A hands‐off approach may be more successful in treating chronic hand eczema

Dermatology has entered an exciting new era of drug development in the treatment of atopic dermatitis (AD) and related skin disorders. With a sophisticated understanding of the pathogenesis of eczematous diseases, researchers are now focused on drug development to target the culprit inflammatory mediators. Janus kinase (JAK) inhibitors are currently under investigation for the treatment of AD. JAK inhibitors are attractive potential treatment options for AD as they block many of the cytokines critical to the pathogenesis of AD, including interferon (IFN)-c, interleukin (IL)-4, IL-13, IL-31, IL-33, IL-23, IL-22 and IL-17. While blocking these targets is likely to be efficacious, there is concern regarding immunosuppressive side-effects. Topical application of a JAK inhibitor offers the promise of efficacy with less side-effect risk. In this issue, Worm et al. report results from a phase IIa study on a topical JAK inhibitor, delgocitinib, used for chronic hand eczema (CHE). The development of a highly effective and safe topical therapy could be viewed as an exciting development in the treatment of atopic disease. Strengths of the Worm et al. study include the double-blind randomization of the participants, high participant retention through the study end point, and stratification of participants according to irritant or nonirritant CHE status. More participants with CHE who applied delgocitinib ointment twice daily for 8 weeks achieved a Physician’s Global Assessment of 0 or 1 (46%) compared with participants with CHE who applied vehicle emollients (15%, P < 0 05). While topical delgocitinib was clearly more effective than vehicle, the results should be viewed with caution. Topical delgocitinib did not begin to show greater efficacy compared with vehicle until 4 weeks into the study; we expect that topical steroids would work much faster. Moreover, patient global assessment was not as enthusiastic as provider global assessment and failed to achieve statistical significance. Although we want to believe that the introduction of additional nonsteroidal topical agents would be beneficial for patients with atopic disease, unless these new drugs are as potent as high-potency and super-high-potency topical steroids and are significantly safer, they are unlikely to be of much benefit in a real-world setting. Adherence to topical treatments for dermatitis is abysmally poor. For topical treatment of AD, adherence tends to be greatest in the first few days of treatment and rapidly decreases with time. If a medication takes several weeks to work, patients are likely to discontinue the treatment long before seeing significant results. We anticipate that adherence for patients in a real-world setting will be worse than for those enrolled and continuously monitored in a clinical trial. Drugs that show modest efficacy in clinical study are at risk of underperforming for patients treated in real-world clinics. Nonsteroidal topical agents could be useful in patients with safety concerns regarding the use of topical steroids, and the three currently approved topical agents (crisaborole, tacrolimus and pimecrolimus) for dermatitis certainly use that advantage in their direct-to-consumer marketing. Unless a new topical treatment has some feature that transforms patients’ adherence or is so overwhelmingly effective that the drug works despite poor adherence, it seems unlikely that the drug would significantly enhance outcomes for patients. Enhanced tolerability (less burning and stinging compared with current nonsteroidal agents) would be a modest improvement, but is unlikely to overcome the pervasiveness and severity of patient nonadherence to topical medications. A safe and effective oral treatment may be more promising.