Blood gene expression reveals endotypes of atopic dermatitis patients with distinct responses to dupilumab
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Presented at: Society for Investigative Dermatology 2025
Date: 2025-05-07 00:00:00
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Summary: Abstract Body: Dupilumab (DUP), an IL-4/IL-13 antagonist, reduces Atopic Dermatitis (AD) severity, but its molecular effects and variability in clinical response remain unclear. To identify AD endotypes (eTypes) with distinct gene expression changes in response to DUP, we analyzed bulk RNA-seq data from 47 AD patients pre-and post-DUP treatment (Möbus et al. 2022, GSE208405). Gene Set Variation Analysis (GSVA) using informative gene signatures (Hubbard et al. 2023) identified 3 eTypes via k-means clustering of GSVA scores. eType-1 was enriched in OXPHOS, immunoproteasome, plasma cell (PC), and Treg signatures; eType-2 in GD T cells and T cell signatures; and eType-3 in neutrophil, granulocyte, and monocyte signatures. DUP-induced changes after 3 months varied per eType: eType-1 showed GD T cells (p=0.03), NK cells (p=0.04), and B cells (p=0.00005) upregulated, and PC (p=0.002), immunoproteasome (p=0.004), cell cycle (p=0.001), and LDG (p=0.007) downregulated; eType-2 showed reductions in cell cycle (p=0.03) and IL-1 pathway (p=0.04); eType-3 showed IL-23 complex (p=0.03), GD T cells (p=0.009), and regulatory T cells (p=0.02) upregulated, and cell cycle (p=0.0005), neutrophil (p=0.04), granulocyte (p=0.006), and inflammasome (p=0.01) downregulated. These results show blood gene expression analysis identifies distinct AD eTypes, each with unique responses to DUP manifested by selective changes in cell or molecular pathway signatures. eTypes-1 and 3 exhibited broader immunomodulation in response to DUP across innate and adaptive pathways, whereas eType-2 showed more restricted changes. This study underscores AD heterogeneity and the systemic effects of DUP, emphasizing molecular endotyping's value for personalized AD treatment. Sneha Shrotri<sup>1</sup>, Andrea Daamen<sup>1</sup>, Prathyusha Bachali<sup>1</sup>, Amrie Grammer<sup>1</sup>, Peter Lipsky<sup>1</sup> 1. AMPEL BioSolutions LLC, Charlottesville, VA, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics