NIH scientists find treatment for rare genetic skin disorder

National Institutes of Health researchers and their colleagues have identified the genomic variants that cause a rare and serious inflammatory skin disease known as disabling pansclerotic morphea and found a potential treatment. Scientists have found that people with the disorder have an overactive version of a protein called STAT4, which regulates inflammation and wound healing. The work also identified a drug that targets an important feedback loop controlled by the STAT4 protein and significantly improves symptoms in these patients. The results were published in New England Journal of Medicine.

The study was conducted by researchers at the National Human Genome Research Institute (NHGRI), part of the NIH, in collaboration with researchers at the University of California, San Diego (UCSD) and the University of Pittsburgh. Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases, both part of the NIH, also participated in the study.

Only a handful of patients have been diagnosed with disabling pansclerotic morphea, a disorder first described in the medical literature about 100 years ago. The disorder causes severe skin breakdown and poor wound healing, leading to deep scarring of all layers of the skin and muscles. Muscles eventually harden and break down as joints stiffen, leading to reduced range of motion. Because the disorder is so rare, its genetic cause hadn’t been identified until now.

Researchers previously thought this disorder was caused by the immune system attacking the skin, said Sarah Blackstone, a researcher within the inflammatory diseases section of NHGRI, a medical student at the University of South Dakota and co-first author of study. However, we have found that this is an oversimplification and that both the skin and the immune system play an active role in disabling pansclerotic morphea.

Comparison of fibroblast cells

The researchers used genome sequencing to study four individuals with disabling pansclerotic morphea and found that all four have genomic variants in the STAT4 gene. THE STAT4 gene encodes a type of protein that helps turn genes on and off, known as a transcription factor. The STAT4 protein not only plays a role in fighting infection, but also controls important aspects of wound healing in the skin.

The findings of this study open the door for JAK inhibitors as a potential treatment for other inflammatory skin disorders or disorders related to tissue scarring, whether scarring of the lungs, liver or bone marrow.

Scientists have discovered that the STAT4 the genomic variants result in an overactive STAT4 protein in these four patients, creating a positive feedback loop of inflammation and impaired wound healing that worsens over time. To stop this harmful feedback loop, they targeted another protein in the inflammatory pathway that interacts with the STAT4 molecule and is called Janus kinase, also known as JAK. When the researchers treated the patients with a JAK inhibitor drug called ruxolitinib, the patients’ skin rashes and ulcers improved markedly.

Until now, there hasn’t been a standard treatment for this disorder because it’s so rare and not well understood. However, our study offers an important new treatment option for these patients, Blackstone said.

Existing treatments to disable pansclerotic morphea are designed to halt the progression of the disorder, but previous therapies have been mostly ineffective, often with serious side effects. People with the disorder typically don’t live more than 10 years after diagnosis.

The study suggests that ruxolitinib could be an effective treatment for patients with this disorder. Ruxolitinib is part of a larger class of drugs called JAK inhibitors, which are commonly used to treat arthritis, eczema, ulcerative colitis, and other chronic inflammatory diseases.

The findings of this study open the door for JAK inhibitors as a potential treatment for other inflammatory skin disorders or tissue scarring disorders, whether scarring of the lungs, liver or bone marrow, said Dan Kastner, MD. , Ph.D., an NIH Distinguished Research Scientist, head of NHGRI’s inflammatory diseases section, and senior author of the paper.

We hope to continue studying other molecules in this pathway and how they are altered in patients with disabling pansclerotic morphea and related conditions to find clues to understanding a broader range of more common diseases, said Lori Broderick, MD, Ph.D., a senior author of the paper and associate professor at UCSD.

Fibroblast cells

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