An Update on JAK Inhibitors in Skin Disease

A topic dermatitis (AD) is a chronic inflammatory skin disorder affecting 7% of adults and 13% of children in the United States.1,2 Atopic dermatitis is characterized by pruritus, dry skin, and pain, all of which can negatively impact quality of life and put patients at higher risk for psychiatric comorbidities such as anxiety and depression.3 The pathogenesis of AD is multifactorial, involving genetics, epidermal barrier dysfunction, and immune dysregulation.Overactivation of helper T cell (T H 2) pathway cytokines, including IL-4, IL-13, and IL-31, is thought to propagate both inflammation and pruritus, which are central to AD.The JAK-STAT signaling pathway plays a pivotal role in the immune system dysregulation and exaggeration of T H 2 cell response, making JAK-STAT inhibitors (or JAK inhibitors) strong theoretical candidates for the treatment of AD. 4 In humans, the Janus kinases are composed of 4 different members-JAK1, JAK2, JAK3, and tyrosine kinase 2-all of which can be targeted by JAK inhibitors.5 JAK inhibitors such as tofacitinib have already been approved by the US Food and Drug Administration (FDA) to treat various inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, and psoriatic arthritis; other JAK inhibitors such as baricitinib are only approved for patients with rheumatoid arthritis.6,7 The success of these small molecule inhibitors in these immune-mediated conditions make them attractive candidates for the treatment of AD.Several JAK inhibitors are in phase 2 and phase 3 clinical trials as oral therapies (moderate to severe AD) or as topical treatments (mild to moderate AD).Currently, ruxolitinib (RUX) is the only topical JAK inhibitor that is FDA approved for the treatment of AD in the United States.8 In this editorial, we focus on recent trials of JAK inhibitors tested in patients with AD, including topical RUX, as well as oral abrocitinib, upadacitinib, and baricitinib. Topical RUX in ADRuxolitinib is a topical JAK1/2 small molecule inhibitor approved by the FDA for the treatment of AD in 2021.In a randomized trial by Kim et al 9 in 2020, all tested regimens of RUX demonstrated significant improvement in eczema area and severity index (EASI) scores vs vehicle; notably, RUX cream 1.5% applied twice daily achieved the greatest mean percentage change in baseline EASI score vs vehicle at 4 weeks (76.1% vs 15.5%; P<.0001).Ruxolitinib cream was well tolerated through week 8 of the trial, and all adverse events (AEs) were mild to moderate in severity and comparable to those in the vehicle group.9 Topical JAK inhibitors appear to be effective for mild to moderate AD and have had an acceptable safety profile in clinical trials thus far.Although topical corticosteroids and calcineurin inhibitors can have great clinical benefit in AD, they are recommended for short-term use given side effects such as thinning of the skin, burning, or telangiectasia formation.10,11 The hope is that topical JAK inhibitors may be an alternative to standard topical treatments for AD, as they can be used for longer periods due to a safer side-effect profile.

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