Pathogenesis-based therapies are revolutionizing medicine, including dermatology. In atopic dermatitis (AD), cytokines such as interleukin (IL)-4, IL-5, IL-13 and IL-31 have been identified as drivers of disease pathogenesis, leading to the development of agents such as dupilumab, a monoclonal antibody targeting IL-4 and IL-13. The JAK-STAT (Janus kinase-Signal Transducer and Activator of Transcription) pathway is essential for signalling downstream of multiple cytokines, including IL-4, IL-5 and IL-13. Inhibition of the JAK-STAT pathway provides a means of blocking the effects of these pathogenic cytokines. There are currently two U.S. Food and Drug Administration-approved JAK inhibitors, ruxolitinib and tofacitinib, indicated for the treatment of myelofibrosis and rheumatoid arthritis, respectively. Both of these JAK inhibitors are beginning to find utility in dermatology. JAK inhibition has shown efficacy in multiple preclinical models of dermatitis, where it can block IL-4 and IL-13 signalling and improve the skin barrier. Our group recently published a case series showing the efficacy of oral tofacitinib in six patients with treatment-recalcitrant AD. In this issue of the BJD Bissonnette et al. report the results of a phase IIa study of the efficacy of topical tofacitinib 2% ointment in mild-to-moderate AD. In this randomized, doubleblind, vehicle-controlled study patients treated with tofacitinib 2% ointment (n = 35) achieved an 81 7% mean reduction in baseline EASI (Eczema Area and Severity Index) scores compared with only 29 9% in the control group (n = 34) over the 4-week study period. In the treatment group, approximately 80%, 60% and 40% of patients achieved EASI50, EASI75 and EASI90, respectively. Bissonnette et al. observed a rapid decrease in pruritus with topical tofacitinib measured by the Itch Severity Item (ISI) score. This effect may be related to inhibition of pruritogenic IL-31 signalling via the JAK-STAT pathway. This rapid and potent effect of JAK inhibition on pruritus has been observed previously in AD and psoriasis and, interestingly, the improvement sometimes occurred prior to or even independently of improvement of the skin. Tofacitinib 2% ointment was well tolerated and no serious adverse events were reported, although there did appear to be some systemic absorption. Further studies will be needed to address its long-term efficacy and safety. Other new targeted topical agents, such as crisaborole, a phosphodiesterase 4 inhibitor, are being developed and also appear promising in AD. Head-to-head trials involving these agents and superpotent topical steroids would be useful in establishing their place in AD treatment algorithms. The emergence of targeted therapies for AD and other dermatological disorders is exciting, and the results of the current study highlight the promising road ahead in treating inflammatory skin disease.
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