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

Eric L Simpson; Patrick M Schlievert; Takeshi Yoshida; Stephanie Lussier; Mark Boguniewicz; Tissa Hata; Zelma Fuxench; Anna De Benedetto; Peck Y Ong; Justin Ko; Agustin Calatroni; Amanda K Rudman Spergel; Marshall Plaut; Sally A Quataert; Samuel H Kilgore; Liam Peterson; Ann L Gill; Gloria David; Tim Mosmann; Steven R Gill; Donald Y M Leung; Lisa A Beck

doi:10.1016/j.jaci.2023.05.026

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

J Allergy Clin Immunol. 2023 Nov;152(5):1179-1195. doi: 10.1016/j.jaci.2023.05.026. Epub 2023 Jun 13.

Authors

Eric L Simpson¹, Patrick M Schlievert², Takeshi Yoshida³, Stephanie Lussier⁴, Mark Boguniewicz⁵, Tissa Hata⁶, Zelma Fuxench⁷, Anna De Benedetto³, Peck Y Ong⁸, Justin Ko⁹, Agustin Calatroni⁴, Amanda K Rudman Spergel¹⁰, Marshall Plaut¹⁰, Sally A Quataert¹¹, Samuel H Kilgore², Liam Peterson³, Ann L Gill¹², Gloria David⁴, Tim Mosmann¹¹, Steven R Gill¹², Donald Y M Leung¹³, Lisa A Beck¹⁴

Affiliations

¹ Department of Dermatology, Oregon Health and Science University, Portland, Ore.
² Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa.
³ Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, NY.
⁴ Rho, Inc, Durham, NC.
⁵ Division of Allergy-Immunology, Department of Pediatrics, National Jewish Health and University of Colorado School of Medicine, Denver, Colo.
⁶ Department of Dermatology, University of California, San Diego, Calif.
⁷ Department of Dermatology, University of Pennsylvania, Philadelphia, Pa.
⁸ Department of Pediatrics, University Southern California, Los Angeles, Calif.
⁹ Department of Dermatology, Stanford University, Stanford, Calif.
¹⁰ Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
¹¹ Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, NY.
¹² Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY.
¹³ Division of Allergy-Immunology, Department of Pediatrics, National Jewish Health and University of Colorado School of Medicine, Denver, Colo. Electronic address: LeungD@NJHealth.org.
¹⁴ Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, NY. Electronic address: Lisa_Beck@urmc.rochester.edu.

Abstract

Background: 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.

Objectives: This study characterized the changes in the host-microbial interface in subjects with AD following type 2 blockade with dupilumab.

Methods: 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.

Results: 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 T_H17-cell subsets (day 14), and increased expression of genes relevant for IL-17, neutrophil, and complement pathways (day 7) were also observed.

Conclusions: 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 T_H17 cells, neutrophils, and complement activation as potential mechanisms to explain these findings.

Keywords: Atopic dermatitis; IL-13; IL-17; IL-4; Staphylococcus aureus; barrier; cytotoxins; dupilumab; microbiome; type 2 immunity.

Publication types

Randomized Controlled Trial
Research Support, N.I.H., Extramural

MeSH terms

Antibodies, Monoclonal, Humanized / therapeutic use
Dermatitis, Atopic* / genetics
Humans
Severity of Illness Index
Skin / metabolism
Staphylococcal Infections* / drug therapy
Staphylococcus aureus
Treatment Outcome

Substances

dupilumab
Antibodies, Monoclonal, Humanized

Abstract

Publication types

MeSH terms

Substances

Grants and funding