Clinical Trial Demonstrates JAK Inhibitor Improves Autoimmune Conditions in Patients with Down Syndrome

A recent study published in eLIFE showcases the initial results of a groundbreaking clinical trial. This research, conducted by the Linda Crnic Institute for Down Syndrome at the University of Colorado Anschutz Medical Campus, focuses on a JAK inhibitor's safety and efficacy. The aim is to alleviate autoimmune conditions among individuals with Down syndrome. This clinical trial is part of a series funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, alongside the NIH INCLUDE Project.

The trial builds upon the discovery made in 2016 that individuals with Down syndrome experience persistent activation of the interferon response. The research team targeted prevalent autoimmune and inflammatory skin conditions, including alopecia areata, psoriasis, atopic dermatitis, and hidradenitis suppurativa. They utilized the JAK inhibitor tofacitinib, marketed as XELJANZ® by Pfizer. Additionally, the effects on associated autoimmune diseases, such as autoimmune thyroid disease, celiac disease, and arthritis, were monitored.

Dr. Emily Gurnee, an assistant professor in dermatology and a principal investigator of the trial, remarks, "Individuals with Down syndrome are at a high risk of developing autoimmune skin conditions." She highlights the challenges of treatment and their impact on patients’ quality of life. The insufficient data complicates discussions around treatment options, but this study supports the notion that JAK inhibitors can serve as effective treatments.

Significant improvements in skin pathology were noted, particularly in alopecia areata patients. The researchers also observed improvements in arthritis and lowered autoimmune thyroid disease biomarkers. Following the trial's conclusion, many participants opted to continue using the medication, often through off-label prescriptions.

Dr. Joaquín Espinosa, executive director of the Crnic Institute, explains the findings: "Inflammatory markers known to cause autoimmunity were brought down to normal levels with this JAK inhibitor." He emphasizes that the immune system appears to be moderated while maintaining essential immune functions. Though more data is necessary to determine the safety profile of these inhibitors specifically in Down syndrome, the research team is eager for further analysis of the trial’s data.

The study offers the most detailed characterization of immune system dysregulation associated with Down syndrome to date. This was achieved through the analysis of clinical data and biospecimens collected from the ongoing Human Trisome Project study.

Utilizing multi-omics technologies, the Crnic Institute's team analyzed clinical data and blood samples from numerous participants involved in the Human Trisome Project. They found that trisomy 21—underlying Down syndrome—leads to early onset of various autoimmune conditions in childhood, accompanied by elevated levels of inflammatory factors and significant dysregulation among numerous immune cell types.

Dr. Matthew Galbraith, a research professor and co-author of the study, notes a crucial finding: "Inflammatory markers and immune dysregulation occur from a very early age, sometimes before signs of autoimmunity appear." This suggests an ongoing immune dysregulation triggered by the presence of an extra chromosome, eventually resulting in a range of autoimmune conditions that differ in timing and severity among individuals.

Reflecting on prior hypotheses, Dr. Angela Rachubinski, lead author and principal investigator, notes that JAK inhibitors could lead to therapeutic advantages in the Down syndrome population. While these medications have gained approval for various autoimmune and inflammatory disorders in the broader population, this trial represents the first structured examination of a JAK inhibitor’s effects on individuals with Down syndrome.

Looking ahead, the Crnic Institute's research team is managing a second trial on the safety and efficacy of JAK inhibitors compared to other treatments for Down Syndrome Regression Disorder. A third trial aimed at children with Down syndrome is anticipated to begin recruitment in late 2024.

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