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Thanks to a robust pipeline and an enhanced understanding of the inflammatory process, atopic dermatitis (AD) is finally getting its day in the sun. There’s lots to be optimistic about, and pediatric dermatologist Amy Paller, MD, Chair and Walter J. Hamlin Professor of Dermatology at Northwestern University’s Feinberg School of Medicine in Chicago, shares the highlights.

What exciting treatments are in the pipeline for AD?

Amy Paller, MD: As a systemic agent, we now have dupilumab (Dupixent), and we are looking forward to having other biologics soon, including those that target interleukin-13 (IL-13), which is likely the predominant cytokine in AD. We have three JAK inhibitors coming, two of which are approved for use in rheumatoid arthritis—upadacitinib and baricitinib. The third is abrocitinib. Results look promising with respect to efficacy; all eyes are on safety. We will likely need labs to monitor patient safety, which is not currently done with dupilumab or expected with the IL-13 inhibitors. I am excited about topical ruxolitinib, a JAK inhibitor, coming soon, which would allow the benefit of nonsteroidal JAK inhibition without having systemic levels and thus may be particularly valuable for pediatric patients. I expect topical JAK inhibitors would be widely used, including for inflammatory disorders that involve Th1 pathway activation.

What do we know about AD comorbidities?

Dr Paller: We have known for decades that so many patients with AD, especially of moderate and high severity, have allergic disorders and risk of secondary infection. We have increasingly recognized the increased risk of allergic contact dermatitis and need to consider this diagnosis if patients are responding poorly to what should be effective medication. In the past decade, we have learned more about the associated neuropsychiatric symptoms in AD—not just anxiety and depression, but also ADHD. As more attention is focused on alopecia areata, it’s very clear that there is overlap. The majority of my pediatric patients with alopecia areata have active AD or a history of AD. This doesn’t mean that their AD is severe (most are mild), but the percentage with AD and alopecia areata is far higher than in the general population. There is also growing evidence based on blood and imaging studies of an increased risk of cardiovascular disease, although not to the same level seen in psoriasis and not associated with obesity. With all these potential comorbidities, we need to ask whether aggressive early treatment of AD, especially systemic treatment, could reduce the risk of their development.

Can AD be prevented?

Dr. Paller: We have been very disappointed with the results of large trials of daily emollient in neonates at increased risk, especially after promising results were seen in preliminary trials showing daily emollient use starting in the first month of life could reduce the risk of AD. More trials are ongoing, but perhaps we need to more specifically treat the deficit of very long-chain ceramides or replace filaggrin in those with filaggrin deficiency and low natural moisturizing factor. We also still need to better understand the relationship between early AD and the development of atopic multimorbidities—and whether aggressive short-term suppression of AD inflammation, even with systemic therapy, would alter the course of the atopic march.

What are AD research priorities for 2021 and beyond?

Dr. Paller: We need to understand more about neurologic, autoimmune, and cardiovascular comorbidities—and whether there is improvement with systemic intervention. We need to better understand the role of the microbiome and whether microbiome manipulation in the skin or gut can be effective therapeutically. There is still plenty to learn about patient-reported outcomes. We have done a great job understanding immune system changes in AD and leveraging this knowledge toward new therapy. The major knowledge gap is about itch and how to control it by direct effects on dorsal root ganglia. We know that IL-31 and its receptor play a critical role, given the quick disruption of itch with nemolizumab, but this is just the tip of the iceberg in understanding the role of peripheral nerve afferents, especially in terms of generating topical therapies against itch. We diagnose and treat AD based on clinical findings and patient-reported outcomes but are still trying to find biomarkers—including those gathered noninvasively from tape strips in children—to predict outcome of disease, risk of allergies and infection, persistence of AD, and medication response. These biomarkers may be ones that have nothing to do with type 2 immunity, and it will require longitudinal studies and big data analyses to potentially find them.

Any information on AD and COVID-19 vaccine safety?

Dr. Paller: There is no reason to think that patients on dupilumab won’t mount an immune response to the COVID-19 vaccine. There is more concern with other systemic agents sometimes used to treat AD, such as steroids, methotrexate or cyclosporine, but patients can mount partial responses with these onboard and short pauses in therapy (days) hopefully would not lead to a flare.

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