title: Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis.
abstract: BACKGROUND
  Severe atopic dermatitis (AD) has a high unmet need for effective and safe therapeutics. In early-phase trials, dupilumab, a fully human mAb targeting IL-4 receptor α, markedly improved disease activity, but the effect of IL-4/IL-13 blockade on AD at the molecular level has not been characterized.
  
  
  OBJECTIVE
  We sought to evaluate dupilumab modulation of the AD molecular signature.
  
  
  METHODS
  We performed transcriptomic analyses of pretreatment and posttreatment skin biopsy specimens from patients with moderate-to-severe AD treated weekly with 150 or 300 mg of dupilumab or placebo.
  
  
  RESULTS
  Exacerbation of the AD transcriptome was observed in placebo-treated patients. Dupilumab improved the AD signature in a dose-dependent manner. Expression of genes upregulated in AD lesions decreased in patients treated with dupilumab by 26% (95% CI, 21% to 32%) and 65% (95% CI, 60% to 71%) for treatment with 150 and 300 mg, respectively. Genes downregulated in AD lesions increased by 21% (95% CI, 16% to 27%) and 32% (95% CI, 26% to 37%) with dupilumab (150 and 300 mg, respectively). The molecular changes paralleled improvements in clinical scores. A dupilumab treatment signature of 821 probes (>2-fold change, P < .05) significantly modulated in the 300-mg dupilumab group at week 4 compared with baseline was identified in this sample set. Significant (P < .05) decreases in mRNA expression of genes related to hyperplasia (K16 and MKI67), T cells, and dendritic cells (CD1b and CD1c) and potent inhibition of TH2-associated chemokines (CCL17, CCL18, CCL22, and CCL26) were noted without significant modulation of TH1-associated genes (IFNG).
  
  
  CONCLUSIONS
  This is the first report showing rapid improvement of the AD molecular signature with targeted anti-IL-4 receptor α therapy. These data suggest that IL-4 and IL-13 drive a complex, TH2-centered inflammatory axis in patients with AD.
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Hamilton
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
authors.forename: Mayte
authors.initials: M
authors.lastname: Suárez-Fariñas
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Dhingra
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
authors.forename: Irma
authors.initials: I
authors.lastname: Cardinale
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY.
authors.forename: Ana
authors.initials: A
authors.lastname: Kostic
authors.affiliation: Sanofi, Bridgewater, NJ.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Ming
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY.
authors.forename: Allen R
authors.initials: AR
authors.lastname: Radin
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY.
authors.forename: Neil
authors.initials: N
authors.lastname: Graham
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Sanofi, Bridgewater, NJ.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Pirozzi
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: Emma.Guttman@mountsinai.org.
authors.forename: Emma
authors.initials: E
authors.lastname: Guttman-Yassky
mesh_terms: D000328:Adult; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012867:Skin / Q000187:drug effects* / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D055815:Young Adult
chemical_list: D018926:Anti-Allergic Agents; D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; C582203:dupilumab
keywords: Atopic dermatitis; IL-4 receptor α inhibition; T(H)2 axis; dupilumab; gene expression; skin; transcriptome