Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disease first identified nearly a hundred years ago, though only a handful of patients have been diagnosed with it since. Characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma, the cause of DPM is unknown, treatments are limited, and rates of mortality remain high. 
Despite its rare occurrence in patients, Kathryn Torok, MD, Associate Professor of Pediatrics and Clinical and Translational Science in our Division of Rheumatology, along with researchers from across the country and world, was able to publish a new study evaluating four patients from three unrelated families with an autosomal dominant pattern of DPM inheritance. Titled, “Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome” and published in The New England Journal of Medicine, this research establishes valuable gain-of-function variants in the families studied, illuminating directions for future research to pursue in developing treatments and greater understanding of DPM.
In order to develop these gain-of-function variants, Torok and the collaborative research group utilized genomic sequencing to independently identify three heterozygous variants in a specific region of the gene that encodes signal transducer and activator of transcription 4 (STAT4). In order to define the functional nature of the related DPM genetic defect, primary skin fibroblast and cell-line assays were utilized.
Ultimately, the genome sequencing revealed three novel heterozygous missense gain-of-function variants in STAT4. In vitro, primary skin fibroblasts showed the genetic cause behind impaired wound healing, and other related DPM symptoms. Inhibition of Janus kinase (JAK)-STAT signaling with ruxolitinib, an available pharmaceutical treatment for myelofibrosis in adults, demonstrated improvement in hyperinflammatory fibroblast phenotype in vitro and resolution of other inflammatory symptoms without adverse effects.
This research could help find future treatments for DPM and its related symptoms, as research continues to progress among in vitro models. Though limited by the rarity of the disease among patients, this research is a key step forward in treating a disease that very little is known about.
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