How Should I Use JAK Inhibitors in My Practice

JAK inhibitors have exploded in the dermatopharmacologic market over the past few years, with myriad disease indications and formulations available. Raj Chovatiya, MD, PhD, started this vigorous session with multiple cases including atopic dermatitis, alopecia areata, and vitiligo, all well suited to treatment with JAK inhibitors. He postulated that the JAK inhibitors work well for numerous dermatologic conditions as, though they themselves are very targeted, the JAK family of proteins impacts many different downstream cytokines. For example, in alopecia areata, MHC Class I expression is increased through JAK 1 and JAK 2, and the activated CD8+ NKG2D+ cells release IFN-gamma, which binds on follicular epithelial cells leading to transition into the catagen phase. JAK inhibitors are perfectly targeted to interfere with the feedback loop that is perpetuated in this disorder. 

In addition, because they are small-molecule-based treatments, they do not develop immunologic memory like other biologics or theoretical tachyphylaxis. First-generation JAK inhibitors are ATP competitive, meaning they are less inherently selective and have a higher risk of adverse events while they target the highly conserved JAK H1 domain. First-generation JAK inhibitors include tofacitinib, baricitinib, ruxolitinib, and oclacitinib. Second-generation JAK inhibitors are also ATP competitive but are more selective. Conserved adverse effects include cytopenias, hyperlipidemia, and infections. The shared box warning for this class of medications was derived from a 10-year oral surveillance study of patients with rheumatoid arthritis on tofacitinib compared to those on TNF-alpha inhibitors. All of the patients were on methotrexate and many were over 50 years old with more than one cardiovascular risk factor. There was an increased incidence in opportunistic infections, major cardiac events, and malignancy. While this highly conserved evolutionary pathway is important in many pathways, including many that are not related to dermatology, adverse event rates seem to reflect underlying risk factors of the treated population. Dr Chovatiya emphasized the importance of knowing where the warning comes from and how to educate your patients on their own risk to decide if JAK inhibitors are an appropriate treatment.

He finalized his talk by driving home the uses of the various FDA-approved JAK inhibitors. Ruxolitinib 1.5% cream is excellent for atopic dermatitis, simplifying complicated treatment routines, and vitiligo, especially in combination with NB-UVB. Abrocitinib and upadacitinib are approved for atopic dermatitis, while the latter has many clinical trials underway for other indications. Both of these JAK1 selective inhibitors demonstrated remarkable responses within 12 weeks of treatment. Baricitinib, a JAK1 and 2 selective inhibitor, was the first JAK inhibitor approved for alopecia areata in the US and is in studies for juvenile idiopathic arthritis. Ritlecitinib shortly followed baricitinib for alopecia areata. Lastly, deucravacitinib, the TYK-2 inhibitor, may be the superior oral option for patients with psoriasis.