Immunopathogenesis of Immune-Mediated Necrotizing Myopathy: Insights Drawn from Pathological Phenotypes and Mechanistic Elaboration

Abstract

Immune-mediated necrotizing myopathy (IMNM) is a distinct subtype of idiopathic inflammatory myopathies (IIMs), classified by serum autoantibody status into anti-signal recognition particle (anti-SRP)-positive, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR)-positive, and seronegative subgroups. Its hallmark is a pathological paradox: extensive myofiber necrosis and regeneration accompanied by strikingly sparse inflammatory infiltrates, a feature that distinguishes IMNM from dermatomyositis and inclusion body myositis. In this review, we integrate preclinical and clinical evidence to build an immune-mechanistic pathogenesis model grounded in pathological observations: anti-SRP and anti-HMGCR autoantibodies trigger myofiber injury via both complement-dependent and complement-independent pathways; necrotic myofibers release damage-associated molecular patterns (DAMPs) that activate Toll-like receptor signaling, thereby establishing a complement-independent, self-perpetuating injury-amplification loop; T-cell-dominated adaptive-immune responses, characterized by Th1-M1 pathway activation alongside widespread T-cell exhaustion, may only function as a secondary modulator; and aberrant vascular remodeling coupled with impaired tissue regeneration contributes to long-term prognosis. Variations in macrophage polarization, angiogenic potential, and malignancy risk between anti-SRP-positive and anti-HMGCR-positive IMNM may constitute intrinsic drivers underlying their disparate histopathological features, clinical trajectories, and treatment responses. This model accounts for the limited therapeutic benefit observed with complement-blockade monotherapy and proposes that regimens combining autoantibody suppression with the inhibition of necrosis-driven injury amplification could yield improved clinical outcomes, providing a theoretical basis for pathological subtyping and stratified therapy in IMNM.