Project Summary Down syndrome (DS) affects 1 in 700 newborns in the United States. It is the most common genetic cause of intellectual disability. DS individuals also frequently present with cardiac anomalies and are at increased risk for Alzheimer's disease, hematological neoplasia, autoimmune conditions (e.g., hypothyroidism, celiac disease, type I diabetes, arthritis), and inflammatory skin diseases such as atopic dermatitis (AD), alopecia areata (AA), and vitiligo, but also psoriasis and hidradenitis suppurativa. Studies have shown that the inflammatory and autoimmune comorbidities associated with DS may be due to overt inflammation caused by increases in many cytokines which signal through the JAK/STAT pathway. This inflammation may also be due to increased presence of type I, II and III interferon receptors, all encoded on chromosome 21, which also use JAK/STAT pathway to signal. Treatment of inflammatory skin diseases in individuals with DS involves broad immunosuppressive medications, which are often associated with multiple side effects and limited efficacy. Given the term hyperactivation of JAK/STAT signaling in DS, JAK inhibition presents an appealing alternative for better long- disease control.Several case reports, case series, and studies across inflammatory joint and skin conditions showed the efficacy, safety and tolerability of the pan-JAK inhibitor tofacitinib in individuals with DS. Importantly, none of these studies reported new safety concerns. Further, more selective JAK inhibitors, such as the JAK1/JAK2 inhibitor ruxolitinib, demonstrated potential in synergistically ameliorating hematologic conditions associated with DS. This is consistent with our own studies, in which ex vivo tofacitinib successfully attenuated hyperinflammation in individuals with DS. However, while tofacitinib is approved in rheumatoid arthritis, it has not been FDA-approved for any skin indications (risk was determined by the FDA to outweigh benefit in psoriasis), and nor has oral ruxolitinib. Thus, individuals with DS deserve timely and appropriate evaluation of the long-term safety and efficacy of newer and more specific JAK inhibitors that are currently FDA- approved for dermatological indications, such as AD and AA. Since a particularly higher inflammatory tone has been shown in DS, the dosing of these newer drugs and their long-term safety and efficacy should also be evaluated in patients with DS. Such drugs include abrocitinib, a JAK1 inhibitor that was recently approved for moderate-to-severe AD in both typical adults and typical adolescents aged at least 12 years, and ritlecitinib, a JAK3/TEC inhibitor that has completed phase 3 studies in AA and has just obtained FDA approval in AA. Herein we propose a clinical trial to evaluate the long-term safety and efficacy of 60 weeks of treatment of the low and high dose of abrocitinib in individuals with DS presenting with AD and AA, and of ritlecitinib in those individuals with AA that did not adequ...