The role of complement and complement therapeutics in neuromyelitis optica spectrum disorders

Introduction Neuromyelitis optica spectrum disorders (NMOSD) are characterized in the majority of cases by the presence of IgG1 autoantibodies against aquaporin 4 (AQP4) and myelin-oligodendrocyte glycoprotein (MOG), both capable of activating complement. Areas covered We review evidence of complement involvement in NMOSD pathophysiology from pathological, in vitro, in vivo, human studies, and clinical trials. Expert opinion In AQP4 NMOSD, complement deposition is a prominent pathological feature, while in vitro and in vivo studies have demonstrated complement-dependent pathogenicity of AQP4 antibodies. Consistent with these studies, the anti-C5 monoclonal antibody eculizumab was remarkably effective and safe in a phase 2/3 trial of AQP4-NMOSD patents leading to FDA-approved indication. Several other anti-complement agents, either approved or in trials for other neuro-autoimmunities, like myasthenia, CIDP, and GBS, are also relevant to NMOSD generating an exciting group of evolving immunotherapies. Limited but compelling in vivo and in vitro data suggest that anti-complement therapeutics may be also applicable to a subset of MOG NMOSD patients with severe disease. Overall, anticomplement agents, along with the already approved anti-IL6 and anti-CD19 monoclonal antibodies sartralizumab and inebilizumab, are rapidly changing the therapeutic algorithm in NMOSD, a previously difficult-to-treat autoimmune neurological disorder.