Assessing the Adverse Events of Roflumilast and Tapinarof Use in Pediatric and Young Adult Patients with Atopic Dermatitis: A Systematic Review.

BACKGROUND AND

objectivesAtopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intensely pruritic episodes and eczematous lesions. This disease is prevalent in up to 25% of children, with about half of these cases persisting into adulthood. This systematic review aims to examine two new topical therapies for AD, roflumilast and tapinarof, and investigate the adverse events  associated with their use.

methodsA systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and registered in PROSPERO (CRD420251066719). A search was performed in Scopus, Embase, PubMed, Cochrane Library, and Web of Science on 2 June 2025. Randomized controlled trials were included if they reported adverse event outcomes in pediatric patients with AD after either roflumilast or tapinarof treatment; studies with mixed pediatric and adult patients were eligible for inclusion. Studies were excluded if they lacked roflumilast or tapinarof treatment, did not include pediatric patients with AD, or did not report adverse event outcomes. Risk of bias was assessed using the Cochrane Risk of Bias tool. Adverse events were reported as occurrence (n) and frequency (n/N, %) within pooled studies for the roflumilast and tapinarof groups. Risk ratios (RR) and 95% confidence intervals (CI) comparing treatment with vehicle control were calculated using the Mantel-Haenszel fixed-effect model.

resultsSeven studies with a total of 3615 patients with AD using roflumilast (N = 1979), tapinarof (N = 658), or vehicle control (N = 978) were included in the final data extraction and analysis. Analyses included adverse event outcomes for mixed pediatric and adult patients. Three studies assessed once-daily 0.05% or 0.15% roflumilast cream use in patients with a mean age of 19.8 years. Four studies assessed once-daily 0.5% or 1% tapinarof cream use in patients with a mean age of 8.15 years. Both therapies displayed significant risks of treatment-emergent adverse events (TEAE) compared with vehicle controls (roflumilast: RR = 1.46, 95% CI = [1.20-1.77] with p = 0.0001; tapinarof: RR = 1.49, 95% CI = [1.24-1.79], p < 0.0001). Treatment-related TEAEs were significantly increased with roflumilast use (RR = 1.92, 95% CI = [1.15-3.19], p = 0.01), but not tapinarof use (RR = 1.30, 95% CI = [0.89-1.91], p = 0.17). Roflumilast was associated with nondermatologic adverse events, while tapinarof was found to have an association with dermatologic adverse events.

conclusionsSome limitations include the lack of direct comparative studies, limited data in pediatric and young adult populations, and heterogeneity of reported adverse events. Despite this, roflumilast and tapinarof demonstrate distinct adverse event profiles. Roflumilast was associated with an increased risk of treatment-related and nondermatologic adverse events, while tapinarof was associated with dermatologic adverse events. These findings highlight the importance of individualized treatment selection and careful monitoring of adverse events  when incorporating these therapies into the management of atopic dermatitis.