Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Guttman-Yassky, Emma^1,3  Bissonnette, Robert⁴  Ungar, Benjamin^1,3  Suarez-Farinas, Mayte^1,2,3  Ardeleanu, Marius⁵  Esaki, Hitokazu⁶  Suprun, Maria²  Estrada, Yeriel¹  Xu, Hui¹  Peng, Xiangyu¹  Silverberg, Jonathan I.⁷  Menter, Alan⁸  Krueger, James G.³  Zhang, Rick⁵  Chaudhry, Usman⁵  Swanson, Brian⁹  Graham, Neil M. H.⁵  Pirozzi, Gianluca⁹  Yancopoulos, George D.⁵  Hamilton, Jennifer D. D.⁵ 

[1] Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA

[3] Rockefeller Univ, Lab Invest Dermatol, 1230 York Ave, New York, NY 10021 USA

[4] Innovaderm Res, Montreal, PQ, Canada

[5] Regeneron Pharmaceut, Tarrytown, NY USA

[6] Kyushu Univ, Grad Sch Med Sci, Dept Dermatol, Fukuoka, Fukuoka, Japan

[7] Northwestern Univ, Dept Dermatol Prevent Med & Med Social Sci, Feinberg Sch Med, Chicago, IL 60611 USA

[8] Baylor Univ, Med Ctr, Dept Dermatol, Dallas, TX USA

[9] Sanofi, Bridgewater, NJ USA

关键词: Atopic dermatitis;    IL-4 receptor a inhibition;    dupilumab;    transcriptome;    gene expression;    skin;    type 2 inflammation;    epidermal pathology;   

DOI  :  10.1016/j.jaci.2018.08.022

来源: Elsevier

【 摘 要 】

Background: Dupilumab is an IL-4 receptor a 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 T(H)17/T(H)22 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 allergenspecific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor a 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.

【 授权许可】

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