Esoinophilic fasciitis and morphea share gene signatures of inflammatory cell death, self-DNA recognition, and JAK/STAT signaling

The pathogenesis of eosinophilic fasciitis (EF) and morphea is poorly understood. We analyzed skin biopsies from EF and morphea patients compared to adult healthy skin (HS) using gene expression profiling, Ingenuity Pathway Analysis, and immunostaining. EF gene expression showed significant overlap with morphea. 51/61 differentially expressed genes (DEG), 80/99 canonical pathways, and 40/51 upstream regulators were shared in EF and morphea. Both conditions exhibited robust T cell activation and cytotoxic signatures despite their pauci-inflammatory histological appearance, suggesting small numbers of T cells may drive injury, inflammation, and fibrosis. EF and morphea shared signatures of necroptosis, self-DNA recognition, cGAS/STING activation, induction of types I, II, and III interferon signaling, and fibrosis. Seven JAK/STAT molecules were significantly upregulated in EF and nine were upregulated in morphea. Compared to HS, TYK2 was the most significant JAK molecule upregulated in EF (p=0.0007) and morphea (p=0.0002). Immunostaining demonstrated activated interferon-related molecules JAK1 and STAT1 in T cells, dendritic cells, and macrophages in both diseases. This study identifies shared molecular mechanisms of EF and morphea and demonstrates strong pathophysiologic similarities between the two diseases. Our findings indicate that targeted inhibition of JAK/STAT molecules and mediators of necroptosis may be beneficial in treating these fibrotic diseases. This study uses Nanostring transcriptional profiling with the Human Autoimmune Panel (NS_Hs_AI_Pro_v1.1). Samples incluce lesional biopsies from patients with morphea (n=8), eosinophilic fasciitis (n=6), and healthy adults (n=8). We used nSolver 4.0 for analysis to compare morphea samples vs. normal skin, and separately compared eosinophilic fasciitis samples vs. normal skin.