828 Early intervention with secukinumab may affect the establishment of tissue memory in psoriasis: Results from a DNA methylation analysis

Biologics targeting the interleukin (IL)-17A pathway are efficacious in the treatment of plaque psoriasis (PsO). However, psoriatic skin lesions often recur after treatment cessation, potentially driven by a tissue memory. We hypothesize that early intervention with secukinumab (SEC) in new-onset PsO may lead to sustained skin clearance by preventing the establishment of a tissue memory. The Mechanistic Sub-study of the STEPIn trial assessed molecular changes in the skin of patients with new-onset (≤1 year) and chronic (≥5 years) moderate to severe plaque PsO treated with SEC 300 mg by profiling lesional (LS) biopsies collected at baseline (BL), week (Wk) 16, and Wk 52, with non-lesional (NL) skin biopsies collected at Wk 52 as reference. Previously published results showed that LS transcriptomes at BL were relatively similar between cohorts, but SEC treatment-induced normalization to NL levels of global gene expression and IL-17 pathway signatures occurred faster in patients with new-onset vs chronic PsO (Iversen et al. ESDR 2022). Epigenetic analysis now revealed that differences in DNA methylation observed in LS skin were normalized only in the new-onset cohort at Wk 52, while in the chronic cohort, residual differential DNA methylation remained, suggesting a "molecular scar". Intersecting these non-resolved differentially methylated regions with gene expression, known PsO genetic risk loci, and enrichment for transcription factor binding site motifs provided functional annotation and first insights into the molecular mechanisms underlying the hypothesized tissue memory. In summary, early intervention with SEC may lead to sustained skin clearance in patients with PsO by preventing the establishment of a tissue memory in psoriatic skin.