Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals.

Drugs

Ellen and Martin Prosserman Centre for Neuromuscular Diseases, University Health Network, 5EC-309, Toronto General Hospital, University of Toronto, 200 Elizabeth St, Toronto, M5G 2C4, Canada.

Published: June 2022

AI Article Synopsis

  • - Myasthenia gravis (MG) is an autoimmune disorder affecting muscle function, with treatments traditionally relying on acetylcholinesterase inhibitors and corticosteroids, though newer therapies are emerging.
  • - Conventional treatments can be slow to act and have significant side effects, whereas new biologic agents like eculizumab and efgartigimod offer faster, targeted immunotherapy with fewer adverse effects.
  • - Ongoing research includes various agents targeting different mechanisms, but there are concerns like the risk of Neisseria meningitis with complement inhibitors, emphasizing the need for vaccinations.

Article Abstract

Myasthenia gravis (MG) is a chronic, fluctuating, antibody-mediated autoimmune disorder directed against the post-synaptic neuromuscular junctions of skeletal muscles, resulting in a wide spectrum of manifestations ranging from mild to potentially fatal. Given its unique natural course, designing an ideal trial design for MG has been wrought with difficulties and evidence in favour of several of the conventional agents is weak as per current standards. Despite this, acetylcholinesterases and corticosteroids have remained the cornerstones of treatment for several decades with intravenous immunoglobulins (IVIG) and therapeutic plasma exchange (PLEX) offering rapid treatment response, especially in crises. However, the treatment of MG entails long-term immunosuppression and conventional agents are viable options but take longer to act and have a number of class-specific adverse effects. Advances in immunology, translational medicine and drug development have seen the emergence of several newer biological agents which offer selective, target-specific immunotherapy with fewer side effects and rapid onset of action. Eculizumab is one of the newer agents that belong to the class of complement inhibitors and has been approved for the treatment of refractory general MG. Zilucoplan and ravulizumab are other agents in this group in clinical trials. Neisseria meningitis is a concern with all complement inhibitors, mandating vaccination. Neonatal Fc receptor (FcRn) inhibitors prevent immunoglobulin recycling and cause rapid reduction in antibody levels. Efgartigimod is an FcRn inhibitor recently approved for MG treatment, and rozanolixizumab, nipocalimab and batoclimab are other agents in clinical trial development. Although lacking high quality evidence from randomized clinical trials, clinical experience with the use of anti-CD20 rituximab has led to its use in refractory MG. Among novel targets, interleukin 6 (IL6) inhibitors such as satralizumab are promising and currently undergoing evaluation. Cutting-edge therapies include genetically modifying T cells to recognise chimeric antigen receptors (CAR) and chimeric autoantibody receptors (CAAR). These may offer sustained and long-term remissions, but are still in very early stages of evaluation. Hematopoietic stem cell transplantation (HSCT) allows immune resetting and offers sustained remission, but the induction regimens often involve serious systemic toxicity. While MG treatment is moving beyond conventional agents towards target-specific biologicals, lack of knowledge as to the initiation, maintenance, switching, tapering and long-term safety profile necessitates further research. These concerns and the high financial burden of novel agents may hamper widespread clinical use in the near future.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9152838PMC
http://dx.doi.org/10.1007/s40265-022-01726-yDOI Listing

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