Rapid reduction in Staphylococcus aureus in atopic dermatitis subjects following dupilumab treatment

• Published in: Journal of allergy and clinical immunology Vol. 152; no. 5; pp. 1179 - 1195
• Main Authors: Simpson, Eric L., Schlievert, Patrick M., Yoshida, Takeshi, Lussier, Stephanie, Boguniewicz, Mark, Hata, Tissa, Fuxench, Zelma, De Benedetto, Anna, Ong, Peck Y., Ko, Justin, Calatroni, Agustin, Rudman Spergel, Amanda K., Plaut, Marshall, Quataert, Sally A., Kilgore, Samuel H., Peterson, Liam, Gill, Ann L., David, Gloria, Mosmann, Tim, Gill, Steven R., Leung, Donald Y.M., Beck, Lisa A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2023
• Subjects: Antibodies, Monoclonal, Humanized - therapeutic use; Atopic dermatitis; barrier; cytotoxins; Dermatitis, Atopic - genetics; dupilumab; Humans; IL-13; IL-17; IL-4; microbiome; Severity of Illness Index; Skin - metabolism; Staphylococcal Infections - drug therapy; Staphylococcus aureus; Treatment Outcome; type 2 immunity; NGAL; ADRN; cytotoxins; OLE; type 2 immunity; NRS; AUC; EASI; barrier; Atopic dermatitis; FDR; qPCR; Staphylococcus aureus; RDBPC; SCORAD; TEWL; IGA; AD; AMP; DEG; IL-4; IL-13; microbiome; dupilumab; s; rCFUs; IL-17; FC
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2023.05.026

[Display omitted] 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. This study characterized the changes in the host-microbial interface in subjects with AD 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 time points: S aureus and virulence factor quantification, 16s ribosomal RNA 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), which was 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-cell 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 subjects with AD, 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 cells, neutrophils, and complement activation as potential mechanisms to explain these findings.