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Myasthenia Gravis in the North of Portugal: Epidemiological, Clinical and Serological Study and Immunopathology of the Thymus

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Myasthenia Gravis in the North of Portugal: Epidemiological, Clinical and Serological Study and Immunopathology of the Thymus VITAMIN D DEFICIENCY AND RESISTANCE STATE ASSOCIATIONMyasthenia gravis WITH CLIin theNICAL North AND of IMMUNOLOGI Portugal: CAL DEREGULATIONepidemiological, INclinical SYST EMICand serological LUPUS ERYTHEMAT study and OSUS immunopathology of the thymus ANTÓNIO JOAQUIM DOS SANTOS PEREIRA SÁ MARINHO 3º Ciclo – Doutoramento em Ciências Médicas Maria DoctoralErnestina Programme Azevedo Moreirain Medical dos Sciences Santos Tese de Doutoramento em Ciências Médicas 2017 2016 Maria Ernestina Azevedo Moreira dos Santos Myasthenia gravis in the North of Portugal: epidemiological, clinical and serological study and immunopathology of the thymus Tese de Candidatura ao grau de Doutor em Ciências Médicas, submetida ao Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto Orientador Professora Doutora Maria Isabel Leite Nuffield Department of Clinical Neurosciences Oxford University Hospitals and University of Oxford Co-orientadores Professor Doutor Guilherme Gonçalves Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto Professor Doutor Carlos Lopes Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto 1 Aos meus pais Ao Gabriel Ao Luís, Henrique e Eduardo 2 Esta tese foi escrita de acordo com a legislação e regulamentos aplicáveis ao Doutoramento em Ciências Médicas: Regulamento Geral dos Terceiros Ciclos de Estudos da Universidade do Porto, aprovado por despacho reitoral de 10 de abril de 2015 e publicado em Diário da República, 2.a série, n.o 90 de 11 de maio de 2015, por Despacho n.o 4889/2015. Decreto-lei n.o 63/2016 – Diário da República n.o 176/2016, Série I de 13 de setembro de 2016 do Ministério da Ciência, Tecnologia e Ensino Superior. Plano de estudos do doutoramento em Ciências Médicas, do Instituto de Ciências Biomédicas Abel Salazar – Universidade do Porto. 3 Table of Contents Publications……………………………………………………………………………………... 5 Abbreviations ………………………………………………………………………………….. 10 Abstract………………………………………………………………………………………….. 12 Resumo …………………………………………………………………………………........... 16 Chapter 1. Introduction………………………………………………………………………. 21 1.1. Clinical features of Myasthenia gravis…………………………………………… 22 1.1.1. Clinical presentations………………………………………………………… 22 1.1.2. Antibodies in Myasthenia gravis…………………………………………… 23 1.1.3. Thymus and Myasthenia gravis…………………………………………… 25 1.1.4. Diagnosis………………………………………………………………………. 26 1.1.5. Treatments……………………………………………………………………… 29 1.1.6. Myasthenia gravis classification and subgroups………………………. 34 1.2. Etiopathogeny………………………………………………………………………… 36 1.2.1. Immunology – thymus………………………………………………………. 37 1.2.2. Environment…………………………………………………………………… 37 1.2.3. Genetics………………………………………………………………………… 38 1.3. Epidemiology of Myasthenia gravis……………………………………………… 39 1.4. Other relevant subjects……………………………………………………………. 40 1.4.1. Polyautoimmunity in Myasthenia gravis……………………………….. 40 1.4.2. Refractory Myasthenia gravis…………………………………………….. 40 1.4.3. Myasthenia gravis in children…………………………………………….. 41 1.4.4. Late Onset Myasthenia gravis…………………………………………….. 42 1.4.5. Pregnancy and Myasthenia gravis……………………………………….. 45 Chapter 2. Aim and Objectives…………………………………………………………….. 46 Chapter 3. Results…………………………………………………………………………….. 49 3.1. Epidemiological study……………………………………………………………….. 50 3.2. Immunogenetic study……………………………………………………………….. 74 3.3. Pregnancy and Myasthenia gravis………………………………………………… 84 3.4. Polyautoimmunity in Myasthenia gravis…………………………………………. 109 3.5. Refractory Myasthenia gravis………………………………………………………. 115 3.6. Infections, neoplasms and other autoimmunity in thymoma associated 128 Myasthenia gravis……………………………………………………………………. Chapter 4. Summary and Discussion……………………………………………………... 150 Chapter 5. Conclusions and Final Comments………………………………………….. 158 References………………………………………………………………………………………. 162 Acknowledgments…………………………………………………………………………….. 190 4 Publications This work generated seven main scientific articles, that are included in this thesis (four published papers, one manuscript is under the process of review and other two are under submission). There are other six published articles related to this work that were also cited here. The original data presented was published in international peer-reviewed journals. The text in the results chapters is exactly as published, but the page formatting was adapted to conform with the layout of the thesis and the reference numbers adjusted to a single bibliography of uniform style. As a consequence, there is some overlap amongst these chapters and between them and the introductory chapter which reviews the literature comprehensively and defines the objectives of each study. The dissertation is completed by general discussion and conclusions. 5 Publications included in the thesis: 1. Epidemiology of Myasthenia gravis in Northern Portugal: Frequency estimates and clinical epidemiological distribution of cases. Ernestina Santos, Ester Coutinho, Isabel Moreira, Ana Martins Silva, Dina Lopes, Henrique Costa, Fernando Silveira, Goreti Nadais, Hugo Morais, Joao Martins, Maria Ceu Branco, Andreia Veiga, Rosa Santos Silva, Augusto Ferreira, Filipa Sousa, Marta Freijo, Ilda Matos, Rui André, Luís Negrão, Carla Fraga, Manuela Santos, Mafalda Sampaio, Carlos Lopes, Maria Isabel Leite, Guilherme Gonçalves. Muscle and Nerve. 2016 Sep;54(3):413-21. 2. HLA and age of onset in myasthenia gravis. Ernestina Santos, Andreia Bettencourt, Ana Martins da Silva, Daniela Boleixa, Dina Lopes, Sandra Brás, Paulo Pinho Costa, Carlos Lopes, Guilherme Gonçalves, Maria Isabel Leite, Berta Martins da Silva. Neuromuscular Disorders 2017; 27(7):650-654. 3. Myasthenia gravis in Pregnancy – experience of a Portuguese Centre. Antonio Braga, Ernestina Santos, Clara Pinto, Jorge Sousa Braga. Muscle and Nerve 2016;54(4):715-20. 4. MuSK Myasthenia gravis and Pregnancy. Ernestina Santos, Denis Gabriel, Antonio Braga, Sara Duarte, Ana Martins da Silva, Ilda Matos, Marta Freijo, Joao Martins, Fernando Silveira, Goreti Nadais, Filipa Sousa, Carla Fraga, Rosa Santos Silva, Carlos Lopes, Guilherme Gonçalves, Clara Pinto, Jorge Sousa Braga, Maria Isabel Leite. Resubmitted after minor revison in Neuromuscular Disorders. 6 5. Myasthenia gravis with systemic and neurological polyautoimmunity. Sara Duarte*, Ernestina Santos*, Joana Martins, Ana Martins Silva, Carlos Lopes, Guilherme Gonçalves, Maria Isabel Leite. Journal of Neurological Sciences. 2017 Oct 15;381: 39-40. *the authors contributed equally to the work 6. Refractory Myasthenia gravis: Clinical, demographic and immunogenetic characteristics in a portuguese cohort. Ernestina Santos, Andreia Bettencourt, Sara Duarte, Denis Gabriel, Vanessa Oliveira, Ana Martins Silva, Carlos Lopes, Guilherme Gonçalves, Berta Martins Silva, Maria Isabel Leite. Under submission. 7. Thymoma following thymectomy of hyperplastic thymus in young onset Myasthenia gravis: clinical features heralding the thymoma. Ernestina Santos, Ana Martins Silva, Philipp Stroebel, Antonio Marinho, Nick Wilcox, Guilherme Gonçalves, Carlos Lopes, Alexander Marx, Maria Isabel Leite. Under submission. 7 Publications related with this work and cited in the thesis: 1. Inflammatory myopathy associated with myasthenia gravis with and without thymic pathology: report of four cases and literature review. Ernestina Santos, Ester Coutinho, Ana Martins da Silva, António Marinho, Carlos Vasconcelos, Ricardo Taipa, Manuel Melo Pires, Guilherme Gonçalves, Carlos Lopes, Maria Isabel Leite. Autoimmunity Reviews. 2017 Jun;16(6):644-649. 2. Congenital myasthenic syndrome due to mutation in CHRNE gene with clinical worsening and thymic hyperplasia attributed to association with autoimmune-myasthenia gravis. Ernestina Santos, Isabel Moreira, Ester Coutinho, Guilherme Gonçalves, Carlos Lopes, Jose Lopes Lima, Maria Isabel Leite. Neuromuscular Disorders. 2015 Dec;25(12):928-31. 3. Lambert-Eaton myasthenic syndrome and prostatic adenocarcinoma. Cecília Monteiro, Isabel Moreira, Jose Lopes Lima, Ernestina Santos. Neurological Sciences 2015 Nov;36(11):2145-6. 4. The protective role of HLA-DRB1 13 in autoimmune diseases. Andreia Bettencourt, Cláudia Carvalho, Bárbara Leal, Sandra Brás, Dina Lopes, Ana Martins da Silva, Ernestina Santos, Tiago Torres, Isabel Almeida, Fátima Farinha, Paulo Barbosa, António Marinho, Manuela Selores, João Correia, Carlos Vasconcelos, Paulo Pinho Costa, Berta Martins Silva. Journal of Immunology Research 10/2015; 2015:948723. DOI:10.1155/2015/948723. 8 5. Myasthenia gravis and neuromyelitis optica spectrum disorder: a multicenter study of 16 patients. Maria Isabel Leite, Ester Coutinho, Marco Lana-Peixoto, Samira Apostolos, Patrick Waters, Douglas Sato, Luciana Melamud, Monica Marta, Andrew Graham, Jennifer Spillane, Andres Villa, Dagoberto Callegaro, Ernestina Santos, Ana Martins da Silva, Sven Jarius, Robin Howard, Ichiro Nakashima, Gavin Giovannoni, Camilla Buckley, David Hilton-Jones, Angela Vincent, Jacqueline Palace. Neurology. 2012 May 15;78(20):1601-7. 6. Myasthenia gravis and pregnancy: anaesthetic management - a series of cases. Carlos Almeida, Ester Coutinho, Daniela Moreira, Ernestina Santos, Jose Aguiar. European Journal of Anaesthesiology. 2010 Nov; 27(11):985-90. 9 Abbreviations AChE - acetylcholinesterase AChR - acetylcholine receptor AChR Ab– MG – antibody negative acetylcholine receptor myasthenia gravis AChR-MG – antibody-positive acetylcholine receptor myasthenia gravis AID- autoimmune disease AIRE - autoimmune regulatory gene APECED - autoimmune polyendocrinopathy, chronic mucocutaneous candidiasis and ectodermal dystrophy ATD - autoimmune
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