Neuromuscular junction and the complement system

Abstract

Nearly 90 % of generalized myasthenia gravis (MG) patients have IgG1 or IgG3 antibodies against the acetylcholine receptor (AChR). Acetylcholine receptor antibodies induce neuromuscular transmission defect by various potential mechanisms including internalisation of AChR, receptor blockade and by activation of the classical complement pathway. Membrane attack complex (MAC) which is the final end product of complement activation leads to architectural destruction of the neuromuscular junction (NMJ). Several experimental models (EAMG) have shown evidence for complement in the pathogenesis of MG, with demonstration of prevention or reversal of the disease using complement inhibitory therapies. Various molecules that target the complement system have been developed to treat myasthenia gravis. Most of the currently studied molecules inhibit complement protein 5 (C5), which prevents the formation of MAC and subsequent NMJ destruction. The currently studied anti-complement therapies for MG include eculizumab, zilucoplan, ravulizumab, pozelimab, cemdisiran, gefurilimab, danicopan and few others in the pipeline. Many of these have also been shown to have long term benefit in different sub-groups of patients with MG. Given the risk of Gram-negative septicaemia (especially by meningococcus), patients would need vaccination prior to initiation of treatment and in some countries prophylactic antibiotics during treatment is recommended, although no major safety signatures have been noted in the studies so far. Future studies identifying specific biomarkers might help clinicians select the most appropriate patients who are more likely to respond to complement inhibitory therapies.

Keywords: C5; Complement; Eculizumab; Myasthenia gravis; Ravulizumab; Zilucoplan.