Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis - 05/12/14
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Atopic dermatitis, dupilumab, IL-4 receptor α inhibition, transcriptome, gene expression, skin, TH2 axis
Abbreviations used : AD, CsA, DC, EASI, IL-4Rα, LS, NL, NB-UVB, qRT-PCR
Plan
| Supported by Regeneron Pharmaceuticals and Sanofi (NCT01259323, NCT01385657). |
|
| Disclosure of potential conflict of interest: J. D. Hamilton and A. R. Radin are employed by Regeneron, have patents through Regeneron, and receive stock/stock options as part of their compensation. M. Suárez-Fariñas has received research support from and has consultant arrangements with Regeneron. I. Cardinale and X. Li have received research support from Regeneron. A. Kostic and N. Graham are employed by Regeneron and receive stock/stock options as part of their compensation. J. E. Ming and G. Pirozzi are employed by Sanofi and receive stock/stock options as part of their compensation. J. G. Krueger has received grants paid to the institution and personal fees from Novartis, Pfizer, Janssen, Lilly, Merck, Kadmon, Dermira, Boehringer, BMS, and Paraxel during the conduct of the study; grants paid to the institution from Amgen, Innovaderm and Kyowa; and personal fees from Serono, Biogen Idec, Delenex, AbbVie, Sanofi, Baxter, Xenoport, and Kineta.G. D. Yancopoulos is a board member for Regeneron, is employed as Chief Science Officer for Regeneron, and receives stock/stock options as part of his compensation. E. Guttman-Yassky has received research support from Regeneron, BMS, Janssen, Celgene, and Leo Pharma; has board memberships with Regeneron, Sanofi, Celgene, GlaxoSmithKline/Stiefel, MedImmune, and Leo Pharma; and has consultant arrangements with Regeneron, Celgene, BMS, Dermima, MedImmune, GlaxoSmithKline/Stiefel, and Galderma. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 134 - N° 6
P. 1293-1300 - décembre 2014 Retour au numéro
Article précédent
- Impairment of cilia architecture and ciliogenesis in hyperplastic nasal epithelium from nasal polyps
- Ying Ying Li, Chun Wei Li, Siew Shuen Chao, Feng Gang Yu, Xue Min Yu, Jing Liu, Yan Yan, Liang Shen, William Gordon, Li Shi, De Yun Wang
- Acinetobacter species in the skin microbiota protect against allergic sensitization and inflammation
- Nanna Fyhrquist, Lasse Ruokolainen, Alina Suomalainen, Sari Lehtimäki, Ville Veckman, Johanna Vendelin, Piia Karisola, Maili Lehto, Terhi Savinko, Hanna Jarva, Timo U. Kosunen, Jukka Corander, Petri Auvinen, Lars Paulin, Leena von Hertzen, Tiina Laatikainen, Mika Mäkelä, Tari Haahtela, Dario Greco, Ilkka Hanski, Harri Alenius
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?