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Differences in the Pattern of Muscular and Extramuscular Involvement In Differences in the pattern of muscular and extramuscular involvement in patients with inflammatory myopathy according to the clinical groups and specific autoantibodies María Casal Domínguez ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) y a través del Repositorio Digital de la UB (diposit.ub.edu) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR o al Repositorio Digital de la UB (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tdx.cat) service and by the UB Digital Repository (diposit.ub.edu) has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized nor its spreading and availability from a site foreign to the TDX service or to the UB Digital Repository. Introducing its content in a window or frame foreign to the TDX service or to the UB Digital Repository is not authorized (framing). Those rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author. Universitat de Barcelona Departament de Medicina Differences in the pattern of muscular and extramuscular involvement in patients with inflammatory myopathy according to the clinical groups and specific autoantibodies Doctoral Dissertation María Casal Domínguez 2018 Directors María del Carme Roca Saumell Andrew L Mammen To my husband, Iago. To my parents and sister. To the memory of my grandparents, Lalo and Lala. To my mentors. 3 “Science, my lad, is made up of mistakes, but they are mistakes which it is useful to make, because they lead little by little to the truth” Jules Verne 5 ACKNOWLEDGEMENTS Firstly, I would like to express my sincere gratitude to my advisors, Prof. Carme Roca Saumell and Prof. Andrew Mammen, for the continuous support of my Ph.D study and related research, for their patience, motivation, and immense knowledge. Their guidance helped me in all the time of research and writing of this thesis. Besides my advisors, I would like to thank my Residency mentor, Dr. Joan Bayó i Lliure, who taught me to be a doctor. I also want to thank all past and present members of the CLOT Primary Care Center, who have contributed immensely to my personal and professional growth. I am grateful to my parents and sister, who have provided me through moral and emotional support in my life. I am also grateful to my other family members and friends who have supported me along the way. Finally, I would like to acknowledge the most important person in my life, my husband Iago. He has been a constant source of strength and inspiration. 7 INDEX ABBREVIATIONS ...................................................................................................... 11 I. INTRODUCTION .................................................................................................... 17 1. Concept, history, and classification of inflammatory myositis ................................ 19 2. Autoantibodies in inflammatory myositis .............................................................. 25 3. Epidemiology of inflammatory myositis ................................................................. 38 4. Etiology and pathogenesis of inflammatory myositis ............................................. 40 5. Clinical manifestations ........................................................................................... 45 6. Diagnosis ............................................................................................................... 55 7. Prognosis ............................................................................................................... 62 8. Treatment .............................................................................................................. 63 II. HYPOTHESIS AND OBJECTIVES ............................................................................. 71 1. Hypothesis ............................................................................................................. 73 2. Objectives .............................................................................................................. 74 III. PUBLICATIONS .................................................................................................... 77 1. Thigh magnetic resonance imaging in immune-mediated necrotizing myositis ....... 79 2. High-resolution manometry in myositis ............................................................... 103 3. Cohort study of the antisynthetase syndrome ...................................................... 113 IV. DISCUSSION ..................................................................................................... 129 1. General discussion ............................................................................................... 131 2. Thigh magnetic resonance imaging in immune-mediated necrotizing myositis ..... 132 3. High-resolution manometry in myositis ............................................................... 137 4. Cohort study of the antisynthetase syndrome ...................................................... 142 V. CONCLUSIONS ................................................................................................... 147 9 1. Conclusions of the different studies ..................................................................... 149 2. General conclusions ............................................................................................. 150 BIBLIOGRAPHY ...................................................................................................... 153 10 ABBREVIATIONS 11 ABBREVIATIONS A-V blocks Atrioventricular blocks APC Antigen presenting cell ASyS Antisynthetase syndrome AZA Azathioprine BAL Bronchoalveolar lavage CADM Clinically amyopathic dermatomyositis CHD3 Chromodomain Helicase DNA Binding Protein 3 CHD4 Chromodomain Helicase DNA Binding Protein 4 CTL Cytotoxic T cells CYA Cyclosporine CYC Cyclophosphamide DLCO Diffusing capacity for carbon monoxide DM Dermatomyositis EMG Electromyography ENMC European Neuromuscular Centre FEV1 Forced expiratory volume in one second FHLF Four and a half LIM domain FVC Forced vital capacity HLA Human leucocyte antigen HMGCR 3-hydroximethyl-3-methyl-glutaryl CoA reductase HRM High resolution manometry HRCT High resolution computerized tomography IBM Inclusion bodies myositis IDL Interstitial lung disease 13 IL Interleukin IM Inflammatory myopathy IMNM Immune-mediated necrotizing myopathy INF Interferon IVIg Intravenous immunoglobulins JDM Juvenile dermatomyositis MAA Myositis-associated autoantibody MAC Membrane attack complex MCTD Mixed connective tissue disease MDA5 Melanoma Differentiation-Associated protein 5 MHC Major histocompatibility complex MMF Mycophenolate mophetil MRI Magnetic resonance image MSA Myositis-specific autoantibody MSG Muscle Study Group MTX Methotrexate NF-kβ Nuclear factor-kappa beta NSIP Non-specific interstitial pneumonia NT5C1A 5'-nucleotidase, cytosolic IA NuRD Nucleosome Remodeling Deacetylase OP Organizing pneumonia PAH Pulmonary arterial hypertension PFT Pulmonary functional tests PM Polymyositis 14 PDM/SSc Overlap syndrome between PM/DM and scleroderma RP Raynaud´s phenomenon RTX Rituximab SLE Systemic lupus erythematosus SnRNPs Small nuclear ribonucleoproteins SSc Scleroderma SUMO Small ubiquitin-like modifier activating enzyme heterodimer STIR Short tau inversion recovery tMRI Thigh magnetic resonance image TAC Tacrolimus TGF- β Transforming growth factor beta Th T helpers TIF1 γ Transcriptional intermediary factor 1-gamma TLC Total lung capacity TLRs Toll –like receptors TNF Tumor necrosis factor Treg T regulator UIP Usual interstitial pneumonia U1RNP U1 ribonucleoprotein UV Ultraviolet 15 I. INTRODUCTION 17 1. Concept, history, and classification of inflammatory myositis Inflammatory myositis (IM) is a heterogeneous group of diseases
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