Dermatomyositis is a classic paraneoplastic autoimmune disease causing multi-organ inflammation and significant morbidity, with 15-25% of those diagnosed–particularly in older-age–harboring an occult malignancy expressing antigen the cross-react with muscle and skin. Emerging evidence implicates cytokine signaling via TYK2 and JAK1 pathways, leading to the phase 3 VALOR trial where the oral TYK2–JAK1 inhibitor brepocitinib at 30 mg daily significantly improved disease activity, skin and muscle outcomes, quality of life, and glucocorticoid tapering with a 10% rate of serious infections. As a disruptor of cytokine signaling, it remains unclear how, if at all, brepocitinib can safely be combined with either chemotherapy, where it may lead to additive immunosuppression, or with immunotherapy, where it may blunt interferon pathways critical of efficacy. | Vleugels, N Engl J Med 2026
