Crisaborole reverses dysregulation of the mild to moderate atopic dermatitis proteome toward nonlesional and normal skin

Background: Safe and effective long-term topical treatments for atopic dermatitis (AD) remain limited. Objective: In this phase 2a, single-center, intrapatient, and vehicle-controlled study, we examine the mechanism of action of crisaborole 2% ointment, a topical nonsteroidal PDE4 (phosphodiesterase-4) inhibitor, in a proteomic analysis of 40 adults with mild to moderate AD and 20 healthy subjects. Methods: Within the AD cohort, 2 target lesions were randomized in an intrapatient (1:1) manner to doubleblind crisaborole/vehicle applied twice daily for 14 days. Punch biopsy specimens were collected for biomarker analysis at baseline from all participants, then from AD patients only at day 8 (optional) and day 15. Results: Compared to the vehicle, crisaborole significantly reversed dysregulation of the overall lesional proteome and of key markers and pathways (eg, Th2, Th17/Th22, and T-cell activation) associated with AD pathogenesis toward both nonlesional and normal skin. Significant clinical correlations were observed with markers associated with nociception and Th2, Th17, and neutrophilic activation. Limitations: Study limitations include predominance of white patients in the cohort, relatively short treatment time, and regimented administration of crisaborole. Conclusion: Our results demonstrate crisaborole-induced normalization of the AD proteome toward a nonlesional molecular phenotype and further support topical PDE4 inhibition in the treatment of mild to moderate AD. ( J Am Acad Dermatol 2023;89:283-92.)