Researchers from the National Institutes of Health (NIH) and their colleagues have made a breakthrough in identifying the genomic variants that cause the rare skin disorder known as disabling pansclerotic morphea. This inflammatory skin disorder causes severe skin lesions and impedes wound healing, leading to deep scars in all skin layers and muscles. The muscles eventually harden and break down while the joints stiffen, causing reduced mobility. Previously, researchers believed that the immune system attacked the skin, but the current study found that the disease is an oversimplification, and both the skin and the immune system play an active role in crippling pansclerotic morphea.
In collaboration with researchers from the University of California San Diego (UCSD) and the University of Pittsburgh, NIH researchers used genome sequencing to examine four individuals with disabling pansclerotic morphea and discovered that all four had genomic variants in the STAT4 gene. The STAT4 gene produces a type of protein that regulates inflammation and wound healing, inviting transcription factor. The STAT4 protein does not only help in fighting infections but also controls important aspects of wound-healing in the skin.
The researchers found that the STAT4 genomic variants resulting in an overactive STAT4 protein created a positive feedback loop of inflammation and impaired wound-healing that worsens over time. The researchers targeted another protein in the inflammatory pathway that interacts with the STAT4 molecule, Janus kinase, also known as JAK, to stop this harmful feedback loop. Upon treating the patients with a JAK-inhibiting drug called ruxolitinib, the patients’ rashes and ulcers dramatically improved.
The study found that ruxolitinib could be an effective treatment for the rare disorder. Ruxolitinib is part of JAK inhibitors, which are commonly used to treat arthritis, eczema, ulcerative colitis, and other chronic inflammatory diseases. Existing treatments for disabling pansclerotic morphea are designed to halt the progression of the disorder, but previous therapies have been mostly ineffective, often with severe side effects. People with the disorder typically do not live more than ten years after their diagnosis.
Researchers at the National Human Genome Research Institute (NHGRI), part of the NIH, who led the study in collaboration with researchers from UCSD and the University of Pittsburgh, have identified the genomic variants causing the rare and severe inflammatory skin disorder, disabling pansclerotic morphea, and found a potential treatment. 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. The researchers discovered 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 improves symptoms in these patients.
The scientists found that the STAT4 genomic variants resulted 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, Janus kinase, also known as JAK. Upon treating the patients with a JAK-inhibiting drug called ruxolitinib, the patients’ rashes, and ulcers dramatically improved.
By examining the genome sequencing of four patients with disabling pansclerotic morphea, the researchers found that all four had genomic variants in the STAT4 gene, producing an overactive STAT4 protein. This discovery has paved the way for potential treatment of the disease by administering JAK inhibitors. The study has also opened doors to JAK inhibitors as a potential treatment for other inflammatory skin disorders or disorders relating to tissue scarring, inclusive of scarring of the lungs, liver, or bone marrow. Therefore, JAK inhibitors could revolutionize how we treat rare diseases that previously had no effective treatment, as they target the inflammatory pathway while avoiding severe side effects seen with previous therapies.
