Abstract

Atopic dermatitis (AD) is an inflammatory disorder characterized by dominant type 2 inflammation leading to chronic pruritic skin lesions, allergic comorbidities and Staphylococcus aureus skin colonization and infections. S. aureus is thought to play a role in AD severity.We characterized the changes in the host-microbial interface in AD subjects following type 2 blockade with dupilumab.Participants (n=71) with moderate-severe AD were enrolled in a randomized (dupilumab vs placebo; 2:1), double-blind study at Atopic Dermatitis Research Network centers. Bioassays were performed at multiple timepoints: S. aureus and virulence factor quantification, 16s rRNA microbiome, serum biomarkers, skin transcriptomic analyses and peripheral blood T-cell phenotyping.At baseline, 100% of participants were S. aureus colonized on the skin surface. Dupilumab treatment resulted in significant reductions in S. aureus after only 3 days (compared to placebo); 11 days before clinical improvement. Participants with the greatest S. aureus reductions had the best clinical outcomes, and these reductions correlated with reductions in serum CCL17 and disease severity. Reductions (10-fold) in S. aureus cytotoxins (day 7), perturbations in Th17 subsets (day 14), and increased expression of genes relevant for IL-17, neutrophil and complement pathways (day 7) were also observed.Blockade of IL-4 and IL-13 signaling, very rapidly (day 3) reduces S. aureus abundance in AD subjects, and this reduction correlates with reductions in the type 2 biomarker, CCL17 and measures of AD severity (excluding itch). Immunoprofiling and/or transcriptomics suggest a role for Th17, neutrophils and complement activation as potential mechanisms to explain these findings.

View details for DOI 10.1016/j.jaci.2023.05.026

View details for PubMedID 37315812