Immune dysregulation and infection susceptibility in Anti-MDA5 dermatomyositis

Antibodies targeting melanoma differentiation-associated gene 5 protein (MDA5) are associated with a distinct subtype of dermatomyositis characterised by cutaneous ulceration, systemic inflammation, and a high risk of rapidly progressive lung disease. Beyond these manifestations, patients experience disproportionately high rates of infection compared with other inflammatory myopathies, including viral, bacterial, and fungal complications. This review synthesises cohort data demonstrating an excess burden of infections, particularly Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus, attributed to both disease-specific factors and immunosuppression. We summarise adult and paediatric cohorts in which anti-MDA5 dermatomyositis confers a higher risk of serious and opportunistic infection, early clustering of events after diagnosis, and markedly increased short-term mortality. Emerging translational evidence suggests that persistent type I and III interferon signalling, abnormal neutrophil extracellular trap formation, lymphocyte and natural killer cell depletion, and antibody-mediated vascular injury may converge to impair host defence at cutaneous and pulmonary barriers, and may also contribute to complications such as spontaneous pneumomediastinum. Current recommendations for screening, vaccination, and antimicrobial prophylaxis are largely extrapolated from other autoimmune diseases and may underestimate risk in patients with anti-MDA5 dermatomyositis. On the basis of available data, we argue that disease-specific protocols, including routine PJP prophylaxis in high-risk phenotypes and surveillance for viral reactivation, are warranted, and we outline key priorities for prospective and mechanistic studies aimed at reducing infection-related morbidity and mortality in this high-risk subgroup.