tofacitinib for immune skin conditions in down syndrome

Conditions: Down Syndrome; Alopecia Areata; Atopic Dermatitis / Eczema; Hidradenitis Suppurativa; Vitiligo; Psoriasis

Summary: people with down syndrome (ds) display widespread immune dysregulation, including several immune skin conditions. this study hypothesizes that pharmacological inhibition of the increased interferon (ifn) signaling seen in ds is safe and could improve associated skin conditions. the study evaluates the safety and efficacy treatment with tofacitinib, an fda-approved drug known to block ifn signaling, in adolescents and adults with ds and an autoimmune and/or autoinflammatory skin condition. investigators will also measure the impact of interferon inhibition on a variety of molecular markers, as well as the cognitive abilities and quality of life of participants.

trisomy 21 (t21) is the most common human chromosomal disorder, occurring in \~1/700 live births, leading to the condition known as down syndrome (ds). importantly, people with ds display widespread immune dysregulation and over half of adults with t21 are affected by one or more autoimmune conditions, including several immune skin conditions. the driving hypothesis for this study is that hyperactivation of interferon (ifn) signaling leads to myriad immune-driven diseases and immunological phenotypes in people with ds, and that pharmacological inhibition of ifn signaling could have multidimensional therapeutic benefits in this population. this study utilizes tofacitinib, an fda-approved drug known to block ifn signaling and several accompanying inflammatory pathways, to reduce ifn signaling in ds and to measure its effects via multidimensional endpoints. previous studies and current clinical trials indicate that janus kinase (jak) inhibitors, such as tofacitinib, can block inflammatory pathways and may have beneficial effects on immune skin conditions. further, inhibition of chronically active ifn signaling in ds with tofacitinib may attenuate other core drivers of immune dysregulation, leading to improvements in other immune diseases and conditions common to ds that are potentially driven by inflammation, such as cognitive deficits. investigators will test these hypotheses using a battery of immune and molecular assessments, as well as cognitive testing and quality of life measures. this clinical trial evaluates adolescent and adult participants with ds during eight study visits over an approximate five month period. specific aims: 1. to define the safety profile of jak inhibition in people with ds, 2. to determine the impact of jak inhibition on the immune dysregulation caused by trisomy 21, 3. to define the impact of jak inhibition on immune skin conditions in ds, and 4. to characterize the impact of jak inhibition on cognition and quality of life in ds.

Eligibility criteria:
inclusion criteria: * males or females with ds between 12 and 50 years of age who weigh at least 40 kg. * diagnosis of at least one active immune skin condition, including but not limited to: 1. moderate-to-severe atopic dermatitis 2. alopecia areata affecting at least 25% of the scalp 3. moderate-to-severe hidradenitis suppurativa 4. moderate-to-severe psoriasis 5. moderate-to-severe vitiligo. * be willing to avoid pregnancy or fathering children. * must present with a study partner or legal guardian who can complete, or assist with completing, study materials as appropriate. exclusion criteria * weigh less than 40 kg. * pregnancy or breast feeding. * no study partner or legal guardian. * vaccination with live attenuated virus within six weeks of inclusion in the study or planned during the study. * clinically significant chronic or active viral infection including but not limited to hiv, hepatitis, cmv, ebv, hsv. * severe renal impairment. * history of malignant solid tumor cancer within five years prior to study entry or where there is current evidence of recurrent or metastatic disease. * poor venous access not allowing repeated blood tests or non-compliance with venipuncture requirements. * prior treatment with a jak inhibitor or with an investigational agent, device, or procedure within 21 days of enrollment. * concomitant treatment with other immunosuppressants (e.g. corticosteroids, methotrexate) or strong cp3a4 or cyp2c19 inhibitors or inducers (e.g. ketoconazole, fluconazole). * known allergies, hypersensitivity, or intolerance to tofacitinib. * history of thrombotic disorder. * superficial skin infection within 2 weeks of inclusion in the study. * history of disseminated herpes zoster, disseminated herpes simplex, or recurrent localized dermatomal herpes zoster. * intravenous antimicrobial therapy within 3 months of inclusion in the study. * oral antimicrobials within 2 weeks of inclusion in the study. * participants may be excluded for other unforeseen reasons at the study doctor's discretion. * unable to provide assent in cases where informed consent is obtained from other authorized representative. * kidney transplant within the last two years * any history of heart attack or stroke. * any history of lymphoma. * past or current smokers.

Keywords: interferon autoimmunity down syndrome skin disorder jak inhibitor inflammation jak/stat dermatology