JAK Inhibitor Improves Autoimmune Conditions in Down Syndrome

Emily Gurnee, MD

Credit: University of Colorado Anschutz Medical Campus

A phase 2 trial demonstrated the JAK inhibitor tofacitinib (Xelijanz, Pfizer) improves multiple autoimmune conditions in patients with Down syndrome.

“Limited data exist to guide conversations about treatment options for skin conditions common to individuals with Down syndrome,” said Emily Gurnee, MD, co-lead investigator and assistant professor of dermatology at University of Colorado Anschutz Medical Campus, in a press release. “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.”

Individuals with Down syndrome exhibit signs of immune dysregulation and have high rates of autoimmune disorders. It is known trisomy 21 leads to increased interferon responses, JAK/STAT signaling, elevated autoantibodies, widespread changes in the immune system, and hypercytokinemia. However, the interaction of these processes, how they contribute to the clinical symptoms of Down syndrome, and what therapeutic options might be effective are still not well understood.

In this study, investigators had 3 objectives:

1. Examine the immune dysregulation at the clinical, cellular, and molecular levels.
2. Investigate immune cell changes associated with several clinical and molecular markers of autoimmunity in individuals with Down Syndrome
3. Determine if tofacitinib, a JAK inhibitor, was effective and safe in reducing the burden of autoimmune conditions in people with Down syndrome

Immune Dysregulation at Clinical, Cellular, and Molecular Levels

Investigators conducted a comprehensive analysis of the Human Trisome Project cohort study, where they analyzed the clinical profiles of 441 research participants with Down syndrome, aged 6 months to 57 years.

The most common autoimmune condition among the sample was autoimmune thyroid disease (AITD), affecting nearly half of the participants (53.1%). Autoimmune and inflammatory skin conditions were the second most common category, impacting 43% of the sample: atopic dermatitis (27.9%), hidradenitis suppurativa/folliculitis/boils (20.6%), alopecia areata (7.7%), psoriasis (6.1%), and vitiligo (1.9%).

Investigators observed autoimmune conditions had any early onset in individuals with Down syndrome, with > 80% of cases of AITD and autoimmune /inflammatory skin conditions diagnosed in the first 2 decades of life. Many participants had multiple autoimmune diseases; 75% had a history of ≥ 1 condition, 38.4% had ≥ 2 conditions, and 13.6 had ≥ 3 conditions.

Examining Immune Cell Changes

Investigators analyzed mass cytometry data from 292 individuals with Down syndrome vs 96 controls. Participants were analyzed for potential differences in immune cell subpopulations.

The team observed massive immune remodeling in all major myeloid and lymphoid subsets. For instance, there were increases in basophils and depletions of eosinophils and total B cells. After comparing subgroups with the Down syndrome cohort based on autoimmunity status, investigators noticed global immune changes were largely independent of the clinical diagnosis, with very few changes significantly associated with measures of autoimmunity.

To better understand the interplay between hypercytokinemia, individual elevated cytokines, and the development of autoimmune conditions in Down syndrome, investigators analyzed inflammatory markers in 346 individuals from the sample compared to 131 controls. They found significant hypercytokinemia in Down syndrome along with a significant elevation of multiple acute-phase proteins (CRP, SAA, IL1RA), pro-inflammatory cytokines (TSLP, IL-17C, IL-22, IL-17D, IL-9, IL-6, TNF-α), and chemokines (IP-10, MIP-3a, MIP-1a, MCP-1, MCP-4, Eotaxin). Additionally, they observed the elevation of growth factors linked to inflammation and wound healing (FGF, PlGF, VEGF-A).

Investigators did not observe significant differences based on the number of autoimmune conditions. These results suggest that trisomy 21 leads to hypercytokinemia from early childhood, rather than inflammatory changes increasing with age.

Evaluating JAK Inhibitor in Down Syndrome

Lastly, investigators conducted a phase 2 single-site, open-label clinical trial with individuals with Down syndrome aged 12 – 50 years affected by alopecia areata, hidradenitis suppurativa, psoriasis, atopic dermatitis, or vitiligo. Participants were prescribed 5 mg of tofacitinib twice daily for 16 weeks with the option of a 40-week extension.

Participants had 5 safety monitoring visits during the 16-week trial period. The goal of this trial is for 40 participants to complete 16 weeks of tofacitinib treatment. However, investigators conducted an IRB-approved qualitative interim analysis after the first 10 participants completed the main 16-week trial.

The 10 participants in the analysis had either alopecia areata (n=6), hidradenitis suppurativa (n=3), or psoriasis (n=1). The sample included 2 participants who also presented with concurrent atopic dermatitis, 2 with concurrent vitiligo, and 2 with concurrent hidradenitis suppurativa.

Tofacitinib demonstrated a good safety profile, with no adverse events related to tofacitinib treatment or severe reactions. However, 5 participants experienced upper respiratory infections with common symptoms including a cough and rhinorrhea. These symptoms resolved by the end of the trial, often with over-the-counter medication and sometimes with antibiotic treatment.

The trial monitored skin pathology using global metrics of skin health, such as the Investigator’s Global Assessment (IGA) and the Dermatology Life Quality Index (DLQI). Investigators also used disease-specific scores, such as the severity of alopecia tool (SALT), the psoriasis area and severity index (PASI), or the eczema area and severity index (EASI)

The study revealed 7 of the 10 participants had improved IGA scores, and 8 of the 10 participants had improved life quality related to their skin condition, as indicated by their DLQI score.

The most striking improvement, according to investigators, was regarding alopecia areata; 5 of 6 participants showed scalp hair regrowth. The only one who did not was a male participant who has a history of alopecia totalis for ≥ 20 years, but even he showed facial hair and eyelash regrowth.

One participant with psoriasis experienced an almost complete remission of psoriatic arthritis symptoms. Two participants with atopic dermatitis had reduced clinical manifestations during tofacitinib treatment.

A time-course analysis demonstrated most participants had reduced IFN scores as early as 2 weeks of treatment, which was sustained over time. The exceptions were 1 patient at week 8 who paused taking tofacitinib due to a recent COVID-19 vaccination, and 1 patient at week 16 who developed an upper respiratory infection.

Investigators also observed a decrease in peripheral inflammatory markers, defined as a compositive cytokine score from the measurements of TNF-α, IL-6, CRP, and IP-10.

Seven of the 10 participants at baseline had anti-TPO levels above the upper limit of normal (ULN, 60U/mL), and all 7 participants experienced a reduction in these autoantibodies at 8 weeks and 16 weeks. One participant even decreased below the ULN during the trial.

“Since 2016 we have been hypothesizing that the class of medicines known as JAK inhibitors will provide therapeutic benefits in this population,” said Angela Rachubinski, PhD, director of the Clinical and Translational Sciences Program at the Crnic Institute and co-lead investigator, in the press release. “Although JAK inhibitors have been approved for a range of autoimmune and inflammatory conditions in the general population, this clinical trial, which started activities back in 2020, provides the first systematic investigation of the effects of a JAK inhibitor in people with Down syndrome."

References

1. ^{Rachubinski AL, Wallace E, Gurnee E, et al. JAK inhibition decreases the autoimmune burden in Down syndrome. Preprint. medRxiv. 2024;2024.06.13.24308783. Published 2024 Jun 14. doi:10.1101/2024.06.13.24308783}
2. ^{Crnic Institute Clinical Trial Shows JAK Inhibitor Improves Multiple Autoimmune Conditions In Patients With Down Syndrome. EurekAlert! August 13, 2024. https://www.eurekalert.org/news-releases/1054485. Accessed August 19, 2024.}