Dupilumab in Children Under 6 Years With Moderate‐to‐Severe Atopic Dermatitis: A 16‐Week Real‐World Prospective Study on Efficacy, Safety, and Local‐Systemic Immune Responses

ABSTRACT Background Real‐world data on the clinical and molecular impacts of dupilumab in young children with moderate‐to‐severe atopic dermatitis (AD) remain limited. Objectives To evaluate 16‐week clinical outcomes, cutaneous proteomic changes, and systemic immune responses to dupilumab in children aged 6 months to 5 years. Methods This prospective cohort study enrolled 110 participants, with clinical evaluations performed at weeks 2, 4, 8, 12, and 16. Longitudinal biomarker profiling included skin tape strip (STS) proteomics, flow cytometric analysis of T‐cell subsets, and serum cytokine multiplex assays. Results Of the 96 participants who completed the study, 70.8% achieved EASI‐75, 41.7% attained IGA 0/1, and 84.4% reported a ≥ 4‐point improvement in PP‐NRS, with comparable outcomes and adverse events observed across age subgroups (6 months to < 2 years vs. ≥ 2 to 5 years). Marked reductions in CLA + IL‐4 + /IL‐13 + Th2 cells ( p < 0.001) and an expansion of CLA + Tregs ( p < 0.01) were noted in peripheral blood. However, serum Th2/Th1/Th17 cytokine levels remained unchanged or were elevated posttreatment, particularly IL‐4 ( p < 0.001), despite declines in CCL13/17/22. STS proteomics indicated a restoration of proteins associated with the skin barrier, while markers related to epidermal hyperplasia, innate immune activation, and antimicrobial defense remained unchanged. Utilizing machine‐learning algorithms, PON2 and PRDX1, both involved in anti‐oxidative processes, were identified as predictive biomarkers for treatment response. Conclusions Short‐term dupilumab exhibited favorable outcomes in young children with AD, primarily through the remodeling of CLA + Th2 cells and the restoration of skin barrier functions. Although circulating Th2 inflammation was not completely normalized within a 16‐week period, the significant reductions in TARC and MDC indicate systemic improvement and underscore the importance of maintenance therapy.