Patients with disabling pansclerotic morphea (DPM) caused by gain-of-function variants in the gene for signal transducer and activator of transcription (STAT) 4 (STAT4) responded to ruxolitinib therapy, a study of 4 people from 3 families shows. “The JAK inhibitor … attenuated the dermatologic and inflammatory phenotype in vitro and in the affected family members,” the authors conclude.
“Genome sequencing revealed three novel heterozygous missense gain-of-function variants in STAT4,” write the investigators. “In vitro, primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion. Inhibition of Janus kinase (JAK)–STAT signaling with ruxolitinib led to improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that were appropriately modified through JAK inhibition.”