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Tralokinumab treatment of Atopic dermatitis induces a progressive transcriptomic response

ABSTRACT: Atopic dermatitis (AD) is characterized by a complex epidermal barrier deficiency and exaggerated immune responses dominated by type-2-mechanisms with variable contributions of additional immune axes. Interleukin (IL)-13 is overexpressed in AD skin and a key driver of both barrier dysfunction and inflammation. We here prospectively studied the effects of IL-13 inhibition with tralokinumab on cutaneous transcriptome profiles using RNA sequencing of biopsies from 16 moderate-to-severe AD patients obtained at baseline, week 2 and week 16. Tralokinumab therapy induced early and delayed expression changes, and progressively shifted the transcriptomic profile of lesional towards non-lesional skin by modulating both genes associated with keratinocyte proliferation and differentiation, itch signaling, and downstream inflammatory responses. At week 16, 751 genes were still significantly dysregulated as compared to healthy control skin, reinforcing the need for long-term immunomodulatory therapy of moderate to severe AD to achieve deep responses. The study was registered with ClinicalTrials.gov (NCT04556461)

ORGANISM(S): Homo sapiens

PROVIDER: GSE277961 | GEO | 2024/12/19

REPOSITORIES: GEO

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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.)

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Tralokinumab treatment of Atopic dermatitis induces a progressive transcriptomic response

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