From Serendipity to Science: How Anti-HMGCR Antibodies Changed Our Understanding of Myositis.

Abstract

Although statin-induced muscle toxicity was recognized, a subset of patients presented with severe, persistent necrotizing myopathy despite statin withdrawal. Recognized initially through the serendipitous aggregation of cases in the longitudinal myositis cohort at the Johns Hopkins Myositis Center, the anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibody was identified in patients with previously seronegative necrotizing myopathy who shared a significant history of statin exposure. The autoantigen is the statin's pharmacological target, providing a specific biomarker and a compelling mechanistic link to the drug. Subsequent investigation has delineated a complex, self-perpetuating pathogenesis, in which statin exposure upregulates HMGCR expression on regenerating muscle fibers in genetically susceptible individuals, sustaining the autoimmune response. Pathogenic IgG antibodies drive myofiber necrosis through complement activation on the myofiber surface, and recent evidence indicates that internalized autoantibodies disrupt HMGCR function, leading to pathological lipid accumulation and necrosis. Curiously, the disease also occurs in statin-naïve patients, including children, where it can clinically mimic muscular dystrophy, and the trigger remains unknown. HLA-DRB1*11:01 is a strongly associated risk allele, and certain Indigenous populations have been shown to be at a substantially increased risk. Anti-HMGCR myopathy is distinguished from self-limited toxic myopathy by its persistence- generally presenting years rather than weeks or months after stain exposure-and its response to immunotherapy. Intravenous Ig and rituximab are cornerstone treatments, with emerging therapies targeting the neonatal Fc receptor. Targeting complement in a clinical trial yielded unexpected negative results. This review traces the scientific journey from a clinical conundrum to a paradigm-shifting discovery, highlighting key milestones and future directions.