Researchers have identified genetic variants that cause a rare and severe inflammatory skin disease known as disabling pansclerotic morphea and have found a potential cure.
Researchers at the National Institutes of Health have found that people with this 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 are published in the New England Journal. of Medicine. The study was conducted by scientists at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, in collaboration with researchers at the University of California San Diego (UCSD) and the University of Pittsburgh.
Researchers from the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, also participated in the study.
Only a small number of patients have been diagnosed with disabling sclerosis morphea, a disease first described in the medical literature almost 100 years ago.
This disease causes severe skin lesions and poor wound healing, leading to deep scarring in all layers of the skin and muscles.
Muscles tense up and eventually break down when the joints are stressed, resulting in poor mobility. Since this disease is very rare, its genetic cause has not yet been established.
“Researchers previously thought this disorder was caused by an attack by the immune system on the skin,” said Sarah Blackstone, research associate in the Division of Inflammatory Diseases at the National Human Genome Research Institute, University of South Dakota medical student and co-author. – The first author of the study. simplification, and that both the skin and the immune system play an active role in the appearance of signs of disabling sclerosis.”
The researchers used genome sequencing to study four people with disabling pansclerotic morphea and found that all had genetic variants in the STAT4 gene.
The STAT4 gene codes for a type of protein that helps turn genes on and off, known as a transcription factor.
STAT4 not only plays a role in fighting infection, but also controls important aspects of skin wound healing.
The scientists found that STAT4 genetic variants lead to overactivity of the STAT4 protein in these four patients, creating a positive feedback loop of inflammation and poor wound healing that worsens over time. To stop the malicious feedback loop, they targeted another inflammatory pathway protein that interacts with STAT4 called Janus kinase, also known as JAK. When the researchers treated patients with a JAK-inhibiting drug called ruxolitinib, the patients had a significant reduction in rashes and ulcers.
“Until now, there has been no standard treatment for this disorder because it is so rare and understudied. However, our study provides an important new treatment option for these patients,” said Blackstone.
Current therapies are designed to stop the progression of the disease, but previous treatments were often ineffective and often had serious side effects.
People with this disorder usually do not live more than 10 years after diagnosis.
The study suggests that ruxolitinib could be an effective treatment for patients with this disorder because it is part of a broader class of drugs called JAK inhibitors that are commonly used to treat arthritis, eczema, ulcerative colitis and other chronic inflammatory conditions.
Source: Medical Express