期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 143, 期 1, 页码 155-172出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2018.08.022
关键词
Atopic dermatitis; IL-4 receptor a inhibition; dupilumab; transcriptome; gene expression; skin; type 2 inflammation; epidermal pathology
资金
- Sanofi
- Regeneron Pharmaceuticals
- Sanofi Genzyme
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM062754] Funding Source: NIH RePORTER
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.
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