Immune Skin Conditions Clinical Trial

This study involves adolescents and adults with Down syndrome (ages 12 to 50 years) who have one or more immune-driven skin conditions, including:

• Alopecia areata (hair loss)
• Atopic dermatitis (eczema)
• Hidradenitis suppurativa (boils)
• Psoriasis (itchy, flaky skin)
• Vitiligo (pigmentation loss)

The primary objective of this clinical trial is to establish whether tofacitinib is safe in adults with Down syndrome. To do this, we will be closely monitoring a battery of lab values and any adverse events. We anticipate that tofacitinib will have a similar safety profile in people with Down syndrome as in the typical population.

The second objective of this clinical trial is determine whether tofacitinib is effective at treating any one or more of the above skin conditions in people with Down syndrome. To measure this, we will use common dermatology assessments for each skin condition.

The third objective of this clinical trial is to determine whether tofacitinib can help normalize the immune dysregulation we observe in people with Down syndrome. We will be performing a battery of experiments on blood drawn from participants to look at numerous biomarkers of immune dysregulation.

Finally, our exploratory objectives include beginning to measure the impacts, if any, of tofacitinib on other auto-immune conditions (like celiac disease or hypothyroidism) and on cognition and quality of life.

Tofacitinib is an immunosuppressive drug that inhibits key proteins in the interferon pathway called Janus kinases (or "JAKs"). We found the interferon pathway to be chronically activated in people with Down syndrome and believe it may be the key driver of immune dysregulation in people with Down syndrome. Therefore, inhibiting the JAK proteins may normalize immune function and positively impact multiple aspects of health in people with Down syndrome.

Tofacitinib has been studied in the general population and is approved by the FDA to treat psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis (you may have even seen it marketed under the name Xeljanz^®). Tofacitinib has also been studied in clinical trials to treat alopecia areata, dermatitis and eczema, psoriasis, and other autoimmune disorders that people with Down syndrome are more pre-disposed to. In fact, we are personally aware of several individuals with Down syndrome who have been taking tofacitinib to treat some of these immune conditions with great success. However, tofacitinib has not yet been systemically studied in people with Down syndrome.

In 2016, we discovered that people with Down syndrome have chronically activated interferon signaling.

Interferon signaling is a branch of the immune system involved in fighting off viral infections. On average, people with Down syndrome have more interferon activity in their immune system than the general population, even when they aren't actually fighting a virus. This is probably due to the fact that several important interferon genes are encoded on chromosome 21. We published this discovery in eLife in 2016. Interestingly, scientific literature in the field hinted at this as far back as the 1970's, but the exact mechanism and impacts of increased interferon signaling in Down syndrome had yet to be well characterized. This was the beginning of what has become a robust immune research program at the Crnic Institute. 

 

Interferon signaling likely contributes to many hallmarks of Down syndrome, including common co-occurring conditions.

When interferon signaling is activated, the result is inflammation. And in fact, we showed that biomarkers in the blood of people with Down syndrome point to a state of chronic inflammation, published in Scientific Reports in 2017. 

It's not hard to imagine how systemic inflammation over a sustained time could have significant impacts on the immune system specifically, and the entire body more broadly. We thus embarked on in-depth characterizations of people with Down syndrome using samples from the Human Trisome Project, including:

• Mapping 100 immune cell subsets using mass cytometry, published in Cell Reports in 2019.
• Characterizing T cell differentiation and function, published in PNAS in 2019.
• Evaluating metabolic pathways in plasma and cerebral spinal fluid, published in Nature Communications in 2019.

In each these studies, we found specific changes in the immune systems and metabolism of people with Down syndrome that are known to be associated with various autoimmune, neurological, and neurodegenerative conditions in the general population. We also showed that these changes are likely driven by the interferon genes located on chromosome 21 and are working on more experiments now to better define this.

 

We hypothesize that normalizing interferon signaling in people with Down syndrome could have many benefits.

If chronically active interferon signaling contributes to negative health impacts in people with Down syndrome, one obvious next question is, "how can we stop it?" Thankfully, the interferon signaling pathway has been a popular target for drug development in recent years, so there are a lot of tools already at our disposal. For example, we followed two people with Down syndrome who had alopecia areata (an autoimmune disorder causing hair loss) that didn't respond to traditional treatment. They both started taking a drug called tofacitinib, which inhibits a family of proteins called JAKs in the interferon pathway, and both saw remarkable re-growth of their hair. We published these case reports in JAAD Case Reports in 2019 and continue to follow these and other individuals who are benefiting from tofacitinib. 

Now, in this clinical trial, we aim to more comprehensively test the safety of tofacitinib in people with Down syndrome and evaluate its ability to treat various immune-driven skin conditions, including alopecia. In a more exploratory manner, we will also ask whether reducing interferon signaling can improve other autoimmune conditions, like celiac disease and hypothyroidism, and whether it can improve cognition and overall quality of life. This clinical trial will greatly advance our understanding of how interferon signaling contributes to many hallmarks of Down syndrome, eventually leading to better, more personalized medical care for people with Down syndrome.

Trisomy 21 consistently activates the interferon response. Sullivan KD, Lewis HC, Hill AA, Pandey A, Jackson LP, Cabral JM, Smith KP, Liggett LA, Gomez EB, Galbraith MD, DeGregori J, Espinosa JM. Elife. 2016 Jul 29;5. pii: e16220. PMID: 27472900. PMCID: PMC5012864. doi: 10.7554/eLife.16220.

 

Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation. Sullivan KD, Evans D, Pandey A, Hraha TH, Smith KP, Markham N, Rachubinski AL, Wolter-Warmerdam K, Hickey F, Espinosa JM, Blumenthal T. Sci Rep. 2017 Nov 1;7(1):14818. PMID: 29093484. PMCID: PMC5665944. doi: 10.1038/s41598-017-13858-3.

 

Janus kinase inhibition in Down syndrome: 2 cases of therapeutic benefit for alopecia areata. Rachubinski AL, Estrada BE, Norris D, Dunnick CA, Boldrick JC, Espinosa JM. JAAD Case Rep. 2019 Apr 5;5(4):365-367. PMID: 31008170. PMCID: PMC6453941. doi: 10.1016/j.jdcr.2019.02.007.

 

Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors. Powers RK, Culp-Hill R, Ludwig MP, Smith KP, Waugh KA, Minter R, Tuttle KD, Lewis HC, Rachubinski AL, Granrath RE, Carmona-Iragui M, Wilkerson RB, Kahn DE, Joshi M, Lleó A, Blesa R, Fortea J, D'Alessandro A, Costello JC, Sullivan KD, Espinosa JM. Nat Commun. 2019 Oct 18;10(1):4766. PMID: 31628327. PMCID: PMC6800452. doi: 10.1038/s41467-019-12739-9.

 

Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome. Waugh KA, Araya P, Pandey A, Jordan KR, Smith KP, Granrath RE, Khanal S, Butcher ET, Estrada BE, Rachubinski AL, McWilliams JA, Minter R, Dimasi T, Colvin KL, Baturin D, Pham AT, Galbraith MD, Bartsch KW, Yeager ME, Porter CC, Sullivan KD, Hsieh EW, Espinosa JM. Cell Rep. 2019 Nov 12;29(7):1893-1908.e4. PMID: 31722205. PMCID: PMC6871766. doi: 10.1016/j.celrep.2019.10.038.

 

Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity. Araya P, Waugh KA, Sullivan KD, Núñez NG, Roselli E, Smith KP, Granrath RE, Rachubinski AL, Enriquez Estrada B, Butcher ET, Minter R, Tuttle KD, Bruno TC, Maccioni M, Espinosa JM. Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24231-24241. PMID: 31699819. PMCID: PMC6883781. doi: 10.1073/pnas.1908129116.