Preventing myofibre necrosis in immune-mediated necrotising myopathy—is complement inhibition effective?

Immune-mediated necrotising myopathy is histologically distinguished from other subsets of idiopathic inflammatory myopathies by the dominant finding of myofibre necrosis and serologically distinguished, in many patients, by the presence of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or signal recognition particle (SRP). A pathogenic role for complement in anti-HMGCR-positive and anti-SRP-positive immune-mediated necrotising myopathy has been inferred from sarcolemmal deposits of membrane attack complex (MAC) and their correlation with fibre necrosis. 1 Allenbach Y Arouche-Delaperche L Preusse C et al. Necrosis in anti-SRP+ and anti-HMGCR+ myopathies: role of autoantibodies and complement. Neurology. 2018; 90: e507-e517 Crossref PubMed Scopus (93) Google Scholar Diffuse, prominent sarcolemmal deposition of MAC on non-necrotic fibres is an early feature of immune-mediated necrotising myopathy, and the extent of deposition correlates with disease severity. 2 Day J Otto S Cash K Limaye V Clinical and histological features of immune-mediated necrotising myopathy: a multi-centre South Australian cohort study. Neuromuscul Disord. 2020; 30: 186-199 Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar The detection of complement C1q and IgG in proximity to the sarcolemma supports a role for antibody-mediated activation of the classical complement pathway in myonecrosis. 1 Allenbach Y Arouche-Delaperche L Preusse C et al. Necrosis in anti-SRP+ and anti-HMGCR+ myopathies: role of autoantibodies and complement. Neurology. 2018; 90: e507-e517 Crossref PubMed Scopus (93) Google Scholar Immunomodulatory treatments that are effective in the management of pathogenically distinct subsets of idiopathic inflammatory myopathies, and are used by extrapolation in people with immune-mediated necrotising myopathy, have led to incomplete muscle recovery, with many people having persistent disabling weakness. 2 Day J Otto S Cash K Limaye V Clinical and histological features of immune-mediated necrotising myopathy: a multi-centre South Australian cohort study. Neuromuscul Disord. 2020; 30: 186-199 Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar A pressing need exists for more effective treatments for people with immune-mediated necrotising myopathy. Zilucoplan in immune-mediated necrotising myopathy: a phase 2, randomised, double-blind, placebo-controlled, multicentre trialC5 inhibition does not appear to be an efficacious treatment modality for people with immune-mediated necrotising myopathy. Rather than being the primary driver for disease activity, complement activation might be secondary to muscle injury. Full-Text PDF