Scientists Identify Treatment Option for Rare Pansclerotic Morphea

Scientists affiliated with the National Institutes of Health (NIH) and their colleagues have identified a potential treatment option for disabling pansclerotic morphea (DPM).

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DPM is a rare systemic inflammatory skin disorder associated with poor wound healing, squamous cell carcinoma, high rates of mortality, and more. There is currently no associated cause, and it the most rare form of morphea. Due to poor wound healing, patients’ skin and muscles become deeply scarred. When their muscles harden, their joints stiffen and begin to limit mobility.¹

According to a press release¹ from the NIH, researchers from the National Human Genome Research Institute (NHGRI); University of California, San Diego; University of Pittsburgh; National Institute of Arthritis and Musculoskeletal and Skin Diseases; and the National Institute of Allergy and Infectious Diseases collaborated in an investigative study² related to the condition.

In the study, researchers evaluated 4 patients with DPM, all of whom had an autosomal dominant pattern of inheritance. They conducted genomic sequencing, primary skin fibroblast and cell-line assays, and gene expression in the process.

They discovered that all 4 patients with the disease had overreactive signal transducer and activator of transcription 4 (STAT4) proteins. They also made the following discoveries:

• Genome sequencing revealed 3 novel heterozygous missense gain-of-function variants in STAT4
• 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

“Researchers previously thought that this disorder was caused by the immune system attacking the skin,” said Sarah Blackstone in the press release. Blackstone is a predoctoral fellow within NHGRI's Inflammatory Disease Section, a medical student at the University of South Dakota and co-first author of the study. “However, we found that this is an oversimplification, and that both skin and the immune system play an active role in disabling pansclerotic morphea.”

Researchers said they hope to continue studying molecules within this pathway in order to make further advancements for patients with DPM and related conditions. Dan Kastner, MD, PhD, is an NIH distinguished investigator, head of NHGRI’s Inflammatory Disease Section, and a senior author of the study. Kastner said these results play a role in the future of treating patients with wound healing and scarring conditions.

“The findings of this study open doors for JAK inhibitors to be a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring, whether it is scarring of the lungs, liver or bone marrow,” he said.

References

1. NIH scientists find treatment for rare genetic skin disorder. National Institutes of Health. May 31, 2023. Accessed June 1, 2023. https://www.nih.gov/news-events/news-releases/nih-scientists-find-treatment-rare-genetic-skin-disorder.
2. Baghdassarian H, Blackstone SA, Clay OS, et al. Variant stat4 and response to ruxolitinib in an autoinflammatory syndrome. N Engl J Med. Published online 2023. doi:10.1056/nejmoa2202318