In a groundbreaking new study published in eLIFE, researchers from the Linda Crnic Institute for Down Syndrome (Crnic Institute) at the University of Colorado Anschutz Medical Campus have reported promising initial results from a first-of-its-kind clinical trial. The study aims to test the safety and efficacy of a JAK inhibitor in reducing the burden of autoimmune conditions in individuals with Down syndrome. This clinical trial, funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, is part of a series of new trials supported by the National Institutes of Health INCLUDE Project.
Building on their 2016 discovery that individuals with Down syndrome have a constantly activated interferon response, the research team designed the trial to address the autoimmune and inflammatory skin conditions that are prevalent in this population. These conditions include alopecia areata, psoriasis, atopic dermatitis, and hidradenitis suppurativa. The team utilized the JAK inhibitor tofacitinib, marketed as XELJANZ® by Pfizer, and monitored its effects on co-occurring autoimmune conditions such as autoimmune thyroid disease, celiac disease, and arthritis.
Dr. Emily Gurnee, an assistant professor of dermatology and principal investigator in the trial, explains, “Individuals with Down syndrome often develop autoimmune skin conditions that are challenging to treat and significantly impact their quality of life. The findings from the Crnic Institute suggest that JAK inhibitors could be a valuable treatment not only for skin conditions but also for other autoimmune conditions common in this population.”
The study team observed significant improvements in skin pathology, particularly in individuals affected by alopecia areata, as well as improvements in arthritis and decreased biomarkers of autoimmune thyroid disease. Most participants chose to continue taking the medication, often through off-label prescriptions, after the trial ended.
Dr. Joaquín Espinosa, executive director of the Crnic Institute and one of the principal investigators, notes, “Our findings show that the JAK inhibitor effectively reduces major inflammatory markers associated with autoimmunity in Down syndrome, indicating that the immune system is being regulated while maintaining its functionality. Further studies are needed to fully assess the safety profile of JAK inhibitors in this population.”
In addition to the clinical trial results, the study also provides a comprehensive analysis of immune system dysregulation in individuals with Down syndrome. Through the ongoing Human Trisome Project study, the Crnic Institute team collected and analyzed clinical data and biospecimens to better understand autoimmune conditions and inflammatory processes in this population.
Dr. Matthew Galbraith, co-author of the study, highlights, “The triplication of chromosome 21 in Down syndrome leads to the early onset of diverse autoimmune conditions and significant dysregulation of the immune system. This dysregulation begins at a young age, even before clinical symptoms appear, indicating a constitutive state of immune dysfunction triggered by the extra chromosome.”
Dr. Angela Rachubinski, lead author of the paper and another principal investigator, states, “Since 2016, we have believed that JAK inhibitors could offer therapeutic benefits for individuals with Down syndrome. This trial, initiated in 2020, represents the first systematic investigation of the effects of a JAK inhibitor in this population.”
The Crnic Institute team is now conducting a second trial to assess the efficacy of the JAK inhibitor for treating Down Syndrome Regression Disorder, with a third trial focused on children with Down syndrome set to begin recruitment in late 2024.
