treatments such as corticosteroids on morphology has not yet been clarified. Importantly, patients with IMNM do not harbor features of DM, such as the presence of specific type I interferon-signature gene markers including ISG15, ISG20, MX1, or SIGLEC1 [53]. In addition, prominent complement deposits on vessels or capillary tubuloreticular inclusions that are usually observed in DM are not present in biopsies from patients with IMNM, although enlarged vessel walls and pipestem capillaries can be observed on rare occasions [58]. The diagnosis of IMNM should be made from a biopsy taken from a muscle that is clinically moderately to severely weak in acute to sub-acutely ill patients, whereas in patients who are chronically ill and for whom a biopsy is performed at an advanced stage of the disease, a moderately affected, still palpable muscle of the proximal legs is best chosen for biopsy. Where there is doubt as to which muscle to biopsy, an MRI or electromyography should be performed to assist with this decision. Muscle MRI is indeed an important tool for assessing the characteristic muscle damage in IMNM, but muscular signs on MRI are not specific enough for diagnostic purposes compared with the detection of MSA or muscle biopsy [59].

5.6 Disease Course and Prognosis IMNM is a chronic disease with a long disease duration. The two major concerns in patients with an IIM are mortality and disability, with malignancy and heart involvement as common causes of death. Patients with seronegative and anti-HMGCR-­ positive IMNM must be screened for cancer and patients with anti-SRP-positive IMNM must be screened for myocarditis, as these conditions have been associated with reduced survival for patients with these subclasses of IMNM [43]. Also of note, all patients with IIM who are exposed to high cumulative doses of glucocorticoids are at an increased risk of coronary artery disease [60].

5.6.1 Seropositive IMNM Among IIM, with the notable exception of sIBM, patients with seropositive IMNM have the most severe disease in terms of muscle-related morbidities such as muscle atrophy and concomitant weakness. Both occur frequently early on in the disease course without treatment or at long-term follow-up when treatment has been

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insufficient. Studies have shown that 2 years after the initiation of immunotherapy, a quarter of patients with seropositive IMNM had difficulties in their daily life [35, 45]. Patients with seropositive IMNM also have a poor recovery of muscle strength over the years after immunotherapy; less than half of patients positive for anti-­ HMGCR autoantibodies recovered normal muscle strength within 2 years of disease onset and only two-thirds reached this level of improvement within 4  years [46]. However, this outcome depends on the age of the patient at disease onset, as only half of the younger patients (60 years), reached normal muscle strength 4 years after disease onset. Patients positive for anti-SRP autoantibodies also had a poor outcome, as only half of them reached near-full or full muscle strength after 4 years of immunotherapy, and younger age at onset was associated with more severe muscle weakness [36]. The poor outcome of patients with IMNM is likely to be linked to the extent of muscle damage assessed by MRI of skeletal muscles. The severity of muscle damage is dependent on the time from symptom onset to treatment initiation and on disease duration. Indeed, compared with other IIMs (except sIBM), IMNM has a higher proportion of atrophied thigh muscles with fatty replacement and this muscle damage begins early during the disease. As suggested by clinical observations, patients with anti-SRP-positive IMNM have more muscle atrophy and fatty replacement than patients with anti-HMGCR-positive IMNM. Whole-body MRI of patients with IMNM demonstrates that muscle damage is not confined to thigh muscles but also involves axial muscle. This study also shows that disease duration is an important predictor of muscle damage and that the damage burden in IMNM and sIBM patients is comparable [59]. Finally, it must be noted that the disease duration is long and the large majority of patients require immunosuppressants or immunomodulatory drugs for years after diagnosis, with the side effects and comorbidities of these treatments accumulating.

5.6.2 Seronegative IMNM Compared with patients with seropositive IMNM, patients with seronegative IMNM have a lower survival rate (97% versus 83% at 3 years; P  male 4–13%

Up to 64%

Up to 53%

15–70% Proximal symmetric muscle weakness and muscle atrophy

Sub-acute/ progressive form Dysphagia Extramuscular manifestations Myopathology

2/3–1/3

No association Proximal symmetric muscle weakness (more severe), muscle atrophy (more frequent) and axial muscle involvement/dropped head syndrome  NA

MRI

Outcome prognosis Cancer risk

~40% Very rare Elevated CK level necrosis/ regeneration pattern MHC-I upregulation on regenerative fibers; sarcolemmal MAC deposits on nonnecrotic fibers Sparse infiltrates with lymphocytes Muscle edema Muscle atrophy Fatty replacement of muscle Age-dependent recovery rate (young = poor outcome) Weak association

~60% 10–20% interstitial lung disease; cardiac involvement Necrosis/regeneration pattern MHC-I upregulation on regenerative fibers; sarcolemmal MAC deposits on nonnecrotic fibers (more frequent) Sparse infiltrates with lymphocytes

Muscle edema Muscle atrophy (more severe) Fatty replacement of muscle (more severe) ~50% recovery; frequent relapses No association

IMNM immune-mediated necrotizing myopathy, anti-HMGCR anti-3-HydroXy-3-methylglutaryl-­­ coenzyme A reductase, anti-SRP anti-signal recognition particle, CK creatine kinase, MHC major histocompatibility complex, MAC membrane attack complex (C5b-9), MRI magnetic resonance imaging, NA not available

5.10  Antisynthetase Syndrome

87

cases. Patients with anti-SRP and anti-HMGCR autoantibodies have a high serum creatine kinase level and no clinically relevant autoimmune-related extramuscular manifestation. Malignancy may be associated with IMNM mainly in patients with seronegative disease and not in patients with anti-SRP-positive IMNM.  IMNM presents as a muscle-predominant autoimmune disease, among the most severe within the IIMs. Very frequently, patients with IMNM do not recover normal muscle strength, even after a long remission from disease activity, as some level of irreversible muscle damage occurs. Most patients have a very long disease duration, with a high risk of relapse when corticosteroids and/or immunosuppressants are tapered or withdrawn. Recent in vitro and in vivo data from the past 5 years have highlighted new pathomechanisms in the field of myology and suggest that autoantibody-­ mediated activation of the complement cascade has a key role. This progress is crucial as it has allowed the emergence of targeted therapeutic approaches, such as the use of complement inhibitors, to treat chronic impairing diseases such as IMNM.

5.10 Antisynthetase Syndrome 5.10.1 Introduction ASS is defined as a subtype of IIM, however, its clinical presentation extends far beyond muscles [79]. Frequent pulmonary involvement, arthritis, an exceptional pattern in muscle biopsy, fever of unknown origin, typical cutaneous lesions, and Raynaud’s phenomenon cover the unique spectrum with aminoacyl-tRNA-­ synthetases being both the hallmark and the trigger.

5.10.2 Epidemiology Although the first incidences of ASS were described over 30 years ago, the prevalence and pathogenesis remain not fully recognized [80]. First description of ASS is credited to Hochberg et al., who not only noted a high prevalence of anti-Jo-1 antibodies in patients with PM or PM-overlapping syndrome but also reported for the first time the association between anti-Jo-1 and interstitial lung disease. A few years later, the spectrum of symptoms such as myositis, pulmonary fibrosis, arthritis, sclerodactyly, Raynaud’s phenomenon, dry eyes, hepatitis, and calcinosis in 29 patients with antisynthetase antibodies was described by Marguerie [81]. The global prevalence of ASS is estimated to be 1-9/100,000; however, no precise data on the disease incidence is available [79]. Antisynthetase antibodies can be found in 11.1–39.19% of patients with IIM [82, 83]. According to the EuroMyositis registry, ASS is less prevalent than DM and PM, but more frequent than sIBM and IMNM. Like other IIM subtypes apart from sIBM, ASS more frequently affects females (female to male ratio is estimated to be approximately 7:3). Mean age at the onset of the disease is 48 ± 15 years, which is similar to DM and PM patients but younger than in sIBM and IMNM [84].

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5.10.3 Pathogenesis Antisynthetase antibodies (ARS) are directed against cytoplasmic aminoacyl-tRNA synthetases that catalyze the ATP-dependent reaction of single amino acid attachment to its specific tRNA and ensure the proper protein synthesis. Although 20 amino acids can be distinguished, antibodies have been detected against eight of them, including anti-Jo-1 (histidyl-tRNA synthetase), anti-PL-7 (threonyl), anti-­ PL-­12 (alanyl), anti-EJ (glycyl), anti-OJ (isoleucyl), anti-KS (asparaginyl), anti-Zo (phenylalanyl), and anti-Ha (tyrosyl) [85, 86]. ARS can be found in approximately 30% of IIM with anti-Jo-1 being the most common type. Anti-Jo-1 specificity is detected in approximately 20–30% of myositis patients, while each of the other ARS occurs in not more than 5% of patients [87]. ARS are generally considered to be mutually exclusive, yet cases of ARS co-occurrence have been described [88]. Antibodies against Ro (including Ro52) are considered the most common type of associated antibodies in ARS-positive patients, occurring in 30–65% of cases [89, 90]. Apart from its basic function, aminoacyl-tRNA synthetases play an important role in different immune processes. As extracellular signals, aminoacyl-tRNA synthetases are capable of targeting versatile immune cells, endothelial cells, fibroblasts, and also cancer cells [91, 92]. Those enzymes participate in the immune system activation as antigens and serve chemoattractive and cytokine-resembling roles. By initiating innate and adaptive pathways, they impose immune tolerance, breakdown, or tissue damage [91, 93]. Histydyl-tRNA synthetase (HisRS) and asparaginyl-tRNA synthetase have been found to regulate the migration of lymphocytes, activation of monocytes, and immature dendritic cells. Histydyl-tRNA synthetase also induced migration of CCR5-transfected HEK-293 cells, while asparaginyl-tRNA and seryl-tRNA synthetases stimulated migration of CCR3-­ transfected cells [94]. Depending on the subtype, aminoacyl-tRNA synthetases can impose an angiostatic or angiogenic effect. Some of the synthetases may promote apoptosis of cancer cells. In murine models, immunization with intact or cleaved HisRS leads to the formation of autoreactive B cells [95]. IgG fraction of sera of anti-Jo-1 positive patients was also observed to induce IFN-α production [96]. HisRS was found to be overexpressed in immune cells that infiltrate inflamed and regenerating myofibers of patients with IIM, but also in the normal lung tissue [97]. Two different conformations of HisRS have been distinguished based on their susceptibility to granzyme B cleavage and modification by autoantibody binding. The isoform sensitive to granzyme B cleavage was found to be highly expressed in the alveolar epithelium [98]. Antibodies against aminoacylo-tRNA are typically assessed in the serum, yet the presence of antibodies against HisRS (anti-Jo-1) was recently detected also in BALF (bronchoalveolar lavage fluid), which supports the hypothesis of the respiratory tract as the place where the cleavage of aminoacylo-­ tRNA is initiated, leading to activation of T cells that acquire a pro-inflammatory phenotype with subsequent stimulation of B cells to mature and produce anti-Jo-1 antibodies [99]. Since the release of granzyme B may be triggered by environmental factors such as pathogens or smoking, hypothesis of environmental factors initiating immune dysregulation appears to be captivating and promising. Exposure to various

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inhaled antigens may induce the autoimmune cascade leading to ASS. Exposure to potential environmental triggers such as mold, birds, and feather pillows, acting as initiating symptoms, is exceptionally high mostly in individuals with pulmonary involvement [100]. As compared to patients with other subtypes of IIM, those with ASS were statistically more frequently exposed to inhaled antigens such as dust, gases, or fumes [101]. In the large international cohort tobacco smoking was associated with an increased risk of anti-Jo-1 formation in genetically susceptible IIM patients [102]. Furthermore, a positive association of respiratory tract infections and diseases with a subsequent risk of developing IIM was suggested [103]. Murine models of autoimmune myopathies confirm that activation of Toll-like receptors 7 and 8 is crucial in the initiation and maintenance of the disease, which might suggest the role of intracellular respiratory pathogens like viruses. Subsequent cellular damage leads to release of microparticles and activation of innate responses [104]. The pivotal role is attributed to NK cells which are differentiated in active ASS. Hervier et al. described a significantly lower percentage of fully functional NK cells in patients with ASS as compared to healthy controls. NK cells in active ASS are characterized by increased CD57 and Ig-like transcript 2 but decreased NKp30. The ability to produce IFN-γ, both spontaneously and after stimulation, is significantly impaired, while the production of proteolytic enzymes and the degranulation process remain intact. NK cells infiltrate the perimysium and surround the myofibers. As compared to healthy controls, in the lungs of ASS patients exceptionally high numbers of NK cells were found. Furthermore, in patients with ASS, higher percentages of NK cells expressing granzyme A and granzyme B were observed [105]. NETosis was also suggested to be important in the pathogenesis of IIM and IIM-associated ILD (interstitial lung disease). In patients with IIM, NET-­inducing capacity is increased, while NETs degradation and DNase I activity are impaired, especially in individuals with ILD, in the course of IIM. Patients with anti-Jo1 antibodies were reported to have exceptionally low activity of DNAase I [106]. Seto et al. displayed that NET formation in IIM contributes to skeletal muscle disruption and decreased myotubes viability, probably via citrullinated histones-­ mediated mechanisms. Increased neutrophil gene signature in DM skeletal muscles correlated with markers of myocyte injury and enhanced type I and II IFN responses. Levels of NETs were found to be significantly higher in patients with anti-MDA5 and antiTIF1 antibodies, yet not in anti-Jo-1 positive patients [107]. Further studies are needed to evaluate the significance of neutrophil dysregulation in ASS.  Anti-Jo-1 antibodies were found to be strongly associated with HLA-B*08:01 and HLA-­DRB1 03:01 polymorphisms. Associations between particular amino acid positions and ARS subtypes were identified as potentially even stronger than classical HLA associations [38]. Risk variants observed in patients with IIM were found to be similar to those revealed in other seropositive autoimmune diseases. Performed so far genetic analysis supports the idea of shared etiology between ethnicities [108]. However, in the study by Johnson et  al. ASS patients with autoantibodies other than anti-Jo-1 were more likely to be African-American than Caucasian or other races, suggesting a possible association between ethnicity and ARS subtype [109]. Further studies are needed to assess the importance of racial differences in the pathogenesis of ASS.

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5.10.4 Diagnosis In recent years, new classifications and diagnostic criteria for IIM and its subtypes have been proposed. Based on the analysis of 260 patients, four separate clusters were distinguished such as sIBM, IMNM, DM, and ASS [12]. ASS differs from other IIM due to its unique features. Studies suggest that none of the criteria proposed so far corresponds entirely with the clinically based diagnoses. In the latest EULAR/ACR criteria the distinctness of ASS was not reflected. Since those criteria do not include autoantibodies other than anti-Jo-1, some of the ASS cases may be omitted [110]. According to Greco et al., EULAR/ACR criteria were met by 59.5% of the patients with clinical suspicion of ASS or myositis, including all anti-Jo1-­ positive patients but only 20% of patients with other ARS. The authors proposed to modify the EULAR/ACR criteria by attributing the same weight as anti-Jo-1 now has to all ARS. If so, in 95% of patients clinically based diagnosis would be reflected by meeting the formal criteria. Compliance with Solomon’s criteria was even weaker in less than half of the 34 patients with suspected ASS or myositis meeting the criteria [111]. As the spectrum of the ASS is heterogeneous and not all of the typical symptoms have to be present, establishing a proper diagnosis at the onset of the disease may be challenging. Patients with antisynthetase antibodies are frequently diagnosed with undifferentiated connective tissue diseases, idiopathic ILD, interstitial pneumonia with autoimmune feature (IPAF), and other connective tissue diseases or remain under observation with no final diagnosis [112]. Due to numerous diagnostic challenges, final diagnosis is often delayed. An average diagnostic delay of 6 months was described in patients with anti-Jo-1 antibodies [113]. In anti-­ PL-­7 and anti-PL-12-positive patients, a delay period is believed to be even longer [114]. Evaluation by rheumatologists is highly indicated in patients with ILD. Compared to the standard assessment performed by the team of pulmonologists, radiologists, and pathologists, independent evaluation by a rheumatologist enabled to increase in the number of connective tissue disease (CTD)-ILD with autoimmune features by 77% (13 cases of CTD-ILD diagnosed by standard team vs 24 CTD-ILD by rheumatologist). Noteworthy, standard assessment missed three out of four cases of ASS, proving the critical role of the cooperation of medical professionals in diagnostic and therapeutic procedures [115]. In addition, ASS criteria interfere partly with the criteria of a novel diagnostic entity—interstitial pneumonia with autoimmune feature (IPAF). IPAF was proposed in 2015 by the European Respiratory Society (ERS) and American Thoracic Society (ATS)—Task Force on undifferentiated Forms of connective tissue disease-associated interstitial lung disease to describe patients with ILD and features of autoimmune disorders, yet not fulfilling the criteria of any connective tissue disease. Diagnosis of IPAF may be stated if a patient presents at least one feature in each of at least two domains clinical domains (including symptoms such as Raynaud phenomenon, mechanic’s hands, Gottron’s sign, arthritis, palmar telangiectasia, digital edema, distal digital tip ulcers), serologic domain (ANA in the titer of at least 1:320, nuclear or centromere pattern of ANA regardless of the ANA titer, presence of several specific antinuclear autoantibodies including antisynthetase antibodies, anti-CCP or rheumatoid

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factor exceeding twice or more the upper limit), and morphologic domain (ILD in high resolution computed tomography or lung biopsy, multi-compartment involvement) [116]. Fulfilling the criteria of any connective tissue disorder excludes IPAF.  However, an oligosymptomatic patient not classified as ASS according to EULAR/ACR or Solomon criteria may be diagnosed with IPAF or either with ASS according to the broadest Connor’s criteria.

5.10.5 Clinical Symptoms ASS is characterized by a combination of symptoms such as myositis, arthritis, interstitial lung disease, Raynaud phenomenon, mechanic’s hands, and fever. Although some of the symptoms are more commonly seen in patients with definite ARS type, patients with ASS develop in general alike clinical presentation. The prevalence of each symptom varies depending on the study. According to Euro-­ Myositis Registry, patients with ASS most often suffer from muscular lesions and interstitial lung disease (90% and 71%, respectively), while the other symptoms are less prevalent. It is noteworthy that clinical presentation may alter with time as symptoms continue to emerge gradually. At the onset of the disease, patients with anti-Jo-1 antibodies commonly present isolated arthritis, whereas in those with anti­OJ, the sole symptom observed most frequently was myositis, while isolated ILD was the most common manifestation in anti-PL-7, anti-PL-12, and anti-EJ-positive individuals. With time, other symptoms appeared, and in the majority of the patients the complete triad, i.e. myositis, arthritis, ILD, was found, yet isolated ILD remained the most common presentation in anti-PL-12 and isolated myositis in anti-OJ-­ positive patients. It should be noted that cohorts vary significantly for the number of patients and selection criteria, which could lead to biased conclusions. It cannot be excluded that the incidence of symptoms, especially in the subgroups of patients with less prevalent autoantibodies, may be falsely high due to the limited number of cases described.

5.10.6 Myositis The spectrum of muscular involvement in ASS ranges from isolated increased serum concentrations of muscle enzymes to severe weakness and mobility impairment [117]. Muscle weakness was observed in 41.3–100% of ASS patients, while 30.4–88.9% of them were affected by myalgia. Noteworthy, in the most numerous cohorts, a high incidence of muscle symptoms was described. Both myalgia and muscle weakness occur more frequently in anti-Jo-1-positive patients than in those with anti-PL-7 and anti-PL-12 [118]. As compared to patients with other ARS, anti-­ OJ-­positive patients could be at risk of developing more debilitating myositis with severe muscle weakness and atrophy [119]. Typically, ASS patients experience weakness in the proximal muscles of upper and lower extremities, approximately one in three patients is affected by neck muscle weakness and muscle atrophy.

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Hypomyopathic or amyopathic onset is less typical in patients with ARS.  It was observed in 33.3% of patients with anti-OJ but in 15.2% of anti-Jo-1 patients only, however, the differences did not reach statistical significance [114, 119]. Involvement of the esophageal muscles with subsequent dysphagia was observed in one-third of patients. Isolated myalgia without muscle weakness was also described. Peripheral limb muscle involvement with fasciitis remains rather oversubtle [120]. According to Andersson et al., MRI examinations of the thigh muscle revealed abnormalities in 65% of patients with ASS. Muscle edema was observed predominantly in the anterior compartment, while lesions indicated muscle damage and fatty replacement mostly in the posterior compartment. Reduction of muscle volume was confirmed in 14% of ASS patients. In most cases, muscular lesions were symmetrical [121]. Perifascicular necrosis and macrophagocytosis are the most characteristic findings in muscle biopsies (Fig. 5.2a–d). Perimysium, predominantly areas around the vessels, is infiltrated by macrophages and CD8 lymphocytes. Alkaline phosphatase activity is highly expressed in the perimysium [122]. Contrary to PM and sIBM, no infiltrates in the endomysium are observed. Increased expression of major histocompatibility complexes class I and II (MHC-I and MHC-II) are observed in the cytoplasm and on the sarcolemma of myofibers, predominantly in the perifascicular region (Fig. 5.2e). Fibers in the perimysial area accumulate C5b-9 complexes on the sarcolemma or within the sarcoplasm. Diffuse necrotic and regenerating myofibers are less frequently observed, yet may be associated with anti-OJ antibodies as biopsy-based studies revealed a higher prevalence of diffuse myofiber necrosis in anti-OJ-positive patients as compared to the anti-OJ-negative group. The presence of myonuclear actin filament inclusions distinguishes ASS from other IIM subtypes with 93.3% specificity and 80.1% sensitivity.

5.10.7 Extramuscular Manifestations Interstitial lung disease, arthritis and arthralgia, Raynaud phenomenon, fever, and cutaneous symptoms are other key manifestations included in the diagnostic criteria for the diagnosis of ASS [79]. Apart from the symptoms included in the classification criteria, a broad spectrum of other manifestations such as gastrointestinal manifestations, laryngeal involvement, ophthalmic complications, progressive renal failure, hypertension, and thrombotic microangiopathy resembling scleroderma renal crisis and cardiovascular involvement have been described [79, 123].

5.10.8 Outcome and Prognosis Mortality in ASS is considered to be significantly higher than in the general population [124]. Main causes of death in anti-Jo-1-positive patients included interstitial lung disease, neoplasm, infectious diseases including pneumonia, severe myositis, and cardiovascular disorders [125, 126].

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a

b

c

d

e

Fig. 5.2 (a) H&E stain shows perifascicular distribution of numerous necrotic fibers in a case of ASS. (b) MGT stain shows perifascicular distribution of numerous necrotic fibers in a case of ASS. (c) NADH-TR stain shows perifascicular distribution of numerous necrotic fibers which appear unstained in a case of ASS. (d) MAC (C5b-9) immunostain highlights the perifascicular distribution of numerous necrotic fibers in a case of ASS. (e) MHC-I immunostain highlights the perifascicular accentuation of staining in a case of ASS

5.10.9 Overview of Treatment Possibilities As IIM are rare disorders, no large randomized controlled trials are available. Therefore, therapy recommendations are based on trials with a limited number of cases, retrospective analyses, and expert opinion. Despite the significant clinical differences between the IIM subtypes, the majority of the studies were conducted on the IIM group as a whole. Randomized control studies on larger groups are required to assess the effectiveness of different therapeutic options.

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5.10.10 Conclusion ASS is a complex disease with a lot of possible clinical presentations. Although classified as IIM, myositis may not necessarily be the prominent manifestation. The currently available classification criteria do not fully correspond with the clinical patterns of the disease. Since symptoms of ASS can emerge gradually, sometimes after a long time, the disease should be considered as a heterogeneous spectrum rather than a homogenous disease entity. To prevent underdiagnoses, each patient with confirmed presence of ARS and at least one symptom representing the ASS spectrum should remain under long-term interdisciplinary observation. Randomized controlled trials, dedicated to patients with ASS are needed to form treatment algorithms.

5.11 IIMs that Mimic IMNM Of note, forms of myositis with extramuscular manifestation may also harbor necrotic myofibers [14]. Indeed, patients with autoantibodies against ribonucleoprotein (anti-RNP antibodies), or Ku DNA-binding protein complex (anti-KU antibodies), that both are myositis-associated antibodies, and/or with systemic scleroderma, may display myopathological features suggestive of IMNM [14, 16]. All of these patients also present extramuscular manifestations, including skin changes (for example, scleroderma and/or puffy hands), arthralgia or synovitis (for example, in cases of systemic lupus or mixed connective tissue disorder), and/or interstitial lung diseases (for example, in cases of scleroderma or anti-KU diseases), but the co-existence of important signs of muscle inflammation and the sarcolemmal positivity for MHC class II does not correspond with the definition of IMNM.

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51. Pitlick M, Ernste F.  Anti-HMGCR myopathy presenting with acute systolic heart failure. BMJ Case Rep. 2019;12:e230213. 52. Rigolet M, Hou C, Baba Amer Y, et al. Distinct interferon signatures stratify inflammatory and dysimmune myopathies. RMD Open. 2019;5:e000811. 53. Uruha A, Allenbach Y, Charuel JL, et  al. Diagnostic potential of sarcoplasmic myxovirus resistance protein A expression in subsets of dermatomyositis. Neuropathol Appl Neurobiol. 2019;45:513–22. 54. Knauss S, Preusse C, Allenbach Y, et al. PD1 pathway in immune-mediated myopathies: pathogenesis of dysfunctional T cells revisited. Neurol Neuroimmunol Neuroinflamm. 2019;6:e558. 55. Preusse C, Goebel HH, Held J, et al. Immune-mediated necrotizing myopathy is characterized by a specific Th1-M1 polarized immune profile. Am J Pathol. 2012;181:2161–71. 56. Fischer N, Preusse C, Radke J, et al. Sequestosome-1 (p62) expression reveals chaperone-­ assisted selective autophagy in immune-mediated necrotizing myopathies. Brain Pathol. 2020;30:261–71. 57. Girolamo F, Lia A, Annese T, et al. Autophagy markers LC3 and p62 accumulate in immune-­ mediated necrotizing myopathy. Muscle Nerve. 2019;60:315–27. 58. Schroder NW, Goebel HH, Brandis A, Ladhoff AM, Heppner FL, Stenzel W. Pipestem capillaries in necrotizing myopathy revisited. Neuromuscul Disord. 2013;23:66–74. 59. Landon-Cardinal O, Koumako C, Hardouin G, et al. Severe axial and pelvifemoral muscle damage in immune-mediated necrotizing myopathy evaluated by whole-body MRI. Semin Arthritis Rheum. 2020;50:1437–40. 60. Pimenta E, Wolley M, Stowasser M.  Adverse cardiovascular outcomes of corticosteroid excess. Endocrinology. 2012;153:5137–42. 61. Arouche-Delaperche L, Allenbach Y, Amelin D, et al. Pathogenic role of anti-signal recognition protein and anti-3-hydroxy-3-methylglutaryl-CoA reductase antibodies in necrotizing myopathies: myofiber atrophy and impairment of muscle regeneration in necrotizing autoimmune myopathies. Ann Neurol. 2017;81:538–48. 62. Pinal-Fernandez I, Amici DR, Parks CA, et al. Myositis autoantigen expression correlates with muscle regeneration but not autoantibody specificity. Arthritis Rheumatol. 2019;71:1371–6. 63. Horsley V, Jansen KM, Mills ST, Pavlath GK. IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell. 2003;113:483–94. 64. Jacquemin V, Butler-Browne GS, Furling D, Mouly V.  IL-13 mediates the recruitment of reserve cells for fusion during IGF-1-induced hypertrophy of human myotubes. J Cell Sci. 2007;120:670–81. 65. Trapani L, Segatto M, La Rosa P, et al. 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibition impairs muscle regeneration. J Cell Biochem. 2012;113:2057–63. 66. Meyer A, Troyanov Y, Drouin J, et al. Statin-induced anti-HMGCR myopathy: successful therapeutic strategies for corticosteroid-free remission in 55 patients. Arthritis Res Ther. 2020;22:5. 67. Grable-Esposito P, Katzberg HD, Greenberg SA, Srinivasan J, Katz J, Amato AA. Immune-­ mediated necrotizing myopathy associated with statins. Muscle Nerve. 2010;41:185–90. 68. Ramanathan S, Langguth D, Hardy TA, et  al. Clinical course and treatment of anti-­ HMGCR antibody-associated necrotizing autoimmune myopathy. Neurol Neuroimmunol Neuroinflamm. 2015;2:e96. 69. Landon-Cardinal O, Allenbach Y, Soulages A, et al. Rituximab in the treatment of refractory anti-HMGCR immune-mediated necrotizing myopathy. J Rheumatol. 2019;46:623–7. 70. Tansley SL, Betteridge ZE, Simou S, et  al. Anti-HMGCR autoantibodies in juvenile idiopathic inflammatory myopathies identify a rare but clinically important subset of patients. J Rheumatol. 2017;44:488–92. 71. Kusumoto T, Okamori S, Masuzawa K, et  al. Development of necrotizing myopathy following interstitial lung disease with anti-signal recognition particle antibody. Intern Med. 2018;57:2045–9. 72. Giudizi MG, Cammelli D, Vivarelli E, et  al. Anti-HMGCR antibody-associated necrotizing myopathy: diagnosis and treatment illustrated using a case report. Scand J Rheumatol. 2016;45:427–9.

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73. Mammen AL, Tiniakou E.  Intravenous immune globulin for statin-triggered autoimmune myopathy. N Engl J Med. 2015;373:1680–2. 74. Tiniakou E, Rivera E, Mammen AL, Christopher-Stine L. Use of proprotein convertase subtilisin/kexin type 9 inhibitors in statin-associated immune-mediated necrotizing myopathy: a case series. Arthritis Rheumatol. 2019;71:1723–6. 75. Alemo Munters L, Alexanderson H, Crofford LJ, Lundberg IE. New insights into the benefits of exercise for muscle health in patients with idiopathic inflammatory myositis. Curr Rheumatol Rep. 2014;16:429. 76. Van Thillo A, Vulsteke JB, Van Assche D, Verschueren P, De Langhe E.  Physical therapy in adult inflammatory myopathy patients: a systematic review. Clin Rheumatol. 2019;38:2039–51. 77. Ducours M, El-Hout S, Desclaux A, et al. Short duration antibiotic therapy for native joint arthritis caused by Neisseria infection? Ann Rheum Dis. 2022;81(11):e230. 78. Pinal-Fernandez I, Casal-Dominguez M, Carrino JA, et al. Thigh muscle MRI in immune-­ mediated necrotising myopathy: extensive oedema, early muscle damage and role of anti-­ SRP autoantibodies as a marker of severity. Ann Rheum Dis. 2017;76:681–7. 79. Opinc AH, Makowska JS.  Antisynthetase syndrome  – much more than just a myopathy. Semin Arthritis Rheum. 2021;51:72–83. 80. Hochberg MC, Feldman D, Stevens MB, Arnett FC, Reichlin M. Antibody to Jo-1 in polymyositis/dermatomyositis: association with interstitial pulmonary disease. J Rheumatol. 1984;11:663–5. 81. Marguerie C, Bunn CC, Beynon HL, et al. Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyl-tRNA synthetase enzymes. Q J Med. 1990;77:1019–38. 82. Zhang Y, Ge Y, Yang H, et al. Clinical features and outcomes of the patients with anti-glycyl tRNA synthetase syndrome. Clin Rheumatol. 2020;39:2417–24. 83. Ghirardello A, Zampieri S, Tarricone E, et al. Clinical implications of autoantibody screening in patients with autoimmune myositis. Autoimmunity. 2006;39:217–21. 84. Lilleker JB, Vencovsky J, Wang G, et al. The EuroMyositis registry: an international collaborative tool to facilitate myositis research. Ann Rheum Dis. 2018;77:30–9. 85. Wasicek CA, Reichlin M, Montes M, Raghu G. Polymyositis and interstitial lung disease in a patient with anti-Jo1 prototype. Am J Med. 1984;76:538–44. 86. Ghirardello A, Doria A.  New insights in myositis-specific autoantibodies. Curr Opin Rheumatol. 2018;30:614–22. 87. Ghirardello A, Bassi N, Palma L, et al. Autoantibodies in polymyositis and dermatomyositis. Curr Rheumatol Rep. 2013;15:335. 88. Gelpi C, Kanterewicz E, Gratacos J, Targoff IN, Rodriguez-Sanchez JL.  Coexistence of two antisynthetases in a patient with the antisynthetase syndrome. Arthritis Rheum. 1996;39:692–7. 89. Trallero-Araguas E, Grau-Junyent JM, Labirua-Iturburu A, et al. Clinical manifestations and long-term outcome of anti-Jo1 antisynthetase patients in a large cohort of Spanish patients from the GEAS-IIM group. Semin Arthritis Rheum. 2016;46:225–31. 90. Gonzalez-Perez MI, Mejia-Hurtado JG, Perez-Roman DI, et  al. Evolution of pulmonary function in a cohort of patients with interstitial lung disease and positive for antisynthetase antibodies. J Rheumatol. 2020;47:415–23. 91. Gallay L, Gayed C, Hervier B.  Antisynthetase syndrome pathogenesis: knowledge and uncertainties. Curr Opin Rheumatol. 2018;30:664–73. 92. Son SH, Park MC, Kim S.  Extracellular activities of aminoacyl-tRNA synthetases: new mediators for cell-cell communication. Top Curr Chem. 2014;344:145–66. 93. Ascherman DP. The role of Jo-1 in the immunopathogenesis of polymyositis: current hypotheses. Curr Rheumatol Rep. 2003;5:425–30. 94. Howard OM, Dong HF, Yang D, et al. Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. J Exp Med. 2002;196:781–91.

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95. Soejima M, Kang EH, Gu X, Katsumata Y, Clemens PR, Ascherman DP.  Role of innate immunity in a murine model of histidyl-transfer RNA synthetase (Jo-1)-mediated myositis. Arthritis Rheum. 2011;63:479–87. 96. Eloranta ML, Barbasso Helmers S, Ulfgren AK, Ronnblom L, Alm GV, Lundberg IE.  A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies. Arthritis Rheum. 2007;56:3112–24. 97. Zhou JJ, Wang F, Xu Z, et al. Secreted histidyl-tRNA synthetase splice variants elaborate major epitopes for autoantibodies in inflammatory myositis. J Biol Chem. 2014;289:19269–75. 98. Levine SM, Raben N, Xie D, et  al. Novel conformation of histidyl-transfer RNA synthetase in the lung: the target tissue in Jo-1 autoantibody-associated myositis. Arthritis Rheum. 2007;56:2729–39. 99. Galindo-Feria AS, Albrecht I, Fernandes-Cerqueira C, et  al. Proinflammatory histidyl-­ transfer RNA synthetase-specific CD4+ T cells in the blood and lungs of patients with idiopathic inflammatory myopathies. Arthritis Rheumatol. 2020;72:179–91. 100. Costa AN, Kawano-Dourado L, Shinjo SK, Carvalho CR, Kairalla RA. Environmental exposure in inflammatory myositis. Clin Rheumatol. 2014;33:1689–90. 101. Labirua-Iturburu A, Selva-O’Callaghan A, Zock JP, Orriols R, Martinez-Gomez X, Vilardell-­ Tarres M.  Occupational exposure in patients with the antisynthetase syndrome. Clin Rheumatol. 2014;33:221–5. 102. Chinoy H, Adimulam S, Marriage F, et al. Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study. Ann Rheum Dis. 2012;71:961–5. 103. Svensson J, Holmqvist M, Lundberg IE, Arkema EV.  Infections and respiratory tract disease as risk factors for idiopathic inflammatory myopathies: a population-based case-control study. Ann Rheum Dis. 2017;76:1803–8. 104. Sciorati C, Monno A, Doglio MG, et al. Exacerbation of murine experimental autoimmune myositis by toll-like receptor 7/8. Arthritis Rheumatol. 2018;70:1276–87. 105. Hervier B, Perez M, Allenbach Y, et  al. Involvement of NK cells and NKp30 pathway in antisynthetase syndrome. J Immunol. 2016;197:1621–30. 106. Zhang S, Shu X, Tian X, Chen F, Lu X, Wang G. Enhanced formation and impaired degradation of neutrophil extracellular traps in dermatomyositis and polymyositis: a potential contributor to interstitial lung disease complications. Clin Exp Immunol. 2014;177:134–41. 107. Seto N, Torres-Ruiz JJ, Carmona-Rivera C, et al. Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathies. JCI Insight. 2020;5(3). 108. Rothwell S, Lamb JA, Chinoy H.  New developments in genetics of myositis. Curr Opin Rheumatol. 2016;28:651–6. 109. Johnson C, Connors GR, Oaks J, et al. Clinical and pathologic differences in interstitial lung disease based on antisynthetase antibody type. Respir Med. 2014;108:1542–8. 110. Bottai M, Tjarnlund A, Santoni G, et al. EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: a methodology report. RMD Open. 2017;3:e000507. 111. Greco M, Garcia de Yebenes MJ, Alarcon I, et al. Idiopathic inflammatory myopathies and antisynthetase syndrome: contribution of antisynthetase antibodies to improve current classification criteria. Ann Rheum Dis. 2019;78:1291–2. 112. Masiak A, Marzec M, Kulczycka J, Zdrojewski Z. The clinical phenotype associated with antisynthetase autoantibodies. Reumatologia. 2020;58:4–8. 113. Cavagna L, Nuno L, Scire CA, et al. Clinical spectrum time course in anti Jo-1 positive antisynthetase syndrome: results from an international retrospective multicenter study. Medicine (Baltimore). 2015;94:e1144. 114. Cavagna L, Trallero-Araguas E, Meloni F, et  al. Influence of antisynthetase antibodies specificities on antisynthetase syndrome clinical spectrum time course. J Clin Med. 2019;8(11):2013.

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115. Levi Y, Israeli-Shani L, Kuchuk M, Epstein Shochet G, Koslow M, Shitrit D. Rheumatological assessment is important for interstitial lung disease diagnosis. J Rheumatol. 2018;45:1509–14. 116. Fernandes L, Nasser M, Ahmad K, Cottin V. Interstitial pneumonia with autoimmune features (IPAF). Front Med (Lausanne). 2019;6:209. 117. Gusdorf L, Morruzzi C, Goetz J, Lipsker D, Sibilia J, Cribier B. Mechanics hands in patients with antisynthetase syndrome: 25 cases. Ann Dermatol Venereol. 2019;146:19–25. 118. Marie I, Hatron PY, Dominique S, et  al. Short-term and long-term outcome of anti-Jo1-­ positive patients with anti-Ro52 antibody. Semin Arthritis Rheum. 2012;41:890–9. 119. Vulsteke JB, Satoh M, Malyavantham K, Bossuyt X, De Langhe E, Mahler M. Anti-OJ autoantibodies: rare or underdetected? Autoimmun Rev. 2019;18:658–64. 120. Ebbo M, Chagnaud C, Figarella-Branger D, Legall S, Harle JR, Schleinitz N. Antisynthetase syndrome presenting as peripheral limb fasciitis. Joint Bone Spine. 2013;80:528–30. 121. Andersson H, Kirkhus E, Garen T, Walle-Hansen R, Merckoll E, Molberg O. Comparative analyses of muscle MRI and muscular function in anti-synthetase syndrome patients and matched controls: a cross-sectional study. Arthritis Res Ther. 2017;19:17. 122. Stenzel W, Preusse C, Allenbach Y, et  al. Nuclear actin aggregation is a hallmark of anti-­ synthetase syndrome-induced dysimmune myopathy. Neurology. 2015;84:1346–54. 123. Huang K, Aggarwal R. Antisynthetase syndrome: a distinct disease spectrum. J Scleroderma Relat Disord. 2020;5:178–91. 124. Hervier B, Devilliers H, Stanciu R, et al. Hierarchical cluster and survival analyses of antisynthetase syndrome: phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity. Autoimmun Rev. 2012;12:210–7. 125. Rojas-Serrano J, Herrera-Bringas D, Mejia M, Rivero H, Mateos-Toledo H, Figueroa JE.  Prognostic factors in a cohort of antisynthetase syndrome (ASS): serologic profile is associated with mortality in patients with interstitial lung disease (ILD). Clin Rheumatol. 2015;34:1563–9. 126. Marie I, Hatron PY, Cherin P, et al. Functional outcome and prognostic factors in anti-Jo1 patients with antisynthetase syndrome. Arthritis Res Ther. 2013;15:R149.

6

Overlap Myositis

Overlap syndrome could be defined as a disease in which clinical features of two or more connective tissue diseases (CTDs) in the same patient are detectable [1]. In particular, the overlap myositides include idiopathic inflammatory myositis (IIM) with extramuscular symptoms, peculiar systemic lupus erythematosus (SLE), systemic sclerosis (SSc) or Sjögren’s syndrome, frequently associated with specific autoantibodies [2]. The so-called myositis-associated autoantibodies (MAA), mostly represented by anti-Ku, anti-PM/Scl, anti-Ro/Sjögren’s syndrome antibodies (SSA), and anti-U1-RNP, are typically characterized by overlap myositis in which they can be found alone or associated with other autoantibodies [3]. Additional autoantibodies have recently been reported as potential markers of overlap myositis [RuvBL1/2, poly-U-binding factor 60 kDa protein (PUF-60), antifibrillarin (anti-­ U3-­RNP), anticytosolic 50-nucleotidase 1A (NT5C1A)]. Furthermore, the classical myositis specific autoantibodies (MSAs) can be found when clinical overlap from different diseases is observed (i.e. MDA-5, EJ). The concept of overlap myositis, as a distinct clinical entity with associated antibodies, was previously proposed in 2005 by Troyanov et al. [4]. Overlap myositis is defined by the association of myositis with CTD features, such as Raynaud’s phenomenon, arthritis, and interstitial lung disease (ILD), as well as features of SSc and SLE, which most commonly are present at the time of diagnosis. In addition, about 15% of patients without overlap clinical features show an overlap antibody (15 overlap antibodies, including antisynthetase antibodies, are listed) often with suggestive biopsy findings while overlap features developed at follow-up [5]. In such a view, more than 50% of myositis should be accounted as overlap myositis, whereas “pure” polymyositis (PM) accounts for only 5% of patients and remains a diagnosis of exclusion because its nonspecific phenotype is at high risk for mimickers. Although not always satisfactory, the spread of multiparametric assays, such as immunoline blot, for antibodies specific for myositis or SSc or associated antibodies, allows a higher sensitivity [6, 7]. Furthermore, some antigens are now divided

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. L. Gaspar, Immune-Mediated Myopathies and Neuropathies, https://doi.org/10.1007/978-981-19-8421-1_6

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into major epitopes of different molecular weights that can be detected alone or together. Although not yet defined, the recognition of a single epitope may be associated with a different clinical profile of the disease. One of the tasks of the upcoming years will be to consider each new result to redesign the clinical–serological picture of myositis overlap. The serological spectrum of overlap myositis has recently been enriched by the discovery of new autoantibodies [8]. The spread of multiparametric methods has facilitated the identification of the autoantibody marker of overlap myositis and the better definition of the clinical profiles associated with them. Further studies are necessary to confirm the new findings.

References 1. Iaccarino L, Gatto M, Bettio S, et al. Overlap connective tissue disease syndromes. Autoimmun Rev. 2013;12:363–73. 2. Benveniste O, Stenzel W, Allenbach Y. Advances in serological diagnostics of inflammatory myopathies. Curr Opin Neurol. 2016;29:662–73. 3. Ghirardello A, Borella E, Beggio M, Franceschini F, Fredi M, Doria A. Myositis autoantibodies and clinical phenotypes. Auto Immun Highlights. 2014;5:69–75. 4. Troyanov Y, Targoff IN, Tremblay JL, Goulet JR, Raymond Y, Senecal JL. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine (Baltimore). 2005;84:231–49. 5. Senecal JL, Raynauld JP, Troyanov Y. Editorial: a new classification of adult autoimmune myositis. Arthritis Rheumatol. 2017;69:878–84. 6. Cavazzana I, Fredi M, Ceribelli A, et al. Testing for myositis specific autoantibodies: comparison between line blot and immunoprecipitation assays in 57 myositis sera. J Immunol Methods. 2016;433:1–5. 7. Ghirardello A, Bettio S, Bassi N, et al. Autoantibody testing in patients with myositis: clinical accuracy of a multiparametric line immunoassay. Clin Exp Rheumatol. 2017;35:176–7. 8. Fredi M, Cavazzana I, Franceschini F. The clinico-serological spectrum of overlap myositis. Curr Opin Rheumatol. 2018;30:637–43.

7

Vasculitic Myopathy

7.1 Introduction Vasculitis is defined as inflammation of blood vessel (arteries, veins, and capillaries) wall at some point of time during the disease course [1, 2]. Zeek was the first who classified vasculitis into five based on vessel size [3]. These include hypersensitivity angiitis, allergic granulomatous angiitis, rheumatic arteritis, periarteritis nodose, and temporal arteritis. This study used the term “necrotizing angiitis” to denote the vessel wall injury associated with inflammation rather than the mere presence of inflammation. This classification laid the foundation for subsequent classifications of vasculitis. In 1990, the American College of Rheumatology (ACR) classified vasculitis into seven types, viz. giant cell arteritis, Takayasu’s arteritis, Wegener’s granulomatosis, Churg–Strauss syndrome, polyarteritis nodosa, Henoch– Schönlein purpura and hypersensitivity vasculitis [4]. The major limitation of ACR classification is the non-inclusion of microscopic polyangiitis and antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis. In 1994, the Chapel Hill Consensus Conference (CHCC) was held to provide standardized diagnostic terms and definitions of various vasculitides because different names were being used for the same disease and the same name was being used for different diseases [5]. The salient features of conclusions and proposals were: 1. Age was considered a useful discriminator between Takayasu arteritis and giant cell (temporal) arteritis; 2. The term “polyarteritis nodosa” was restricted to medium-sized arteritis and hence vasculitis affecting arterioles, venules, or capillaries were excluded from this diagnostic category; 3. The term Wegener’s granulomatosis” was restricted to patients with granulomatous inflammation. Patients with non-granulomatous small-vessel vasculitis of the upper or lower respiratory tract were categorized under microscopic

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. L. Gaspar, Immune-Mediated Myopathies and Neuropathies, https://doi.org/10.1007/978-981-19-8421-1_7

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polyangiitis (microscopic polyarteritis); 4. The usage of “cutaneous leukocytoclastic angiitis” was restricted to vasculitis in the skin without the involvement of vessels in any other organ; 5 Mucocutaneous lymph node syndrome was essential to making a diagnosis of Kawasaki disease. In 2012, another CHCC was held to improvise the 1994 CHCC nomenclature, change names and definitions as appropriate, and add important categories of vasculitis that were not included previously [6]. The 2012 CHCC reemphasizes the previous CHCC statement that CHCC is a nomenclature system (nosology) and therefore does not provide diagnostic and classification criteria, but provides a framework for inferring and rigorously verifying such criteria. The vasculitides were subdivided based on combinations of features that separate different forms of vasculitis into definable categories. Vasculitides were broadly categorized into infectious vasculitis (direct invasion of the pathogens in vessel walls resulting in inflammation) and noninfectious vasculitis (absence of direct vessel wall invasion by pathogens). Of note, an infection can indirectly result in vasculitis as an immune-mediated phenomenon. The noninfectious vasculitis by integrating knowledge about etiology, pathogenesis, pathology, demographics, and clinical manifestations. The first categorization level is based on the predominant type of vessels involved, i.e. large vessel vasculitis, medium vessel vasculitis, and small-vessel vasculitis. These terms refer to vessels that differ not only in size but also in structural and functional attributes (Table 7.1). Table 7.1  Names for vasculitides adopted by the 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides [6] Large vessel vasculitis (LVV): Takayasu arteritis (TA) and Giant cell arteritis (GCA) Medium vessel vasculitis (MVV): Polyarteritis nodosa (PAN) and Kawasaki disease (KD) Small-vessel vasculitis (SVV) Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV): Microscopic polyangiitis (MPA), Granulomatosis with polyangiitis (Previously Wegener’s granulomatosis) (GPA), and Eosinophilic granulomatosis with polyangiitis (Previously Churg-Strauss syndrome) (EGPA) Immune complex SVV, Anti-glomerular basement membrane (anti-GBM) disease, Cryoglobulinemic vasculitis (CV), IgA vasculitis (Henoch-Schönlein) (IgAV), Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis) Variable vessel vasculitis (VVV): Behcet’s disease (BD) and Cogan’s syndrome (CS) Single-organ vasculitis (SOV): Cutaneous leukocytoclastic angiitis, Cutaneous arteritis, Primary central nervous system vasculitis and Isolated aortitis Others Vasculitis associated with systemic disease Lupus vasculitis, Rheumatoid vasculitis, Sarcoid vasculitis and Others Vasculitis associated with probable etiology Hepatitis C virus-associated cryoglobulinemic vasculitis, Hepatitis B virus-associated vasculitis, Syphilis-associated aortitis, Drug-associated immune complex vasculitis, Drug-associated ANCA-associated vasculitis, Cancer-associated vasculitis and Others

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7.2 Large Vessel Vasculitis Large vessel vasculitis is a vasculitis that affects large arteries more often than other vasculitides. Takayasu arteritis (TA) and giant cell arteritis (GCA) are the 2 major variants. By the 2012 CHCC definitions, the aorta and its major branches (before they enter a viscera) are large vessels. In other words, there are no “large vessels” inside the organs. The histopathologic features of TA and GCA are indistinguishable. Both TA and GCA occur predominantly in females. The age at onset has been used by many but not all investigators to distinguish between GCA and TA. Some have suggested that they are the same disease. This remains unsettled, and 2012 CHCC participants did not seek to resolve this important question. Previous guidelines consider TA as often granulomatous large vessel arteritis that usually occurs before the age of 50 years. In contrast, GCA, although granulomatous large vessel arteritis usually occurs after age 50 with a predilection for the branches of the carotid and vertebral arteries. The term “temporal arteritis” is not a suitable alternative for GCA because not all patients have temporal artery involvement, and other categories of vasculitis can affect the temporal arteries.

7.3 Medium Vessel Vasculitis Medium vessel vasculitis is a vasculitis predominantly affecting medium arteries, defined as the main visceral arteries and their branches (except arterioles, capillaries, or venules). Polyarteritis nodosa (PAN)  and Kawasaki disease (KD)  are the major variants. The onset of inflammation in medium vessel vasculitis is more acute and necrotizing than the onset of inflammation in large vessel vasculitis. PAN is defined as a necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules and is not associated with antineutrophil cytoplasmic antibodies (ANCA). This is a useful discriminator because PAN and ANCA-associated vasculitis can exhibit clinically and pathologically indistinguishable necrotizing arteritis of medium and small arteries. KD is medium vessel arteritis associated with mucocutaneous lymph node syndrome. Coronary arteries are often involved. KD usually occurs in infants and young children.

7.4 Small-Vessel Vasculitis Small-vessel vasculitis is vasculitis predominantly affecting small vessels, defined as small intraparenchymal arteries, arterioles, capillaries, and venules. In essence, all intraparenchymal vessels are small vessels, except for the initial penetrating branches of medium arteries. Small biopsy specimens usually contain only small vessels, thus even the largest arteries in such specimens are small arteries. The ANCA-associated vasculitis is necrotizing small-vessel vasculitis, with few or no immune deposits

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associated with ANCA specific for myeloperoxidase (MPO-­ANCA) or proteinase 3 (PR3-ANCA). A prefix should be added to the name to indicate ANCA reactivity, i.e. MPO-ANCA, PR3-ANCA, or ANCA-negative. The ANCA-negative ANCAassociated vasculitis is analogous to seronegative lupus or seronegative rheumatoid arthritis and is used if the patient otherwise fulfills the definition for an ANCAassociated vasculitis but has negative results on serologic testing for ANCA. Patients with ANCA-negative ANCA-associated vasculitis may have ANCA that cannot be detected with current methods or may have ANCA of as-yet-undiscovered specificity, or pathogenic mechanisms that do not involve ANCA at all. The small number (pauci-immune) or lack of immune deposits in vessel walls are characteristic of ANCA-associated vasculitis in contrast to the moderate to marked vessel wall immune deposition that is characteristic of immune complex mediated small-vessel vasculitis. Antibodies binding to antigens appear to be a major initiator of pathogenic effector mechanisms in both categories of vasculitis, but the exact mechanisms have not been fully elucidated. The major clinicopathologic variants of AAV are microscopic polyangiitis, granulomatosis with polyangiitis (Previously Wegener’s granulomatosis), eosinophilic granulomatosis with polyangiitis (Previously Churg-Strauss syndrome), and single-organ AAV (for example, renal-limited AAV).

7.4.1 ANCA-Associated/Pauci-Immune Vasculitis Microscopic polyangiitis (MPA) is a necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e. capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Inflammation that is not centered on vessels, including granulomatous inflammation, is absent. Granulomatosis with polyangiitis (GPA) is a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels (i.e. capillaries, venules, arterioles, arteries, and veins). Necrotizing glomerulonephritis is common. Ocular vasculitis and pulmonary capillaritis with hemorrhage are frequent. Granulomatous and non-granulomatous extravascular inflammation are common. Eosinophilic granulomatosis with polyangiitis (EGPA) is an eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels and associated with asthma and eosinophilia. Nasal polyps are common. Granulomatous and nongranulomatous extravascular inflammation, such as non-granulomatous eosinophil-­ rich inflammation of the lungs, myocardium, and gastrointestinal tract, is common.

7.4.2 Immune-Complex Mediated Vasculitis Immune complex small-vessel vasculitis is a vasculitis with moderate to marked vessel wall deposits of immunoglobulin and/or complement, predominantly affecting small vessels (i.e. capillaries, venules, arterioles, and small arteries). Arterial

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involvement is much less common in immune complex small-vessel vasculitis compared to ANCA-associated small-vessel vasculitis. When appropriate, immune complex vasculitis can be categorized as a vasculitis associated with probable etiologies (e.g. hepatitis C virus-associated cryoglobulinemic vasculitis) or as a vasculitis associated with systemic disease (e.g. lupus vasculitis or rheumatoid vasculitis).

7.4.3 Anti-glomerular Basement Membrane Disease Anti-glomerular basement membrane (anti-GBM disease) is vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with basement membrane deposition of anti-basement membrane autoantibodies. Lung involvement causes pulmonary hemorrhage, and renal involvement causes glomerulonephritis with necrosis and crescents. “Anti-GBM disease” is a misnomer because anti-GBM antibodies are reactive not only with GBM but also with pulmonary alveolar-capillary basement membranes; however, the use of “anti-GBM disease” is so conventional that the consensus was that this term should be retained. The eponym “Goodpasture’s syndrome” has been used in the past for combined pulmonary and renal expression of anti-GBM disease.

7.4.4 Cryoglobulinemic Vasculitis Cryoglobulinemic vasculitis (CV) is a vasculitis with cryoglobulin immune deposits affecting small vessels (predominantly capillaries, venules, or arterioles) and associated with cryoglobulins in serum. Skin, glomeruli, and peripheral nerves are often involved. The term “idiopathic” or “essential” may be used as a prefix to indicate that the etiology of CV is unknown. As with other vasculitides, when the etiology is known, this can be designated in the diagnosis, e.g. hepatitis C-associated cryoglobulinemic vasculitis.

7.4.5 IgA Vasculitis (Henoch–Schönlein Purpura) IgA vasculitis (IgAV) is a form of vasculitis with IgA1-dominant immune deposits, affecting small vessels (predominantly capillaries, venules, or arterioles). IgAV often involves the skin and gastrointestinal tract and frequently causes arthritis. Glomerulonephritis indistinguishable from IgA nephropathy  (IgAN) may occur. Any segment of the gastrointestinal tract can be affected, but small bowel involvement is the most common. Emerging data suggest that patients with IgAV have circulating abnormally glycosylated IgA1 and possibly glycan-specific IgG antibodies that form IgA1–IgG anti-IgA1 immune complexes. IgG antibodies directed against the abnormal glycosylation putatively bind to IgA1 molecules and localize in vessel walls, causing inflammation. As with other vasculitides, IgAV can occur as a single-organ vasculitis. Isolated cutaneous IgAV is analogous to IgAN without systemic disease. Patients with renal-limited IgAN or single-organ cutaneous IgAV

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may subsequently develop systemic IgAV. IgAV can be associated with and possibly caused by other diseases, such as liver disease, inflammatory bowel disease, and ankylosing spondylitis. The onset of symptomatic IgAV is often associated with an upper respiratory tract or gastrointestinal infection.

7.4.6 Hypocomplementemic Urticarial Vasculitis (Anti-C1q Vasculitis) Hypocomplementemic urticarial vasculitis (HUV/anti-C1q vasculitis) is a form of vasculitis accompanied by urticaria and hypocomplementemia affecting small vessels (i.e. capillaries, venules, or arterioles), and associated with anti-C1q antibodies. Glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation are common features. Anti-C1q antibodies are one of the most distinctive findings in HUV. Hypocomplementemia, and to lesser extent urticaria, occurs in other immune complex SVV, such as lupus vasculitis.

7.4.7 Variable Vessel Vasculitis Variable vessel vasculitis (VVV) is a form of vasculitis with no predominant type of vessel involved that can affect vessels of any size (small, medium, and large) and type (arteries, veins, and capillaries). Behçet's disease (BD)  and Cogan’s syndrome (CS) are the 2 examples included in the 2012 CHCC. They are included as primary categories of vasculitis rather than vasculitis associated with a systemic disease, because of the frequency of vasculitis. BD is a form of vasculitis that can affect arteries or veins. It is characterized by recurrent oral and/or genital aphthous ulcers accompanied by cutaneous, ocular, articular, gastrointestinal, and/or central nervous system (CNS) inflammatory lesions. Small-vessel vasculitis, arteritis, arterial aneurysms, and venous and arterial thromboangiitis and thrombosis may occur. CS is a form of vasculitis characterized by ocular inflammatory lesions, including interstitial keratitis, uveitis, and episcleritis, and inner ear disease, including sensorineural hearing loss and vestibular dysfunction. Vasculitic manifestations may include arteritis (affecting small, medium, or large arteries), aortitis, aortic aneurysms, and aortic and mitral valvulitis. The primary ocular vascular target for inflammation is the small vessels in the vascularized layers of the anterior globe, i.e. from outer to inner: conjunctiva (conjunctivitis), episclera (episcleritis), sclera (scleritis), and uvea (uveitis). Inflamed small blood vessels invade the adjacent normally avascular corneal stroma and cause the very distinctive interstitial keratitis of CS.

7.4.8 Single-Organ Vasculitis Single-organ vasculitis is a form of vasculitis involving arteries or veins of any size in a single organ, with no features that indicate that it is a limited expression

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of systemic vasculitis. The involved organ and vessel type should be included in the name (e.g. cutaneous small-vessel vasculitis, testicular vasculitis, central nervous system vasculitis). Vasculitis distribution may be unifocal or multifocal (diffuse) within an organ or organ system. Some patients originally diagnosed as having single-­organ vasculitis will develop additional disease manifestations that warrant reclassifying the vasculitis as one of the systemic vasculitides (e.g. cutaneous arteritis later becoming systemic polyarteritis nodosa). If the features of a vasculitis that is confined to one organ indicate that it is a limited expression of one of the systemic vasculitides, this vasculitis should be considered a limited expression of that category of vasculitis rather than an independent single-organ vasculitis. Clinical, laboratory, and pathologic features are useful in distinguishing single-organ vasculitis from an isolated expression of systemic vasculitis. Concluding that an isolated vasculitis is a limited expression of a systemic vasculitis does not imply that the vasculitis will or will not subsequently evolve into systemic disease. There is a distinctive form of central nervous system singleorgan vasculitis (primary CNS vasculitis) that is not an isolated expression of systemic vasculitis. As with other single-organ vasculitides, a diagnosis of primary central nervous system vasculitis requires determining that central nervous system vasculitis is not a component of systemic vasculitis (e.g. GCA, BD, MPA, GPA, EGPA), caused by infection (e.g. syphilis), or associated with a systemic disease (e.g. lupus, sarcoidosis). Vasculitis can be associated with and may be caused by a systemic disease. The name (diagnosis) should have a prefix term specifying the systemic disease (e.g. rheumatoid vasculitis, lupus vasculitis, sarcoidosis vasculitis, relapsing polychondritis vasculitis, etc.). This category of vasculitis is associated with systemic diseases and the following category associated with probable etiologies often is considered to be secondary vasculitides, whereas the other categories have been considered primary (or idiopathic) vasculitides. Categorization into primary versus secondary vasculitis becomes problematic as more and more etiologies of the former are discovered. Vasculitis is associated with probable etiology. If vasculitis is associated with a probable specific etiology, the name (diagnosis) should have a prefix specifying the association (e.g. hydralazine-associated microscopic polyangiitis, hepatitis B virus-­ associated polyarteritis nodosa, hepatitis C virus-associated cryoglobulinemic vasculitis, syphilis-associated aortitis, serum sickness-associated immune complex vasculitis, cancer-associated vasculitis, and many others). Hematologic and solid organ neoplasms, as well as clonal B cell lymphoproliferative disorders and myelodysplastic syndrome, can be associated with and may cause vasculitis.

7.5 Skeletal Muscle Vasculitis Almost all organs and systems may be threatened by vasculitis: eye and brain in GCA; brain, kidney, lung, and heart in TA; skin and heart in KD; skin, kidney, testicles, ear, eye, and gut in PAN; skin, kidney, heart, eye, upper and lower respiratory tract, peripheral (PNS) and central nervous system (CNS) in AAV; eye and ear

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in CS; skin, lung, kidney, and joints in cryoglobulinemic vasculitis; skin, kidney, gut, and joints in IgAV; lung and kidney in anti-GBM disease; and skin, pleura, pericardium, respiratory tract in HUV/anti-C1q vasculitis. As briefly summarized, muscle does not represent a “classical” target of systemic vasculitis: skeletal muscle inflammation usually occurs within the spectrum of idiopathic inflammatory myopathies (IIM) or connective tissue diseases (CTD) in which myositis may be an accompanying or overlapping feature [7]. Nevertheless, in clinical practice, it is not so uncommon, albeit unusual, to find patients affected by a definite systemic vasculitis with concomitant muscle inflammation. At the same time, it is not unusual, in definite IIM, to find histological features of vasculitis, often non-necrotizing [7]. The exact meaning of these findings, whether an organ-specific manifestation of vasculitis or a random association, is far from being fully understood nor extensive data are available.

7.5.1 Takayasu Arteritis The first, and to date, the only case of TA with demonstrated muscle involvement was reported by Wang et  al. in a 31-year-old lady, who was previously diagnosed with TA and was not taking any drug, presented with myalgia and weakness of calves. Markers of inflammation were slightly increased, while muscle enzymes were within the normal range [8]. Gastrocnemius biopsy displayed inflammatory infiltrate all around the small arteries, while muscle appeared spared. The patient was effectively treated with prednisone (PDN) and cyclophosphamide (CYC).

7.5.2 Giant Cell Arteritis The association between GCA and myositis was hypothesized as early as the 1950s, but muscle biopsies were negative or unhelpful [9, 10]. The very first clear demonstration was made in 1960 in a patient who developed progressive muscle weakness one year after vasculitis diagnosis [11]. Muscle biopsy evidenced fibroinflammatory infiltration of medium-sized muscular arteries, associated with inflammatory and destructive alterations of the surrounding muscle. For the purpose of understanding, an example of a temporal artery biopsy in a case of GCA shown (Fig. 7.1a–d). After a few years, similar histologic findings were incidentally evidenced in a 57-year-old woman who died from cranial complications of GCA: notably, the patient did not complain of any muscular symptoms [12]. No further cases were reported until 2014, when Veldhoen et al. published a large, organic, attempt to systematically individuate muscle involvement in GCA in a prospective cohort of 99 patients, up to 13 displayed MRI findings of inflammatory alterations within the territory of both temporal muscles [13]. Notably, all these patients displayed a concomitant involvement of both deep and superficial temporal arteries, but only a moderate correlation was found between myositis and jaw claudication,

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a

b

c

d

Fig. 7.1 (a) H&E stain demonstrating inflammation of temporal (large) artery with luminal narrowing in a case of GCA. (b) Masson’s trichrome stain highlights luminal narrowing due to fibrointimal proliferation and inflammation in a case of GCA. (c) Orcein stain highlights the breach and reduplication of the internal elastic lamina in a case of GCA. (d) H&E stain (high power) demonstrating inflammation comprising of giant cells in a case of GCA

which does not seem related to muscle involvement, but vasculitis of deep temporal artery [14, 15]. Interestingly, similar findings were reported in 2019 by Na et  al. in a patient fulfilling 1990 ACR classification criteria for GCA, MRI showed a marked enhancement in the territory of both homolateral pterygoid and temporal muscle [16]. Kadoba reported the case of a patient affected by GCA, whose only presenting symptom was both legs discomfort [17]. MRI displayed signal hyperintensity in perimysium, particularly in the territory of the vessels feeding thigh muscles. The strict correlation between vasculitis and myopathy was witnessed both by the elevated FDG uptake in the territory of the iliac and femoral arteries and by radiological remission after the treatment with GCs and Tocilizumab.

7.5.3 Polyarteritis Nodosa The association between PAN and IIM was reported as early as 1970, when Golding described the case of a 40-year-old man suffering from recurrent episodes of calf pain, with an overall good response to GCs, in whom muscle biopsy showed medium vessel

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vasculitis and disruption of surrounding muscle fibers [18]. A similar clinical presentation, as well as a rapid improvement after steroid treatment, was reported by the authors who, during the subsequent two decades, reported 3 further cases of calves’ muscle involvement of PAN, all diagnosed through muscle biopsy and all displaying an excellent and rapid response to GCs [18–21]. In 1992, Hofman et al. reported the very first evidence of MRI in the diagnosis and follow-up of a patient suffering from PAN and displaying biopsy and EMG findings of muscle vasculitis [21]. GCs prompted an excellent response, witnessed by the improvement of MRI findings. MRI was also useful in the definite diagnosis of two patients, who had been suffering for years from nonspecific systemic and muscle symptoms [22, 23]. During the following years, MRI became the preferred procedure for the diagnosis of muscular involvement in PAN patients, being performed in the majority of further published case reports and case series [24–27]. In all of them, T2 and STIR sequences displayed signal hyperintensity in the muscles surrounding the vessels, while T1 sequences were usually normal or only slightly hyperintense. Among the other imaging procedure employed for the diagnosis of muscle involvement, positron emission tomography (PET), reported in 4 cases, was negative in 2 and displayed FDG uptake in the other 2, while scintigraphy showed high gallium uptake in iliopsoas muscle in the only patient who underwent this procedure [28, 29]. Blood exams usually displayed an elevation of inflammatory markers, while creatine kinase was usually within normal range, exceptions made for 5 patients who suffered from proximal muscle involvement [30, 31]. Indeed, while almost all patients had an inflammatory localization to calves, usually bilateral, only a minority of them suffered from proximal upper and/or lower limb myositis, sometimes restricted to the fascia. Axial involvement was described only in two subjects, in which MRI displayed edema of the iliopsoas and paraspinal muscles. The main symptoms and signs were muscle pain, swelling, and induration, as well as fever of unknown origin and malaise, while a systemic PAN, with a definite extra-muscular involvement, was assessed only in 4 cases [32–34]. Finally, an association with hepatitis B virus (HBV) or C (HCV) was evidenced only in one each. Muscle biopsy shows vasculitis with temporal and anatomical heterogeneity, i.e. both active and chronic lesion within the same artery as well as different arteries. The vasculitis is typically necrotizing, segmental (non-circumferential) non-­ granulomatous involving small- to medium-sized arteries (Fig.  7.2a, b). Myoinfarction is rare (Fig. 7.2c). All patients were treated with a medium to high dosage of GCs and, in less than 50% of cases, with immunosuppressants, such as colchicine, AZA, MTX, CYC, IVIG, RTX, MMF, and Tacrolimus. The overall response to treatment was good and relapses were reported only in 3 cases.

7.5.4 Kawasaki Disease The first evidence of the coexistence of KD and muscular involvement occurred in 1982 when Koutras described the onset of proximal muscular involvement of the four limbs, dysphonia, dysphagia, and inability to stand up and walk in an

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18-month-­old girl shortly after the diagnosis of vasculitis; myositis was assessed via EMG evaluation, while laboratories investigations demonstrated a moderate elevation of lactate dehydrogenase and creatine kinase [35, 36]. A similar case was reported a few years later by Sugie et al. that described the onset of proximal muscle weakness and pain, associated with Gower’s sign positivity and mildly reduced tendon reflexes, in a 3-year-old boy with a concomitant diagnosis of KD [36]. Quadriceps muscle biopsy evidenced a mononuclear leukocyte cell infiltrate in the perivascular area and peri-endomysium, along with sporadic muscular fiber necrosis and type II fiber atrophy. Both patients were effectively treated with acetylsalicylic acid (ASA).

a

b

c

Fig. 7.2 (a) H&E stain (low and high power) demonstrating necrotizing vasculitis with fibrinoid necrosis of the vessel wall in a case of PAN. (b) Acid fuchsin orange G (AFOG) stain demonstrating segmental (non-circumferential) vasculitis of different ages within the same vessel as well as different vessels in a case of PAN. (c) H&E stain demonstrating myoinfarction in a case of PAN

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An even more severe presentation was reported in 1990 by Gama et al.: a 3-year-­ old boy with a recent diagnosis of KD, despite a good response to ASA and gamma-­ globulins, presented with a marked increase of creatine kinase, a rapidly progressing proximal weakness, and respiratory failure. Electromyogram (EMG) showed brief, small action potentials suggestive of a myopathic pattern, while muscle biopsy was consistent with type II fiber atrophy [37]. Respiratory failure, although not histologically demonstrated, was hypothesized as secondary to inflammatory diaphragm involvement. The first case of adult-onset KD complicated by muscle involvement was described by Hicks et  al. in a 40-year-old black man with lower limb weakness, elevated serum creatine kinase levels, and pathological EMG [38]. Muscle biopsy, which to date remains the only one performed in an adult patient affected by KD, displayed granular necrosis of several muscle fibrils and rare foci of mononuclear cell aggregations and IgG deposits in the sarcolemma. The patient, who did not respond to ASA and acetaminophen, was eventually treated with GCs. Another atypical presentation of myositis was reported in 1999 by Lin et al., who described the occurrence of orbital myositis 35 days after the diagnosis of KD, apparently responsive to intravenous immunoglobulin (IVIG) and GCs [39]. The patient developed progressive erythema and distension of the left upper eyelid, with bulb displacement and inability to look upward at the homolateral eye. Biopsy revealed arteritis and myositis of levator palpebrae superioris muscle as well as orbicularis muscle thickening. Remission was rapidly achieved after the administration of i.v. high dosage GCs. Recently, Lee et al. reported, for the first and to date only time, the role of imaging procedures in a KD patient with rapidly progressing left calf tenderness: MRI revealed muscle edema consistent with the suspicion of myositis, and the patient was effectively treated with IVIG [40]. Finally, Vigil-Vazquez reported the use of Infliximab (IFX), 6 mg/kg, in a case of refractory KD presenting as severe left iliopsoas myositis and complicated by hemodynamic shock. To date, this remains the only evidence supporting the use of biological agents in KD-associated myositis [41].

7.5.5 Granulomatosis with Polyangiitis The first case of GPA-associated myositis was reported in 2009 in a patient suffering from calves’ claudication and whose muscle biopsy displayed granulomatous vasculitis [42]. Muscle biopsy in GPA shows typically necrotizing, granulomatous/ non-granulomatous vasculitis involving small arteries (Fig. 7.3a, b). Over the years, larger data came from the retrospective work of a French group (University of Nantes) that reported, for the first time in 2010 and then in 2020, ANCA-associated vasculitis (AAV) patients who underwent muscle biopsy [17, 43]. Histology was consistent with a diagnosis of IIM in 17 out of 33 GPA patients, displaying inflammatory infiltrate in vessel walls, with or without fibrinoid necrosis. ANCA-MPO represented the strongest predicting factor of biopsy positivity (OR 12.4), whereas only 6 patients were carrying ANCA-PR3. While all the above-mentioned cases

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b

Fig. 7.3 (a) H&E stain demonstrating necrotizing vasculitis with fibrinoid necrosis and inflammation of the vessel wall in a case of GPA. (b) MGT stain demonstrating necrotizing vasculitis with fibrinoid necrosis and inflammation of the vessel wall in a case of GPA

presented with lower limb involvement, Lee et al. reported the first occurrence of back muscle myositis in GPA, as the only feature of small-vessel vasculitis in a patient carrying ANCA-MPO positivity [44].

7.5.6 Microscopic Polyangiitis The first cases of myositis in MPA occurred in subjects presenting concomitant, “classical” features of AAV, such as interstitial lung disease, described by the authors as “pulmonary-muscle syndrome,” or mononeuritis multiplex [45, 46]. Subsequently, Benz et al., in their small case series, described the first MPA patients in whom muscle was the only organ involved in vasculitis. The growing number of evidence about the occurrence of myositis in MPA was confirmed by the research group of Nantes University that showed compelling findings of inflammatory myopathy (granulomatous or, more commonly, necrotizing vasculitis) in 16 out of 25 MPA patients who underwent muscle biopsy [43]. A similar study, with comparable findings, was carried out by Nunokawa et al. showing 15 GPA patients with histological findings of myositis [47]. It should be remarked that, unlike the French cohort, fibrinoid necrosis was considered an essential criterion for the pathological confirmation of vasculitis [43]. From a histological point of view, aside from granulomatous and necrotizing fibrinoid vasculitis, the latter being the most common presentation of myositis, definite muscle necrosis seldom occurs [48]. Similarly, fascia is usually spared, reported only a single case of histologically proven fascial vasculitis in a patient with MPA. Nevertheless, fasciitis may represent a diagnostic tool in differential diagnosis: in a recently published paper, fascial hyperintensity, as well as subcutaneous fat hyperintensity, seemed to be the only MRI findings capable of distinguishing between MPA-associated myositis and polymyositis (PM) or dermatomyositis (DM) [49]. Finally, Yamada et al. reported a unique case of a patient concomitantly affected by MPA and sporadic inclusion body myositis (sIBM), it is unclear whether sIBM represented a true muscular localization of vasculitis or a random occurrence [50].

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7.5.7 Eosinophilic Granulomatosis with Polyangiitis In 2002, Della Rossa et al. described a cohort of 19 patients affected by EGPA [51]. Among these patients the authors reported one case of muscular vasculitis whose diagnosis was based on histopathology. In 2004, Suresh et al. reported the first case of EGPA presenting with muscle vasculitis [52]. In this patient, presenting with generalized asthenia and positivity of ANCA-MPO antibodies the authors decided to perform a muscular biopsy despite the slight increase of CK and a normal EMG. Histopathology showed active vasculitis with inflammation extending into surrounding skeletal muscle fascicles. Remission was induced with GCs, MMF, and IVIG.  In the same year, Billing et  al. reported the first and to date only case of orbital myositis in EGPA presenting with lid swelling [53]. Computed tomography (CT) orbital scan of the patient showed enlargement of the right muscle superior rectus. Although lesion biopsy showed focal eosinophilic inflammatory cell infiltrate with no granuloma or evidence of vasculitis, the diagnosis was made six months later, based on a nasal polyp biopsy after considering the history of rhinitis and asthma associated with hypereosinophilia. In 2008 Uehara et. reported a singular case, presenting a 68-year-old woman with muscular vasculitis diagnosed after a vigorous and unaccustomed amount of exercise, demonstrated by muscular biopsy showing eosinophil interstitial infiltrate [54]. Moreover, it was reported two cases describing biopsy proved myositis in EGPA patients presenting with myalgia and diffuse weakness and responsive to GCs and IS treatment [55, 56]. It is very interesting to note that in both cases muscle symptoms were the first clinical feature of EGPA and muscular histopathology led to a prompt diagnosis, underlying how myositis could be, sometimes, the first significant clinical presentation element of EGPA. Recently, histological findings of vasculitis were assessed in 2 and 12 patients from the experience by Nunokawa and Lacou, respectively [43, 47]. The latter showed the largest cohort of EGPA patients with a definite diagnosis of muscle vasculitis. Nevertheless, no data about treatment and prognosis were reported by the authors.

7.5.8 Cryoglobulinemic Vasculitis In 1992, Gemignani et al. evaluated a cohort of patients affected by essential mixed cryoglobulinemia (EMC) aiming to assess neurological involvement. Twenty-one out of 37 subjects displayed EMG abnormalities (muscle spontaneous activity of distal muscles), while 5 of them presented evidence of muscle vasculitis at peroneus brevis muscle biopsy, though histopathological characteristics were not specified [57]. The first consistent histological detection of PM in cryoglobulinemic vasculitis was reported in 1993 by Voll et al. describing the case of a male patient affected by EMC presenting with four limb hyposthenia [58]. Blood exams showed an increase of creatine kinase, associated with EMG pathological findings of decreased amplitude and duration of motor unit potentials, and an increase in polyphasia, of upper and lower extremities. Biopsy specimens from the right quadriceps femoris muscle

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showed necrotic and degenerating myofibers with a dense perivascular, perimysial, and endomysial inflammatory cell infiltrate comprising predominantly plasma cells. The patient was effectively treated with GCs and plasmapheresis. More recently, Rodriguez-Perez et al. reported another case of cryoglobulinemic vasculitis presenting as PM. The authors reported the history of a 31-year-old man presenting with upper and lower extremity muscle weakness with a notable creatine kinase increase [59]. An EMG showed signs of myopathy while muscle biopsy revealed endomysial inflammation with muscle fiber necrosis and regeneration. In this case, a proper treatment with steroid and CYC pulses allowed a control with an improvement of the symptomatology.

7.5.9 IgA Vasculitis In 2000 Agraharkar et al. reported the death of a 63-year-old man due to myocardial necrosis of the right atrium attributable to IgAV with postmortem histology revealing cardiac vasculitis [60]. Nevertheless IgA-immunofixation was not performed. Stronger evidence of myocardial IgAV involvement was reported by Carmichael et al. that described the case of a cardiac arrest in a male patient, who eventually died [61]. The postmortem examination showed a 10  mm diameter hemorrhagic area localized on the left ventricle, with histological findings of subendocardial leukocytoclastic vasculitis. Stronger evidence, supported by imaging findings, was reported in a Korean young patient affected by IgAV, who presented lower limbs muscle edema at MRI [62].

7.5.10 Anti-C1q Vasculitis To date, there is only one evidence of muscle involvement in anti-C1q vasculitis (HUVS) [63], reported by Chew et al. describing a case of a gentleman with a history of HUV, complicated by diffuse membranoproliferative-glomerulonephritis under IS treatment with CYC and GCs [63]. Despite the IS regimen, the patient developed hyposthenia of the four limbs associated with a marked increase in creatine kinase levels. The patient underwent a muscle biopsy suggestive of inflammatory myositis with vasculitis with moderate mononuclear inflammation between fascicles and muscle fibers. The patient was successfully treated with MTX and a high dosage of GCs.

7.5.11 Cogan’s Syndrome The first, and to date, the only case of muscle involvement in CS was described by Zhou et  al. reporting a case of atypical CS with a visual deficit. Inferior rectus muscle biopsy revealed fibrosis and lymphocytic infiltration and the patient was successfully treated with GCs [64].

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7.5.12 Behçet’s Disease Myositis is an uncommon manifestation of BD [65]. Nevertheless, there is a growing research interest in muscle inflammatory involvement in such a disease. The first evidence was reported in the early 1980s when 3 consecutive papers from different countries (USA, Turkey, and Italy) described an inflammatory infiltrate in muscle vessels of patients affected by BD [66–68]. In the following years, several other cases of focal or, more commonly, generalized myositis were described: in all cases, the patients displayed a good response to GCs and/or conventional immunosuppressants, but the discontinuation of the treatment lead to further relapses [17]. Creatine kinase levels were within normal range or, more seldom, increased, while histological findings showed inflammatory infiltrates surrounding necrotic areas in case of long-standing disease. A limited localization to the eye, although extremely uncommon, has also been reported in two patients suffering from orbital myositis; in one of them, myositis was the only evidence of eye involvement, while in the other one the patient had previously suffered from scleritis and retrobulbar neuritis [69, 70]. Among imaging procedures employed for diagnosis, MRI is by far the most commonly performed in clinical practice: typical findings include T2 and STIR hyperintensity, while T1 sequences are usually normal or hypointense [71, 72]. Conversely, conflicting data are available about the usefulness of muscle US, which was performed on 3 patients [73]. Finally, myositis in pediatric BD is even rarer: to date, only 2 definite cases have been reported in the literature and the clinical course was often treacherous [74, 75].

7.5.13 Single-Organ Vasculitis The first, and largest cohort of muscle vasculitis without a definite diagnosis of systemic disease was described by Prayson et al. in 2002 [7]. They retrospectively enrolled a cohort of 40 patients who underwent muscle biopsy and displayed necrotizing vasculitis affecting multiple vessels; a concomitant sural nerve vasculitis was found in 26 out of 33 patients. Notably, 3 patients were ANCA positive, 1 had a previous diagnosis of EGPA, and 11 presented histological findings strongly suggestive of PAN. Nevertheless, no patient fulfilled definite criteria or presented an extra-muscular involvement suggestive of systemic vasculitis. Conversely, different histological findings (leukocytoclastic vasculitis) were reported in the smaller cohort by Khellaf et al. in which 7 out of 11 patients with calves-restricted muscle myositis did not display any evidence of systemic vasculitis. They interpreted the cases of granulomatous, medium vessels, and vasculitis as features of muscle-restricted PAN unequally from the above authors [76]. Finally, an extremely unusual localization was reported by Nielsen et al. describing the case of a patient suffering from dropped head syndrome due to neck extensor muscles vasculitis, with no sign or symptom of systemic involvement [77].

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7.5.14 Vasculitis Associated with Systemic Disease The earliest available record of an arteritic muscular involvement in systemic diseases is dated back to 1945 when Gibson et al. [4] reported vascular and muscular changes suggestive of an arteritic process in 9 rheumatoid arthritis (RA) patients who underwent a muscle biopsy [9]. Soon after Steiner et al. described neuroinflammatory changes in peripheral nerves in RA and documented the nodular inflammatory infiltration of an artery close to the left tibialis muscle of an RA middle-aged woman [78]. Ellman et al. in a small case series described the histologic infiltration of macrophages and other inflammatory cells within the walls of muscular arteries in RA patients during a postmortem investigation [79]. Sokoloff et al. and Levin et al. reported, in different studies, evidence of muscular involvement due to vasculitic changes of artery walls, histologically suggestive for PAN [80–82]. Other authors studied the histology of RA patients documenting the presence of “lymphorrhages,” vasculitic changes of intima and media of arteries, as well as rheumatic heart disease suggesting an arteritic insult histologically mimicking PAN [83, 84]. In 1956 Skogrand et al. and Taubenhaus et al. reported two cases of RA patients with a biopsy-proven necrotizing vasculitis and myositis [85, 86]. Moreover, other researchers described biopsy-proven arteritis and myositis in RA patients presenting with foot drop, numbness of extremities, and neuropathic symptoms [17]. As previously reported, Schmid et al. in 1961 documented via muscule biopsy the presence of arterial vascular involvement in a case series of 17 RA patients presenting with numbness or drop of the extremities, most of them displaying a necrotizing arterial as well as peripheral nerve involvement [87]. Later on, Magyar et al. conducted a histopathological study of muscular involvement during RA evaluating specimens of 100 patients, documenting 61 nodular perivascular myositis as well as acute, subacute, and chronic vasculitis [88]. Conversely, in the last 30 years, only 3 papers (for a total of 4 patients) reported a biopsy-proven muscle vasculitis in patients with a previous diagnosis of RA. Notably, the last one, which dated back to 2007, was the first and, to date, only, paper reporting the use of MRI in this condition [17]. A few other autoimmune systemic conditions were associated with muscle vasculitis: Till date, only 2 cases of Crohn’s disease and one of systemic lupus erythematosus (SLE) have been reported [89–91]. Notably, among the SLE subgroup, a good correlation between muscle vasculitis and systemic disease activity was evidenced.

7.6 Conclusion In conclusion, muscle vasculitis is an uncommon, but not an exceptional manifestation of systemic vasculitis. Striated muscles are involved in the vast majority of cases, but concomitant myocarditis has been also reported. Muscle biopsy displays different histological findings, the most common a necrotizing, non-granulomatous, vasculitis of the perimysial vessels. Muscle atrophy and disruption may also be

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evidenced, as well as clinical features, such as hypereosinophilia for EGPA and granulomas for GPA, resembling concomitant systemic vasculitis. Creatine kinase is usually within the normal range but can be elevated just like in IIM. In those cases, they may herald a more aggressive, difficult-to-treat, disease, requiring a higher dosage of immunosuppressants aside from GCs. Among imaging procedures, MRI, as commonly used in IIM, is by far the most performed and shows good diagnostic accuracy mainly referring to T2 and STIR hyperintensity; T1 scans are normal or, more seldom, hyperintense, with no clear-­ cut difference with IIM. Conversely, no robust data are to date available for PET, which may have a promising role when combined with MRI, for the differential diagnosis between vasculitis, IIM, and muscle vasculitis. The presentation of the disease is tricky, difficult to diagnose, but often severe and, in a minority of cases, life-threatening. Nevertheless, patients usually display a good response to GCs and conventional immunosuppressants and relapses occur in a minority of cases; scanty evidence is available about the use of biological drugs. A deeper insight into this condition will probably increase in the following years' numerosity and knowledge about this neglected, specific, localization of vasculitis.

References 1. Demir S, Sonmez HE, Ozen S.  Vasculitis: decade in review. Curr Rheumatol Rev. 2019;15:14–22. 2. Watts RA, Robson J. Introduction, epidemiology and classification of vasculitis. Best Pract Res Clin Rheumatol. 2018;32:3–20. 3. Zeek PM. Periarteritis nodosa: a critical review. Am J Clin Pathol. 1952;22:777–90. 4. Hunder GG, Arend WP, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction. Arthritis Rheum. 1990;33:1065–7. 5. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37:187–92. 6. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 2013;65:1–11. 7. Prayson RA.  Skeletal muscle vasculitis exclusive of inflammatory myopathic conditions: a clinicopathologic study of 40 patients. Hum Pathol. 2002;33:989–95. 8. Wang ZW, Li SH, Yu YW, Dai SM.  Intra-muscular arteries are also affected in Takayasu’s arteritis. Rheumatol Int. 2013;33:2683–5. 9. Gibson HJ, Kersley GD, Desmarais MH.  Lesions in muscle in arthritis. Ann Rheum Dis. 1946;5:131–8. 10. Bagratuni L. A rheumatoid syndrome occurring in the elderly. Ann Rheum Dis. 1953;12:98–104. 11. Russell RW. Muscular involvement in giant-cell arteritis. Ann Rheum Dis. 1962;21:171–5. 12. Kennedy LJ Jr, Mitchinson MJ. Giant cell arteritis with myositis and myocarditis. Calif Med. 1971;115:84–7. 13. Veldhoen S, Klink T, Geiger J, et al. MRI displays involvement of the temporalis muscle and the deep temporal artery in patients with giant cell arteritis. Eur Radiol. 2014;24:2971–9. 14. Imai N, Kuroda R, Konishi T, Serizawa M, Kobari M. Giant cell arteritis: clinical features of patients visiting a headache clinic in Japan. Intern Med. 2011;50:1679–82. 15. Kleinegger CL, Lilly GE. Cranial arteritis: a medical emergency with orofacial manifestations. J Am Dent Assoc. 1999;130:1203–9. 16. Na S, Lee ES, Kim YD. Teaching NeuroImages: pterygoid myositis mimicking giant cell arteritis. Neurology. 2019;92:e2297.

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17. Conticini E, d’Alessandro M, Al Khayyat SG, et al. Inflammatory muscle involvement in systemic vasculitis: a systematic review. Autoimmun Rev. 2022;21:103029. 18. Golding DN. Polyarteritis presenting with leg pains. Br Med J. 1970;1:277–8. 19. Ferreiro JE, Saldana MJ, Azevedo SJ. Polyarteritis manifesting as calf myositis and fever. Am J Med. 1986;80:312–5. 20. Garcia F, Pedrol E, Casademont J, et  al. Polyarteritis nodosa confined to calf muscles. J Rheumatol. 1992;19:303–5. 21. Hofman DM, Lems WF, Witkamp TD, Putte VD, Bijlsma JW. Demonstration of calf abnormalities by magnetic resonance imaging in polyarteritis nodosa. Clin Rheumatol. 1992;11:402–4. 22. Reading PJ, Hudgson P, Johnson MA, Jenkins A. A sartorial challenge. Lancet. 1999;354:996. 23. Esteva-Lorenzo FJ, Ferreiro JL, Tardaguila F, de la Fuente A, Falasca G, Reginato AJ. Case report 866.Pseudotumor of the muscle associated with necrotizing vasculitis of medium- and small-sized arteries and chronic myositis. Skeletal Radiol. 1994;23:572–6. 24. Gallien S, Mahr A, Rety F, et al. Magnetic resonance imaging of skeletal muscle involvement in limb restricted vasculitis. Ann Rheum Dis. 2002;61:1107–9. 25. Nakamura T, Tomoda K, Yamamura Y, Tsukano M, Honda I, Iyama K.  Polyarteritis nodosa limited to calf muscles: a case report and review of the literature. Clin Rheumatol. 2003;22:149–53. 26. Haroon M, Bermingham N, Keohane C, Harney S. Polyarteritis nodosa presenting with clinical and radiologic features suggestive of polymyositis. Rheumatol Int. 2012;32:1079–81. 27. Yang SN, Cho NS, Choi HS, Choi SJ, Yoon ES, Kim DH. Muscular polyarteritis nodosa. J Clin Rheumatol. 2012;18:249–52. 28. Ganeshanandan LR, Brusch AM, Dyke JM, McLean-Tooke APC. Polyarteritis nodosa isolated to muscles-A case series with a review of the literature. Semin Arthritis Rheum. 2020;50:503–8. 29. Taniguchi Y, Ogata K, Yoshimatsu R, Yamagami T, Terada Y. Polyarteritis nodosa of the iliopsoas muscle. Arthritis Rheumatol. 2015;67:2426. 30. Plumley SG, Rubio R, Alasfar S, Jasin HE. Polyarteritis nodosa presenting as polymyositis. Semin Arthritis Rheum. 2002;31:377–83. 31. Ushiyama S, Shimojima Y, Ueno KI, Kishida D, Miyazaki D, Sekijima Y. Clinical characteristics of patients with myalgia as the initial manifestation of small and medium-sized vasculitis: a retrospective study. Rheumatol Int. 2020;40:1667–74. 32. Zahoor S, Siddique S, Mahboob HM. An unusual presentation of polyarteritis nodosa: a case report. Reumatol Clin (Engl Ed). 2020;2020:S1699-258X(20)30227-8. 33. Kamimura T, Hatakeyama M, Torigoe K, et  al. Muscular polyarteritis nodosa as a cause of fever of undetermined origin: a case report and review of the literature. Rheumatol Int. 2005;25:394–7. 34. Hervier B, Durant C, Masseau A, Ponge T, Hamidou M, Mussini JM. Use of muscle biopsies for diagnosis of systemic vasculitides. J Rheumatol. 2011;38:470–4. 35. Koutras A. Myositis with Kawasaki'’s disease. Am J Dis Child. 1982;136:78–9. 36. Sugie H, Sugie Y, Ichimura M, Mizuno Y, Nishida M, Igarashi Y. A case of polymyositis associated with Kawasaki disease. Brain Dev. 1985;7:513–5. 37. Gama C, Breeden K, Miller R. Myositis in Kawasaki disease. Pediatr Neurol. 1990;6:135–6. 38. Hicks JT, Korenyi-Both A, Utsinger PD, Baran EM, McLaughlin GE.  Neuromuscular and immunochemical abnormalities in an adult man with Kawasaki disease. Ann Intern Med. 1982;96:607–10. 39. Lin H, Burton EM, Felz MW.  Orbital myositis due to Kawasaki’s disease. Pediatr Radiol. 1999;29:634–6. 40. Lee EY, Oh JY, Chong CY, Choo JT, Mahadev A, Tan NW. A case of atypical Kawasaki disease with myositis Glob Pediatr. Health. 2015;2:2333794X15599649. 41. Vigil-Vazquez S, Butragueno-Laiseca L, Lopez-Gonzalez J, Garcia-San Prudencio M, Rincon-Lopez E. A case of Kawasaki disease presenting as severe myositis. Indian J Pediatr. 2019;86:1066–7. 42. Kim MY, Bae SY, Lee M, et al. A case of ANCA-associated vasculitis presenting with calf claudication. Rheumatol Int. 2012;32:2909–12.

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43. Lacou M, Leroy M, Le Lan N, et al. Muscle biopsy in anti-neutrophil cytoplasmic antibody-­ associated vasculitis: diagnostic yield depends on anti-neutrophil cytoplasmic antibody type, sex and neutrophil count. Rheumatology (Oxford). 2021;60:699–707. 44. Lee YM, Chung SW. Granulomatosis with polyangiitis restricted to the back muscle: the first case report. Medicina (Kaunas). 2020;2020:56. 45. Birnbaum J, Danoff S, Askin FB, Stone JH.  Microscopic polyangiitis presenting as a “pulmonary-­muscle” syndrome: is subclinical alveolar hemorrhage the mechanism of pulmonary fibrosis? Arthritis Rheum. 2007;56:2065–71. 46. Sassi SB, Ghorbel IB, Mizouni H, Houman MH, Hentati F. Microscopic polyangiitis presenting with peripheral and central neurological manifestations. Neurol Sci. 2011;32:727–9. 47. Nunokawa T, Yokogawa N, Shimada K, Enatsu K, Sugii S. The use of muscle biopsy in the diagnosis of systemic vasculitis affecting small to medium-sized vessels: a prospective evaluation in Japan. Scand J Rheumatol. 2016;45:210–4. 48. Akagi T, Nishimura H, Mukai T, Morita Y. Necrosis of the gastrocnemius muscle in microscopic polyangiitis. BMJ Case Rep. 2018;2018:bcr2017223585. 49. Kawaguchi M, Kato H, Nagasawa T, et al. MR imaging findings of musculoskeletal involvement in microscopic polyangiitis: a comparison with inflammatory myopathy. Radiol Med. 2021;126:1601–8. 50. Yamada S, Yamashita H, Taira K, et  al. A case of inclusion body myositis complicated by microscopic polyangiitis. Scand J Rheumatol. 2018;47:243–5. 51. Della Rossa A, Baldini C, Tavoni A, et al. Churg-Strauss syndrome: clinical and serological features of 19 patients from a single Italian centre. Rheumatology (Oxford). 2002;41:1286–94. 52. Suresh E, Dhillon VB, Smith C, Ironside JW. Churg-Strauss vasculitis diagnosed on muscle biopsy. J Clin Pathol. 2004;57:334. 53. Billing K, Malhotra R, Selva D, Dodd T. Orbital myositis in Churg-Strauss syndrome. Arch Ophthalmol. 2004;122:393–6. 54. Uehara M, Hashimoto T, Sasahara E, Higuchi K, Matsubara K, Ikeda S.  Churg-Strauss syndrome presenting as myositis following unaccustomed exercise. J Clin Neurosci. 2009;16:1232–3. 55. Parent ME, Larue S, Ellezam B. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) presenting as diffuse myositis. BMC Musculoskelet Disord. 2014;15:388. 56. Koppikar S, Al-Dabie G, Jerome D, Vinik O. Eosinophilic granulomatosis with polyangiitis presenting with myositis: case based review. Rheumatol Int. 2020;40:1163–70. 57. Gemignani F, Pavesi G, Fiocchi A, Manganelli P, Ferraccioli G, Marbini A. Peripheral neuropathy in essential mixed cryoglobulinaemia. J Neurol Neurosurg Psychiatry. 1992;55:116–20. 58. Voll C, Ang LC, Sibley J, Card R, Lefevre K. Polymyositis with plasma cell infiltrate in essential mixed cryoglobulinaemia. J Neurol Neurosurg Psychiatry. 1993;56:317–8. 59. Rodriguez-Perez N, Rodriguez-Navedo Y, Font YM, Vila LM. Inflammatory myopathy as the initial presentation of cryoglobulinaemic vasculitis. BMJ Case Rep. 2013;2013:bcr2013010117. 60. Agraharkar M, Gokhale S, Le L, Rajaraman S, Campbell GA. Cardiopulmonary manifestations of Henoch-Schonlein purpura. Am J Kidney Dis. 2000;35:319–22. 61. Carmichael P, Brun E, Jayawardene S, Abdulkadir A, O’Donnell PJ. A fatal case of bowel and cardiac involvement in Henoch-Schonlein purpura. Nephrol Dial Transplant. 2002;17:497–9. 62. Hwang JJ, Ahn J, Kim KP, et al. Henoch-Schonlein purpura with muscle involvement, presenting as myositis. J Clin Rheumatol. 2017;23:60–2. 63. Chew GY, Gatenby PA. Inflammatory myositis complicating hypocomplementemic urticarial vasculitis despite on-going immunosuppression. Clin Rheumatol. 2007;26:1370–2. 64. Zhou HW, Tran AQ, Tooley AA, Miyauchi JT, Kazim M. Atypical Cogan Syndrome featuring orbital myositis and dacryoadenitis. Ophthalmic Plast Reconstr Surg. 2021;37:S160–S2. 65. Worthmann F, Bruns J, Turker T, Gosztonyi G. Muscular involvement in Behcet’s disease: case report and review of the literature. Neuromuscul Disord. 1996;6:247–53. 66. Arkin CR, Rothschild BM, Florendo NT, Popoff N. Behcet syndrome with myositis. A case report with pathologic findings. Arthritis Rheum. 1980;23:600–4.

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67. Yazici H, Tuzuner N, Tuzun Y, Yurdakul S. Localized myositis in Behcet’s disease. Arthritis Rheum. 1981;24:636. 68. Di Giacomo V, Carmenini G, Meloni F, Valesini G.  Myositis in Behcet’s disease. Arthritis Rheum. 1982;25:1025. 69. Dursun D, Akova Y, Yucel E. Myositis and scleritis associated with Behcet’s disease: an atypical presentation. Ocul Immunol Inflamm. 2004;12:329–32. 70. Chebbi W, Jerbi S, Ammari W, Younes M, Sfar MH. Orbital myositis in Behcet’s disease. Joint Bone Spine. 2014;81:264. 71. Akansel G, Akgoz Y, Ciftci E, Arslan A, Demirci A. MRI findings of myositis in Behcet disease. Skeletal Radiol. 2004;33:426–8. 72. Roh JH, Koh SB, Kim JH. Orbital myositis in Behcet’s disease: a case report with MRI findings. Eur Neurol. 2006;56:44–5. 73. Uziel Y, Lazarov A, Cordoba M, Wolach B. Paediatric Behcet disease manifested as recurrent myositis: from an incomplete to a full-blown form. Eur J Pediatr. 2000;159:507–8. 74. Lang BA, Laxer RM, Thorner P, Greenberg M, Silverman ED. Pediatric onset of Behcet’s syndrome with myositis: case report and literature review illustrating unusual features. Arthritis Rheum. 1990;33:418–25. 75. Ogose T, Tamaki W, Shinahara K, Kaneko M, Wakata Y, Naruse K. A case of recurrent myositis as the main manifestation of Behcet disease. Pediatr Int. 2010;52:e101–4. 76. Khellaf M, Hamidou M, Pagnoux C, et al. Vasculitis restricted to the lower limbs: a clinical and histopathological study. Ann Rheum Dis. 2007;66:554–6. 77. Nielsen AA, Smith BE, Engel AG, Bosch EP. Muscle restricted vasculitis causing dropped head syndrome: a case report and review of the literature. J Clin Neuromuscul Dis. 2012;13:117–21. 78. Steiner G, Freund HA, Leichtentritt B, Maun ME. Lesions of skeletal muscles in rheumatoid arthritis: nodular polymyositis. Am J Pathol. 1946;22:103–45. 79. Ellman P, Ball RE.  Rheumatoid disease with joint and pulmonary manifestations. Br Med J. 1948;2:816–20. 80. Sokoloff L, Bunim JJ. Vascular lesions in rheumatoid arthritis. J Chronic Dis. 1957;5:668–87. 81. Sokoloff L, Wilens SL, Bunim JJ. Arteritis of striated muscle in rheumatoid arthritis. Am J Pathol. 1951;27:157–73. 82. Levin MH, Rivo JB, Scott W, Figueroa WG, Fred L, Barrett TF. The prolonged treatment of rheumatoid arthritis with cortisone and corticotropin. Am J Med. 1953;14:265–74. 83. Cruickshank B. Focal lesions in skeletal muscles and peripheral nerves in rheumatoid arthritis and other conditions. J Pathol Bacteriol. 1952;64:21–32. 84. Golding JR, Hamilton MG, Gill RS.  Arteritis of rheumatoid arthritis. Br J Dermatol. 1965;77:207–10. 85. Taubenhaus M, Eisenstein B, Pick A.  Cardiovascular manifestations of collagen diseases. Circulation. 1955;12:903–20. 86. Skogrand A. Visceral lesions in rheumatoid arthritis. Acta Rheumatol Scand. 1956;2:17–30. 87. Schmid FR, Cooper NS, Ziff M, Mc EC.  Arteritis in rheumatoid arthritis. Am J Med. 1961;30:56–83. 88. Magyar E, Talerman A, Mohacsy J, Wouters HW, de Bruijn WC. Muscle changes in rheumatoid arthritis. A review of the literature with a study of 100 cases. Virchows Arch A Pathol Anat Histol. 1977;373:267–78. 89. Disdier P, Swiader L, Harle JR, et al. Crohn’s disease and gastrocnemius vasculitis: two new cases. Am J Gastroenterol. 1997;92:880–2. 90. Christopoulos C, Savva S, Pylarinou S, Diakakis A, Papavassiliou E, Economopoulos P. Localised gastrocnemius myositis in Crohn’s disease. Clin Rheumatol. 2003;22:143–5. 91. Lim KL, Lowe J, Powell RJ. Skeletal muscle lymphocytic vasculitis in systemic lupus erythematosus: relation to disease activity. Lupus. 1995;4:148–51.

8

Sarcoid Myopathy and Other Immune-­Mediated Granulomatous Myopathies

8.1 Introduction Granulomatous myositis is a rare disorder characterized by noncaseating granulomatous inflammation of the skeletal muscles, which can configure either an idiopathic entity or accompany several conditions such as sarcoidosis and other inflammatory and infectious diseases. Granulomatous inflammation is infrequently found in skeletal muscle biopsy material. In a large muscle biopsy series, of 2985 specimens reviewed over 12 years, 12 (0.4%) were identified as having granulomatous inflammation, regardless of the clinical manifestations [1]. The incidence and prevalence of granulomatous myositis are unknown since data about this entity is based on case reports or short series of patients. In the setting of sarcoidosis, muscular involvement is reported to occur in 20–80% of patients, but almost always in an asymptomatic fashion [2]. Although the clinical profile together with electromyography (EMG) studies may be useful, a definite diagnosis requires pathological examination. Giant cell myositis shows the presence of giant cells in the absence of granuloma formation and is a close differential diagnosis of granulomatous myositis. Granulomatous myositis and giant cell myositis will be the focus of the discussion.

8.2 Sarcoid Myopathy 8.2.1 Introduction Sarcoidosis is a systemic immune-mediated disease characterized by the presence of non-necrotizing granulomas in various organs [3]. The prevalence varies with geography and race. The etiopathogenesis of sarcoidosis is not clear, but an © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. L. Gaspar, Immune-Mediated Myopathies and Neuropathies, https://doi.org/10.1007/978-981-19-8421-1_8

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extraneous trigger likely leads to the formation of non-necrotizing granulomas in multiple organ systems in genetically susceptible individuals [4]. Sarcoidosis is primarily a disease in adolescents and adults [5]. The adult disease is often insidious, whereas in the pediatric population it is more often asymptomatic. In symptomatic children, extra-pulmonary manifestations are more common. The lungs are more commonly involved [6]. Although previously thought that skeletal muscle is rarely involved in sarcoidosis, studies have shown that sarcoid myopathy (including asymptomatic muscle involvement) occurs in 50–80% of all individuals with sarcoidosis [7]. Currently, sarcoid myopathy is a diagnosis of exclusion based on a combination of clinical, radiographic, and histopathological features.

8.2.2 Clinical Features Asymptomatic/subclinical muscle involvement in sarcoidosis is the most common manifestation of sarcoid myopathy that is almost exclusively observed in the early stages of the disease. Erythema nodosum and polyarthritis are often seen in association with asymptomatic/subclinical sarcoid myopathy. Symptomatic sarcoid myopathy is seen in trace);    c. ESR 100 mm/h;    d. SSA, SSB, Smith, RNP, Scl-70, centromere, double-stranded DNA, CCP antibodies only if patient also satisfies clinical criteria for corresponding connective tissue disease  4. Biopsy evidence of vasculitis in tissue other than peripheral nerve;    a. Muscle excepted by convention  5. Serologic, PCR, or culture evidence of specific infection associated with vasculitis (such as HBV, HCV, HIV, CMV, leprosy, Lyme disease, HTLV-I) OR;  6. Predisposing conditions or factors:a    a. Connective tissue diseases;    b. Sarcoidosis;    c. Inflammatory bowel disease;    d. Active malignancy;    e. Hypocomplementemic urticarial vasculitis syndrome;    f. Cutaneous polyarteritis nodosa;    g. Drugs likely to be causing vasculitis. Diabetes mellitus does not exclude NSVN ANCA antineutrophil cytoplasmic antibodies, CCP cyclic citrullinated peptide, CNS central nervous system, ESR erythrocyte sedimentation rate, CMV cytomegalovirus, HBV hepatitis B virus, HCV hepatitis C virus, HIV human immunodeficiency virus, HTLV human T-lymphotropic virus, MPO myeloperoxidase, NSVN nonsystemic vasculitic neuropathy, PCR polymerase chain reaction, PR3 proteinase 3 a

attributable to a lack of standardized definitions for these patterns. In the largest series of NSVN, the prevalence of each pattern has varied widely: MFN 10–60%, asymmetric polyneuropathy 18–85%, and DSPN 2–41%. Combining data from all series and case reports yields the following prevalence: 45% asymmetric polyneuropathy (108/242), 33% MFN (79/242), and 23% DSPN (55/242). How these three

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patterns overlap with lumbosacral radiculoplexus neuropathy (LRPN) (discussed below) is not entirely clear. Most patients present with weakness and sensory loss, but 15% have purely or predominantly sensory signs and symptoms. Vasculitis rarely causes purely motor neuropathy. Vasculitic neuropathy is generally painful, but 20% of reported patients with NSVN have had no pain. NSVN is more apt to affect certain nerves than others, but at presentation, the most commonly affected nerves are a diffuse, overlapping mixture of lower limb nerves derived from the lumbosacral plexus. Common peroneal (or peroneal division of sciatic) 91%, tibial (or tibial division of sciatic) 61%, ulnar 58%, femoral 53%, superior gluteal 42%, median 41%, radial 35%, axillary 33%, and musculocutaneous 26%. Cranial neuropathies occur in 6% of patients.

18.2.4 Nonsystemic Vasculitic Neuropathy with Proximal Involvement (Nondiabetic Lumbosacral Radiculoplexus Neuropathy) Neurological deficits in NSVN are generally distally accentuated, but milder proximal involvement is common. A clinical phenotype featuring both proximal and distal lower limb involvement is often designated an LRPN. In studies of LRPN at the Mayo Clinic, inclusion criteria required the involvement of at least two lumbosacral nerve roots and at least two peripheral nerves by clinical or electrodiagnostic measures (excluding isolated sciatic mononeuropathies). Concomitant thoracic or cervical involvement was allowed. In the largest study of 57 patients with nondiabetic LRPN, symptoms were more commonly proximal than distal-predominant, but most patients had both proximal and distal involvement [14]. A small minority had purely distal clinical presentations accompanied by subclinical proximal electrophysiological findings. A more recent cohort of 20 patients with nondiabetic LRPN was population-based, and thus representative of the disease. Unlike the prior cohort, unilateral involvement predominated in this study [15]. On re-analysis of unpublished data from a cohort of 48 patients with NSVN reported in 2003 (ascertained by first selecting sural or superficial peroneal nerve biopsies exhibiting definite, probable, or possible vasculitic neuropathy), 92% of patients were reclassified as having an LRPN by application of Mayo criteria, albeit one that was distally rather than proximally accentuated, more commonly involved the upper limbs, and compared to the 2019 Mayo cohort—more frequently affected both lower limbs [13, 16]. These differences emphasize the challenges in comparing published series on “NSVN” with those describing “LRPN.” Both labels apply to patients with single-organ vasculitis of the PNS, but patients diagnosed with “NSVN” have more commonly had distal-predominant and four-extremity involvement than those diagnosed with “LRPN.” Whether these phenotypic distinctions are pathologically, pathogenically, or prognostically important remains to be determined. LRPN is a neuropathic phenotype in which at least two lumbosacral nerve roots and two peripheral nerves are involved by clinical, electrodiagnostic, or radiographic (e.g. MRI) criteria, with or without concomitant involvement of cervical

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and thoracic nerves. These cases will usually have proximal involvement clinically but may still be distally predominant.

18.2.5 Subtypes Subtypes of single-organ vasculitis of the PNS have distinctive associations, manifestations, and/or clinical courses. They include Wartenberg migratory sensory neuropathy, postsurgical inflammatory neuropathy, diabetic radiculoplexus neuropathies (RPNs), nonsystemic skin/nerve vasculitides, and, arguably, neuralgic amyotrophy. No new insights into the skin/nerve vasculitides have emerged in the last few years. Wartenberg Migratory Sensory Neuropathy Wartenberg migratory sensory neuropathy is a chronic, sensory, relapsing, multifocal neuropathy characterized by episodes of sudden-onset numbness in the distribution of individual cutaneous nerves, often accompanied by pain and paraesthesia [17, 18]. Electrodiagnostic studies are normal, except for low-amplitude or absent sensory nerve action potentials. Stretch of the involved nerve was the originally proposed mechanism, but in the largest study, only 50% described prodromal stretching [13]. Sural nerve biopsies in two patients revealed epineurial vasculitis. Biopsies in three other patients were suspicious of vasculitis. The Peripheral Nerve Society guideline group concluded that some cases are probably a pure sensory form of NSVN. Postsurgical Inflammatory Neuropathy Postsurgical inflammatory neuropathy is an acute-to-subacute, focal or multifocal, axonal neuropathy that develops within 30  days of a surgical procedure in the absence of known trauma to the involved nerves. As initially defined, the condition had to develop after the immediate postoperative period or involve nerves remote from the surgical field. However, more recent reports have included patients whose symptoms appeared immediately after the operation and then progressed [19, 20]. Most common patterns are widespread RPN, unilateral or bilateral LRPN, and sciatic mononeuropathy. Nerve biopsies show findings consistent with probable vasculitis. Both treated and untreated patients have improved. This entity is probably a self-limited NSVN triggered by surgery. Diabetic Lumbosacral Radiculoplexus Neuropathy The lumbosacral, thoracic, and cervical diabetic RPNs are self-limited and evolve stereotypically, commencing in one region and then spreading to another, even as the first site is resolving [21, 22]. They are also characterized by acute onset, proximal, and distal asymmetric involvement, pain, and weight loss. Diabetic RPN most commonly affects lumbosacral nerve roots/plexus and lower limb nerves; it is then labeled diabetic LRPN (DLRPN) [5, 23–26]. Median age of onset is 60 years. Men are more often affected than women. Most patients develop severe pain in their hip/thigh or, less commonly, lower leg or entire lower limb, but

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5–10% of cases are painless. Ipsilateral weakness emerges within days to weeks. Pain and/or weakness then spread to previously unaffected regions of the leg. Weakness is usually proximal-predominant, but distal weakness occurs in 60%. Symptoms are usually unilateral at the onset but become bilateral in 85%. Concurrent cervical RPN occurs in 10–15% of patients and thoracoabdominal symptoms develop in 12–14%. Electrodiagnostic studies reveal denervation involving multiple lumbosacral nerve roots and peripheral nerves. In two recent reports, magnetic resonance (MR) neurography of 24 patients revealed T2 hyperintensity and/or enlargement in multiple lumbosacral nerve roots and femoral nerves and, to a lesser extent, sciatic and obturator nerves [27, 28]. The condition is self-limited, but 10–15% of patients relapse. Symptoms progress for a median of 4  months and then slowly improve. Most patients have a residual distal weakness. Nerve biopsies reveal changes suspicious for microvasculitis and ischemic injury, but diagnostic changes of necrotizing vasculitis are rare because of the involvement of microvessels. Whether diabetic LRPN should be separated from nondiabetic LRPN and “other” forms of NSVN is a matter of ongoing debate. Diabetic Cervical Radiculoplexus Neuropathy Diabetic RPN predominating in the upper limbs was first reported in 2012 [29]. Median age of onset was 62 years. The male:female ratio was 2:1. Pain was the most common initial symptom (80% of patients). Sixty percent developed abrupt-onset symptoms and reached a nadir within 1 week. After progression, 47% had bilateral deficits. 20% of patients developed concurrent thoracic radiculopathy, and 25% had a concurrent LRPN. Electrodiagnostic studies revealed the involvement of the upper plexus in 56% of patients, the middle plexus in 49%, the lower plexus in 58%, and the entire plexus in 30%. Cutaneous nerve biopsies revealed alterations consistent with probable vasculitic neuropathy (microvasculitis). Many of these patients might have also been classified as neuralgic amyotrophy, that is, those with hyperacute onset and progression to the maximal deficit within 1 week, but distinguishing features included the absence of pain in 20%, progression for more than 1 month in 15%, lower plexus involvement in 58%, autonomic dysfunction in 96%, and more common involvement outside the brachial plexus (38%). Neuralgic Amyotrophy Neuralgic amyotrophy is a clinical syndrome characterized by acute pain in the shoulder/arm followed by focal/multifocal weakness with slow recovery over months to years [30–32]. Most cases are idiopathic, but a hereditary form exists (SEPT9 gene) [33]. In the largest study, the median age of onset was 41.3 (10–80) years for the idiopathic cohort and 28.0 (3–56) years for the hereditary cohort. Male:female ratio is 2:1. Clinical and electrodiagnostic assessments reveal multiple mononeuropathies more commonly than root, trunk, or cord lesions [34]. Patients present with acute, severe, continuous pain that is bilateral but asymmetric in 30%. Acute pain lasts a median of 20 days, but 65% then develop “musculoskeletal” pain. Weakness usually follows within 1–2  weeks but can be delayed by 2–4  weeks. Unlike NSVN, the disease is predilected for motor-predominant nerves, especially

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those derived from the upper plexus (long thoracic, suprascapular, axillary, musculocutaneous, dorsal scapular, pronator teres motor branch, and interosseous nerves), but the accompanying pain suggests concomitant sensory involvement. Nerves outside of the brachial plexus are affected in 56% of patients with hereditary and 17% with idiopathic neuralgic amyotrophy. In the largest series, of 49 patients followed for at least 3  years, only 4% reported full recovery, 50% had chronic pain, and 85–90% had a residual weakness. Standard MRI of the brachial plexus proper is usually normal or shows minimal findings, but studies evaluating the upper limbs with high-resolution MRI or sonography have suggested that neuralgic amyotrophy is an MFN that usually affects proximal nerves derived from the plexus rather than the plexus itself [35–38]. In one investigation, MRI showed abnormalities in 26/27 patients, including T2 hyperintensity, enlargement, and focal “hourglass constrictions” in terminal and more distal nerves [39]. What these hourglass constrictions represent pathologically requires further work. Ultrasonography reveals focal, multifocal, or diffuse enlargement; multiple complete or incomplete hourglass-like constrictions; and fascicular entwinement (rotation) of nerves derived from the plexus. Overall sensitivity is 74%. Complete constriction is predictive of poor long-term outcomes in affected nerves. The surgical literature contains many reports of acute, nontraumatic mononeuropathy of the arm associated with “hourglass-like fascicular constrictions” [40–42]. Their sonographic appearance is similar to that of the focal constrictions in patients with neuralgic amyotrophy [43]. Radial and median nerves are most frequently involved. Patients present with acute pain in the arm followed by severe weakness in a single-nerve distribution, analogous to neuralgic amyotrophy. The constricted area is often resected, usually months after the acute event. Histopathology of the resected segments is suboptimally described, but in 75% of patients, there were nonspecific, occasionally perivascular inflammatory infiltrates in the endoneurium, perineurium, or epineurium [44–49]. Other findings include diffuse perineurial thickening and fibrosis at the constriction, endoneurial edema, and severe distal loss of nerve fibers. In two cases, the resected nerve exhibited vasculitis and in another, a biopsy of adjacent triceps muscle and skin showed vasculitis, indicating that PNS vasculitis can present in this fashion. Further work is needed to understand the pathological mechanisms of these constrictions and their relationship to vasculitis. The pathogenesis of neuralgic amyotrophy is unknown. Five nerve biopsies performed during attacks of neuralgic amyotrophy have been reported. Brachial plexus biopsies in two patients with idiopathic neuralgic amyotrophy revealed mononuclear perivascular inflammation in the epineurium and endoneurium, but no other findings were detailed [50]. In another report, superficial radial nerve biopsies in three patients with hereditary neuralgic amyotrophy revealed findings indicative of probable vasculitis [51]. Considering histopathological evidence of probable vasculitis in some patients with neuralgic amyotrophy, frequent inflammation, and rare vasculitis in biopsies of hourglass-like constrictions in patients with an analogous syndrome, and the clinical phenotype itself (acute, painful, axonal, multifocal, sensory-­motor neuropathy), neuralgic amyotrophy might represent a self-limited variant of NSVN, but more neuropathological studies are needed.

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18.2.6 Imaging There is no established imaging technique for diagnosing or monitoring disease activity in vasculitic neuropathy. MRI guidance before targeted fascicular biopsies of proximal nerves is routinely performed at some centers, but the comparison of its diagnostic accuracy in vasculitic neuropathy to that of distal lower limb cutaneous nerve biopsies has not been reported. One recent study analyzed MR diffusion tensor imaging (DTI) in patients with NSVN [52]. DTI evaluates not only the magnitude but also the direction of diffusion in biological tissues. Diffusion is equal in all directions in isotropic but not anisotropic tissues. Fractional anisotropy is a scalar measure of anisotropy, ranging from zero in completely isotropic tissues to 1 in completely anisotropic tissue. It is generally high in the PNS because of its longitudinal organization with parallel cell membranes, but it is reduced by axonal degeneration. In the cited study, mean fractional anisotropy was significantly decreased in tibial nerves of 10 patients with NSVN compared with 10 age-matched normal controls. DTI is thus a candidate biomarker for NSVN-related disease activity. Peripheral nerve ultrasonography has been more extensively investigated in vasculitic neuropathy. Mean cross-sectional area (CSA) was significantly larger in clinically involved distal tibial nerves in eight patients with SVN compared with healthy controls in one early study [53]. In another study of 14 patients with SVN, an ultrasound of 31 clinically involved nerves revealed focal enlargements in 22 [54]. Mean CSA of the tibial, peroneal, median, and ulnar nerves was larger than that in healthy controls. In a third study, the sural, superficial peroneal, tibial, and peroneal nerves were assessed in six patients with vasculitic neuropathy (four with NSVN), six with CIDP, five with nonimmune neuropathies, and 26 healthy controls [55]. In patients with vasculitic neuropathy, CSA of the sural nerve was significantly greater than that in healthy and disease controls, and the longitudinal diameter of the superficial peroneal nerve was greater than that in healthy controls. A fourth study compared ultrasonography of bilateral brachial plexus, median, ulnar, tibial, peroneal, and sural nerves in 16 patients with vasculitic neuropathy (11 SVN, 5 NSVN) to 16 controls with noninflammatory axonal neuropathies; multifocal nerve enlargements in proximal arm nerves were 94% sensitive and 88% specific for vasculitic neuropathy [56]. In eight patients with Wartenberg migratory sensory neuropathy, an ultrasound revealed focal enlargements in multiple nerves (proximal and distal median, proximal ulnar, sural, and brachial plexus) in all patients. CSA of proximal median and sural nerves was significantly higher than in 16 controls with noninflammatory axonal neuropathies [57]. Hence, focal nerve enlargements might have a role in directing biopsies and monitoring disease activity in NSVN, but further study is necessary.

18.2.7 Conclusion Further advances in our understanding of NSVN and other vasculitic neuropathies will require the collaboration of neurologists and vasculitis experts to develop a

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comprehensive registry, validate better outcome measures, and conduct prospective trials. This level of investigation is long overdue. Vasculitic neuropathies are commoner than other acute and chronic inflammatory neuropathies, which have received far more attention from clinicians and scientists. Neuropathy measures used in current vasculitis clinical trials are simplistic, ambiguous, and insensitive to change. A registry of patients with vasculitic neuropathy would permit the acquisition of prospective data that would better define the clinical spectrum, natural history, and outcomes of various types of vasculitic neuropathies.

18.3 Connective Tissue Disorders While polyneuropathy is frequent among the connective tissue disorders, most cases are subclinical or due to diabetes mellitus and other causes. Symptomatic inflammatory polyneuropathy is usually manifested as a sensory predominant or axonal sensorimotor polyneuropathy in systemic lupus erythematosus, scleroderma, and rheumatoid arthritis [58–60]. Sjögren syndromes are more often associated with small fiber neuropathy and sensory neuronopathy.

18.4 Sarcoidosis Knowledge of neuropathic involvement in sarcoidosis is derived mostly from studies of large fiber neuropathies, in which granulomatous inflammatory infiltration of the nerves, vasculitis, or necrotizing vasculitic changes are observed. In patients with clinical evidence of amyopathy or features characteristic of muscle involvement on magnetic resonance imaging (MRI) or fluorodeoxyglucose positron emission tomographic (FDG-PET)  scans, muscle biopsies are valuable for the demonstration of a granulomatous inflammatory reaction. Concurrent muscle and nerve biopsies may be valuable, as some patients with sarcoidosis involving large fiber nerves have subclinical muscle involvement [61]. Sarcoidosis is an immune-mediated multisystemic disorder that is pathologically characterized by noncaseating granulomas. While any portion of the nervous system may be affected, symptomatic polyneuropathy is rare and seen in only 1% to 2% of patients with systemic disease [33]. Axon loss polyneuropathy usually manifests as either a stocking-glove polyneuropathy or subacute non-length-dependent polyradiculoneuropathy in which patients present with asymmetric limb pain and sensorimotor deficits [62]. Other polyneuropathy types include pure sensory or motor neuropathy and, rarely, mononeuritis multiplex. As the clinical manifestations and electrodiagnostic findings are nonspecific, nerve biopsy and evaluation for systemic sarcoidosis are often required for diagnosis when neuropathy is the presenting symptom. In those with known sarcoidosis, nerve biopsy may still be necessary to exclude other potential causes (e.g. infection or malignancy) that may be related to chronic immunosuppression. A biopsy may

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demonstrate granulomatous compression or direct infiltration of large nerve fibers as well as vasculitis [63, 64]. Prompt treatment with IV corticosteroids or IVIG can result in improvement, although several patients may go on to a relapsing-­remitting course or chronic progressive decline. Unlike large fiber disease, small fiber neuropathy is frequently seen in sarcoidosis and has been found in over 30% of patients with systemic disease [65]. Patients often present with migratory burning pain and paresthesia that affect various parts of the face, trunk, and proximal limbs in a non-length-dependent distribution, although distal painful neuropathy is also common. In one series, autonomic involvement (e.g. orthostatic hypotension, sweating abnormalities, and gastrointestinal disturbances) accompanied the somatic symptoms in about half of the cases. Also of note, sarcoidosis-associated small fiber neuropathy was seen more often in whites (87%) than African Americans (10%), which is unusual as the latter group has a higher prevalence of systemic disease [66]. Sarcoidosis small fiber neuropathy is categorized under “paraneurosarcoidosis” rather than true neurosarcoidosis as the underlying pathophysiology is not granulomatous but likely cytokine-mediated [67, 68]. As with large fiber nerve involvement, the clinical presentation of sarcoidosis small fiber neuropathy is also nonspecific. Diagnosis thus requires histologically confirmed systemic disease in addition to specialized testing (e.g. skin biopsy) to detect small fiber involvement. Response to standard immune-modulating therapies such as corticosteroids is poor [66]. In some patients, IVIG and infliximab may help treat both the somatic and autonomic manifestations. More recently, cibinetide, an experimental erythropoietin agonist that reduces inflammation, was shown to improve nerve fiber density in the skin and corneas of patients with sarcoidosis small fiber neuropathy [69].

18.4.1 Neurosarcoidosis Consortium Consensus Group Definition and Consensus Diagnostic Criteria for Neurosarcoidosis The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis (Table 18.6) [70]. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease. The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable

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Table 18.6  Proposed diagnostic criteria for central nervous system and peripheral nervous system neurosarcoidosis Possible  1. The clinical presentation and diagnostic evaluation suggest neurosarcoidosis, as defined by the clinical manifestations and MRI, CSF, and/or EMG/NCS findings typical of granulomatous inflammation of the nervous system after rigorous exclusion of other causes  2. There is no pathologic confirmation of granulomatous disease Probable  1. The clinical presentation and diagnostic evaluation suggest neurosarcoidosis, as defined by the clinical manifestations and MRI, CSF, and/or EMG/NCS findings typical of granulomatous inflammation of the nervous system after rigorous exclusion of other causes  2. There is pathologic confirmation of systemic granulomatous disease consistent with sarcoidosis. Definite  1. The clinical presentation and diagnostic evaluation suggest neurosarcoidosis, as defined by the clinical manifestations and MRI, CSF, and/or EMG/NCS findings typical of granulomatous inflammation of the nervous system after rigorous exclusion of other causes  2. The nervous system pathology is consistent with neurosarcoidosis. Type a. Extraneural sarcoidosis is evident; Type b. No extraneural sarcoidosis is evident (isolated CNSsarcoidosis). CSF cerebrospinal fluid, EMG electromyogram, MRI magnetic resonance imaging, NCS nerve conduction study

according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or neural tissue to support a diagnosis of definite neurosarcoidosis. Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue examination. The diagnostic criteria are designed to focus investigations on neurosarcoidosis as accurately as possible, recognizing that multiple pathophysiologic pathways may lead to the clinical manifestations termed neurosarcoidosis. Research recognizing the clinical heterogeneity of this diagnosis may open the door to identifying meaningful biologic factors that may ultimately contribute to better treatments.

18.5 Immune-Mediated Gastrointestinal Disorders Polyneuropathy is well known to be associated with inflammatory bowel disease and celiac disease. Although the etiology of polyneuropathy is multifactorial in these disorders, an immune-mediated mechanism is thought to be a potential cause as well.

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18.5.1 Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative Colitis Polyneuropathy is one of the most frequent neurologic complications of inflammatory bowel disease and, in most cases, can be attributed to non-immunologic factors such as medication exposures (e.g. metronidazole) and vitamin deficiencies [71, 72]. In studies evaluating the incidence of neuropathy in inflammatory bowel disease that excluded these and other potential etiologies, an axon loss large fiber polyneuropathy was found in 0.56% to 7.3% of patients. Inflammatory bowel disease-associated polyneuropathy may occur in the absence of active bowel disease (sometimes decades after the initial inflammatory bowel disease diagnosis) and equally affects both sexes, with onset around the fifth to sixth decades [71–73]. Multiple neuropathy subtypes have been reported with inflammatory bowel disease, including demyelinating polyneuropathy and painful small fiber neuropathy, but the most commonly reported presentations are distal sensorimotor polyneuropathy and radiculoplexus neuropathy affecting the lower limbs [71–74]. The underlying mechanism of nerve damage is thought to be immune complex mediated, as IgG and IgM antibodies to Schwann cells have been demonstrated on nerve biopsy in patients with axon loss polyneuropathy related to Crohn’s disease [75]. Favorable treatment responses reported with corticosteroids, IVIG, and plasma exchange, either as monotherapy or in combination, also support a primary autoimmune etiology. Thus, immunomodulatory treatment may be considered for patients with inflammatory bowel disease and neuropathy, although a rigorous search for other contributing causes, especially diabetes mellitus and vitamin deficiencies, should be undertaken.

18.5.2 Celiac Disease Celiac disease is an autoimmune enteropathy characterized by gluten intolerance that has been associated with various types of polyneuropathy, most commonly painful small fiber neuropathy [76, 77]. A distal large fiber sensorimotor polyneuropathy is less common and in one series was seen in only 2 of 400 patients with celiac disease, although one of the two also had IgM MGUS with a remote foot drop [46]. In another series, 6 of 26 (23%) patients with celiac disease were reported to have a distal axonopathy that in two patients could be attributed to other etiologies [78]. However, this may be an overestimation as neuropathy diagnosis was based on the sole finding of chronic motor axon loss changes on needle EMG of distal leg muscles in the absence of sensory nerve conduction study abnormalities or fibrillation potentials. Mononeuritis multiplex has rarely been associated with celiac disease and may occur in the absence of gastrointestinal symptoms. In one series, the neuropathy

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preceded gastrointestinal symptoms in six of six cases [79]. No improvement was seen with dietary treatment in any of the patients, and only two experienced benefits with IVIG therapy. No change was seen in the remaining cases despite treatment with aggressive immunosuppression. Villous atrophy on small bowel biopsy is the gold standard for diagnosis, although serologic testing for antigliadin, anti-tissue transglutaminase, and anti-­ endomysial antibodies can help screen patients [77]. However, one study reported elevated IgG antigliadin antibodies in 12% of healthy individuals [80]. Pathogenesis of the neuropathy is unknown and causation is unclear but, as in inflammatory bowel disease, may be antibody-mediated. Dietary treatment consisting of strict gluten avoidance is recommended but is sometimes not helpful. Immune-modulating therapy for more subacute and severe nerve involvement has also been met with mixed results. Nonimmune-mediated neuropathies associated with celiac disease should be distinguished from immune causes. As seen with inflammatory bowel disorders, chronic malabsorption leading to vitamin deficiencies involving vitamin B12 and, less commonly, vitamin B1 (thiamine) may occur in severe cases of celiac disease, typically resulting in a length-dependent sensory polyneuropathy manifested as numbness and burning in the feet [81]. Sensory neuronopathy associated with vitamin E deficiency may also be seen.

18.6 Paraprotein-Associated Neuropathy Paraproteins are monoclonal immunoglobulins secreted by cells clonally expanded within the B cell lineage. They are also known as monoclonal (M-) proteins and occur in monoclonal gammopathies. Monoclonal gammopathies associated with neurology include monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, lymphoplasmacytic lymphomas, and Waldenström macroglobulinemia, and less frequently non-Hodgkin’s lymphoma and other lymphoproliferative disorders. The monoclonal protein can be the complete immunoglobulin, comprising heavy (IgG, IgM, IgA) and light chains (kappa or lambda) or the light chain alone. Light chains can be of lambda or kappa subtype with significant differences in pathogenicity and phenotype of the resulting neuropathy. Paraproteinaemic neuropathies are a heterogeneous group of neurological and hematological disorders where the hematological problem drives the neurological impairments [82]. They can result in significant morbidity for affected individuals. Until relatively recently, treatments for paraprotein-associated disorders were limited either by toxicity or lack of neurological effects. Paraproteinaemic neuropathies are therefore often nihilistically lumped together as untreatable, limiting the investigation, trials of therapy, and optimization of pathogenesis-driven management. In the current era of improved targeted therapies, it is essential to optimize the classification and investigation of these disorders to allow access to appropriate management and improve patient outcomes.  Although this chapter focuses on axonal neuropathies, it is appropriate to discuss both demyelinating and axonal paraprotein-­ associated neuropathies together for the benefit of the readers.

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18.6.1 Epidemiology Both paraproteins and neuropathy are common, and so they frequently coexist and any causative link is often uncertain. The population prevalence of a paraprotein is 3%–4% in those over 50, increasing from 1% when aged 50 to 8%–9% when aged 90 [83]. Similarly, peripheral neuropathy is common, present in 2.4%–5.5% of the general population, but in up to 32% when aged 80 [84, 85]. Approximately 10% of patients with neuropathy of unknown cause have paraproteins; however, some clinicians find it difficult to know if the monoclonal protein is involved in causing the neuropathy or merely present by chance [86]. Paraproteinaemic neuropathies most commonly occur with overproduction of IgM (50%–75%, compared with IgG 17%–35% or IgA 8%–15%) [87, 88]. Conversely, neuropathy develops in 31% of patients with an IgM MGUS, compared with 14% with IgA and 6% with IgG [89].

18.6.2 Pathogenesis A paraprotein can be associated with causing neuropathy in several ways [90]. Epitope targeted antibody-mediated: Direct binding of a known antibody to epitopes on peripheral nerve, for example, binding of antibodies to myelinassociated glycoprotein (MAG) and glyco-lipid sulfoglucuronyl-paragloboside epitopes of the myelin sheath. Putative antibody-mediated damage with antibodies to known epitopes (e.g. antiganglioside antibodies in chronic ataxic neuropathy with ophthalmoplegia, M-protein, cold agglutinins, and disialosyl ganglioside antibodies (CANOMAD) or multifocal motor neuropathy with conduction block with high titer paraproteinaemic IgM anti-GM1 antibodies) or unknown antibodies (e.g. non-­MAG distal acquired demyelinating sensory neuropathy). Paraprotein associated but not targeted, driven by proinflammatory cytokines: The paraproteinaemic disorder is low volume, and the paraprotein is a by-product, but cytokine release results in nerve damage (e.g. POEMS syndrome). Deposition: Whole immunoglobulin (IgM deposition disease) or fragments (amyloid light chain (AL) amyloidosis) deposited within the endoneurial, perineurial, epineurial spaces, or vessels. Ischemic: Inflammatory (e.g. vasculitis) or noninflammatory obstruction of blood vessels (e.g. cryoglobulins or hyperviscosity). Compressive: Plasma cell expansions (e.g. myeloma) or infiltration of ligamentous tissue (e.g. amyloid) directly compress nerves causing mononeuropathies (e.g. carpal tunnel syndrome in amyloidosis).

18.6.3 IgM Paraproteinaemic Disorders Anti-MAG Paraproteinaemic Demyelinating Peripheral Neuropathy Anti-MAG antibodies occur in approximately 50% of IgM-associated demyelinating neuropathies and are most commonly kappa [91]. All patients with an IgM

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paraprotein and demyelinating neuropathy should be tested for anti-MAG antibodies. Anti-MAG paraproteinaemic demyelinating peripheral neuropathy is the most common in men in their seventh decade. The typical clinical phenotype is an insidious, distal, sensory predominant, sensorimotor neuropathy with unsteadiness and tremor. The key clinical features of anti-MAG neuropathy are the high vibratory loss, the small fiber sensory loss only in the feet, and the almost normal joint position sense despite ataxia and tremor. Typical neurophysiology has prolonged distal motor latencies in the setting of conduction slowing, but without other demyelinating features such as conduction block or temporal dispersion, as seen in chronic inflammatory demyelinating peripheral neuropathy (CIDP). The terminal latency index (TLi = distal conduction distance (mm)/(Conduction velocity (m/s) × distal motor latency (ms))) provides a quantifiable measure of this finding and a TLi of 70,000 BTU (“strong positive”) is likely causally related to neuropathy. However, 7000–70,000 BTU (“positive”) or 1000–7000 BTU (“weakly positive”) titers are less specific and can occur in asymptomatic people or with other neuropathies. Neither the anti-­ MAG titer nor the level of IgM paraprotein predicts the disease severity or treatment response and titers changing by 1000s of BTU have no clinical utility [93]. The prognosis of anti-MAG paraproteinaemic demyelinating peripheral neuropathy is generally favorable [94]. Given the usual slow, insidious progression, many patients do not require treatment. Motor involvement or rapid progression is an indication for treatment, best started within 5 years of diagnosis. Despite a single randomized controlled trial of short-term intravenous immunoglobulin suggesting benefit, any effect diminishes rapidly. Corticosteroids with cyclophosphamide are sometimes useful. Trials of rituximab (375 mg/m2 weekly for 4 weeks) provide low-­ to-­moderate certainty evidence of improvement. Thus, when treatment is indicated, rituximab is the current recommended treatment [95]. Stabilization of the neuropathy is most likely, although significant improvements have been reported. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, looks promising in early studies [96]. IgM Demyelinating Paraproteinaemic Neuropathy Without MAG Antibodies About 35% of patients with an IgM paraprotein and neuropathy have no identifiable nerve target [91]. IgM-associated anti-MAG antibody-negative neuropathies can have a similar distal acquired demyelinating sensory neuropathy phenotype to anti-­ MAG paraproteinaemic demyelinating peripheral neuropathy [97]. Underlying hematological conditions include IgM MGUS, Waldenström macroglobulinemia, chronic lymphocytic lymphoma, or B-lymphoproliferative disorders. There may be conduction velocity slowing, without temporal dispersion or conduction block. The presence of atypical features, such as rapid progression, prominent early motor involvement, early axonal damage, and autonomic or other organ involvement, should prompt assessment for AL amyloidosis or cryoglobulinemic vasculitis.

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Uncomplicated slowly progressive IgM paraprotein/ distal acquired demyelinating sensory neuropathy alone can be monitored for unexpected progression of either the neuropathy or hematological disease, to initiate treatment. Treatment should be directed at the hematological diagnosis if appropriate and required [93]. Multifocal Motor Neuropathy with Conduction Block Occasionally a multifocal motor neuropathy with conduction block phenotype occurs in conjunction with an IgM paraprotein with antiganglioside GM1 or GD1b antibodies [93]. When the antiganglioside titer is very high, the paraprotein is likely to harbor the GM1/GD1b activity. Although there are no data to support treatment in this situation, where IVIG is ineffective, treatment might be directed at the gammopathy. Multifocal motor neuropathy with conduction block typically presents as an asymmetric, pure motor, upper limb predominant multiple mononeuropathies with a male preponderance. The key feature is the anatomically identifiable individual motor nerve involvement with the only sensory deficit being mild vibration loss at the toes. More information can be found in Yeh et al. [98] Chronic Ataxic Neuropathy with Ophthalmoplegia, M-protein, Cold Agglutinins, and Disialosyl Ganglioside Antibodies (CANOMAD) CANOMAD is a very rare chronic neuropathy, characterized by sensory neuropathy with ataxia, ophthalmoplegia, and occasionally other cranial neuropathies, typically bulbar [99, 100]. A slowly progressive course is common but there may be a relapsing-­ remitting phenotype. The IgM paraprotein has one or more anti-­ disialylated ganglioside activities. An acellular CSF with raised protein is expected and occasionally the only abnormalities in neurophysiology are in the evoked potentials. The underlying gammopathy may be IgM MGUS, B-lymphoproliferative disorder, or Waldenström macroglobulinemia. In some cases, intravenous immunoglobulin is effective, but others need rituximab or chemotherapy directed to the clonal population. IgM Deposition Disease IgM deposition-associated neuropathy is an extremely rare form of paraproteinaemic neuropathy, mimicking amyloidosis and requiring nerve biopsy, often using direct immunofluorescence (DIF) and electron microscopic (EM) features for diagnosis [101]. The clinical phenotype is an asymmetric, painful, distal, sensory neuropathy, sometimes with cranial nerve involvement with onset in the seventh and eighth decades [102–105]. Motor neuropathy and wasting appear late but autonomic involvement does not occur. Neurophysiological changes are axonal. The long-term prognosis is more favorable than amyloid, with a survival of up to 13 years. Bing–Neel Syndrome Bing–Neel syndrome is a rare complication of Waldenström macroglobulinemia, caused by the infiltration of lymphoplasmacytic cells into the CSF, meninges, or cerebral parenchyma as well as the proximal nerve roots and peripheral nerves. As a result, the presentation is diverse and should always be considered in

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lymphoplasmacytic lymphoma. Raised intracranial pressure headaches, cognitive and psychiatric dysfunction, seizures, cranial and peripheral neuropathies, and gait disorders may occur [106]. Bing–Neel syndrome can be an initial lymphoplasmacytic lymphoma manifestation but usually presents in Waldenström macroglobulinemia relapse, with a gradually progressive course over weeks to months. It can arise with other pre-existing Waldenström macroglobulinemia-associated diseases (e.g. anti-­MAG paraproteinaemic demyelinating peripheral neuropathy); thus, Bing– Neel syndrome should be considered if central or atypical features develop. The diagnosis is made by an MR scan of the brain with gadolinium followed by a clean CSF analysis to prevent false positive results. MRI abnormalities are seen in 80%, most commonly leptomeningeal enhancement, and less frequently parenchymal lesions. CSF analysis should always include flow cytometry with molecular testing to confirm the diagnosis with the surface immunohistochemical signature, immunoglobulin heavy-chain rearrangement for clonality, and identification of the somatic MYD88 L256P mutation (positive in 94%–100%). Treatment of Bing–Neel syndrome follows published guidelines but is changing rapidly [107]. Corticosteroids, CNS-penetrating chemotherapy, and radiotherapy are all used to reverse clinical symptoms and provide protracted progression-free survival. Ibrutinib is very effective and next-generation Bruton’s tyrosine kinase inhibitors (zanubrutinib), proteasome inhibitors (marizomib), and B cell lymphoma-2 (BCL2) antagonists (venetoclax) all hold promise.

18.6.4 IgG or IgA Paraproteinaemic Disorders Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Lesions: POEMS Syndrome POEMS syndrome is a rare paraneoplastic condition characterized by a monoclonal proliferation of plasma cells, producing an M-protein, almost always with a lambda light chain, a disabling inflammatory peripheral neuropathy, and additional widespread multisystem features. POEMS is frequently misdiagnosed as CIDP, Guillain– Barré syndrome, or another neuropathy, with the correct diagnosis delayed by an average of 15 months [108]. This delay in diagnosis has significant morbidity implications with 76% of patients losing independent mobility and 36% being bed or wheelchair users at diagnosis [108, 109]. CIDP is the most common misdiagnosis but POEMS very seldom has a proximal weakness at presentation, has an early axonal loss on neurophysiology, and nearly always has obvious multisystem involvement; by the time of diagnosis, patients have a median of seven features. This symphony of features makes diagnosis easy. The neuropathy in POEMS is easily identifiable. It is subacute with progressive, ascending, length-dependent positive and negative sensory symptoms. Almost every patient describes aching calf pain at onset, which later develops into a more typical dysesthetic neuropathic pain. Distal weakness with a sharp demarcation of weakness at the ankles and then wrists is the norm. Proximal weakness, typical of CIDP, occurs only in severely progressed disease. The Castleman’s (lymphadenopathy

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with typical histopathological features) variant of POEMS syndrome has a much milder, often pure sensory neuropathy. A length-dependent, sensorimotor neuropathy, with upper limb conduction slowing (no conduction block or temporal dispersion) and lower limb axonal loss is typical of the neurophysiology; lower limb sensory and motor responses are usually absent. CSF protein is elevated (often very high) in 96%–100% [109–115]. Brachial and lumbosacral plexus thickening, with appearances undifferentiated from CIDP, develops in 59%. Patients with POEMS occasionally present with large- or small-vessel ischemic infarcts or subarachnoid hemorrhage. Diffuse asymptomatic pachymeningeal thickening, dural fluid collections, and white matter lesions develop in more than 70% of cases and can help to distinguish POEMS from CIDP. Identifying the diagnostic criteria for POEMS makes the diagnosis. Serum VEGF is elevated in 94% of cases, typically >1000  pg/mL, and is a diagnostic, therapeutic, and relapse biomarker. Failure of VEGF suppression with treatment portends a poor prognosis. The VEGF cannot be interpreted without a lambda light chain monoclonal disorder, which occurs in 98%. The serum-free light chains can be misleading as the ratio is frequently normal with polyclonal kappa and lambda stimulation. If serum and urine investigations do not identify an M-protein, patients need a bone marrow aspirate and trephine, targeted bony lesion, or plasmacytoma biopsy. The bone marrow aspirate and trephine typically contain a low volume (1%–5%) of CD138 positive and light chain restricted clonal plasma cells with megakaryocyte hyperplasia. The optimal treatment for systemic disease is autologous stem cell transplantation; however, it is not appropriate for all. Chemotherapy (lenalidomide, melphalan, bortezomib or cyclophosphamide, and dexamethasone) can debulk disease, to allow a future autologous stem cell transplantation (but note that the use of melphalan is not compatible with later stem cell harvest), or may also be used as a long-term treatment in those unfit for this procedure. Radiotherapy is preferred for those with two or fewer bony lesions. The overall treated 5-year survival is 90%, and 82% at 10 years (progression-free survival 65% and 53%). Improvement of the neuropathy typically starts 2  years after disease suppression in severely affected patients. Rehabilitation strategies to promote mobility and reduce contractures are essential. Myeloma Peripheral neuropathy develops as a consequence of myeloma in fewer than 3% of cases. The mechanisms are usually a result of cryoglobulinemia, amyloidosis, or treatments, or more commonly bony or extranodal lesions causing neural compression.

18.6.5 IgM, IgG, or IgA Paraproteinaemic Disorders Light Chain (AL) Amyloidosis AL amyloidosis should be considered in any paraproteinaemic neuropathy. As with POEMS, if the diagnosis is delayed there are significant effects on morbidity and

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mortality. AL amyloidosis is the deposition of monoclonal light chains, usually lambda, in tissues and organs. AL amyloid neuropathy presents as a rapidly and relentlessly progressive, (usually) painful, length-dependent, small fiber, and autonomic neuropathy, with sequential development of length-dependent sensory and then motor nerve involvement [116]. Carpal tunnel syndrome from flexor retinaculum amyloid deposition is common. Plexus, brachial and lumbar radiculopathies, and cranial neuropathies may occur [116, 117]. Autonomic neuropathy causing postural hypotension, erectile dysfunction, gastroparesis, changed bowel habit, sweating and pupillary abnormalities occur in up to 65%. The neurophysiology identifies a symmetrical, length-dependent, axonal, sensory predominant, sensorimotor neuropathy but not infrequently conduction slowing, and asymmetric and patchy alterations promote electrophysiological diagnostic uncertainty. Frequently the clinical picture is so clear as to not need formal assessment of autonomic function beyond bedside assessments. As with POEMS, the co-occurrence of a typical neuropathy with additional organ involvement is the key to the diagnosis of AL amyloidosis. Autonomic involvement, in a patient without diabetes but with an acquired neuropathy, suggests amyloid until proven otherwise. Carpal tunnel syndrome, or cardiac arrhythmia, and an appropriate neuropathy should also stimulate investigation. “Textbook” systemic features of amyloid (macroglossia), periorbital ecchymoses (“raccoon eyes”), renal dysfunction with proteinuria, and gastrointestinal bleeding are much less common but give valuable clues. Genetics for hereditary transthyretin amyloidosis (ATTRv) should be performed in parallel as 10%–20% of patients with ATTRv have a concurrent paraprotein [118]. Tissue biopsies from accessible sites are recommended; quoted diagnostic yields are good from periumbilical subcutaneous fat (75%), rectum (81%), or salivary gland (86%) [119–121]. A concurrent bone marrow aspirate and trephine can improve the sensitivity to 90%. Targeted flexor retinaculum, skin, gastrointestinal, endomyocardial, nerve, or muscle biopsies can be performed and may increase yield. The sensitivity of nerve biopsy varies widely in studies (30%–100%), limited by both disease and investigational expertise. Amyloid has an easily recognizable microscopic appearance. Genetics, laser microdissection, and mass spectrometry on biopsies have been used, when immunohistochemical staining is negative, to identify the amyloid subtype [122, 123]. Suppression of the clonal process can slow progressive morbidity. In general, in low-risk patients, an autologous stem cell transplantation with or without bortezomib induction and conditioning provides the best long-term outcomes [124]. Cryoglobulinemia and Cryoglobulinemic Vasculitis Type I cryoglobulins are monoclonal immunoglobulin (IgM > IgG > IgA > light chain) only and occur in monoclonal gammopathies (MGUS: 40%, multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic lymphoma: 60%). Cryoglobulinemia may be asymptomatic, incidentally identified, or symptomatic, where it results in cryoglobulinemic vasculitis. Type I cryoglobulins undergo temperature and concentration-dependent crystallization and aggregation

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leading to small-vessel occlusion with the occasional development of small-vessel vasculitis. This causes predominant distal extremity and renal dysfunction. Nerve involvement occurs in 19%–44% of cases [125]. The neuropathy is typical of other confluent vasculitides with predominant small fiber sensory change in 25% and no autonomic involvement; mononeuritis multiplex is uncommon [126].

18.6.6 Investigations Serum Protein Electrophoresis Serum proteins are separated through agarose gel by molecular weight, shape, and charge and visualized as coalescent bands. Stained bands can be quantified by densitometry. As the serum protein electrophoresis provides a quantification of the paraprotein, it can be used for diagnosis and monitoring. Serum protein electrophoresis alone is not sensitive enough as a screening test in neurology (lower limit of gamma region detection >0.5  g/L). In low-burden diseases such as MGUS and many relevant low-grade lymphomas serum protein electrophoresis often cannot detect the paraprotein. Immunofixation After electrophoresis, antibody fixation with anti-heavy and anti-light chain antibodies increases sensitivity (lower limit of detection ~0.1  g/L) and types the M-protein. The addition of immunofixation to serum protein electrophoresis improves detection rates from 87.6% to 94.4% in multiple myeloma and 65.9% to 73.8% in AL amyloidosis. Immunofixation is qualitative and can be used for diagnosis and assessment of complete remission but not for monitoring. Biochemistry or immunology laboratories often need assistance to understand why the sensitivity of the immunofixation is required as they may be unaware of the low-level pathological paraproteins that are not detected by serum protein electrophoresis but are crucial to diagnosis and treatment. Urine Protein Electrophoresis and Immunofixation Urinary protein electrophoresis is performed in the same way as in serum and has the same benefits and limitations. Urine-free light chains (Bence Jones proteins) can occur with or without a detectible serum paraprotein. The urinary protein electrophoresis has only 37.7% sensitivity for paraprotein screening but can help in prognostication and monitoring treatment response. Serum-Free Light Chains In this assay, free light chains are detected using antibodies to light chain epitopes hidden when immunoglobulins are intact. This assay does not demonstrate monoclonality; however, monoclonality is inferred when there is an abnormal ratio (normal 0.26–1.65) between the kappa and lambda free light chains. The serum-free light chains assay plays a useful role in prognostication, disease monitoring, and measuring treatment response. However, great care must be taken if using

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serum-­free light chain assays as they do not distinguish between polyclonal or monoclonal light chains and can be abnormal in renal impairment and autoimmune disease. Furthermore, false negatives can occur where there is a low-level paraprotein, in biclonal disorders, and in diseases where there is both monoclonal and polyclonal immunoglobulin (e.g. in POEMS syndrome).

18.6.7 Nerve Biopsy In a significant number of cases, the clinical, electrophysiological, and biological data do not identify a lesional mechanism: as a direct link between peripheral neuropathy and monoclonal gammopathy has to be confirmed, the microscopic examination may be of special importance. In some conditions (anti-MAG IgM antibodies are negative; CIDP clinical and electrophysiological criteria are not present, or its course is atypical; amyloid deposits have not been found in other tissue biopsies; IgG-VEGF is not elevated; there are no malignant cells in the CSF), nerve biopsy should be considered [127]. This procedure may also reveal a combination of pathologies in the same case. For instance, serum anti-MAG antibodies have been described along with amyloidosis or malignant epineural B cell infiltrates. The initial symptoms of nerve involvement often begin several years before the first clinical examination when monoclonal gammopathy is identified. At that time, the diagnosis of malignant hemopathy is suspected but can be difficult to confirm, particularly if peripheral neuropathy is clinically isolated or asymmetric (as in mononeuropathy multiplex), so hematologists/oncologists may decide to defer chemotherapy. If peripheral neuropathy gets worse, nerve biopsy should be performed. Otherwise, in cases of chemotherapy, it might be difficult to establish the mechanism of the PNS involvement (drug-induced peripheral neuropathy or another pathophysiological mechanism). Moreover, considering chemotherapy as the cause of peripheral neuropathy risks delaying nerve biopsy. In such a context of monoclonal gammopathy, most peripheral neuropathy is sensorimotor or pure sensory, length-dependent peripheral neuropathy, so that they all involve sensory nerves of the lower limbs; nerve biopsy is carried out on a sensory nerve of one limb so that the sensitivity of the microscopic examination is high (the nerve being always microscopically abnormal). As for the specificity of this technique, it is the only one that clearly shows the various types of nerve injuries in cases of monoclonal gammopathy. In such contexts (malignant hemopathy, severe and disabling neuropathy), nerve biopsy should not be considered “aggressive”: these patients commonly suffer intense neuropathic sensory symptoms and signs, and the temporary pain and sensory deficits which may be induced a by nerve biopsy are not usually perceptible. In any event, the indication of nerve biopsy should be discussed on a case-by-case basis.

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18.6.7.1 Endoneural Immunoglobulin Deposits Intramyelinic infiltration: IgM-MG with anti-MAG activity As discussed above, the possible link with anti-MAG antibodies has to be looked at first: it is usually suspected by analyzing the clinical, electrophysiological, and biochemical data. In such cases, nerve biopsy is not recommended. Nevertheless, it has been shown that the characteristic anti-MAG ultrastructural lesions (regular widenings of the myelin lamellae, WML) may be observed by careful EM examination, even several years before monoclonal gammopathy is evidenced in the serum of the patient. Otherwise, some associations with WML may be evidenced only by nerve biopsy: [128, 129]. Amyloid deposits, as well as IgM endoneurial deposits, can also be discovered [130]; Julien et  al. also described a patient who had biclonal gammopathy in his serum (one with IgM-kappa and anti-myelin activity, another with IgG-lambda linked to amyloid deposits) [131]. It is clear that, in this context, such multiple lesions can only be identified by a complete and careful microscopic examination of a peripheral nerve fragment. It may help explain why these patients do not respond to treatment. Intramyelinic infiltration: IgG-MG and IgA-MG The association between peripheral neuropathy and IgA-MG or IgG-MG (MGUS) is often considered as being coincidental. Nevertheless, in a few rare cases of nerve biopsy, DIF (using specific antibodies) may demonstrate annular bindings to many myelinated fibers, and numerous WML (comparable to that described in IgM-MG and anti-MAG neuropathies) are observed by EM. In these patients, the antigens are not yet known. Deposits in the interstitial tissue IgG, IgA, IgM, and light chain deposits in the intraneural collagen may induce diffuse axonal type lesions of the peripheral nerves, but the mechanism leading to the destruction of axons by Ig deposits is still not established [101]. Such deposits can only be evidenced by nerve biopsy. In most cases monoclonal gammopathies are malignant [132], and very few are MGUS. As they are usually scarce, randomly distributed, and sometimes quite small, the identification of these kinds of deposits on paraffin sections may be hard in practice: such lesions are not to be confused with amyloidosis on routine staining and should be differentiated by specific staining. Their specificity is confirmed either by DIF on frozen sections or only by EM and/or ultrastructural immunocytochemistry if they are too small to be detected by light microscopic examination. Ultrastructurally, at high magnification, they may have a quite characteristic aspect (digitiform, fibrillar, granular, tubular, mixed structures, etc.). In any case, cryoprotein should be looked for carefully in the blood sample: if present, fixation is recommended to compare its ultrastructure with those of the endoneurial deposits, their morphological similarities confirming the presence of abnormal Ig in the PNS [133]. In these cases, the identification of such small specific deposits in the endoneurium is usually quite late, so efficient treatment is delayed. A few isolated cases of such immunoglobulin intra-nervous deposits have been presented, but their incidence is probably underestimated, as they can only be evidenced by nerve biopsy [134].

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Amyloidosis deposits (AD) As already mentioned, AD have to be carefully looked for when there are patent symptoms/signs suggestive of autonomic dysfunction (Fig.  18.3a–e). Nevertheless, it is not constant, so some amyloid neuropathies may be initially mistaken for axonal polyneuropathy of unknown origin or even CIDP.  The absence of response to immunomodulatory treatment (intravenous immunoglobulins, plasma exchange) may prompt nerve biopsy with the aim of detecting a condition that may mimic CIDP. As recalled by Kaku and Berk, peripheral neuropathy occurs in up to 17–35% of patients with AL amyloidosis; it is an initial involvement in 7–12% of them [135]. AD results from the transformation of monoclonal gammopathy to Ig-light chain. As stressed by Gertz and Merlini, the structural subunits of the amyloid protein in light chain (AL) amyloidosis is the fragments of monoclonal Ig heavy chains (HC) or light chain (LC) [136]. The amyloid deposits consist either of LC fragments or HC fragments. AL amyloidosis may be encountered in myeloma or other B cell malignancy (WM or lymphoplasmacytic lymphoma): the underlying plasma cell dyscrasia would be classified as MGUS in most cases [137]. In suspected AL amyloidosis, histological diagnosis is essential. The positivity of nerve biopsy for the diagnosis of systemic AL amyloidosis is usually estimated to be about 85%. In this systemic disease, the biopsies of subcutaneous fat tissue or salivary glands are usually quite sensitive, and nerve biopsy should be carried out only if no amyloid deposit was found by analyzing these tissues. In most cases, it is possible to routinely observe AD deposits on paraffin-embedded sections (round deposits, scattered in the endoneurium, sometimes joined to thickened capillary walls): both Congo red and thioflavin stainings confirm their amyloid nature. Given that AD can greatly vary between different nerve fascicles and is randomly distributed, it is recommended to scrutinize every fascicle or several blocks and make serial cuts. The EM of AD is composed of extracellular bundles of unbranched irregular wide fibrils (7–10 nm). Since specific staining of amyloidosis and EM observation cannot distinguish among the various types of systemic amyloidosis, specific antibodies need to be used for optical (frozen specimen) or/and EM examinations. Lambda-LC is more common than kappa-LC (2:1 in AL amyloidosis), but the opposite is observed in multiple myeloma and monoclonal gammopathy. In all cases, the axonal loss is very severe and involves myelinated as well as unmyelinated fibers, explaining the pain, decreased sensation, and autonomic disturbances.

18.6.8 Conclusion Paraproteinaemic neuropathies are an interesting group of neurohematological conditions with distinct clinical phenotypes. The diagnosis of these disorders is complex but rewarding, requiring equal parts of awareness, judicious phenotyping, and

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a

b

c

d

e

Fig. 18.3 (a) H&E stain demonstrating endoneurial pale eosinophilic amorphous material consistent with amyloid deposits. Some appear irregular (black arrows) that are conventionally seen, whereas some appear spherical with a central dark spot or zone (red arrows) referred to as amyloid spherulites. (b) Congo red stain demonstrating Congophilic material consistent with amyloid deposits. (c) Congo red stain under polarized light gives apple green birefringence in the Congophilic material confirming amyloid deposits (white arrows). (d) Congo red stain under polarized light gives apple green birefringence in the Congophilic material confirming amyloid deposits (white arrows). (e) Congo red stain viewed under fluorescent light using Texas red filter gives red fluorescence to amyloid deposits (white arrows)

the correct application of diagnostic tests. Making an accurate diagnosis and instituting early appropriate management limits disability. The involvement of a multidisciplinary team provides optimal care for these patients who can require neurology, hematology, radiation oncology, surgery, pathology, and allied health teams. Management of these conditions often involves immunomodulatory and

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chemotherapeutic agents targeting the underlying clonal proliferation, and new treatments are frequently emerging from the hematology world with the potential to dramatically improve treatment outcomes. An improved understanding of the underlying pathogenic mechanisms driving each phenotype is essential to optimally choose treatments.

18.7 Paraneoplastic Disease Neurological impairments in patients with malignancies can arise from a variety of factors, including chemotherapy, malnutrition, infection, direct tumor invasion into the nervous system, or a remote effect of the malignancy mediated via the immune system. This latter cause, known as paraneoplastic neurological syndrome, involves neurological symptoms or signs resulting from damage to parts of the nervous system that are remote from the site of malignancy or its metastases [138]. This derangement can modulate function at any level of the neuromuscular system, including the central nervous system, peripheral nervous system, neuromuscular junction, and muscle itself. Thus, these syndromes are composed of many different clinicopathological entities, including encephalomyelitis, limbic encephalitis, cerebellar degeneration, opsoclonus-myoclonus, sensory neuronopathy, intestinal pseudo-obstruction, Lambert–Eaton myasthenic syndrome, and dermatomyositis, among others [139, 140]. In some of these disorders, neuronal antigens expressed by the malignancy induce an immune response that results in an inappropriate recognition of endogenous nervous system elements as “foreign” [141–144]. The antibodies involved in such immune mechanisms are referred to as paraneoplastic or onconeural antibodies. Recent studies have characterized a multitude of new onconeural antibodies. Along with recent progress in serological screening for such onconeural antibodies and diagnostic imaging techniques to detect malignancies, the concept of paraneoplastic neurological syndromes, including paraneoplastic neuropathy, has been broadened by integrating nonclassic clinical features. Definitive diagnosis of paraneoplastic neurological syndromes at an early clinical stage is important for a variety of reasons, including detection of occult malignancies, avoidance of unnecessary testing for other diseases, and immediate institution of therapy for cancers and paraneoplastic-mediated neurological compromise. Therefore, recognition of the wide clinical spectrum of paraneoplastic syndromes is important in this context [145, 146]. According to the Paraneoplastic Neurological Syndrome Euronetwork database, the peripheral nervous system is the primary site of involvement in one-third of patients with paraneoplastic syndromes [140]. Although a classic syndrome of subacute sensory neuronopathy is often present in patients with paraneoplastic neuropathy, there can also be extensive variation in the progression of neuropathy, the pattern of neuropathy, degree of sensory, motor, and autonomic involvement, and presence or absence of specific onconeural antibodies.

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18.7.1 Types of Neuropathy Sensory Neuronopathy The most frequent entities encountered in patients with paraneoplastic neurological syndromes are paraneoplastic cerebellar degeneration and sensory neuronopathy [140]. Subacute sensory neuronopathy is the typical presentation and constitutes a classic form of the paraneoplastic neurological syndrome [139]. The primary pathological mechanism for subacute sensory neuronopathy is related to autoimmune-­ induced impairments in sensory neuronal cell bodies in the dorsal root ganglia, most often involving onconeural anti-Hu antibodies [139, 147, 148]. Combined sensory and motor neuropathy, cerebellar degeneration, brainstem, and limbic encephalitis, and clinical evidence of the Lambert–Eaton myasthenic syndrome or gastrointestinal pseudo-obstruction have also been reported in patients with anti-Hu antibodies [149]. Subacute sensory neuronopathy is most commonly associated with small cell lung cancer but may also occur in the context of other malignancies, including breast cancer, ovarian cancer, sarcoma, or Hodgkin lymphoma [150, 151]. Like other paraneoplastic syndromes, subacute sensory neuronopathy is seen more frequently in middle-aged and elderly patients, and neuropathic symptoms precede the detection of cancer in a majority of cases [147, 152–154]. In histopathology, the major lesions associated with subacute sensory neuronopathy are localized within the dorsal root ganglia [147, 150, 155–158]. In a typical case with marked sensory ataxia, autopsy studies have shown marked loss of large sensory neurons in the dorsal root ganglia as well as the loss of predominantly large sensory axons in the central and peripheral rami. Lymphocytic infiltration, especially CD8+ cytotoxic T cells, has also been noted in the dorsal root ganglia [159]. The severity of pathology may differ among individual dorsal root ganglia, manifesting as variable clinical features among patients. Even the lesions within the dorsal root ganglia tend to be circumscribed but multifocal. Lymphocytic infiltration into the endoneurium and demyelinated fibers has been found in nerve trunks [160]. Findings suggestive of vasculitis have also been reported in the nerve trunk of patients with anti-Hu antibodies and ataxia in the extremities, suggesting concomitant subacute sensory neuronopathy [161, 162]. Lesions may extend to the sympathetic ganglia. Sural nerve biopsy in patients with subacute sensory neuronopathy and marked sensory ataxia tend to show loss of predominantly large myelinated fibers. In contrast, biopsy in patients with predominant pain and less sensory ataxia symptoms shows nerve fiber loss of small myelinated and unmyelinated fibers [153]. In the painful form of paraneoplastic sensory neuropathy, loss of the small dorsal root ganglia neuron occurs, which eventually leads to small fiber loss in peripheral nerves. This notion is consistent with the distribution of sensory impairment that suggests ganglionopathy and with scant regenerating fibers within biopsied specimens [153, 163].

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Sensorimotor Neuropathies As mentioned above, sensorimotor neuropathy represents a significant proportion of neuropathies associated with anti-Hu antibodies. However, published reports differ according to whether clinical or electrophysiological criteria are used to determine whether motor involvement is present [139, 148, 164, 165]. Indeed, lower motor neuron involvement has been reported in patients with anti-­ Hu-­associated paraneoplastic syndrome [147]. Further, motor neuron degeneration in the spinal cord has been noted during autopsy and is considered to be a common cause of motor deficit in patients with anti-Hu-associated paraneoplastic neuropathy. Some patients with anti-Hu antibodies may also have anti-CV2/CRMP-5 antibodies [160]. According to a previous study of neuropathy associated with anti-Hu and anti-CV2/CRMP-5 antibodies, patients with anti-Hu antibodies alone displayed subacute sensory neuronopathy, while those with anti-CV2/CRMP-5 antibodies experienced mixed axonal and demyelinating sensorimotor neuropathy. When both anti-Hu and anti-CV2/CRMP-5 antibodies were present, subacute sensory neuronopathy was superimposed on demyelinating sensorimotor neuropathy [166]. A host of other antibodies have been associated with paraneoplastic neuropathies. For example, a subacute motor axonal neuropathy with serum anti-GQ1b antibodies has also been reported in association with recurrent melanoma, while a patient with B cell lymphoma and anti-GM1 and GD1b antibodies had widespread weakness secondary to multifocal motor neuropathy with conduction block [167, 168]. In another report, a patient with pure lower motor neuron syndrome and breast cancer had antibodies against beta IV spectrin in initial axon segments and nodes of Ranvier [169]. Finally, a patient with small cell lung cancer who experienced a rapid onset of tetraplegia and respiratory failure mimicking Guillain–Barre´ syndrome (GBS) did not have anti-Hu antibodies or antiganglioside antibodies but did have infiltration of T cells into the dorsal root ganglia and loss of spinal anterior horn cells on autopsy, which suggested the presence of both motor and sensory neuronopathy [170]. In addition to the neuropathies described above, other rare types of neuropathy, including GBS, chronic inflammatory demyelinating polyneuropathy (CIDP), brachial plexopathy, or vasculitic neuropathy, can also occur as a paraneoplastic syndrome and manifest as sensory-motor neuropathy.

18.7.2 Diagnosis In 2004, the Paraneoplastic Neurological Syndrome Euronetwork suggested two levels of diagnostic evidence to define a neurological syndrome as paraneoplastic: “definite” and “possible” [140]. Criteria for definite paraneoplastic neurological syndromes were: (1) a classic syndrome and cancer that develops within 5 years of the diagnosis of the neurological disorder; (2) a nonclassic syndrome that resolves or significantly improves after cancer treatment without concomitant immunotherapy, provided that the syndrome is not susceptible to spontaneous remission; (3) a

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nonclassic syndrome with onconeural antibodies (well characterized or not) and cancer that develops within 5 years of the diagnosis of the neurological disorder; and (4) a neurological syndrome (classic or not) with well-characterized onconeural antibodies (anti-Hu, Yo, CV2, Ri, Ma2, or amphiphysin) and no cancer. Criteria for possible paraneoplastic neurological syndromes were: (1) a classic syndrome, no onconeural antibodies, no cancer but at high risk of having an underlying tumor; (2) a neurological syndrome (classic or not) with partially characterized onconeural antibodies and no cancer; and (3) a nonclassic syndrome, no onconeural antibodies, and cancer present within 2 years of diagnosis. Concerning paraneoplastic neuropathy, only subacute sensory neuronopathy, and chronic intestinal pseudo-­obstruction were classified as “classic.” Multiple autoantibodies may be found within a single patient, and the distinct profile of autoantibodies may aid to predict the site of cancer, rather than a specific neurological syndrome. For example, anti-Hu antibodies are strongly associated with small cell lung cancer. Patients with paraneoplastic disease tend to have limited tumor spread, suggesting that cancer may be at an early stage that is more amenable to treatment [143]. Thus, patients with suspected paraneoplastic polyneuropathy should undergo malignancy screening that includes body computed tomography (CT), mammogram, and fludeoxyglucose-positron emission tomography (FDG-PET) if all testing has failed to identify a tumor. Management consists of treating the underlying malignancy, which can improve or prevent further worsening of the polyneuropathy, along with immune-modulating therapies specifically for polyneuropathy. Some benefit has been reported with corticosteroids, plasma exchange, and IVIG, while cyclophosphamide and rituximab may be helpful in refractory cases [143, 166, 171].

18.7.3 Conclusion Although many patients with axon loss polyneuropathy are limited to supportive measures for therapy, the presence of an immune-mediated etiology may allow for specific treatment and potential improvement. Recognition of the distinct clinical features and early diagnosis is crucial to providing optimal care for the patient with immune axonal polyneuropathy.

18.8 Axonal GBS By the mid-1980s, GBS was considered to be a primary demyelinating T-cell-­ mediated autoimmune disorder of peripheral nerves and nerve roots [172]. Secondary axonal degeneration and Wallerian-like degeneration after severe demyelination was felt to represent the severe end of the demyelinating process. In 1985, however, Thomas Feasby and colleagues cared for a patient with severe post-­ diarrheal GBS who became tetraplegic and developed respiratory failure within

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36 h. Nerve conduction studies revealed inexcitable nerves—an unusual finding— and she died from a cardiac arrest on day 28 after the onset of weakness. The autopsy revealed severe, widespread axonal degeneration in the nerve roots and periphery without lymphocytic inflammation, rather than the usual characteristic segmental demyelination. The team was convinced they had seen something new and published their findings from several similar cases in 1986 [173]. Their proposal of a pure axonal form of GBS met with much skepticism, and Feasby had to fiercely defend his findings until similar cases were reported and the concept gained some ground by the early 1990s [174, 175]. At a similar time, a collaborative group reported on a unique GBS-like syndrome—the Chinese paralytic syndrome (CPS)—that occurred in seasonal outbreaks among children in rural China and was characterized by severe flaccid tetraplegia that progressed rapidly and often necessitated ventilator support [176]. Most patients exhibited high CSF protein levels and low or absent white cell counts, typical of GBS. Electrophysiological recordings of reduced motor amplitudes, preserved conduction velocities and preserved sensory nerve action potentials, however, pointed to severe axonal neuropathy [177]. Autopsy tissue from 12 patients did not show demyelination typical of GBS, but extensive Wallerian-like degeneration of sensory and/or motor axons. The condition was classified as a type of GBS and subdivided according to the axons affected; the terms acute motor and sensory axonal neuropathy (AMSAN) and acute motor axonal neuropathy (AMAN) were coined. The pathology identified in this work—macrophage invasion of the periaxonal space at the paranodal and nodal regions, where there is immunoglobulin and complement deposition, and displacement of the axon—is in marked contrast to the macrophage-mediated myelin stripping and the antibody and complement deposition in Schwann cells in the demyelinating form of GBS, which became known as acute inflammatory demyelinating polyneuropathy (AIDP) to reflect the pathological distinction from AMAN and AMSAN [178–180]. Subsequent studies confirmed the existence of AMAN and AMSAN in populations globally, although the proportions of patients with GBS subtypes vary geographically; for example, AMAN and AMSAN are more common in China and Asia, whereas AIDP is more common in North America and Europe. AMAN is classically an acute and progressive ascending flaccid quadriparesis, frequently complicated by respiratory failure and accompanied by minimal to no sensory symptoms, and has a high mortality rate with slow and poor recovery [181]. It is still unclear whether AMAN and AMSAN should be categorized under one axonal GBS variant since a minority of patients with AMAN also have sensory symptoms, neurophysiological studies revealing a subclinical involvement of sensory fibers, and both possibly share the same pathogenesis [182]. Miller Fisher syndrome (MFS) is classically characterized by the triad of ophthalmoplegia, ataxia, and areflexia, while Bickerstaff's brainstem encephalitis (BBE) is described as ophthalmoplegia, ataxia, and hypersomnolence [183]. Despite the different presentations, there is an overlap in the pathophysiology and clinical phenotype between classic GBS and these variants.

References

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18.9 Idiopathic Perineuritis Idiopathic perineuritis is a wastebasket entity of immune-mediated neuropathy comparable to polymyositis of muscle. In other words, idiopathic sensory perineuritis is a diagnosis of exclusion. The histological finding of perineuritis should prompt a search for etiologies such as leprosy and sarcoidosis and consideration of the possibility of certain toxic exposures, cryoglobulinemia, Lyme disease, systemic vasculitis, and ulcerative colitis.

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164. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology. 1998;50:652–7. 165. Camdessanche JP, Antoine JC, Honnorat J, et al. Paraneoplastic peripheral neuropathy associated with anti-Hu antibodies. A clinical and electrophysiological study of 20 patients. Brain. 2002;125:166–75. 166. Antoine JC, Camdessanche JP.  Paraneoplastic disorders of the peripheral nervous system. Presse Med. 2013;42:e235–44. 167. Kloos L, Sillevis Smitt P, Ang CW, Kruit W, Stoter G. Paraneoplastic ophthalmoplegia and subacute motor axonal neuropathy associated with anti-GQ1b antibodies in a patient with malignant melanoma. J Neurol Neurosurg Psychiatry. 2003;74:507–9. 168. Noguchi M, Mori K, Yamazaki S, Suda K, Sato N, Oshimi K. Multifocal motor neuropathy caused by a B cell lymphoma producing a monoclonal IgM autoantibody against peripheral nerve myelin glycolipids GM1 and GD1b. Br J Haematol. 2003;123:600–5. 169. Berghs S, Ferracci F, Maksimova E, et al. Autoimmunity to beta IV spectrin in paraneoplastic lower motor neuron syndrome. Proc Natl Acad Sci U S A. 2001;98:6945–50. 170. Nokura K, Nagamatsu M, Inagaki T, et al. Acute motor and sensory neuronopathy associated with small-cell lung cancer: a clinicopathological study. Neuropathology. 2006;26:329–37. 171. Antoine JC, Camdessanche JP.  Paraneoplastic neuropathies. Curr Opin Neurol. 2017;30:513–20. 172. Goodfellow JA, Willison HJ.  Guillain-Barre syndrome: a century of progress. Nat Rev Neurol. 2016;12:723–31. 173. Feasby TE, Gilbert JJ, Brown WF, et al. An acute axonal form of Guillain-Barre polyneuropathy. Brain. 1986;109(Pt 6):1115–26. 174. Yuki N, Yoshino H, Sato S, Miyatake T. Acute axonal polyneuropathy associated with anti­GM1 antibodies following Campylobacter enteritis. Neurology. 1990;40:1900–2. 175. Feasby TE, Gilbert JJ, Brown WF, et  al. Acute “axonal” Guillain-Barre polyneuropathy. Neurology. 1987;37:357. 176. Hafer-Macko C, Hsieh ST, Li CY, et  al. Acute motor axonal neuropathy: an antibody-­ mediated attack on axolemma. Ann Neurol. 1996;40:635–44. 177. McKhann GM, Cornblath DR, Ho T, et al. Clinical and electrophysiological aspects of acute paralytic disease of children and young adults in northern China. Lancet. 1991;338:593–7. 178. Griffin JW, Li CY, Macko C, et al. Early nodal changes in the acute motor axonal neuropathy pattern of the Guillain-Barre syndrome. J Neurocytol. 1996;25:33–51. 179. Hafer-Macko CE, Sheikh KA, Li CY, et al. Immune attack on the Schwann cell surface in acute inflammatory demyelinating polyneuropathy. Ann Neurol. 1996;39:625–35. 180. Ho TW, McKhann GM, Griffin JW. Human autoimmune neuropathies. Annu Rev Neurosci. 1998;21:187–226. 181. Molnar GK, Mertsola J, Erkko M. Guillain-Barre syndrome associated with campylobacter infection. Br Med J (Clin Res Ed). 1982;285:652. 182. Kaldor J, Speed BR. Guillain-Barre syndrome and Campylobacter jejuni: a serological study. Br Med J (Clin Res Ed). 1984;288:1867–70. 183. Yuki N, Taki T, Takahashi M, et al. Molecular mimicry between GQ1b ganglioside and lipopolysaccharides of Campylobacter jejuni isolated from patients with Fisher’s syndrome. Ann Neurol. 1994;36:791–3.

Mimics of Immune-Mediated Neuropathy

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19.1 Introduction Generally, neuropathies of peripheral nerves are highly prevalent [1]. The immune-­ mediated neuropathies are common and there are certain neuropathies, which mimic immune-mediated neuropathies. Concerning these neuropathies, prevalence figures are hardly available and often questionable due to limited coverage of a region or insufficient workup or cooperation between centers. Generally, neuropathies occur among all subtypes, hereditary, and acquired (metabolic, neoplastic, infectious, toxic). This chapter focuses on recent advances concerning the etiology, clinical presentation, diagnosis, treatment (if available), and outcome of these mimics of immune-mediated neuropathy.

19.2 Diagnosis of Peripheral Neuropathies Multiple algorithms for diagnostic workup of neuropathies are available [2]. They all rely on the history, clinical exam, blood tests, nerve conduction studies (NCSs), CSF investigations, imaging, biopsy, and genetic investigations. The selection of laboratory investigations is variable, depending on the clinical presentation, availability, costs, and expertise of the referring neurologist. Generally, answers to the questions―what (which nerve fiber modalities are involved), where (which are the complaints), when (which is the temporal evolution), and which setting (unique clinical circumstances of a patient)—should be obtained to classify the type of neuropathy [3]. For workup of hereditary neuropathies, it is crucial that a thorough individual and family history are taken and that asymptomatic family members are seen by the managing physician for subclinical weakness, wasting, or foot deformities, since the affected subject may not recognize subtle deficiencies himself. As soon as hereditary neuropathy is suspected, genetic workup (e.g. multigene panel,

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. L. Gaspar, Immune-Mediated Myopathies and Neuropathies, https://doi.org/10.1007/978-981-19-8421-1_19

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next generation sequencing (NGS)) should be initiated. NGS has the disadvantage that it does not reliably detect duplications or deletions, splice-site variants, or intronic variants and is difficult to interpret in the context of non-specific point mutations (variants of unknown significance) with oligogenic inheritance [4–6]. Additionally, NGS has a cost-depth trade-­off, that is, it can screen a small number of genes with good read depth or a large number with less depth.

19.3 Acquired Neuropathies Acquired neuropathies include metabolic, toxic, infectious, and neoplastic/paraneoplastic neuropathies. As with hereditary neuropathies, acquired neuropathies can be the exclusive manifestation of a disease or may occur together with the affection of other organs. The majority of acquired neuropathies are frequently diagnosed but some have to be assessed as rare. Generally, acquired neuropathies are more frequent than hereditary neuropathies.

19.3.1 Metabolic Neuropathies Generally, metabolic neuropathies include diabetic, uremic, endocrine, and nutritive neuropathies. Particularly, among the nutritive neuropathies, rare forms are known. Nutritive neuropathies are most frequently length-dependent, sensory neuropathies except for vitamin-B12 deficiency neuropathy [7, 8]. While diabetic and uremic neuropathies are highly prevalent, most of the other metabolic neuropathies are rare.

19.3.1.1 Endocrine Hypothyroidism: Though hypothyroidism is a frequent abnormality worldwide, neuropathy attributable to hypothyroidism is extremely rare [9]. The reason is that hypothyroidism is well-controlled in the majority of the cases, why the prevalence of neuropathy has declined. The onset of hypothyroid neuropathy is usually in early adulthood. Neuropathy due to hypothyroidism usually starts as small fibre neuropathy (SFN) and may affect large fibers with the progression of the disease. Patients initially complain about paresthesias and numbness of the feet. Hypothyroid neuropathy may manifest as mononeuropathy in the form of carpal tunnel syndrome. NCSs reveal a length-­dependent, sensory-motor axonopathy. Hypothyroid neuropathy can be complicated by myopathy, which is more frequent than neuropathy. Hyperthyroidism: Hyperthyroidism as an etiology of neuropathy is extremely rare and debated. The clinical presentation can be similar to that of hypothyroidism but may also show up as a Guillain-Barre syndrome (GBS)-like presentation [10]. NCSs reveal a symmetric, sensorimotor, mixed, neuropathy with active denervation in lower extremity muscles. More frequent than neuropathy is myopathy due to hypothyroidism.

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19.3.1.2 Vitamin Deficiencies Though vitamin deficiencies are frequently detected in the general population, neuropathy due to vitamin deficiency, with/without the involvement of other systems, has been only rarely reported. Low vitamin levels may be due to dietary causes (malnutrition, malabsorption, diarrhea), autoimmune conditions, certain drugs, alcoholism, chronic colitis, bariatric surgery, or due to another gastrointestinal compromise. Low vitamins that can go along with neuropathy include vitamin B12, folic acid, thiamine (vitamin B1), vitamin B6, and vitamin E.  Why only a small portion of patients with vitamin deficiency develop neuropathy, remain speculative but one hypothesis is that pre-existing nerve pathology may be necessary for the development of a vitamin-deficiency-related neuropathy. Vitamin B12: Vitamin B12 deficiency may be associated with distal, symmetric peripheral neuropathy (PNP) and mainly, as in funicular myelosis, proprioceptive dysfunction. About 4% of the distal symmetric PNPs are caused by vitamin B12 deficiency [11]. Normal blood levels of vitamin B12 do not exclude a clinically relevant, relative vitamin B12 deficiency [12]. In such cases, increased methylmalonate and homo-cysteine levels can support the diagnosis of relative vitamin B12 deficiency. However, methylmalonate and homocysteine can be also increased in hypothyroidism, renal insufficiency, hypovolemia, vitamin-B6 deficiency, or in patients with heterozygous homocysteinemia [13]. Contrary to other nutrition neuropathies, vitamin B12 deficiency manifests with a length-independent, sensory neuropathy. Patients with vitamin B12 deficiency usually present with concomitant myelopathy. Folic acid: PNP due to folate deficiency is rare and manifests with slowly progressive distal symmetric, sensory neuropathy. Folate-deficient neuropathy predominantly affects the lower limbs. Cognitive and affective symptoms of folate deficiency are far more common than PNP and the laboratory test for folate levels is only relevant in this clinical context [14]. Since folate deficiency causes secondary thiamine deficiency, neuropathy in folate deficiency can be blended with thiamine deficiency neuropathy [15]. Thiamine: Not only do central nervous system (CNS) symptoms occur with thiamin-­deficiency (Wernicke encephalopathy, Marchiafava-Bignami, dry beriberi) but also distal axonal, sensory-motor, length-dependent PNP has been described. Thiamine deficiency-related PNP is often painful and has been described in the context of bariatric surgery or severe alcohol abuse. Vitamin B6: Vitamin B6 deficiency almost exclusively develops in the context of drugs that reduce vitamin B6 resorption (e.g. isoniazid) and cause axonal distal sensory-motor PNP [16]. A further cause of vitamin B6 deficiency can be chronic dialysis [17]. Vitamin E: Vitamin E deficiency may cause a distal symmetric PNP with severe, sensory ataxia. Since vitamin E deficiency is frequently associated with spinocerebellar syndrome, concomitant cerebellar ataxia may occur [13–15, 18]. However, vitamin E deficiency is a rare cause of PNP, and serum levels of vitamin E should be determined only in patients with expected vitamin E deficiency.

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19.3.2 Toxic Neuropathies Metals Metal intoxications most frequently not only cause isolated neuropathy but also systemic manifestations. Thus, systemic features should be considered in the diagnostic workup of suspected metal intoxications. Copper: Generally, copper deficiency (hypocupremia) manifests with bone marrow dysplasia, myelopathy, and neuropathy [19]. Neuropathy due to hypocupremia is rare and predominantly occurs after bariatric surgery, gastrectomy, or due to alcoholism [20]. Neuropathy is progressive, ascending, and associated with gait ataxia, cerebellar ataxia, fatigue, dyspnea, macrocytic anemia, neutropenia, and unintentional weight loss. Neuropathy due to copper deficiency is usually sensory and symmetric. The clinical presentation is similar to that of funicular myelosis. Diagnostic is hypocupremia and low copper in the bone marrow biopsy. Serum copper should be particularly determined in patients with a funicular myelosis presentation but normal folic acid and cobalamin levels [11]. Lithium:  Lithium has long been used in psychiatry as adjuvant therapy for bipolar disorders. Occasionally, long-term treatment with lithium results in chronic intoxication, clinically manifesting as nystagmus, ataxia, tremor, memory impairment, myoclonus with generalized triphasic epileptiform discharges, dysarthria, fasciculations, clonus, and PNP [21]. PNP is usually a length-dependent, sensorimotor axonopathy. Frequently, lithium neuropathy shows a rapidly progressive course [22]. Patients under lithium therapy with symptoms and signs of PNP require quantification of the lithium serum level, NCSs, and eventually replacement of the causative agent. Discontinuation of lithium is usually followed by improvement or resolution of the PNP [23]. Lead:  Lead intoxication most frequently results from industrial exposure and can cause a progressive, mostly asymmetric motor PNP that affects the upper extremities more than the lower extremities. Classical lead neuropathy manifests with weakness of the wrist and finger extensors [24]. Lead intoxication often also causes anemia, gingival, dental, and cerebral changes (lead encephalopathy). The most well-known gingival abnormality is Burton’s line [25]. The prognosis of recovery is favorable as long as exposure is terminated promptly. Arsenic:  The causes of arsenic intoxication are poisoning with contaminated water, ingestion of traditional medicine for obesity, or attempted homicide. Neuropathy is one among other manifestations of arsenic intoxication and presents as subacute, progressive, painful, sensory-motor neuropathy with autonomic dysfunction [26]. In some cases, neuropathy can be the only manifestation of intoxication.

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Thallium:  Thallium intoxication has been reported in cases of accidental ingestion, suicide attempt, or criminal adulteration. Thallium intoxication may cause a progressive painful, sensory-motor PNP with autonomic dysfunction. In addition to neuropathy patients may develop visual loss, myalgia, leg weakness, acute gastrointestinal symptoms, or alopecia [1]. Mercury:  Mercury intoxication causes an axonal, sensory PNP with small-fiber involvement and autonomic dysfunction [1]. In addition to neuropathy, patients with mercury intoxication may present with diffuse full-body rash, fever, myalgias, headache, oral paresthesias, and tender cervical posterior lymphadenopathy. Cobalt:  Cobalt toxicity usually results from a failed total hip replacement. Cobalt metallosis is rare but can be devastating [27]. Clinical manifestations of cobalt toxicity include cardiomyopathy, hypothyroidism, skin rash, visual and hearing impairment, polycythemia, muscle weakness, fatigue, cognitive impairment, and neuropathy. Neuropathy is a progressive, length-dependent, sensory axonopathy with normal motor function.

19.3.3 Drugs Neuropathy can be a side effect of several drug intoxications. Most well-known for their neuropathic toxicity are chemotherapeutics and nucleoside analogs. However, neuropathy may be also a side effect of non-chemotherapeutic drugs. Non-Chemotherapeutic Drugs:  Among the non-chemotherapeutic drugs neuropathy is most frequently caused by phenytoin, disulfiram, fluoroquinolones, linezolid, metronidazole, chloroquine dapsone, isoniazid, ethambutol, nitrofurantoin, nucleoside analogs (dideoxycytidine, zalcitabine, dideoxyinosine, stavudine, lamivudine, thalidomide, tacrolimus, leflunomide, amiodarone, or colchicine). Rarely, toxic neuropathy occurs in association with vitamin B6, L-DOPA, or statin overdose [28, 29]. Vitamin B6:  Vitamin B6 is the only vitamin that may cause PNP in the context of increased blood levels, which is mostly due to excess vitamin supplementation. Vitamin-B6 levels need to be elevated 50–100 times the upper level of normal to induce neuropathy. Vitamin-B6 toxicity causes a non-length dependent, sensory PNP with marked ataxia or a painful SFN [1, 30].

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L-DOPA:  Neuropathy due to L-DOPA is a length-dependent, sensory axonopathy, possibly related to elevated homocysteine or neuronal deposition of α-synuclein. In a study of 73 Parkinson's patients without a history of previous PNP, 67.3% of those taking L-DOPA developed a PNP, whereas in the non-L-DOPA group only one patient developed PNP [31]. The results imply that long-term L-DOPA intake can secondarily cause vitamin-B12 and folate deficiency and consecutively PNP [32]. Anticancer Drugs:  Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent complication of various chemotherapeutics [33]. Most frequently neuropathy has been described in association with taxanes, vinca-alkaloids, platanes, and bortezomib. However, there are chemotherapeutics, such as immune checkpoint inhibitors or eribulin, which have been only rarely described to be complicated by neuropathy. Immune checkpoint inhibitors (e.g. pembrolizumab, nivolumab, ipilimumab) are a new class of chemotherapeutic drugs being effective with refractory cancers. Peripheral nervous system (PNS) side effects are rare and occur in