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Clinical Trial
. 2020 Jan;140(1):191-202.e7.
doi: 10.1016/j.jid.2019.05.024. Epub 2019 Jun 25.

IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis

Chris Callewaert  1 , Teruaki Nakatsuji  2 , Rob Knight  3 , Tomasz Kosciolek  4 , Alison Vrbanac  4 , Paul Kotol  2 , Marius Ardeleanu  5 , Thomas Hultsch  6 , Emma Guttman-Yassky  7 , Robert Bissonnette  8 , Jonathan I Silverberg  9 , James Krueger  10 , Alan Menter  11 , Neil M H Graham  5 , Gianluca Pirozzi  12 , Jennifer D Hamilton  5 , Richard L Gallo  13
Affiliations
Clinical Trial

IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis

Chris Callewaert et al. J Invest Dermatol. 2020 Jan.

Abstract

Dupilumab is a fully human antibody to interleukin-4 receptor α that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor α inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus.

Trial registration: ClinicalTrials.gov NCT01979016.

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Conflict of interest statement

CONFLICT OF INTEREST

Outside of the submitted work, NT was an investigator for and has received research grants from Regeneron Pharmaceuticals, Inc.; RK was an scientific advisory board member and consultant for Janssen R&D LLC, Commense, Inc., and Prometheus Lab Inc.; MA, NMHG, and JH were employees and shareholders of Regeneron Pharmaceuticals, Inc.; TH and GP were employees of Sanofi and may hold stock and/or stock options in the company; EG was an investigator for AbbVie, Celgene, Eli Lilly and Company, GlaxoSmithKline, Regeneron Pharmaceuticals, Inc., Sanofi, Leo Pharma, Pfizer, Galderma, and Glenmark; served as a consultant for AbbVie, Anacor, Eli Lilly and Company, Galderma, GlaxoSmithKline, Leo Pharma, Menlo Therapeutics, Kiniksa, Pfizer, Realm, Regeneron Pharmaceuticals, Inc., Sanofi, Asana Biosciences, DBV, Kyowa, Daiichi Sankyo, Glenmark, Novartis, Dermira; and received research grants from Regeneron Pharmaceuticals, Inc., Sanofi, Pfizer, Galderma, Janssen, Celgene, Novartis, Dermira, AbbVie, Innovaderm, and Leo Pharma. RB was an investigator, consultant, advisory board member, speaker, and/or received honoraria from Antibiotx, Aquinox Pharma, Asana, Astellas, Brickell Biotech, Dermavant, Dermira, Dignity Sciences, Galderma, Glenmark, GSK-Stiefel, Hoffman-LaRoche Ltd., Kiniksa, Leo Pharma, Neokera, Pfizer, Regeneron Pharmaceuticals, Inc., Sienna Biopharmaceuticals, and Vitae Pharmaceuticals; and was a shareholder of Innovaderm Research; JIS was an investigator for AbbVie, Celgene, Chugai, Eli Lilly and Company, GlaxoSmithKline, Regeneron Pharmaceuticals, Inc., and Sanofi; a consultant for AbbVie, Anacor, Eli Lilly and Company, Galderma, GlaxoSmithKline, Incyte, Leo Pharma, Menlo, Kiniksa, Pfizer, Realm, Regeneron Pharmaceuticals, Inc., and Sanofi; and a speaker for Regeneron Pharmaceuticals, Inc., and Sanofi; JK was a consultant and recipient of research grants from Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Dermira, Innovaderm, Janssen, Kadmon, Kyowa, Eli Lilly and Company, Merck, Novartis, Parexel, and Pfizer; was consultant and received personal fees from AbbVie, Baxter, Biogen Idec, Delenex, Kineta, Sanofi, Serono, and XenoPort; and was an investigator for Regeneron Pharmaceuticals, Inc.; AM served on the advisory board and was a consultant, investigator, and speaker and received grants and honoraria from AbbVie, Amgen, Janssen Biotech, Inc., and Leo Pharma; served on the advisory board and was a consultant and investigator and received grants and honoraria from Allergan; served on the advisory board and was an investigator and recipient of grants and honoraria from Boehringer Ingelheim; served as a consultant and investigator and was a recipient of grants and honoraria from Novartis, Pfizer, and XenoPort; was investigator and recipient of grants from Anacor, Celgene, Dermira, Merck, Neothetics, Regeneron Pharmaceuticals, Inc., and Symbio/Maruho; served on the advisory board, was an consultant and investigator, and received honoraria from Eli Lilly and Company; and was consultant and received honoraria from Galderma and Vitae Pharmaceuticals; RG was an investigator and recipient of research grants from Regeneron Pharmaceuticals, Inc.; had equity interest in and was co-founder and SAB of MatriSys Bioscience; had equity interest in and was SAB of Sente, Inc.; was a consultant for Roche; received a research grant from Novan; and received a research grant from Colgate Palmolive. The other authors state no conflict of interest.

Figures

Figure 1.
Figure 1.. Pretreatment status of lesional and nonlesional skin.
(a) Absolute quantification of 16S rRNA using qPCR of skin samples at screening (week −2) and baseline (week 0). (b) Absolute quantification of Staphylococcus aureus using qPCR of skin samples at screening and baseline. (c) Shannon diversity results from 16S rRNA sequencing of skin samples at screening and baseline. (d) Shannon diversity results from 16S rRNA sequencing of skin samples at baseline (week 0) from the placebo and dupilumab-treated groups. (e) Shannon diversity results from 16S rRNA sequencing of skin samples at baseline of male and female patients. (f) EASI score at baseline for the placebo group and the dupilumab-treated group for male and female patients. Statistical differences between lesional and nonlesional skin, between treatment groups, and between males and females were assessed using the nonparametric Mann–Whitney U test, with Bonferroni correction for multiple comparison. EASI, Eczema Area and Severity Index; qPCR, quantitative PCR; rCFU, relative colony-forming units; rRNA, ribosomal RNA.
Figure 2.
Figure 2.. Relative abundance of the most dominant phyla and genera over time in lesional and nonlesional skin according to treatment group.
The most abundant operational taxonomic units are presented. (a) Microbial variability over time of placebo group in lesional skin. (b) Microbial variability over time of dupilumab-treated group in lesional skin. (c) Microbial variability over time of dupilumab-treated group in nonlesional skin. (d) Microbial variability over time of placebo group in nonlesional skin. During treatment (weeks 4–16), an overall decrease in relative abundance of Staphylococcus is noted mainly in the dupilumab-treated patients in lesional skin.
Figure 3.
Figure 3.. Shannon microbial α-diversity and β-diversity.
(a–d) α-diversity: (a) Lesional skin, placebo group; (b) Lesional skin, dupilumab-treated group; (c) Nonlesional skin, placebo group; (d) Nonlesional skin, dupilumab-treated group. (e–g) β-diversity: PCoA plots showing Shannon diversity of skin samples; red indicates low diversity and blue indicates high diversity. (e) Large dots depict lesional skin samples from the dupilumab-treated group in periods without treatment (weeks −2, 0, and 32) and small dots represent other samples (nonlesional skin during periods of treatment), showing that without dupilumab treatment, samples are mainly located on the left side with a low Shannon diversity (red circle). (f) Large dots depict lesional skin samples from the dupilumab-treated group taken during the treatment period (weeks 4, 8, 12, and 16); small dots represent other samples (nonlesional skin, no treatment) showing that with dupilumab treatment, samples shift to the right with higher Shannon diversity (blue circle). (g) All samples (placebo and dupilumab, lesional and nonlesional skin) at all time points, indicating a clear separation between lesional skin (left, low Shannon diversity [red]) and nonlesional skin (right, high Shannon diversity [blue]) and significant separation between low and high Shannon diversity (P < 0.001, Adonis test). Each dot represents an individual sample; the color of the dot reflects the bacterial Shannon diversity index on a continuous scale (red indicates low diversity and blue indicates high diversity). *P < 0.05, **P < 0.01, ***P < 0.001; Mann–Whitney U test, with Bonferroni correction for multiple comparison. PCoA, Principal coordinates analysis.
Figure 4.
Figure 4.. Absolute abundance Staphylococcus aureus over time.
(a) Lesional skin samples, placebo group. (b) Lesional skin, dupilumab-treated group. (c) Nonlesional skin samples, placebo group. (d) Nonlesional skin samples, dupilumab-treated group. *P < 0.05, **P < 0.01, ***P < 0.001; Mann–Whitney U test, with Bonferroni correction for multiple comparison. qPCR, quantitative PCR; rCFU, relative colony-forming units.
Figure 5.
Figure 5.. Correlation of EASI score and relative and absolute abundance of Staphylococcus aureus.
At screening (week −2) and baseline (week 0): correlation of EASI score and (a) relative and (b) absolute abundance of S. aureus. Shaded areas around the regression line indicate confidence intervals. (c) Correlation of EASI scores and relative abundance of S. aureus at baseline and week 16 for both treatment groups and both lesional and nonlesional samples, with values from the placebo group at week 0 in yellow and week 16 in green. (d) Same as (c), with values from the dupilumab-treated group at week 0 in yellow and week 16 in green. Values for the same patient from weeks 0 and 16 are connected with a line. EASI, Eczema Area and Severity Index; qPCR, quantitative PCR; rCFU, relative colony-forming units; rRNA, ribosomal RNA.
Figure 6.
Figure 6.. Correlation of absolute abundance of Staphylococcus aureus with biomarkers TARC and PARC.
(a) Correlation of TARC score and absolute abundance of S. aureus at screening (week −2) and baseline (week 0). (b) Correlation of PARC score and absolute abundance of S. aureus at screening (week −2) and baseline (week 0). Shaded areas around the regression line indicate confidence intervals. Correlation of TARC score and absolute abundance of S. aureus at baseline (yellow) and week 16 (green) in the (c) placebo group and the (d) dupilumab-treated group. Correlation of PARC score and absolute abundance of S. aureus at baseline (yellow) and week 16 (green) in the (e) placebo group and (f) dupilumab-treated group. Values for the same patient from weeks 0 and 16 are connected with a line. PARC, pulmonary and activation-regulated chemokine; qPCR, quantitative PCR; rCFU, relative colony-forming units; TARC, thymus and activation-regulated chemokine.
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