Refractory myasthenia gravis: the more we learn, the less we know.
DOI:
https://doi.org/10.17161/rrnmf.v4i3.19555Keywords:
refractory myasthenia gravis, quality of life, acetylcholine receptor, muscle specific kinase, thymectomy, eculizumab, rituximab, tacrolimus, cyclophosphamideAbstract
Refractory myasthenia gravis identifies the group of patients that have inadequate symptom control and persistent muscle weakness and fatigability despite the use of multiple immune modulatory therapies. This manuscript highlights what is currently known about refractory myasthenia gravis and underlines major knowledge gaps, drawing attention to the unmet needs in our understanding of this disease subset. This review raises questions about our current understanding of refractory disease and how emerging data as well as therapies may alter our thinking and patients’ disease course.
Metrics
Downloads
References
Drachman DB, Adams RN, Hu R, Jones RJ, Brodsky RA. Rebooting the immune system with high-dose cyclophosphamide for treatment of refractory myasthenia gravis. Ann NY Acad Sci. 2008;1132:305–14. DOI: 10.1196/annals.1405.033
Suh J, Goldstein JM, Nowak RJ. Clinical characteristics of refractory myasthenia gravis patients. Yale J Biol Med. 2013;86(2):255–60.
Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016;87(4):419–25. DOI: 10.1212/WNL.0000000000002790
Howard JF, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, 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. 2017;16(12):976–86. DOI: 10.1016/S1474-4422(17)30369-1
Mantegazza R, Antozzi C. When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies. Ther Adv Neurol Disord. 2018;11:1–11. DOI: 10.1177/1756285617749134
Tran C, Biswas A, Mendoza M, Katzberg H, Bril V, Barnett C. Performance of different criteria for refractory myasthenia gravis. Eur J Neurol. 2021;28(4):1375–84. DOI: 10.1111/ene.14675
Heckmann JM, Owen EP, Little F. Myasthenia gravis in South Africans : Racial differences in clinical manifestations. 2007;17:929–34. DOI: 10.1016/j.nmd.2007.07.002
Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo H-C, Marx A, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511–22. DOI: 10.1056/NEJMoa1602489
Zebardast N, Patwa HS, Novella SP, Goldstein JM. Rituximab in the management of refractory myasthenia gravis. Muscle and Nerve. 2010;41(3):375–8. DOI: 10.1002/mus.21521
Anderson D, Phan C, Johnston WS, Siddiqi ZA. Rituximab in refractory myasthenia gravis: a prospective, open-label study with long-term follow-up. Ann Clin Transl Neurol. 2016;3(7):552–5. DOI: 10.1002/acn3.314
Gomez-Figueroa E, Garcia-Trejo S, Bazan-Rodriguez L, Cervantes-Uribe R, Chac-Lezama G, Lopez-Hernandez JC, et al. Intravenous cyclophosphamide monthly pulses in refractory myasthenia gravis. J Neurol. 2020;267(3):674–8. DOI: 10.1007/s00415-019-09622-4
Santos E, Bettencourt A, Duarte S, Gabriel D, Oliveira V, Da Silva AM, et al. Refractory myasthenia gravis: characteristics of a Portugese cohort. Muscle Nerve. 2019;60:188–91. DOI: 10.1002/mus.26507
Cortes-Vicente E, Alvarez-Velasco R, Pla-Junca F, Rojas-Garcia R, Paradas C, Sevilla T, et al. Drug-refractory myasthenia gravis: Clinical characteristics, treatments, and outcome. Ann Clin Transl Neurol. 2021;9(2):122–31. DOI: 10.1002/acn3.51492
Boscoe AN, Xin H, L’Italien GJ, Harris LA, Cutter GR. Impact of refractory myasthenia gravis on health-related quality of life. J Clin Neuromuscul Dis. 2019;20(4):173–81. DOI: 10.1097/CND.0000000000000257
Gelinas D, Parvin-Nejad S, Phillips G, Cole C, Hughes T, Silvestri N, et al. The humanistic burden of myasthenia gravis: A systematic literature review. J Neurol Sci. 2022;437:120268. DOI: 10.1016/j.jns.2022.120268
Ruiter AM, Verschuuren JJGM, Tannemaat MR. Fatigue in patients with myasthenia gravis . A systematic review of the literature. 2020;30:631–9. DOI: 10.1016/j.nmd.2020.06.010
Tran C, Bril V, Katzberg HD, Barnett C. Fatigue is a relevant outcome in patients with myasthenia gravis. Muscle Nerve. 2018;58:197–203. DOI: 10.1002/mus.26069
Nadali J, Ghavampour N, Beiranvand F, Takhtegahi MM, Heidari ME, Salarvand S, et al. Prevalence of depression and anxiety among myasthenia gravis (MG) patients : A systematic review and meta-analysis. 2023;(November 2022):1–12. DOI: 10.1002/brb3.2840
Andersen H, Mantegazza R, Wang JJ, O’Brien F, Patra K, Howard JF, et al. Eculizumab improves fatigue in refractory generalized myasthenia gravis. Qual Life Res. 2019;28(8):2247–54. DOI: 10.1007/s11136-019-02148-2
Xin H, Harris LA, Aban IB, Cutter G. Examining the impact of refractory myasthenia gravis on healthcare resource utilization in the United States: Analysis of a Myasthenia Gravis Foundation of America patient registry sample. J Clin Neurol. 2019;15(3):376–85. DOI: 10.3988/jcn.2019.15.3.376
Engel-Nitz NM, Boscoe A, Wolbeck R, Johnson J, Silvestri NJ. Burden of illness in patients with treatment refractory myasthenia gravis. Muscle and Nerve. 2018;58(1):99–105. DOI: 10.1002/mus.26114
Jeong S, Noh Y, Oh I-S, Hong Y-H, Shin J-Y. Survival, prognosis, and clinical feature of refractory myasthenia gravis: a 15-year nationwide cohort study. J Korean Med Sci. 2021;36(39):1–14. DOI: 10.3346/jkms.2021.36.e242
Frost A, Svendsen ML, Rahbek J, Stapelfeldt CM, Nielsen CV, Lund T. Labour market participation and sick leave among patients diagnosed with myasthenia gravis in Denmark 1997 – 2011 : a Danish nationwide cohort study. BMC Neurol. 2016;16(224):1–7. DOI: 10.1186/s12883-016-0757-2
Nagane Y, Murai H, Imai T, Yamamoto D, Tsuda E, Minami N, et al. Social disadvantages associated with myasthenia gravis and its treatment: A multicentre cross-sectional study. BMJ Open. 2017;7(2):e013278. DOI: 10.1136/bmjopen-2016-013278
Harris L, Aban IB, Xin H, Cutter G. Employment in refractory myasthenia gravis: A Myasthenia Gravis Foundation of America Registry analysis. Muscle and Nerve. 2019;60(6):700–6. DOI: 10.1002/mus.26694
Narayanaswami P, Sanders DB, Wolfe G, Benatar M, Cea G, Evoli A, et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114–22. DOI: 10.1212/WNL.0000000000011124
Li T, Zhang GQ, Li Y, Dong SA, Wang N, Yi M, et al. Efficacy and safety of different dosages of rituximab for refractory generalized AChR myasthenia gravis: A meta-analysis. J Clin Neurosci. 2021;85:6–12. DOI: 10.1016/j.jocn.2020.11.043
Tandan R, Hehir MKI, Waheed W, Howard DB. Rituximab treatment of myasthenia gravis: a systematic review. Muscle Nerve. 2017;[Epub ahead of print]. DOI: 10.1002/mus.25597
Nowak RJ, Coffey CS, Goldstein JM, Dimachkie MM, Benatar M, Kissel JT, et al. Phase 2 trial of rituximab in acetylcholine receptor antibody-positive generalized myasthenia gravis: The BeatMG Study. Neurology. 2022;98(4):E376–89. DOI: 10.1212/WNL.0000000000013121
Piehl F, Eriksson-Dufva A, Budzianowska A, Feresiadou A, Hansson W, Hietala MA, et al. Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis: The RINOMAX Randomized Clinical Trial. JAMA Neurol. 2022;1–8. DOI: 10.1001/jamaneurol.2022.2887
Wang L, Zhang S, Xi J, Li W, Zhou L, Lu J, et al. Efficacy and safety of tacrolimus for myasthenia gravis: a systematic review and meta-analysis. J Neurol. 2017;264(11):2191–200. DOI: 10.1007/s00415-017-8616-7
Yoshikawa H, Kiuchi T, Saida T, Takamori M. Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry. 2011;82:970–7. DOI: 10.1136/jnnp-2011-300148
Wu H, Wang Z, Xi J, Liu J, Yan C, Song J, et al. Therapeutic and immunoregulatory effects of tacrolimus in patients with refractory generalized myasthenia gravis. Eur Neurol Neurol. 2020;83(5):500–7. DOI: 10.1159/000510396
Murai H. Japanese clinical guidelines for myasthenia gravis: Putting into practice. Clin Exp Neuroimmunol. 2015;6(1):21–31. DOI: 10.1111/cen3.12180
De Feo LG, Schottlender J, Martelli NA, Molfino NA. Use of intravenous pulsed cyclophosphamide in severe, generalized myasthenia gravis. Muscle and Nerve. 2002;26(1):31–6. DOI: 10.1002/mus.10133
Rowland LP, Lisak RP, Schotland DL, Dejesus P V., Berg P. Myasthenic myopathy and thymoma. Neurology. 1973;23(3):282–8. DOI: 10.1212/wnl.23.3.282
Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo HC, Marx A, 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 randomised trial. Lancet Neurol. 2019;18(March):259–68. DOI: 0.1016/S1474-4422(18)30392-2
Europa TA, Nel M, Heckmann JM. Myasthenic ophthalmoparesis: time to resolution after initiating immune therapies. 2018;1–8. DOI: 10.1002/mus.26172
Xie Y, Meng Y, Li HF, Hong Y, Sun L, Zhu X, et al. GR gene polymorphism is associated with inter-subject variability in response to glucocorticoids in patients with myasthenia gravis. Eur J Neurol. 2016;23(8):1372–9. DOI: 10.1111/ene.13040
Zhang Q, Ge H, Gui M, Yang M, Bi Z, Ma X, et al. Polymorphisms in drug metabolism genes predict the risk of refractory myasthenia gravis. 2022;10(21):0–2. DOI: 10.21037/atm-22-2543
Rose N, Holdermann S, Callegari I, Kim H, Fruh I, Kappos L, et al. Receptor clustering and pathogenic complement activation in myasthenia gravis depend on synergy between antibodies with multiple subunit specificities. Acta Neuropathol. 2022;144(5):1005–25. DOI: 10.1007/s00401-022-02493-6
Obaid AH, Zografou C, Vadysirisack DD. Heterogeneity of acetylcholine receptor autoantibody – mediated complement activity in patients with myasthenia gravis. Neurol Neuroimmunol Neuroinflamm. 2022;9(4):e1169. DOI: 10.1212/NXI.0000000000001169
Downloads
Published
Issue
Section
License
Copyright (c) 2023 Ali A. Habib
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
