Dermatomyositis characterized by selective TYK2-dependent STAT3 activation, distinguishing it from other autoimmune diseases

Dermatomyositis (DM) is a rare, chronic autoimmune disease causing muscle weakness and skin rash, driven by aberrant immune responses. A key signaling pathway in inflammation is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) axis, which mediates cytokine signaling. While JAK/STAT activation is known in DM, the specific contribution of individual JAK family members (JAK1, JAK2, JAK3, TYK2) to this pathology has remained unclear. Identifying the dominant JAK isoform could enable more targeted and effective therapeutic strategies, moving beyond broad-spectrum immunosuppression.

Researchers isolated peripheral blood mononuclear cells (PBMCs) from patients with active Dermatomyositis (n = 5), Rheumatoid Arthritis (n = 7), Systemic Sclerosis (n = 7), and Healthy Donors (n = 5). They assessed phosphorylated STAT3 (pSTAT3) levels in CD4+ and CD14+ cells using flow cytometry. This was done under basal conditions and following selective inhibition of specific JAK isoforms using abrocitinib (JAK1), gandotinib (JAK2), decernotinib (JAK3), or deucravacitinib (TYK2) to determine their individual contributions to STAT3 activation.

Under basal conditions, Dermatomyositis patients displayed the highest pSTAT3 levels in CD4+ cells (median 38.3%), significantly exceeding those in Healthy Donors (0.9%, P < 0.05) and Systemic Sclerosis patients (8.6%, P < 0.05). Rheumatoid Arthritis patients showed intermediate levels (17.7%). CD14+ cells from Dermatomyositis patients also demonstrated increased pSTAT3 (9.7%) compared with Healthy Donors (1.4%, P < 0.05), with no significant differences against Rheumatoid Arthritis or Systemic Sclerosis. Selective JAK inhibition revealed distinct disease-specific patterns:

In Dermatomyositis, only TYK2 inhibition with deucravacitinib significantly reduced pSTAT3 levels in both CD4+ and CD14+ cells (P < 0.05). In contrast, pSTAT3 in Rheumatoid Arthritis was modulated by inhibition of multiple JAK family members, highlighting a unique TYK2-dependent signature in Dermatomyositis. No significant effects were observed in Healthy Donors or Systemic Sclerosis patients.