Heterogeneity in myasthenia gravis: considerations for disease management

References

• Compston DA, Vincent A, Newsom-Davis J, et al. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain. 1980;103:579–601.
   PubMed Web of Science ®Google Scholar
• Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009;8:475–490.
   PubMed Web of Science ®Google Scholar
• Berrih-Aknin S, Frenkian-Cuvelier M, Eymard B. Diagnostic and clinical classification of autoimmune myasthenia gravis. J Autoimmun. 2014;48-49:143–148.
   PubMed Web of Science ®Google Scholar
• Gilhus NE, Tzartos S, Evoli A, et al. Myasthenia gravis. Nat Rev Dis Primers. 2019;5:30.
   PubMed Web of Science ®Google Scholar
• Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015;14:1023–1036.
   PubMed Web of Science ®Google Scholar
• Marx A, Pfister F, Schalke B, et al. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev. 2013;12:875–884.
   PubMed Web of Science ®Google Scholar
• Renton AE, Pliner HA, Provenzano C, et al. A genome-wide association study of myasthenia gravis. JAMA Neurol. 2015;72:396–404.
   PubMed Web of Science ®Google Scholar
• Koneczny I, Herbst R. Myasthenia gravis: pathogenic effects of autoantibodies on neuromuscular architecture. Cells. 2019;8:671.
   PubMed Web of Science ®Google Scholar
• Miyazawa A, Fujiyoshi Y, Unwin N. Structure and gating mechanism of the acetylcholine receptor pore. Nature. 2003;423:949–955.
   PubMed Web of Science ®Google Scholar
• Friese MB, Blagden CS, Burden SJ. Synaptic differentiation is defective in mice lacking acetylcholine receptor beta-subunit tyrosine phosphorylation. Development. 2007;134:4167–4176.
   PubMed Web of Science ®Google Scholar
• Phillips WD, Vincent A. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Res. 2016;5:F1000 Faculty Rev–1513.
   Google Scholar
• Luo J, Taylor P, Losen M, et al. Main immunogenic region structure promotes binding of conformation-dependent myasthenia gravis autoantibodies, nicotinic acetylcholine receptor conformation maturation, and agonist sensitivity. J Neurosci. 2009;29:13898–13908.
   PubMed Web of Science ®Google Scholar
• Masuda T, Motomura M, Utsugisawa K, et al. Antibodies against the main immunogenic region of the acetylcholine receptor correlate with disease severity in myasthenia gravis. J Neurol Neurosurg Psychiatry. 2012;83:935–940.
   PubMed Web of Science ®Google Scholar
• Huijbers MG, Lipka AF, Plomp JJ, et al. Pathogenic immune mechanisms at the neuromuscular synapse: the role of specific antibody-binding epitopes in myasthenia gravis. J Intern Med. 2014;275:12–26.
   PubMed Web of Science ®Google Scholar
• Luo J, Lindstrom J. Acetylcholine receptor-specific immunosuppressive therapy of experimental autoimmune myasthenia gravis and myasthenia gravis. Ann N Y Acad Sci. 2018;1413:76–81.
   PubMed Web of Science ®Google Scholar
• Cao Y, Amezquita RA, Kleinstein SH, et al. Autoreactive T cells from patients with myasthenia gravis are characterized by elevated IL-17, IFN-γ, and GM-CSF and diminished IL-10 production. J Immunol. 2016;196:2075–2084.
   PubMed Web of Science ®Google Scholar
• Kohler S, Keil TOP, Hoffmann S, et al. CD4(+) FoxP3(+) T regulatory cell subsets in myasthenia gravis patients. Clin Immunol. 2017;179:40–46.
   PubMed Web of Science ®Google Scholar
• Villegas JD, Van Wassenhove J, Le Panse R, et al. An imbalance between regulatory T cells and T helper 17 cells in acetylcholine receptor-positive myasthenia gravis patients. Ann N Y Acad Sci. 2018;1413:154–162.
   PubMed Web of Science ®Google Scholar
• Luo C, Li Y, Liu W, et al. Expansion of circulating counterparts of follicular helper T cells in patients with myasthenia gravis. J Neuroimmunol. 2013;256:55–61.
   PubMed Web of Science ®Google Scholar
• Zhang CJ, Gong Y, Zhu W, et al. Augmentation of circulating follicular helper T cells and their impact on autoreactive B cells in myasthenia gravis. J Immunol. 2016;197:2610–2617.
   PubMed Web of Science ®Google Scholar
• Wen Y, Yang B, Lu J, et al. Imbalance of circulating CD4(+)CXCR5(+) FOXP3(+) Tfr-like cells and CD4(+)CXCR5(+) FOXP3(-) Tfh-like cells in myasthenia gravis. Neurosci Lett. 2016;630:176–182.
   PubMed Web of Science ®Google Scholar
• Sheng JR, Rezania K, Soliven B. Impaired regulatory B cells in myasthenia gravis. J Neuroimmunol. 2016;297:38–45.
   PubMed Web of Science ®Google Scholar
• Yilmaz V, Maillard S, Truffault F, et al. Regulatory B cells in myasthenia gravis are differentially affected by therapies. Ann Clin Transl Neurol. 2018;5:1408–1414.
   PubMed Web of Science ®Google Scholar
• Levinson AI, Zheng Y, Gaulton G, et al. Intrathymic expression of neuromuscular acetylcholine receptors and the immunpathogenesis of myasthenia gravis. Immunol Res. 2003;27:399–408.
   PubMed Web of Science ®Google Scholar
• Berrih-Aknin S. Role of the thymus in autoimmune myasthenia gravis. Clin Exp Neuroimmunol. 2016;7:226–237.
   Google Scholar
• Marx A, Yamada Y, Simon-Keller K, et al. Thymus and autoimmunity. Semin Immunopathol. 2021;43:45–64.
   PubMed Web of Science ®Google Scholar
• Myking AO, Skeie GO, Varhaug JE, et al. The histomorphology of the thymus in late onset, non‐thymoma myasthenia gravis. Eur J Neurol. 1998;5:401–405.
   Web of Science ®Google Scholar
• Strobel P, Moritz R, Leite MI, et al. The ageing and myasthenic thymus: a morphometric study validating a standard procedure in the histological workup of thymic specimens. J Neuroimmunol. 2008;201-202:64–73.
   PubMed Web of Science ®Google Scholar
• Blum TG, Misch D, Kollmeier J, et al. Autoimmune disorders and paraneoplastic syndromes in thymoma. J Thorac Dis. 2020;12:7571–7590.
   PubMed Web of Science ®Google Scholar
• Romi F, Bø L, Skeie GO, et al. Titin and ryanodine receptor epitopes are expressed in cortical thymoma along with costimulatory molecules. J Neuroimmunol. 2002;128:82–89.
   PubMed Web of Science ®Google Scholar
• Weksler B, Lu B. Alterations of the immune system in thymic malignancies. J Thorac Oncol. 2014;9:137–142.
   PubMed Web of Science ®Google Scholar
• Skeie GO, Aarli JA, Gilhus NE. Titin and ryanodine receptor antibodies in myasthenia gravis. Acta Neurol Scand. 2006;183:19–23.
   Google Scholar
• Suzuki S, Satoh T, Yasuoka H, et al. Novel autoantibodies to a voltage-gated potassium channel Kv1.4 in a severe form of myasthenia gravis. J Neuroimmunol. 2005;170:141–149.
   PubMed Web of Science ®Google Scholar
• Romi F, Aarli JA, Gilhus NE. Myasthenia gravis patients with ryanodine receptor antibodies have distinctive clinical features. Eur J Neurol. 2007;14:617–620.
   PubMed Web of Science ®Google Scholar
• Suzuki S, Nishimoto T, Kohno M, et al. Clinical and immunological predictors of prognosis for Japanese patients with thymoma-associated myasthenia gravis. J Neuroimmunol. 2013;258:61–66.
   PubMed Web of Science ®Google Scholar
• Szczudlik P, Szyluk B, Lipowska M, et al. Antititin antibody in early- and late-onset myasthenia gravis. Acta Neurol Scand. 2014;130:229–233.
   PubMed Web of Science ®Google Scholar
• Choi Decroos E, Hobson-Webb LD, Juel VC, et al. Do acetylcholine receptor and striated muscle antibodies predict the presence of thymoma in patients with myasthenia gravis? Muscle Nerve. 2014;49:30–34.
   PubMed Web of Science ®Google Scholar
• Wong SH, Huda S, Vincent A, et al. Ocular myasthenia gravis: controversies and updates. Curr Neurol Neurosci Rep. 2014;14:421.
   PubMed Web of Science ®Google Scholar
• Li Y, Peng Y, Yang H. Serological diagnosis of myasthenia gravis and its clinical significance. Ann Transl Med. 2019. DOI:https://doi.org/10.21037/atm.2019.07.86
   Google Scholar
• Chan KH, Lachance DH, Harper CM, et al. Frequency of seronegativity in adult-acquired generalized myasthenia gravis. Muscle Nerve. 2007;36:651–658.
   PubMed Web of Science ®Google Scholar
• Cortés-Vicente E, Álvarez-Velasco R, Segovia S, et al. Clinical and therapeutic features of myasthenia gravis in adults based on age at onset. Neurology. 2020;94:e1171–80.
   PubMed Web of Science ®Google Scholar
• Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol. 2012;8:427–438.
   PubMed Web of Science ®Google Scholar
• Devic P, Petiot P, Simonet T, et al. Antibodies to clustered acetylcholine receptor: expanding the phenotype. Eur J Neurol. 2014;21:130–134.
   PubMed Web of Science ®Google Scholar
• Zhao G, Wang X, Yu X, et al. Clinical application of clustered-AChR for the detection of SNMG. Sci Rep. 2015;5:10193.
   PubMed Web of Science ®Google Scholar
• Rodriguez Cruz PM, Al-Hajjar M, Huda S, et al. Clinical features and diagnostic usefulness of antibodies to clustered acetylcholine receptors in the diagnosis of seronegative myasthenia gravis. JAMA Neurol. 2015;72:642–649.
   PubMed Web of Science ®Google Scholar
• Jacob S, Viegas S, Leite MI, et al. Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis. Arch Neurol. 2012;69:994–1001.
   PubMedGoogle Scholar
• Rodríguez Cruz PM, Cossins J, Beeson D, et al. The neuromuscular junction in health and disease: molecular mechanisms governing synaptic formation and homeostasis. Front Mol Neurosci. 2020;13:610964.
   PubMed Web of Science ®Google Scholar
• Cartaud A, Strochlic L, Guerra M, et al. MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. J Cell Biol. 2004;165:505–515.
   PubMed Web of Science ®Google Scholar
• Yumoto N, Kim N, Burden SJ. Lrp4 is a retrograde signal for presynaptic differentiation at neuromuscular synapses. Nature. 2012;489:438–442.
   PubMed Web of Science ®Google Scholar
• Zong Y, Jin R. Structural mechanisms of the agrin–LRP4–MuSK signaling pathway in neuromuscular junction differentiation. Cell Mol Life Sci. 2013;70:3077–3088.
   PubMed Web of Science ®Google Scholar
• Zhang W, Coldefy AS, Hubbard SR, et al. Agrin binds to the N-terminal region of Lrp4 protein and stimulates association between Lrp4 and the first immunoglobulin-like domain in muscle-specific kinase (MuSK). J Biol Chem. 2011;286:40624–40630.
   PubMed Web of Science ®Google Scholar
• Takamori M. Myasthenia gravis: from the viewpoint of pathogenicity focusing on acetylcholine receptor clustering, trans-synaptic homeostasis and synaptic stability. Front Mol Neurosci. 2020;13:86.
   PubMed Web of Science ®Google Scholar
• Herbst R, Burden SJ. The juxtamembrane region of MuSK has a critical role in agrin-mediated signaling. EMBO J. 2000;19:67–77.
   PubMed Web of Science ®Google Scholar
• Till JH, Becerra M, Watty A, et al. Crystal structure of the MuSK tyrosine kinase: insights into receptor autoregulation. Structure. 2002;10:1187–1196.
   PubMed Web of Science ®Google Scholar
• McConville J, Farrugia ME, Beeson D, et al. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol. 2004;55:580–584.
   PubMed Web of Science ®Google Scholar
• Huijbers MG, Zhang W, Klooster R, et al. MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proc Natl Acad Sci U S A. 2013;110:20783–20788.
   PubMed Web of Science ®Google Scholar
• Koneczny I, Stevens JAA, De Rosa A, et al. IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients. J Autoimmun. 2017;77:104–115.
   PubMed Web of Science ®Google Scholar
• Huijbers MG, Vergoossen DL, Fillié-Grijpma YE, et al. MuSK myasthenia gravis monoclonal antibodies: valency dictates pathogenicity. Neurol Neuroimmunol Neuroinflamm. 2019;6:e547.
   PubMed Web of Science ®Google Scholar
• Huijbers MG, Vink AF, Niks EH, et al. Longitudinal epitope mapping in MuSK myasthenia gravis: implications for disease severity. J Neuroimmunol. 2016;291:82–88.
   PubMed Web of Science ®Google Scholar
• Ohta K, Shigemoto K, Fujinami A, et al. Clinical and experimental features of MuSK antibody positive MG in Japan. Eur J Neurol. 2007;14:1029–1034.
   PubMed Web of Science ®Google Scholar
• Kawakami Y, Ito M, Hirayama M, et al. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology. 2011;77:1819–1826.
   PubMed Web of Science ®Google Scholar
• Yi JS, Guidon A, Sparks S, et al. Characterization of CD4 and CD8 T cell responses in MuSK myasthenia gravis. J Autoimmun. 2014;52:130–138.
   PubMed Web of Science ®Google Scholar
• Li Y, Guptill JT, Russo MA, et al. Imbalance in T follicular helper cells producing IL-17 promotes pro-inflammatory responses in MuSK antibody positive myasthenia gravis. J Neuroimmunol. 2020;345:577279.
   PubMed Web of Science ®Google Scholar
• Guptill JT, Yi JS, Sanders DB, et al. Characterization of B cells in muscle-specific kinase antibody myasthenia gravis. Neurol Neuroimmunol Neuroinflamm. 2015;2:e77.
   PubMed Web of Science ®Google Scholar
• Lauriola L, Ranelletti F, Maggiano N, et al. Thymus changes in anti-MuSK-positive and -negative myasthenia gravis. Neurology. 2005;64:536–538.
   PubMed Web of Science ®Google Scholar
• Leite MI, Ströbel P, Jones M, et al. Fewer Thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol. 2005;57:444–448.
   PubMed Web of Science ®Google Scholar
• Saka E, Topcuoglu MA, Akkaya B, et al. Thymus changes in anti-MuSK-positive and -negative myasthenia gravis. Neurology. 2005;65:782–783.
   PubMed Web of Science ®Google Scholar
• Evoli A, Bianchi MR, Riso R, et al. Response to therapy in myasthenia gravis with anti-MuSK antibodies. Ann N Y Acad Sci. 2008;1132:76–83.
   PubMed Web of Science ®Google Scholar
• Lavrnic D, Losen M, Vujic A, et al. The features of myasthenia gravis with autoantibodies to MuSK. J Neurol Neurosurg Psychiatry. 2005;76:1099–1102.
   PubMed Web of Science ®Google Scholar
• Deymeer F. Myasthenia gravis: muSK-MG, late-onset MG and ocular MG. Acta Myologica. 2020;39:345–352.
   PubMedGoogle Scholar
• Zouvelou V, Psimenou E. AChR-and MuSK-positive myasthenia gravis: double trouble. J Neuroimmunol. 2020;348:577364.
   PubMed Web of Science ®Google Scholar
• Huda S, Waters P, Woodhall M, et al. IgG-specific cell-based assay detects potentially pathogenic MuSK-Abs in seronegative MG. Neurol Neuroimmunol Neuroinflammation. 2017;4:e357.
   PubMed Web of Science ®Google Scholar
• Tsonis AI, Zisimopoulou P, Lazaridis K, et al. MuSK autoantibodies myasthenia gravis detected by cell based assay - A multinational study. J Neuroimmunol. 2015;284:10–17.
   PubMed Web of Science ®Google Scholar
• Park KH, Waters P, Woodhall M, et al. Myasthenia gravis seronegative for acetylcholine receptor antibodies in South Korea: autoantibody profiles and clinical features. PLoS ONE. 2018;13:e0193723.
   PubMed Web of Science ®Google Scholar
• Higuchi O, Hamuro J, Motomura M, et al. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol. 2011;69:418–422.
   PubMed Web of Science ®Google Scholar
• Pevzner A, Schoser B, Peters K, et al. Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol. 2012;259:427–435.
   PubMed Web of Science ®Google Scholar
• Zhang B, Tzartos JS, Belimezi M, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol. 2012;69:445–451.
   PubMed Web of Science ®Google Scholar
• Zisimopoulou P, Evangelakou P, Tzartos J, et al. A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J Autoimmun. 2014;52:139–145.
   PubMed Web of Science ®Google Scholar
• Marino M, Scuderi F, Samengo D, et al. Flow cytofluorimetric analysis of anti-LRP4 (LDL receptor-related protein 4) autoantibodies in Italian patients with myasthenia gravis. PLoS One. 2015;10:e0135378.
   PubMed Web of Science ®Google Scholar
• Bacchi S, Kramer P, Chalk C. Autoantibodies to low-density lipoprotein receptor-related protein 4 in double seronegative myasthenia gravis: a systematic review. Can J Neurol Sci. 2018;45:62–67.
   PubMed Web of Science ®Google Scholar
• Beck G, Yabumoto T, Baba K, et al. Double seronegative myasthenia gravis with anti-LRP4 antibodies presenting with dropped head and acute respiratory insufficiency. Intern Med. 2016;55:3361–3363.
   PubMed Web of Science ®Google Scholar
• Koneczny I, Rennspiess D, Marcuse F, et al. Characterization of the thymus in Lrp4 myasthenia gravis: four cases. Autoimmun Rev. 2019;18:50–55.
   PubMed Web of Science ®Google Scholar
• Aoki S, Nagashima K, Furuta M, et al. Anti-LRP4 antibody-associated myasthenia gravis with a rare complication of thymoma successfully treated by thymectomy. Intern Med. 2020;59:1219–1222.
   PubMed Web of Science ®Google Scholar
• Cossins J, Belaya K, Zoltowska K, et al. The search for new antigenic targets in myasthenia gravis. Ann N Y Acad Sci. 2012;1275:123–128.
   PubMed Web of Science ®Google Scholar
• Zhang B, Shen C, Bealmear B, et al. Autoantibodies to agrin in myasthenia gravis patients. PLoS One. 2014;9:e91816.
   PubMed Web of Science ®Google Scholar
• Rivner MH, Quarles BM, Pan JX, et al. Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: a multicenter study. Muscle Nerve. 2020;62:333–343.
   PubMed Web of Science ®Google Scholar
• Shen C, Lu Y, Zhang B, et al. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J Clin Investig. 2013;123:5190–5202.
   PubMed Web of Science ®Google Scholar
• Yan M, Liu Z, Fei E, et al. Induction of anti-agrin antibodies causes myasthenia gravis in mice. Neuroscience. 2018;373:113–121.
   PubMed Web of Science ®Google Scholar
• Rivner MH, Liu S, Quarles B, et al. Agrin and low-density lipoprotein-related receptor protein 4 antibodies in amyotrophic lateral sclerosis patients. Muscle Nerve. 2017;55:430–432.
   PubMed Web of Science ®Google Scholar
• Farrugia ME, Goodfellow JA. A practical approach to managing patients with myasthenia gravis-Opinions and a review of the literature. Front Neurol. 2020;11:604.
   PubMed Web of Science ®Google Scholar
• Morren J, Li Y. Maintenance immunosuppression in myasthenia gravis, an update. J Neurol Sci. 2020;410:116648.
   PubMed Web of Science ®Google Scholar
• Dalakas MC. Progress in the therapy of myasthenia gravis: getting closer to effective targeted immunotherapies. Curr Opin Neurol. 2020;33:545–552.
   PubMed Web of Science ®Google Scholar
• Keesey JC. Clinical evaluation and management of MG. Muscle Nerve. 2004;29:484–505.
   PubMed Web of Science ®Google Scholar
• Zouvelou V, Zisimopoulou P, Rentzos M, et al. Double seronegative myasthenia gravis with anti-LRP4 antibodies. Neuromuscul Disord. 2013;23:568–570.
   PubMed Web of Science ®Google Scholar
• Morsch M, Reddel SW, Ghazanfari N, et al. Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody. J Physiol. 2013;591:2747–2762.
   PubMed Web of Science ®Google Scholar
• Ghazanfari N, Morsch M, Tse N, et al. Effects of the β2-adrenoceptor agonist, albuterol, in a mouse model of anti-MuSK myasthenia gravis. PLoS ONE. 2014;9:e87840.
   PubMed Web of Science ®Google Scholar
• Evoli A, Alboini PE, Damato V, et al. 3,4-Diaminopyridine may improve myasthenia gravis with MuSK antibodies. Neurology. 2016;86:1070–1071.
   PubMed Web of Science ®Google Scholar
• Karam C, Dimitrova D. Lack of benefit from 3,4-Diaminopyridine in MuSK+ MG. Muscle Nerve. 2018;58:E33–4.
   PubMed Web of Science ®Google Scholar
• Haran M, Schattner A, Mate A, et al. Can a rare form of myasthenia gravis shed additional light on disease mechanisms? Clin Neurol Neurosurg. 2013;115:562–566.
   PubMed Web of Science ®Google Scholar
• Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375:511–522.
   PubMed Web of Science ®Google Scholar
• Wolfe GI, Kaminski HJ, Aban IB, et al. Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomized trial. Lancet Neurol. 2019;18:259–268.
   PubMed Web of Science ®Google Scholar
• Lee I, Kuo HC, Aban IB, et al. Minimal manifestation status and prednisone withdrawal in the MGTX trial. Neurology. 2020;95:e755–66.
   PubMed Web of Science ®Google Scholar
• Aarli JA, Romi F, Skeie GO, et al. Myasthenia gravis in individuals over 40. Ann N Y Acad Sci. 2003;998:424–431.
   PubMed Web of Science ®Google Scholar
• Uzawa A, Kawaguchi N, Kanai T, et al. Two-year outcome of thymectomy in non-thymomatous late-onset myasthenia gravis. J Neurol. 2015;262:1019–1023.
   PubMed Web of Science ®Google Scholar
• Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;296:114–122.
   Google Scholar
• Clifford KM, Hobson-Webb LD, Benatar M, et al. Thymectomy may not be associated with clinical improvement in MuSK myasthenia gravis. Muscle Nerve. 2019;59:404–410.
   PubMed Web of Science ®Google Scholar
• Sanders DB, Evoli A. Immunosuppressive therapies in myasthenia gravis. Autoimmunity. 2010;43:428–435.
   PubMed Web of Science ®Google Scholar
• Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016;87:419–425.
   PubMed Web of Science ®Google Scholar
• Utsugisawa K, Suzuki S, Nagane Y, et al. Health-related quality-of-life and treatment targets in myasthenia gravis. Muscle Nerve. 2014;50:493–500.
   PubMed Web of Science ®Google Scholar
• Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2012;12:CD002277.
   PubMedGoogle Scholar
• Barth D, Nabavi Nouri M, Ng E, et al. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology. 2011;76:2017–2023.
   PubMed Web of Science ®Google Scholar
• Mittal MK, Barohn RJ, Pasnoor M, et al. Ocular myasthenia gravis in an academic neuro-ophthalmology clinic: clinical features and therapeutic response. J Clin Neuromuscul Dis. 2011;13:46–52.
   PubMedGoogle Scholar
• Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology. 2007;68:837–841.
   PubMed Web of Science ®Google Scholar
• Mantegazza R, Antozzi C. From traditional to targeted immunotherapy in myasthenia gravis. Prospects for research. Front Neurol. 2020;11:981.
   PubMed Web of Science ®Google Scholar
• Schneider-Gold C, Hagenacker T, Melzer N, et al. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019;12:1756286419832242.
   Web of Science ®Google Scholar
• Suh J, Goldstein JM, Nowak RJ. Clinical characteristics of refractory myasthenia gravis patients. Yale J Biol Med. 2013;86:255–260.
   PubMedGoogle Scholar
• De Feo LG, Schottlender J, Martelli NA, et al. Use of intravenous pulsed cyclophosphamide in severe, generalized myasthenia gravis. Muscle Nerve. 2002;26:31–36.
   PubMed Web of Science ®Google Scholar
• Bryant A, Atkins H, Pringle CE, et al. Myasthenia gravis treated with autologous hematopoietic stem cell transplantation. JAMA Neurol. 2016;73:652–658.
   PubMed Web of Science ®Google Scholar
• Lee DSW, Rojas OL, Gommerman JL. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov. 2021;20:179–199.
   PubMed Web of Science ®Google Scholar
• Díaz-Manera J, Martínez-Hernández E, Querol L, et al. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology. 2012;78:189–193.
   PubMed Web of Science ®Google Scholar
• Beecher G, Anderson D, Siddiqi ZA. Rituximab in refractory myasthenia gravis: extended prospective study results. Muscle Nerve. 2018;58:452–455.
   PubMed Web of Science ®Google Scholar
• Topakian R, Zimprich F, Iglseder S, et al. High efficacy of rituximab for myasthenia gravis: a comprehensive nationwide study in Austria. J Neurol. 2019;266:699–706.
   PubMed Web of Science ®Google Scholar
• Iorio R, Damato V, Alboini PE, et al. Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. J Neurol. 2015;262:1115–1119.
   PubMed Web of Science ®Google Scholar
• Tandan R, Hehir MK II, Waheed W, et al. Rituximab treatment of myasthenia gravis: a systematic review. Muscle Nerve. 2017;56:185–196.
   PubMed Web of Science ®Google Scholar
• Stathopoulos P, Kumar A, Nowak RJ, et al. Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis. JCI Insight. 2017;2:94263.
   PubMed Web of Science ®Google Scholar
• Fichtner MJ, Jiang R, Bourke A, et al. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020;11:776.
   PubMed Web of Science ®Google Scholar
• Nowak RJ, Coffey C, Goldstein JM, et al. B cell targeted treatment in myasthenia gravis A phase 2 trial of rituximab in MG: topline results. Presented at the 70th American Academy of Neurology Annual Meeting; 2018; Los Angeles, CA.
   Google Scholar
• Brauner S, Eriksson-Dufva A, Hietala MA, et al. Comparison between rituximab treatment for new-onset generalized myasthenia gravis and refractory generalized myasthenia gravis. JAMA Neurol. 2020;77:974–981.
   PubMed Web of Science ®Google Scholar
• Afanasiev V, Demeret S, Bolgert F, et al. Resistant myasthenia gravis and rituximab: a monocentric retrospective study of 28 patients. Neuromuscul Disord. 2017;27:251–258.
   PubMed Web of Science ®Google Scholar
• Kanth KM, Solorzano GE, Goldman MD. PML in a patient with myasthenia gravis treated with multiple immunosuppressing agents. Neurol Clin Pract. 2016;6:e17–9.
   PubMedGoogle Scholar
• Howard JF Jr. Myasthenia gravis: the role of complement at the neuromuscular junction. Ann N Y Acad Sci. 2018;1412:113–128.
   PubMed Web of Science ®Google Scholar
• Howard JF Jr, Utsugisawa K, Benatar M, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2021;20:526-536.
   Google Scholar
• Jacob S, Murai H, Utsugisawa K, et al. Response to eculizumab in patients with myasthenia gravis recently treated with chronic IVIg: a subgroup analysis of REGAIN and its open-label extension study. Ther Adv Neurol Disord. 2020;13:1756286420911784.
   Web of Science ®Google Scholar
• Mantegazza R, Wolfe GI, Muppidi S, et al. Post-intervention status in patients with refractory myasthenia gravis treated with eculizumab during REGAIN and its open-label extension. Neurology. 2021;96:e610–8.
   PubMed Web of Science ®Google Scholar
• Patel DD, Bussel JB. Neonatal Fc receptor in human immunity: function and role in therapeutic intervention. J Allergy Clin Immunol. 2020;146:467–478.
   PubMed Web of Science ®Google Scholar
• Howard JF Jr, Bril V, Burns TM, et al. Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. Neurology. 2019;92:e2661–73.
   PubMed Web of Science ®Google Scholar
• Bril V, Benatar M, Andersen H, et al. Efficacy and safety of rozanolixizumab in moderate to severe generalized myasthenia gravis: a phase 2 randomized control trial. Neurology. 2021;96:e853–65.
   PubMed Web of Science ®Google Scholar
• Peter -H-H, Ochs HD, Cunningham-Rundles C, et al. Targeting FcRn for immunomodulation: benefits, risks, and practical considerations. J Allergy Clin Immunol. 2020;146:479–491.
   PubMed Web of Science ®Google Scholar
• Consonni A, Sharma S, Shön K, et al. A novel approach to reinstating tolerance in experimental autoimmune myasthenia gravis using a targeted fusion protein, mCTA1-T146. Front Immunol. 2017;8:1133.
   PubMed Web of Science ®Google Scholar