Novel therapies for refractory idiopathic inflammatory myopathy-associated interstitial lung disease

Idiopathic inflammatory myopathies (IIM) are systemic autoimmune rheumatic diseases in which interstitial lung disease (ILD) is a frequent extra-muscular manifestation and a major driver of morbidity and mortality. ILD occurs most commonly in antisynthetase syndrome and anti-melanoma differentiation-associated gene 5 (anti-MDA5) dermatomyositis syndrome, the latter carrying a high risk of rapidly progressive ILD (RP-ILD). Although recent guidelines outline conventional immunosuppressive strategies, a subset of patients progress despite escalation, and the definition of refractory IIM-ILD remains poorly standardized.

Because type I and II interferon signaling, other cytokines, and aberrant B-cell activity have been implicated in the pathogenesis of IIM-ILD, novel therapies have been used off-label to target these mechanisms in treatment-resistant disease. This review summarizes emerging off-label and investigational therapies, including Janus kinase inhibitors, direct cytokine inhibitors (anifrolumab, dazukibart, tocilizumab, basiliximab), B-cell- and plasma-cell-targeted approaches (anti-CD20 antibodies, daratumumab, chimeric antigen receptor T-cell therapy, bispecific T-cell engagers), intravenous immunoglobulin, and antifibrotics, and rescue measures.

Across these agents, evidence is confined to case reports, small series, and observational cohorts, with few randomized trials reporting IIM-ILD-specific outcomes. Prospective studies are needed to define patient selection, treatment sequencing and combinations, durability, and safety of novel therapies in IIM-ILD.