Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals

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.

The Management of Generalized Myasthenia Gravis in Adults: New Biological Therapies

“…Currently, this is the only long-acting C5 complement inhibitor approved for the treatment of gMG [8]. The most common side effects of the treatment are upper respiratory tract infections, headaches, nausea, and diarrhea [8,9,12]. In rare cases, ravulizumab-treated patients may develop severe but nonfatal infections, such as Neisseria meningitis [9,12].…”

“…The most common side effects of the treatment are upper respiratory tract infections, headaches, nausea, and diarrhea [8,9,12]. In rare cases, ravulizumab-treated patients may develop severe but nonfatal infections, such as Neisseria meningitis [9,12]. Therefore, vaccination is recommended no more than two weeks before starting ravulizumab therapy to prevent meningococcal disease.…”

“…They act by reversibly inhibiting the action of AChE, preventing the breakdown of acetylcholine (ACh). Thus, increasing the amount of ACh available at the NMJ binds postsynaptic ACh receptors [20,21]. The first AChE in use was physostigmine, which subsequently has been replaced by pyridostigmine and neostigmine.…”

“…The first AChE in use was physostigmine, which subsequently has been replaced by pyridostigmine and neostigmine. These remain the first-line agents for symptomatic treatment of MG. Several formulations, such as oral sustained-release preparations, syrup for pediatric use, and injectables for parenteral administration, have been proven to have significant benefits [21]. Pyridostigmine can reach peak plasma levels 1 to 2 hours after an oral dose, with clinical effects starting in 0.5 hours and wearing off in 3-4h due to plasma cholinesterase activity [21].…”

“…AChE inhibitors may be stopped once clinical remission is achieved or if patients develop incapacitating side effects. Paradoxical weakness (MG crisis) may occur with remarkably high doses of AChE inhibitors [20,21].…”