An innovative study has identified a strategy to alleviate the impact of alopecia areata, atopic dermatitis, psoriasis, and other autoimmune disorders.
A groundbreaking study published in eLIFE by researchers from the Linda Crnic Institute for Down Syndrome at the University of Colorado Anschutz Medical Campus presents initial findings from a novel clinical trial. This trial evaluates the safety and effectiveness of a JAK inhibitor aimed at reducing the impact of autoimmune diseases in individuals with Down syndrome. The study, funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, is part of an array of new clinical trials developed under the National Institutes of Health INCLUDE Project.
Building on their 2016 discovery that individuals with Down syndrome experience a persistent activation of the interferon response, the research team designed the trial to target common autoimmune and inflammatory skin issues in this population, including alopecia areata, psoriasis, atopic dermatitis, and hidradenitis suppurativa. They used the JAK inhibitor tofacitinib (also known as XELJANZ®, marketed by Pfizer). The study also assessed the impact on accompanying autoimmune disorders, such as autoimmune thyroid disease, celiac disease, and arthritis.
“People with Down syndrome have a heightened risk of developing autoimmune skin disorders, which are often challenging to treat and can significantly reduce their quality of life,” states Dr. Emily Gurnee, a dermatology assistant professor involved in the research and a primary investigator in the trial. “There is limited information available to help guide conversations about treatment alternatives for skin issues prevalent among individuals with Down syndrome. The results from the Crnic Institute researchers support the idea that JAK inhibitors are a promising treatment option not only for skin conditions but may also help address other autoimmune disorders that are common in this demographic.”
The research team noted significant improvements in skin symptoms, particularly in participants with alopecia areata, alongside enhancements in arthritis symptoms and reduced biomarkers of autoimmune thyroid disease. After the trial concluded, many participants opted to continue using the medication, often through off-label prescriptions.
“Most importantly, we found that key inflammatory markers that are elevated in Down syndrome and contribute to autoimmunity were reduced to normal levels with this medication. This suggests that the immune response is being moderated by the JAK inhibitor, while still maintaining effective immune function,” explains Dr. JoaquÃn Espinosa, executive director of the Crnic Institute, professor of pharmacology, and one of the principal investigators in the study. “Further research will be necessary to fully understand the safety profile of JAK inhibitors in individuals with Down syndrome, and we are eager to complete the trial and analyze the complete dataset.”
The study also marks the most comprehensive analysis of the immune system dysregulation associated with Down syndrome to date, drawing from clinical data and biospecimens gathered through the ongoing Human Trisome Project study.
The research team from the Crnic Institute examined clinical information and blood samples to map the pattern of autoimmune disorders and related inflammatory processes among hundreds of participants in the Human Trisome Project using advanced multi-omics technologies. Their findings indicate that the triplication of chromosome 21, known as trisomy 21, which causes Down syndrome, leads to an early and diverse onset of autoimmune issues in childhood, alongside increased levels of various inflammatory markers and marked dysregulation of multiple immune cell types.
“A critical observation is that the increase in several inflammatory markers and the dysregulation of all immune system components begins at a very young age, even before any signs of autoimmunity appear,” says Dr. Matthew Galbraith, assistant research professor of pharmacology, director of the Data Sciences Program at the Crnic Institute, and co-author of the study. “This suggests a fundamental state of immune dysregulation initiated by the extra chromosome, which gradually results in the emergence of multiple autoimmune conditions, varying in timing and severity among individuals.”
“Since 2016, we have been proposing that JAK inhibitors could offer therapeutic advantages for this population,” shares Dr. Angela Rachubinski, assistant research professor of pediatrics, director of the Clinical and Translational Sciences Program at the Crnic Institute, the lead author of the study, and one of the principal investigators in the trial. “Even though JAK inhibitors have been authorized for several autoimmune and inflammatory conditions in the general populace, this clinical trial, which began in 2020, represents the first systematic investigation of a JAK inhibitor’s effects in individuals with Down syndrome.”
The Crnic Institute research team is already overseeing a second trial to evaluate the safety and efficacy of the JAK inhibitor compared to other medications for addressing Down Syndrome Regression Disorder. Additionally, a third trial focused on children with Down syndrome is anticipated to commence recruitment in late 2024.
