Dermatomyositis is characterized by TYK2-dependent STAT3 activation

Dermatomyositis (DM) is characterized by activation of cytokine pathways that signal through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) axis, although the relative contribution of individual JAK family members remains unclear. Peripheral blood mononuclear cells were isolated from patients with active DM (n = 5), rheumatoid arthritis (RA, n = 7), systemic sclerosis (SSc, n = 7), and healthy donors (HD, n = 5). Phosphorylated STAT3 (pSTAT3) levels were assessed by flow cytometry in CD4+ and CD14+ cells under basal conditions and following selective inhibition of JAK1 (abrocitinib), JAK2 (gandotinib), JAK3 (decernotinib), or TYK2 (deucravacitinib). Under basal conditions, DM displayed the highest pSTAT3 levels in CD4+ cells (median 38.3%), significantly exceeding those observed in HDs (0.9%, P < 0.05) and SSc (8.6%, P < 0.05), while RA showed intermediate levels (17.7%). CD14+ cells from DM patients also demonstrated increased pSTAT3 compared with HDs (9.7% vs 1.4%, P < 0.05), without significant differences versus RA or SSc. Selective JAK inhibition revealed distinct disease-specific patterns. In DM, only TYK2 inhibition significantly reduced pSTAT3 levels in both CD4+ and CD14+ cells (P < 0.05), whereas in RA, pSTAT3 was modulated by inhibition of multiple JAK family members. No significant effects were observed in HDs or SSc patients. These findings identify a selective TYK2-dependent STAT3 activation signature in circulating immune cells from patients with DM, distinguishing this disease from other autoimmune conditions and supporting TYK2 as a potential therapeutic target in DM.