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Dupilumab-associated head and neck dermatitis shows a pronounced type 22 immune signature mediated by oligoclonally expanded T cells

ABSTRACT: Background: Dupilumab, an IL4R-blocking antibody, has shown clinical efficacy for atopic dermatitis (AD) treatment. In addition to conjunctivitis/blepharitis, the _de novo_ appearance of head/neck dermatitis is now recognized as a distinct side effect, occurring in up to 10% of patients. Histopathological features distinct from AD suggest a drug effect, but exact underlying mechanisms remain unknown. Methods: We profiled punch biopsies from dupilumab-associated head and neck dermatitis (DAHND) by using single-cell RNA sequencing and compared data with untreated AD and healthy control skin. Results: We show that dupilumab treatment was accompanied by normalization of IL-4/IL-13 downstream activity markers such as _CCL13, CCL17_, _CCL18 _and_ CCL26_. By contrast, we found strong increases in type 22-associated markers (_IL22, AHR_) especially in oligoclonally expanded T cells, accompanied by enhanced keratinocyte activation and IL-22 receptor upregulation. Conclusions: Taken together, we demonstrate that dupilumab effectively dampens conventional type 2 inflammation in DAHND lesions, with concomitant hyperactivation of _IL22_-associated responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230575 | GEO | 2024/02/20

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.)

Project description:Background: Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. Dupilumab, a monoclonal antibody that targets the interleukin (IL)-4 and IL-13 receptors, has been widely used in AD because of its efficacy. However, metabolic changes occurring in patients with AD in response to dupilumab remains unknown. In this study, we integrated metabolomics and lipidomics analyses with clinical data to explore potential metabolic alterations associated with dupilumab therapeutic efficacy. In addition, we investigate whether the development of treatment side effects was linked to the dysregulation of metabolic pathways. Methods: A total of 33 patients with AD were included in the current study, with serum samples collected before and after treatment with dupilumab. Comprehensive metabolomic and lipidomic analyses have previously been developed to identify serum metabolites (including lipids) that vary among treatment groups. An orthogonal partial least squares discriminant analysis model was established to screen for differential metabolites and metabolites with variable importance in projection > 1 and p < 0.05 were considered potential metabolic biomarkers. MetaboAnalyst 5.0 was used to identify related metabolic pathways. Patients were further classified into two groups, well responders (n = 19) and poor responders (n = 14), to identify differential metabolites between the two groups. Results: The results revealed significant changes in serum metabolites before and after 16 weeks of dupilumab treatment. Variations in the metabolic profile were more significant in the well-responder group than in the poor-responder group. Pathway enrichment analysis revealed that differential metabolites derived from the well-responder group were mainly involved in glycerophospholipid metabolism, valine, leucine and isoleucine biosynthesis, the citrate cycle, arachidonic acid metabolism, pyrimidine metabolism, and sphingolipid metabolism. Conclusion: Serum metabolic profiles of patients with AD varied significantly after treatment with dupilumab. Differential metabolites and their related metabolic pathways may provide clues for understanding the effects of dupilumab on patient metabolism.

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Dupilumab-associated head and neck dermatitis shows a pronounced type 22 immune signature mediated by oligoclonally expanded T cells

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