Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis
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ABSTRACT:
PROVIDER: PRJNA540690 | ENA |
REPOSITORIES: ENA
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Project description: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 210.5% 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 5 .001; week 16, P 5 .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 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. (J Allergy Clin Immunol 2019;143:155-72.)
2019-05-02 | GSE130588 | GEO
Project description:Dupilumab is an antibody targeting the IL-4/IL-13 receptors indicated for atopic dermatitis patients, but paradoxical psoriasis-like reactions have been reported under treatment. To understand the pathogenesis of DI-Pso, we performed a gene expression profiling study using microarray on skin biopsies of dupilumab-induced psoriasis, plaque psoriasis and AD compared with healthy control skin.
2023-01-16 | GSE185764 | GEO
Project description:Canine atopic dermatitis (AD) is clinically similar to human AD, implicating it as a useful model of human eosinophilic allergic disease. To identify cutaneous gene transcription changes in relatively early inflammation of canine AD, microarrays were used to monitor transcription in normal skin (n=13) and in acute lesional AD (ALAD) and nearby visibly nonlesional AD (NLAD) skin (n=13) from dogs. Scanning the putative abnormally-transcribed genes, several potentially relevant genes, some abnormally transcribed in both NLAD and ALAD (e.g. IL6, NFAM1, MSRA, and SYK), were observed. Comparison for abnormally-transcribed genes common to two related human diseases, human AD and asthmatic chronic rhinosinusitis with nasal polyps (aCRSwNP), further identified genes or gene sets likely relevant to eosinophilic allergic inflammation. These included 1) genes associated with alternatively-activated monocyte-derived cells, including members of the monocyte chemotactic protein (MCP) gene cluster, 2) members of the IL1 family gene cluster, 3) eosinophil-associated seven transmembrane receptor EMR1 and EMR3 genes, 4) interferon-inducible genes, and 5) keratin genes associated with hair and nail formation. Overall, numerous abnormally-transcribed genes were observed only in canine AD; however, many others are common to related human eosinophilic allergic diseases and represent therapeutic targets testable in dogs with AD. Total RNA from skin biopsy specimens from 13 Healthy (i.e. Normal) dogs were compared to total RNA from acute lesional skin biopsy specimens (i.e. ALAD) and nearby visibly nonlesional skin biopsy specimens (i.e. NLAD) from 13 dogs with atopic dermatitis.
2012-07-11 | E-GEOD-39278 | biostudies-arrayexpress
Project description:Atopic dermatitis (AD) is the most common inflammatory skin disease, with high unmet need for new therapies that are safe for chronic use. Emerging data suggest that TH2-cytokines play important roles in a variety of allergic and atopic conditions, including asthma and AD. In early phase clinical trials, dupilumab (a fully human monoclonal antibody against IL-4R? that potently blocks IL-4 and IL-13 signaling) rapidly and markedly improved clinical measures in adults with either asthma (with elevated eosinophil counts) or moderate-to-severe AD. The pathomechanisms that may be impacted by IL-4/13 blockade in these disease settings have not yet been characterized in detail. Transcriptome analyses in pre- and post-treatment skin biopsies from patients with moderate-to-severe AD treated with dupilumab or placebo in two completed clinical trials 18 Patients with AD treated with dupilumab or placebo. 28 biopsies in lesional (LS) Skin (16 pre-treatment and 12 post-treatment). 12 biopsies in non-lesional (NL) Skin (7 pre-treatment and 5 post treatment)
2014-12-04 | E-GEOD-59294 | biostudies-arrayexpress
Project description:To gain a deeper understanding of the atopic dermatitis (AD) skin transcriptome and the effects of systemic treatment with dupilumab and cyclosporine, we conducted a gene expression study of AD using mRNA-Seq data generated from lesional and non-lesional skin biopsies collected from patients included in the TREATgermany registry. We are able to provide deep characterisation of AD skin transcriptomic signatures by using an assortment of bioinformatic approaches such as differential expression, co-expression network and pathway enrichment analysis.
2020-09-01 | GSE157194 | GEO
Project description:mRNA array analysis of total RNA from primary kertinocytes from three healthy controls, three atopic dermatitis patients and three psoriasis patients was carried out
2012-06-01 | E-MTAB-728 | biostudies-arrayexpress
Project description:Clinical overlaps between psoriasis and atopic dermatitis are sometimes undiscernible, and there is no consensus whether to treat the overlap phenotype as psoriasis or atopic dermatitis. We enrolled patients diagnosed with either psoriasis or atopic dermatitis, and clinically re-stratified them into classic psoriasis, classic atopic dermatitis, and the overlap phenotype between psoriasis and atopic dermatitis. We compared gene expression profiles of lesional and nonlesional skin biopsy tissues between the three comparison groups. Global mRNA expression and T-cell subset cytokine expression in the skin of the overlap phenotype were consistent with the profiles of psoriasis and different from the profiles of atopic dermatitis. Unsupervised k-means clustering indicated that the best number of distinct clusters for the total population of the three comparison groups was two, and the two clusters of psoriasis and atopic dermatitis were differentiated by gene expression. Our study suggests that clinical overlap phenotype between psoriasis and atopic dermatitis has dominant molecular features of psoriasis, and genomic biomarkers can differentiate psoriasis and atopic dermatitis at molecular levels in patients with a spectrum of psoriasis and atopic dermatitis.
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Project description:TWEAK Upregulates atopic dermatitis related genes in human kearatinocytes
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Project description:Atopic dermatitis (AD) is the most common inflammatory skin disease, with high unmet need for new therapies that are safe for chronic use. Emerging data suggest that TH2-cytokines play important roles in a variety of allergic and atopic conditions, including asthma and AD. In early phase clinical trials, dupilumab (a fully human monoclonal antibody against IL-4Rα that potently blocks IL-4 and IL-13 signaling) rapidly and markedly improved clinical measures in adults with either asthma (with elevated eosinophil counts) or moderate-to-severe AD. The pathomechanisms that may be impacted by IL-4/13 blockade in these disease settings have not yet been characterized in detail. Transcriptome analyses in pre- and post-treatment skin biopsies from patients with moderate-to-severe AD treated with dupilumab or placebo in two completed clinical trials
2014-12-04 | GSE59294 | GEO
Project description:Characteization host-microbiome interactions in patients with allergic (model: atopic dermatitis) and autoimmune (model: psoriasis) diseases by integration of microarray transcriptome data with 16S microbial profiling. 6mm punch biopsies were collected from the skin of atopic dermatitis and psoriasis patients alongside healthy volunteers, and subjected to analysis using Affymetrix Human Gene ST 2.1 arrays.
2019-09-11 | E-MTAB-8149 | biostudies-arrayexpress