Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.
Atopic dermatitis
IL-4 receptor α inhibition
dupilumab
epidermal pathology
gene expression
skin
transcriptome
type 2 inflammation
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
22
12
2017
revised:
19
07
2018
accepted:
14
08
2018
pubmed:
9
9
2018
medline:
13
11
2019
entrez:
9
9
2018
Statut:
ppublish
Résumé
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. 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). 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. 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 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.
Sections du résumé
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 T
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.
Identifiants
pubmed: 30194992
pii: S0091-6749(18)31266-1
doi: 10.1016/j.jaci.2018.08.022
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antibodies, Monoclonal, Humanized
0
FLG protein, human
0
Filaggrin Proteins
0
dupilumab
420K487FSG
Banques de données
ClinicalTrials.gov
['NCT01979016']
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
155-172Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.