Improving autoimmune conditions in Down syndrome patients

Researchers from the Linda Crnic Institute for Down Syndrome at the University of Colorado Anschutz Medical Campus have reported initial results from a first-in-kind clinical trial testing the safety and efficacy of a JAK inhibitor in decreasing the burden of autoimmune skin conditions in people with Down syndrome, which are often hard to treat and can cause significant discomfort. People with Down syndrome are at particularly high risk of developing such conditions, yet limited data exists to guide conversations about treatment options.

After discovering in 2016 that the interferon response is constantly activated in people with Down syndrome, the research team hypothesised that the class of medicines known as JAK inhibitors would provide therapeutic benefits in this population. But although JAK inhibitors have been approved for a range of autoimmune and inflammatory conditions in the general population, the current clinical trial — which started activities back in 2020 — provides the first known systematic investigation of the effects of a JAK inhibitor in people with Down syndrome.

The research team designed the trial to focus on the autoimmune and inflammatory skin conditions that are very common in people with Down syndrome — including alopecia areata, psoriasis, atopic dermatitis and hidradenitis suppurativa — and employed the JAK inhibitor tofacitinib (marketed as XELJANZ by Pfizer). The study also monitored effects on co-occurring autoimmune conditions, such as autoimmune thyroid disease, celiac disease and arthritis. Their results were published in the journal eLife.

The team observed important improvements in skin pathology, with the most striking results observed for those affected by alopecia areata, as well as improvements in arthritis and decreased biomarkers of autoimmune thyroid disease. Most study participants chose to remain on the medicine, often through off-label prescriptions, after completion of trial activities.

“Most importantly, we observed that major inflammatory markers elevated in Down syndrome that are known to cause autoimmunity were brought down to the normal range with this medicine, indicating that the immune system is being calmed down by this JAK inhibitor, while preserving strong immune function,” said Dr Joaquín Espinosa, Executive Director of the Crnic Institute and a principal investigator on the clinical trial. “More data will be needed to define the safety profile of JAK inhibitors in Down syndrome, and we look forward to the completion of the trial and analysis of the full dataset.”

The researchers also reported what is understood to be the deepest characterisation of the immune system dysregulation characteristic of Down syndrome to date. Using multi-omics technologies, they analysed clinical data and blood samples to characterise the pattern of autoimmune conditions and accompanying inflammatory processes in hundreds of research participants in the ongoing Human Trisome Project. They observed that triplication of chromosome 21, or trisomy 21 — the genetic abnormality underlying Down syndrome — leads to rapid onset of diverse autoimmune conditions during childhood, along with increased levels of many inflammatory factors and strong dysregulation of multiple immune cell types.

“One key observation is that elevation of multiple inflammatory markers and dysregulation of all branches of the immune system occurs from a very early age, even before any clinical manifestations of autoimmunity,” said Dr Matthew Galbraith, Director of the Crnic Institute’s Data Sciences Program and a co-author on the study. “This points to a constitutive state of immune dysregulation triggered by the extra chromosome that eventually leads to the appearance of multiple autoimmune conditions, with variations in timing and severity among individuals.”

“The findings from scientists at the Crnic Institute support the notion that JAK inhibitors are a valuable treatment not only for skin conditions but may benefit other autoimmune conditions prevalent in this population,” said Dr Emily Gurnee, a principal investigator on the trial. The study team is already overseeing a second trial testing the safety and efficacy of the JAK inhibitor relative to other medicines for treating the condition known as Down Syndrome Regression Disorder, and a third trial focused on children with Down syndrome is expected to start recruitment in late 2024.

Image credit: iStock.com/wisely