Scientists Unveil Treatment For A Rare Genetic Skin Disorder

The rare and severe inflammatory skin condition known as debilitating pansclerotic morphea is caused by genetic variations, which researchers from the National Institutes of Health and its associates have discovered. They have also discovered a potential cure. Researchers found that individuals with the illness have an overactive form of the STAT4 protein, which controls inflammation and wound healing.

The research also discovered a medication that significantly reduces symptoms in these patients by aiming at a crucial feedback loop regulated by the STAT4 protein. The New England Journal of Medicine reported the findings. 

Researchers from the University of California, San Diego (UCSD), the University of Pittsburgh, and the National Human Genome Research Institute (NHGRI), a division of the NIH, worked together to conduct the study. The study included researchers from the National Institutes of Health’s National Institutes of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. 

The University of South Dakota student and co-first author of the study, Sarah Blackstone, is a predoctoral scholar in NHGRI’s Inflammatory Disease Section and a medical student. “Researchers previously thought that this disorder was caused by the immune system attacking the skin,” she stated. However, we discovered that this oversimplification is incorrect and that skin and the immune system actively contribute to suppressing pansclerotic morphea. 

Four people with debilitating pansclerotic morphea were studied using genome sequencing, and it was discovered that all four of them have chromosomal variations in the STAT4 gene. A protein known as a transcription factor, which helps turn genes on and off, is encoded by the STAT4 gene. The STAT4 protein regulates critical elements of cutaneous wound healing and plays a role in preventing infections. 

The researchers discovered that in these four patients, the STAT4 genetic variations lead to an overactive STAT4 protein, resulting in an aggravating positive feedback loop of inflammation and poor wound healing. They focused on Janus kinase, also known as JAK, another enzyme in the inflammatory pathway that interacts with the STAT4 molecule to break this negative feedback loop. The patients’ rashes and ulcers significantly diminished after receiving treatment with the JAK-inhibiting medication ruxolitinib from the researchers. 

Considering this illness’s uncommon and poorly understood, there isn’t a widely accepted treatment for it yet. But our research offers these patients a critical new therapeutic alternative,” added Blackstone. 

Existing medications for incapacitating pansclerotic morphea are intended to stop the disease’s progression, but earlier medicines were frequently ineffective and had adverse side effects. People with the illness typically don’t live past 10 years after receiving their diagnosis. 

According to the study, ruxolitinib may be a successful treatment for people with this disease. Ruxolitinib is a member of a larger class of medications known as JAK inhibitors, frequently prescribed to treat ulcerative colitis, arthritis, eczema, and other chronic inflammatory illnesses. 

Lori Broderick, M.D., Ph.D., a senior author of the study and an associate professor at UCSD, said, “We are interested in investigating other molecules in this system as well as how they change in patients with preventing pansclerotic morphea and related circumstances from finding indications for understanding a greater number of more common diseases.”