Researchers have identified genomic variants that cause disabling pansclerotic morphea and have identified a treatment for the rare, severe inflammatory skin disorder.
Published in the New England Journal of Medicine, the research led by investigators at the National Human Genome Research Institute (NHGRI), part of the U.S. National Institutes of Health (NIH), in collaboration with researchers from 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 NIH, also participated in the study.
According to a press release, only a handful of patients have been diagnosed with disabling pansclerotic morphea, a disorder first described in the medical literature around 100 years ago. The disorder causes severe skin lesions and poor wound healing, leading to deep scarring of all layers of the skin and muscles. The muscles eventually harden and break down while the joints stiffen, leading to reduced mobility. Because the disorder is so rare, its genetic cause had not been identified until now.
“Researchers previously thought that this disorder was caused by the immune system attacking the skin,” said the study’s co-first author Sarah Blackstone, in the release.
“However, we found that this is an oversimplification and that both skin and the immune system play an active role in disabling pansclerotic morphea.” Blackstone is a predoctoral fellow within NHGRI's Inflammatory Disease Section and a medical student at the University of South Dakota.
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. This protein both plays a role in fighting infections but also controls important aspects of wound-healing in the skin.
Researchers found that in all four patients, the STAT4 genomic variants resulted in an overactive STAT4 protein. That in turn created a positive feedback loop of inflammation and impaired wound healing that worsens over time. To stop this feedback loop, investigators targeted Janus kinase, which interacts with the STAT4 molecule. When the researchers treated the patients with the JAK inhibitor ruxolitinib, they observed a dramatic improvement in rashes and ulcers.
“So far, there has not been a standard treatment for this disorder because it’s so rare and not well-understood. However, our study gives an important new treatment option for these patients,” said Blackstone.
The authors note that existing treatments for this inflammatory condition are mostly ineffective and often have severe side effects. They note that people with this disorder typically do not live more than 10 years after their diagnosis.
They write that their findings suggest ruxolitinib could be an effective treatment for patients with this disorder.
“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,” said senior author Dan Kastner, MD, PhD, in the release.
Dr. Kastner is an NIH distinguished investigator and head of NHGRI’s Inflammatory Disease Section.
“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 array of more common diseases,” said Lori Broderick, MD, PhD, and another senior author of the paper. Dr. Broderick is an associate professor at UCSD.