Contemporary treatment of myasthenia gravis

Authors

Keywords:

myasthenia gravis

Abstract

Idiopathic autoimmune myasthenia is the most common disease of neuromuscular synapses. The pathogenesis is autoimmune, associated with the occurrence of antigenic targets in nicotinic acetylcholine receptors (AChR) and related proteins, on postsynaptic membranes. It is caused by antibodies against neuromuscular synapse components and impaired neuromuscular transmission.
Clinically, it presents with fluctuating muscle weakness. Treatment depends on age, thymus pathology, presence and type of antibodies, form and activity of disease. It is subdivided into symptomatic treatment, which facilitates neuromuscular transmission, and diseasemodifying treatment, which targets the underlying pathological immune response. Symptomatic treatment is the first choice for most patients. It is conducted with acetylcholinesterase inhibitors, which reversibly block the acetylcholinesterase enzyme and slow the hydrolysis of acetylcholine. Immunomodulatory (disease course modifying) therapy is used to suppress immune-mediated destruction of acetylcholine receptors and postsynaptic membrane architecture. Corticosteroids and classical immunosuppressants (primarily azathioprine) are the drugs of first choice for immunosuppression in patients with active generalized or ocular myasthenia. They are used when the effect of anticholinesterase agents alone or in combination with thymectomy is unsatisfactory. Refractory to standard treatment are 10% of patients. Monoclonal antibodies targeting the immune system have advantages over conventional immunosuppressive treatment in terms of faster onset of action, favorable side-effect profile and the potential for durable and long-term remission. Some of the drugs currently being investigated include C5 terminal complement inhibitors, Fc receptor inhibitors, B cell depleting agents (anti-CD19 and anti-20 and B cell activating factor inhibitors), proteosome inhibitors, cytokine inactivating monoclonal antibodies, monoclonal antibodies inactivating T cell function and subcutaneous immunoglobulin administration. Thymectomy is mandatory in almost all patients with thymoma, but not during disease exacerbation.
In conclusion, advances in the elucidation of the pathophysiological mechanisms of myasthenia have led to new classes of drugs modifying the course of the disease.

References

Milanov, I., Milanova, M. National consensus on the diagnosis and treatment of myasthenia gravis : 2023. Bulgarian Neurology, 24(S1), 1–16. [Миланов, И., Миланова, М. Национален консенсус за диагностика и лечение на myasthenia gravis. Българска неврология, 2023, 24, Suppl. 1, 16 стр.] https://www.nevrologiabg.com/journal/index.php/neurology/article/view/119

Alhaidar, M.K., Abumurad, S., Soliven, B., Rezania, K. Current treatment of myasthenia gravis. J. Clin. Med., 2022, 11, 1597.

Bhandari, V., Bril, V. FcRN receptor antagonists in the management of myasthenia gravis. Front. Neurol., 2023, 14.

Bril, V., Drużdż, A., Grosskreutz, J., Habib, A.A., Mantegazza, R., Sacconi, S., Utsugisawa, K., Vissing, J., Vu, T., Boehnlein, M., Bozorg, A., Gayfieva, M., Greve, B., Woltering, F., Kaminski, H.J., on behalf of the MG0003 study team. Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study. Lancet Neurol., 2023, 22, 383-394.

Cavalcante, P., Mantegazza, R., Antozzi, C. Targeting autoimmune mechanisms by precision medicine in Myasthenia Gravis. Front. Immunol., 2024.

DeHart-McCoyle, M., Patel, S., Du, X. New and emerging treatments for myasthenia gravis. BMJ Med., 2023, 2, e000241.

Dresser, L., Wlodarski, R., Rezania, K., Soliven, B. Myasthenia gravis: epidemiology, pathophysiology and clinical manifestations. Clin. Med., 2021, 10, 2235.

Dziadkowiak, E., Baczynska, D., Waliszewska-Prosół, M. MuSK myasthenia gravis-potential pathomechanisms and treatment directed against specific targets. Cells, 2024,13, 556.

Evoli, A., Antonini, G., Antozzi, C., DiMuzio, A., Habetswallner, F., Iani, C., Inghilleri, M., Liguori, R., Mantegazza, R., Massa, R., Pegoraro, E., Ricciardi, R., Rodolico, C. Italian recommendations for the diagnosis and treatment of myasthenia gravis. Neurol. Sci., 2019, 40, 6, 1111-1124.

Gilhus, N.E. Myasthenia Gravis. N. Engl. J. Med., 2016, 375, 2570-2581.

Gilhus, N.E., Tzartos, S., Evoli, A., Palace, J., Burns, T.M., Verschuuren, J.J.G.M. Myasthenia gravis. Nat. Rev. Dis. Primers, 2019, 5, 1, 30.

Golfinopoulou, R., Giudicelli, V., Manso, T., Kossida, S. Delving into molecular pathways: analyzing the mechanisms of action of monoclonal antibodies integrated in IMGT/mAb-DB for myasthenia gravis. Vaccines, 2023, 11, 1756.

Howard, J.F.Jr, Bresch, S., Genge, A., C., Hewamadduma, J., Hinton, Y., Hussain, R., Juntas-Morales, H.J., Kaminski, A., Maniaol, R., Mantegazza, Masuda, M., Sivakumar, K., Śmiłowski, M., Utsugisawa, K., Vu, T., Weiss, M.D., Zajda, M., Boroojerdi, B., Brock, M., de la Borderie, G., Duda, P.W., Lowcock, R., Vanderkelen, M., Leite, M.I., RAISE Study Team. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Neurol., 2023, 22, 395-406.

Howard, J.F.Jr., Bril, V., Burns, T.M., Mantegazza, R., Bilinska, M., Szczudlik, A., Beydoun, S., Garrido, F.J.R.D.R., Piehl, F., Rottoli, M., Van Damme, P., Vu, T., Evoli, A., Freimer, M., Mozaffar, T., Ward, E.S., Dreier, T., Ulrichts, P., Verschueren, K., Guglietta, A., de Haard, H., Leupin, N., Verschuuren, J.J.G.M., Efgartigimod MG Study Group. Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. Neurology, 2019, 92, e2661-e2673.

Howard, J.F.Jr, Bril, V., Vu, T., Karam, C., Peric, S., Margania, T., Murai, H., Bilinska, M., Shakarishvili, R., Smilowski, M., Guglietta, A., Ulrichts, P., Vangeneugden, T., Utsugisawa, K., Verschuuren, J., Mantegazza, R., the ADAPT Investigator Study Group. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol., 2021, 20, 526-536.

Howard, J.F.Jr., Bril, V., Vu, T., Karam, C., Peric, S., De Bleecker, J.L., Murai, H., Meisel, A., Beydoun, S.R., Pasnoor, M., Guglietta, A., Van Hoorick, B., Steeland, S., Tjoen, C., Utsugisawa, K., Verschuuren, J., Mantegazza, R., on behalf of the ADAPT+ Study Group. Long-term safety, tolerability, and efficacy of efgartigimod (ADAPT+): interim results from a phase 3 open-label extension study in participants with generalized myasthenia gravis. Front. Neurol., 2023, 14.

Howard, J.F.Jr., Utsugisawa, K., Benatar, M., Murai, H., Barohn, R.J., Illa, I., Jacob, S., Vissing, J., Burns, T.M., Kissel, J.T., Muppidi, S., Nowak, R.J., O'Brien, F., Wang, J.J., Mantegazza, R., REGAIN Study Group. 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., 2017, 16, 976-986.

Iorio, R., Damato, V., Alboini, P.E., Evoli, A. Efficacy and safety of rituximab for myasthenia gravis: a systematic review and metaanalysis. J. Neurol., 2015, 262, 1115-1119.

Karam, J.F.H.C.Jr., Yountz, M., O’Brien, F.L., Mozaffar, T., for the REGAIN Study Group. Long-term efficacy of eculizumab in refractory generalized myasthenia gravis: Responder analyses. Ann. Clin. Transl. Neurol., 2021, 8, 1398-1407.

Kerty, E., Elsais, A., Argov, Z., Evoli, A., Gilhus, N.E. EFNS/ENS Guidelines for the treatment of ocular myasthenia. Eur. J. Neurol., 2014, 21, 5, 687-693.

Koneczny, I., Herbst, R. Myasthenia gravis: Pathogenic effects of autoantibodies on neuromuscular architecture. Cells, 2019, 8, 671.

Masi, G., O’Connor, K.C. Novel pathophysiological insights in autoimmune myasthenia gravis. Curr. Opin. Neurol., 2022, 35, 5, 586-596.

Melzer, N., Ruck, T., Fuhr, P., Gold, R., Hohlfeld, R., Marx, A., Zimprich, F., Meuth, S.G., Wiendl, H. Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society. J. Neurol., 2016, 263, 8, 1473-1494.

Narayanaswami, P., Sanders, D.B., Wolfe, G., Benatar, M., Cea, G., Evoli, A., Gilhus, N.E., Illa, I., Kuntz, N.L., Massey, J., Melms, A., Murai, H., Nicolle, M., Palace, J., Richman, D., Verschuuren, J. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology, 2021, 19, 96, 3, 114-122.

Pyzik, M., Sand, K.M.K., Hubbard, J.J., Andersen, J.T., Sandlie, I., Blumberg, R.S. The neonatal Fc receptor (FcRn): A Misnomer? Front. Immunol., 2019, 10, 1540.

Saccà, F., Pane, C., Espinosa, P.E., Sormani, M.P. Efficacy of innovative therapies in myasthenia gravis: A systematic review, meta-analysis and network meta-analysis. Eur. J. Neurol., 2023, 30, 3854-3867.

Saccà, F., Salort-Campana, E., Jacob, S., Cortés-Vicente, E., Schneider-Gold, C. Refocusing generalized myasthenia gravis: Patient burden, disease profiles, and the role of evolving therapy. Eur. J. Neurol. 2023, e16180.

San, P.P., Jacob, S. Role of complement in myasthenia gravis. Front. Neurol., 14, 1277596.

Sanders, D.B., Wolfe, G.I., Benatar, M., Evoli, A., Gilhus, N.E., Illa, I., Kuntz, N., Massey, J.M., Melms, A., Murai, H., Nicolle, M., Palace, J., Richman, D.P., Verschuuren, J., Narayanaswami, P. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology, 2016, 87, 4, 419-425.

Skeie, G.O., Apostolski, S., Evoli, A., Gilhus, N.E., Illa, I., Harms, L., Hilton-Jones, D., Melms, A., Verschuuren, J., Horge, H.W. European Federation of Neurological Societies. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur. J. Neurol., 2010, 17, 7, 893-902.

Stetefeld, H., Schroeter, M. SOP myasthenic crisis. Neurol. Res. Pract., 2019, 19, 1.

Sussman, J., Farrugia, M.E., Maddison, P., Hill, M., Leite, M.I., Hilton-Jones, D. Myasthenia gravis: Association of British Neurologists' management guidelines. Pract. Neurol., 2015, 15, 3, 199-206.

Tandan, R., Hehir II, M.K., Waheed, W., Howard, D.B. Rituximab treatment of myasthenia gravis: a systematic review. Muscle Nerve, 2017, 56, 185-196.

Thapa, B., Mahendraker, N., Ramphul, K. Paraneoplastic syndromes. StatPearls, 2023.

Topakian, R., Zimprich, F., Iglseder, S., Embacher, N., Guger, M., Stieglbauer, K., Langenscheidt, D., Rath, J., Quasthoff, S., Simschitz, P., Wanschitz, J., Windisch, D., Müller, P., Oel, D., Schustereder, G., Einsiedler, S., Eggers, C., Löscher, W. High efficacy of rituximab for myasthenia gravis: A comprehensive nationwide study in Austria. J. Neurol., 2019, 266, 699-706.

Waheed, W., Bacopulos, A., Seyam, M., Kooperkamp, H., Moin, M., Malik, T., Tandan, R. Physiological and pathological roles of the thymus and value of thymectomy in myasthenia gravis: a narrative review. Mediastinum, 2024, 8, 31.

Wiendl, H., Abicht, A., Chan, A., Marina, A.D., Hagenacker, T., Hekmat, K., Hoffmann, S., Hoffmann, H.S., Jander, S., Keller, C., Marx, A., Melms, A., Melzer, N., Müller-Felber, W., Pawlitzki, M., Rückert, J.C., Schneider-Gold, C., Schoser, B., Schreiner, B., Schroeter, M., Schubert, B., Sieb, J.P., Zimprich, F., Meisel, A. Guideline for the management of myasthenic syndromes. Ther. Adv. Neurol. Disord., 2023, 16, 1-31.

Published

30.11.2024

How to Cite

Milanov, I. (2024). Contemporary treatment of myasthenia gravis. Bulgarian Neurology, 25(2), 43–51. Retrieved from https://www.nevrologiabg.com/journal/index.php/neurology/article/view/171

ARK