O23 Single-cell multiomic atlas of systemic treatment action in atopic eczema

Abstract Introduction and aims Atopic eczema is the most common inflammatory skin disease. Epidermal barrier dysfunction and the T helper (Th)2 immune axis are central to disease pathogenesis. In recent years, treatments targeting Th2 immune mediators [e.g. interleukin (IL)-4/IL-13 inhibitor dupilumab] have greatly expanded the therapeutic armamentarium. However, the observed interindividual heterogeneity in real-world outcomes of eczema treatment highlights our limited knowledge of drug action and response. To address this, we embedded a highly powered longitudinal single-cell multiomic and spatial transcriptomic profiling strategy within BEACON (n > 400), the world-first platform trial to compare effectiveness and tolerability of standard (methotrexate) and targeted (dupilumab, Janus kinase inhibitor) eczema drugs. Methods Our initial cohort consisted of 25 individuals (17 male patients; mean age 39.2 years) sampled at day 0, day 3, day 14, week 12 and week 24 of dupilumab therapy. We profiled circulating immune populations through single-cell transcriptome, surface proteome and T-cell receptor repertoire analysis of > 600 000 peripheral blood mononuclear cells. We also used 10 × Multiome and Xenium to profile chromatin accessibility and gene expression of matched eczema skin at single-cell resolution. Results We defined 20 immune populations in peripheral blood, including CD4+, CD8+, myeloid, natural killer and B cells. We observed drug-induced shifts in abundance and gene expression levels in each major cell type as early as 14 days into dupilumab treatment. We also identified dynamic shifts of key skin cell populations during early dupilumab treatment and spatially mapped these cell populations in eczema skin at subcellular resolution. Conclusions Our high-resolution multiomic therapeutics atlas, leveraging a unique clinical platform, maps changes of the skin and blood immune response induced by dupilumab treatment. It provides critical insight into the early effects of dupilumab therapy, which may open avenues for new target discovery and precision medicine approaches to treatment allocation and monitoring in eczema.