Seronegative Immune-Mediated Necrotizing Myopathy: An Overview for Optimal Clinical Management

Immune-mediated necrotizing myopathy (IMNM) is a rare and heterogeneous subgroup of idiopathic inflammatory myopathies. IMNM is broadly classified into seropositive disease, encompassing anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) and anti-signal recognition particle (anti-SRP) antibody-associated forms, and seronegative IMNM. Although seronegative IMNM has traditionally been considered largely analogous to seropositive disease, emerging evidence suggests that it may represent, at least in part, a distinct clinical entity. This review synthesizes the current evidence regarding the clinical management of seronegative IMNM.

Seronegative IMNM typically presents with symmetric proximal muscle weakness, predominantly affecting the lower extremities. Recent data suggest that myalgia at disease onset may occur more frequently in seronegative patients, while evidence also indicates potential associations with prior statin exposure, malignancy, and connective tissue diseases; however, these relationships remain incompletely defined. Furthermore, extramuscular manifestations, particularly cardiac involvement, may be more clinically relevant than traditionally recognized. Muscle biopsy remains central to diagnosis, demonstrating prominent myofiber necrosis and regeneration with minimal inflammatory infiltrates, whereas research suggests that sarcolemmal membrane attack complex deposition may be less frequent than in seropositive IMNM. Immunosuppressive therapy constitutes the cornerstone of treatment, with glucocorticoids as first-line therapy and methotrexate commonly employed as the preferred steroid-sparing agent. Rituximab may be considered in refractory or relapsing disease. Seronegative IMNM is an uncommon and frequently underrecognized disorder. Significant gaps persist regarding its pathogenesis, associated comorbidities, and long-term outcomes. This narrative review provides a practical, evidence-based framework for the clinical evaluation and management of patients with seronegative IMNM.