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.
OBJECTIVES: 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.