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

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.

• Authors: Grayson Beecher, Brendan Nicholas Putko, Amanda Nicole Wagner, Zaeem Azfer Siddiqi
• Journal: Drugs (Drugs) Vol. 79 Issue 4 Pg. 353-364 (Mar 2019) ISSN: 1179-1950 [Electronic] New Zealand
• PMID: 30762205 (Publication Type: Journal Article, Review)

Chemical References

• Antibodies, Monoclonal, Humanized
• Cholinergic Antagonists
• Complement Inactivating Agents
• Immunosuppressive Agents
• Receptors, Cholinergic
• Receptor Protein-Tyrosine Kinases

Topics

• Antibodies, Monoclonal, Humanized (adverse effects, therapeutic use)
• B-Lymphocytes (drug effects)
• Cholinergic Antagonists (therapeutic use)
• Complement Inactivating Agents (therapeutic use)
• Humans
• Immunosuppressive Agents (adverse effects, therapeutic use)
• Immunotherapy (methods)
• Myasthenia Gravis (therapy)
• Randomized Controlled Trials as Topic
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)
• Receptors, Cholinergic (metabolism)