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Drugs

, Volume 79, Issue 4, pp 353–364 | Cite as

Therapies Directed Against B-Cells and Downstream Effectors in Generalized Autoimmune Myasthenia Gravis: Current Status

  • Grayson Beecher
  • Brendan Nicholas Putko
  • Amanda Nicole Wagner
  • Zaeem Azfer SiddiqiEmail author
Leading Article

Abstract

Myasthenia gravis is a rare, heterogeneous, classical autoimmune disease characterized by fatigable skeletal muscle weakness, which is directly mediated by autoantibodies targeting various components of the neuromuscular junction, including the acetylcholine receptor, muscle specific tyrosine kinase, and lipoprotein-related protein 4. Subgrouping of myasthenia gravis is dependent on the age of onset, pattern of clinical weakness, autoantibody detected, type of thymic pathology, and response to immunotherapy. Generalized immunosuppressive therapies are effective in all subgroups of myasthenia gravis; however, approximately 15% remain refractory and more effective treatments with improved safety profiles are needed. In recent years, successful utilization of targeted B-cell therapies in this disease has triggered renewed focus in unraveling the underlying immunopathology in attempts to identify newer therapeutic targets. While myasthenia gravis is predominantly B-cell mediated, T cells, T cell–B cell interactions, and B-cell-related factors are increasingly recognized to play key roles in its immunopathology, particularly in autoantibody production, and novel therapies have focused on targeting these specific immune system components. This overview describes the current understanding of myasthenia gravis immunopathology before discussing B-cell-related therapies, their therapeutic targets, and the rationale and evidence for their use. Several prospective studies demonstrated efficacy of rituximab in various myasthenia gravis subtypes, particularly that characterized by antibodies against muscle-specific tyrosine kinase. However, a recent randomized control trial in patients with acetylcholine receptor antibodies was negative. Eculizumab, a complement inhibitor, has recently gained regulatory approval for myasthenia gravis based on a phase III trial that narrowly missed its primary endpoint while achieving robust results in all secondary endpoints. Zilucoplan is a subcutaneously administered terminal complement inhibitor that recently demonstrated significant improvements in functional outcome measures in a phase II trial. Rozanolixizumab, CFZ533, belimumab, and bortezomib are B-cell-related therapies that are in the early stages of evaluation in treating myasthenia gravis. The rarity of myasthenia gravis, heterogeneity in its clinical manifestations, and variability in immunosuppressive regimens are challenges to conducting successful trials. Nonetheless, these are promising times for myasthenia gravis, as renewed research efforts provide novel insights into its immunopathology, allowing for development of targeted therapies with increased efficacy and safety.

Notes

Compliance with Ethical Standards

Funding

This review was prepared without industry or Grant funding.

Conflict of Interest

Grayson Beecher, Brendan N. Putko, Amanda N. Wagner, and Zaeem A. Siddiqi have no conflicts of interest that are directly relevant to the contents of this article.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Grayson Beecher
    • 1
  • Brendan Nicholas Putko
    • 1
  • Amanda Nicole Wagner
    • 1
  • Zaeem Azfer Siddiqi
    • 1
    Email author
  1. 1.Division of Neurology, Department of Medicine, Faculty of Medicine and DentistryUniversity of Alberta HospitalEdmontonCanada

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