Familial Mediterranean Fever (Rare Diseases of the Immune System Book 3)

This book, written by very well known opinion leaders in the field, covers all aspects of familial Mediterranean fever, the most common monogenic autoinflammatory disease. The opening chapters explain the genetic basis of the disease and provide insights into the pathogenesis derived from recent experimental studies. A large part of the book is then devoted to a detailed description of the typical and atypical clinical presentations, the disease course, and potential complications in both pediatric and adult patients. Guidance is provided on the measurement of disease severity and the management of patients in daily practice. The advice regarding treatment is based on the best currently available evidence and attention is also paid to important emerging treatments. The book is part of Springer’s series __Rare Diseases of the Immune System__, which presents recently acquired knowledge on pathogenesis, diagnosis, and therapy with the aim of promoting a more holistic approach to these conditions. Monogenic autoinflammatory diseases are hereditary disorders that are caused by single-gene defects in innate immune regulatory pathways and are characterized by a clinical and biological inflammatory syndrome in which there is limited, if any, evidence of autoimmunity. Familial Mediterranean fever itself is due to a mutation in the __MEFV__ gene, which codes for the protein pyrin; it is characterized by periodic fever and episodes of painful inflammation in the abdomen, chest, and joints. __Familial Mediterranean Fever__ will be an invaluable source of up-to-date information for all practitioners involved in the care of patients with the disease. Preface 6 Contents 8 1: Genetics 9 1.1 Introduction 9 1.2 Mode of Transmission 9 1.2.1 Classical Autosomal Recessive Transmission 9 1.2.2 Pseudodominance and True Dominance 10 1.3 The MEFV Gene 10 1.3.1 Discovery 10 1.3.2 Structure of the Gene 10 1.3.2.1 Location and Structure 10 1.3.2.2 Mutation Type and Distribution 11 1.4 Population Genetics 12 1.4.1 Mediterranean Founder Effect 12 1.4.2 Other Ethnicities 12 1.5 Genetic Diagnosis 12 1.5.1 Sanger Sequencing 12 1.5.1.1 Benefits 13 1.5.1.2 Limitations 13 1.5.1.3 Consensus Strategy 13 1.5.2 Other Techniques 13 1.6 MEFV Variants 14 1.6.1 The Spectrum of MEFV Variants 14 1.6.1.1 Clearly Pathogenic Variants 14 1.6.1.2 Variants of Unknown Significance 14 1.6.1.3 Benign Variants 14 1.6.2 Databases 14 1.6.2.1 Generalist 14 1.6.2.2 FMF Specific 15 1.6.3 Clinical Interpretation 15 1.6.3.1 Guidelines 15 1.6.3.2 Simple Heterozygotes 16 1.7 Genotype-Phenotype Correlations 16 1.7.1 Phenotypic Heterogeneity 16 1.7.2 p.M694V and Disease Severity 16 1.7.3 E148Q and Variable Penetrance 17 1.7.4 Modifier Genes 17 1.8 Genetic Consultation in FMF 17 Conclusion 17 References 18 2: Pathogenesis 21 2.1 Introduction 21 2.2 The FMF Protein, Pyrin 23 2.2.1 PYRIN Domain 23 2.2.2 Nuclear Localization Signals 25 2.2.3 Coiled-Coil Domain 25 2.2.4 B30.2 Domain 26 2.3 The Function of Pyrin 26 2.3.1 IL-1β and the Inflammasomes 26 2.3.2 The NLRP3 Inflammasome 27 2.3.3 The Role of Non-mutated Pyrin in IL-1β Production: The Case for Inhibition 27 2.3.4 The Role of Non-mutated Pyrin in IL-1β Production: The Case for a Bacterially Induced Pyrin Inflammasome 28 2.4 Pyrin and NF-kB Activation 29 2.5 Animal Model for FMF 30 2.5.1 Inflammatory Phenotypes of FMF KI Mice 30 2.5.2 The Inflammation of FMF KI Mice Is Induced by IL-1β 31 2.5.3 Pyrin with an FMF-Associated B30.2 Mutation Forms an Inflammasome 31 2.6 Inflammation in Human FMF Is Mediated by IL-1β 31 2.7 FMF-Associated Mutations Are Gain of Function 32 2.8 Dosage Effect of FMF-Associated Mutations 32 2.9 Conclusion and Future Directions 33 References 35 3: Special Aspects of Familial Mediterranean Fever in Childhood 39 3.1 Clinical Presentation 39 3.1.1 Age of Manifestation 39 3.1.2 Fever 41 3.1.3 Peritonitis 41 3.1.4 Pleuritis 41 3.1.5 Arthritis 42 3.1.5.1 Acute Arthritis 42 3.1.5.2 Chronic Protracted Arthritis 42 3.1.5.3 Sacroiliitis 43 3.1.6 Pericarditis 43 3.1.7 Skin Lesions 43 3.1.8 Acute Scrotum 44 3.1.9 Myalgias 44 3.1.10 Amyloidosis 45 3.1.11 Neurological Symptoms 45 3.1.12 Vasculitis 45 3.2 Diagnostic Approach to FMF in Children 45 3.3 Treatment 48 3.3.1 Treatment of Colchicine-Intolerant or Colchicine-Resistant Patients 50 References 50 4: Clinical Picture in Adulthood and Unusual and Peculiar Clinical Features of FMF 54 4.1 Introduction 54 4.2 Classic Manifestations of FMF 55 4.2.1 The Peritoneal Attack 55 4.2.2 Attacks of Fever 55 4.2.3 The Synovial Attack 56 4.2.4 The Pleural Attack 56 4.2.5 Erysipelas-Like Erythema (ELE) Attack 57 4.3 Disease Severity 57 4.4 Neurological Manifestations 58 4.4.1 Neurological Manifestations Directly Related to FMF 58 4.4.2 Neurological Diseases Associated with FMF 60 4.4.2.1 Demyelinating Disorders 60 4.4.2.2 Stroke 61 4.4.2.3 Recurrent Aseptic Meningitis 61 4.4.2.4 Autonomic Nervous System (ANS) 62 4.4.3 Neurologic Disorders Secondary to FMF Complications and FMF-Associated Diseases 62 4.4.4 Neurological Manifestations Related to FMF Treatment 63 4.5 Cardiovascular (CV) System in FMF 64 4.6 The Kidney in FMF 65 4.6.1 Proteinuria, Amyloidosis, and Kidney Biopsy 65 4.6.2 The Course of FMF-Amyloid Nephropathy 67 4.6.2.1 Amyloid Storm 67 4.6.3 Treatment of Renal Amyloidosis 67 4.6.4 Non-amyloid Kidney Disease 68 4.7 Dermatologic Manifestations Other than ELE Eruptions 69 4.7.1 Vasculitis and FMF 69 4.7.1.1 Henoch-Schönlein Purpura (HSP) 69 4.7.1.2 Polyarteritis Nodosa (PAN) 70 4.7.1.3 Behcet’s Disease (BD) 70 4.7.2 Other Skin Manifestations 71 4.7.2.1 Sweet’s Syndrome 71 4.7.2.2 Bullous Skin Lesions 71 4.7.2.3 Panniculitis 71 4.7.2.4 Recurrent Urticaria 72 4.7.2.5 Pyoderma 72 4.8 Pulmonary Manifestations of FMF 72 4.8.1 Pseudopneumonia in FMF (Fig. 4.1) 72 4.8.2 FMF and Asthma 72 4.8.3 Pulmonary Thromboembolism and FMF 73 4.8.4 Pulmonary Amyloidosis in FMF 73 4.8.5 FMF and Chest Malignancy 73 4.8.6 FMF and Vasculitis of the Lung 74 4.9 FMF and the Hepatobiliary System 74 4.9.1 Chronic Liver Disease 74 4.9.2 Hyperbilirubinemia and Liver Function During Acute Attacks 75 4.9.3 Liver Amyloidosis 75 4.10 The Reproductive System in FMF 76 4.10.1 FMF and Menstruation 76 4.10.2 Fertility in FMF 77 4.10.2.1 Female Infertility 77 4.10.2.2 Male Infertility in FMF 77 4.10.3 Pregnancy in FMF 78 References 78 5: Epidemiology of FMF Worldwide 88 5.1 Introduction 88 5.2 Epidemiology of FMF in Western Countries and Far East 91 References 94 6: Long-Term Complications of Familial Mediterranean Fever 98 6.1 Introduction 98 6.2 Mortality 98 6.3 Emergency Surgery 99 6.4 Adhesions 99 6.5 Arthritis 99 6.5.1 Monoarthritis 100 6.5.2 Rheumatoid Arthritis 100 6.5.3 Ankylosing Spondylitis/Sacroiliitis 100 6.5.4 Enthesopathy 100 6.5.5 Juvenile Arthritis 101 6.6 Fertility 101 6.6.1 Colchicine and Reproductive Outcomes 101 6.6.2 FMF and Pregnancy 102 6.6.3 Colchicine and Breastfeeding 102 6.6.4 AA Amyloidosis and Pregnancy 102 6.7 Endothelial Dysfunction/Cardiovascular Disease 102 6.8 Vasculitis 103 6.9 Malignancy 103 6.10 AA Amyloidosis 104 6.10.1 Pathology 104 6.10.2 Clinical Features 104 6.10.3 Phenotype II FMF 105 6.10.4 Treatment 105 6.10.5 Outcome 106 References 107 7: Evaluation of the Current Disease Scoring Systems in Familial Mediterranean Fever 113 7.1 Introduction 113 7.2 Scoring Instruments in FMF 114 7.2.1 Autoinflammatory Disease Activity Index (AIDAI) 114 7.2.2 Juvenile Autoinflammatory Disease Multidimensional Assessment Report (JAIMAR) 116 7.2.3 FMF50: A Score for Assessing Treatment Outcome in Familial Mediterranean Fever 117 7.2.4 Medication Adherence Scale in Familial Mediterranean Fever (MASIF) 118 7.2.5 Medication Adherence Scale in Familial Mediterranean Fever (MASIF): Adult Version 119 7.2.6 Severity Scoring Systems 119 7.3 Conclusions 122 References 122 8: How to Manage Familial Mediterranean Fever (FMF) Patients in Daily Practice 125 8.1 Mechanisms of Action of Colchicine 125 8.2 How to Use Colchicine in the Daily Practice 127 8.3 Colchicine Resistance and Alternative Treatments 128 8.4 Long-Term Efficacy and Safety of Colchicine Treatment in FMF 131 8.4.1 Colchicine and Male Fertility 131 8.4.2 Colchicine and Female Fertility 132 8.4.3 Colchicine and Child Growth and Development 134 8.4.4 Colchicine and Other Drugs Interaction 135 8.4.5 Colchicine Adverse Effects and Toxicity 136 References 137 9: The Emerging Treatments in Familial Mediterranean Fever 142 9.1 The Use of Biologics in FMF 144 9.2 Anti-TNF Treatments 146 9.3 Anti-IL-1 Treatments 147 9.4 Anakinra 148 9.5 Rilonacept 150 9.6 Canakinumab 151 9.7 Gevokizumab 153 9.8 Anti-IL-6 Treatment 153 9.9 Conclusion 156 References 156 Index 163 Front Matter....Pages i-vii Genetics....Pages 1-12 Pathogenesis....Pages 13-30 Special Aspects of Familial Mediterranean Fever in Childhood....Pages 31-45 Clinical Picture in Adulthood and Unusual and Peculiar Clinical Features of FMF....Pages 47-80 Epidemiology of FMF Worldwide....Pages 81-90 Long-Term Complications of Familial Mediterranean Fever....Pages 91-105 Evaluation of the Current Disease Scoring Systems in Familial Mediterranean Fever....Pages 107-118 How to Manage Familial Mediterranean Fever (FMF) Patients in Daily Practice....Pages 119-135 The Emerging Treatments in Familial Mediterranean Fever....Pages 137-157 Back Matter....Pages 159-162