Novel nonsteroidal topical therapies for pediatric atopic dermatitis: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Novel nonsteroidal topical therapies are increasingly used for pediatric atopic dermatitis (AD), but their comparative efficacy and safety remain unclear because direct active-comparator evidence is limited. METHODS: We conducted a systematic review and frequentist network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating novel nonsteroidal topical therapies in children with AD. The study was registered in PROSPERO (CRD420261400624). Efficacy outcomes included Investigator's Global Assessment treatment success (IGA-TS), Eczema Area and Severity Index 75 response (EASI-75), and EASI-90. Safety outcomes included treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs). Treatment nodes were defined by drug, concentration, and dosing frequency. Pairwise vehicle-controlled meta-analyses, sensitivity analysis, and subgroup analyses by treatment duration and age were also performed. RESULTS: Twelve articles reporting 15 RCTs involving 3,994 pediatric patients were included. The network was largely centered on vehicle, with only one active-comparator trial. Most active regimens improved IGA-TS versus vehicle, except tapinarof 0.5% once daily. For EASI-75, five of ten evaluated active regimens showed significant benefit, while all six regimens evaluated for EASI-90 were superior to vehicle. Delgocitinib 0.5% twice daily ranked highest for IGA-TS and EASI-75, whereas difamilast 1% twice daily ranked highest for EASI-90. No consistent increase in TEAEs or TRAEs was observed. Pairwise meta-analyses and sensitivity analysis were generally consistent with the primary findings. Subgroup analyses suggested timepoint- and age-related differences, but stratified evidence was limited. CONCLUSION: Novel nonsteroidal topical therapies provide effective short-term steroid-sparing options for pediatric AD without a clear overall safety penalty. Further head-to-head, long-term, and age-stratified trials are needed. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD420261400624.