Tape Strip Transcriptomics Reveal Nemolizumab Effects on Pruritus, Hyperplasia, Inflammation, and Extracellular Matrix Markers in Patients With Moderate‐to‐Severe Atopic Dermatitis

BACKGROUND: Atopic dermatitis (AD) is characterized by pruritus, epidermal hyperplasia, and lichenification that significantly impairs quality of life. Nemolizumab, an anti-IL-31Rα monoclonal antibody, is approved for treating moderate-to-severe AD in patients aged > 12 years. This study investigated nemolizumab's molecular mechanisms using patient samples from the ARCADIA 1 (NCT03985943) and 2 (NCT03989349) trials. METHODS: Tape-strips were collected from the lesional and non-lesional skin of 71 nemolizumab-treated and 39 placebo-treated patients, all receiving background topical corticosteroids ± topical calcineurin inhibitors, at baseline and after 16 weeks of treatment for bulk RNAseq analysis. Single cell RNAseq was performed on a subset of untreated patients and used as a reference to map bulk RNA-seq DEGs, providing cellular context for treatment-associated transcriptional changes. RESULTS: Bulk RNAseq revealed significant transcriptomic modulation following 16 weeks of nemolizumab treatment (797 downregulated/142 upregulated genes), while placebo-treated patients showed minimal changes. Nemolizumab treatment attenuated expression of pruritus-related genes (e.g., OSMR, TRPV3, HRH1, KLK6/7/9) and genes involved in epidermal hyperplasia and ECM remodeling (e.g., COL1A1/12A1, IGFBP3). Inflammatory pathways were also modulated, with downregulation of Th17- and Th1-related genes (e.g., S100A7/8/9, PI3, MX1, OASL). Pathway-level analysis demonstrated normalization of pruritus and inflammatory gene signatures, including Th2 and Th22 pathways. Subgroup analysis showed that patients with severe baseline pruritus (PPNRS ≥ 7) had higher baseline expression of immune-related genes and experienced greater downregulation following treatment compared to patients with moderate baseline itch. Single-cell mapping of differentially expressed genes suggested enrichment of these genes in keratinocyte, fibroblast, endothelial, and nerve cell subpopulations. Clinically, improvements in EASI and pruritus scores (PPNRS) correlated with decreased expression of fibrosis- and pruritus-associated genes. CONCLUSION: Our findings provide molecular evidence supporting nemolizumab's therapeutic efficacy across multiple disease domains, including pruritus, inflammation, and epidermal hyperplasia, highlighting its role in AD treatment and management.