Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis
Journal of Allergy and Clinical Immunology
Atopic dermatitis; dupilumab; epidermal pathology; gene expression; IL-4 receptor α inhibition; skin; transcriptome; type 2 inflammation
© 2018 The Authors Background: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.
Guttman-Yassky, E., Bissonnette, R., Ungar, B., Suárez-Fariñas, M., Ardeleanu, M., Esaki, H., Suprun, M., Estrada, Y., Xu, H., Peng, X., Silverberg, J., Menter, A., Krueger, J., Zhang, R., Chaudhry, U., Swanson, B., Graham, N., Pirozzi, G., Yancopoulos, G., & Jennifer, J. (2019). Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. Journal of Allergy and Clinical Immunology, 143 (1). http://dx.doi.org/10.1016/j.jaci.2018.08.022