Clinical and Molecular Effects of TYK2/JAK1 Inhibition in Dermatomyositis
Mangold, A.; Vleugels, R. A.; Paik, J. J.; Shahriari, N.; Castillo, R. L.; Gehlhausen, J.; Jiang, R.; Sluzevich, J. C.; Haemel, A. K.; Fox, J. C.; Bogle, R.; Roberts, B. T.; Penner, S.; Li, X.; Ramirez, Z.; Tsoi, A.; Shaw, K.; Cascino, M.; Johnson, B. M.; Kahlenberg, J. M.; Christopher-Stine, L.; Fernandez, A. P.; Fiorentino, D. F.; Werth, V. P.; Gudjonsson, J. E.
Show abstract
Dermatomyositis is driven by overactivation of type I and II interferons and other proinflammatory cytokines that signal via the JAK-STAT pathway. We conducted a 12-week, open-label study of brepocitinib, an oral TYK2/JAK1 inhibitor, in five adults with severe cutaneous dermatomyositis. Treatment was associated with rapid, clinically meaningful improvement in cutaneous disease activity. Single-cell and spatial transcriptomic profiling of lesional skin showed marked suppression of interferon-responsive pathways and inflammatory cell states by week 4. Together with findings from a Phase 3 randomized trial in DM patients with skin and muscle involvement (VALOR, NCT05437263), these data support TYK2/JAK1 inhibition as a promising therapeutic strategy for DM.
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