Early intervention with secukinumab prevents epigenetic scar development in new-onset psoriasis: STEPIn mechanistic substudy results

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease characterized by recurrent flares at previously affected locations. Although biologics targeting IL-17 or IL-23 effectively suppress active disease, they rarely result in long-term remission, suggesting that clinically resolved skin retains molecular changes predisposing to relapse. OBJECTIVE: The STEPIn main study indicated that early intervention with secukinumab, an anti-IL-17A monoclonal antibody, may modify the course of psoriasis. This mechanistic substudy sought to define cellular and molecular changes in psoriatic skin lesions during treatment. METHODS: Psoriatic skin was sampled at baseline and at up to 52 weeks of secukinumab treatment in new-onset (≤1 year) and long-standing (≥5 years) cohorts. Biopsy samples were evaluated histologically by immune profiling, global gene expression, and genome-wide DNA CpG methylation analyses. RESULTS: Treatment with secukinumab resulted in marked molecular differences between new-onset and long-standing psoriasis despite similar clinical improvement. Gene expression normalized faster in new-onset disease but ultimately resolved in both cohorts. In contrast, disease-associated CpG methylation detected at baseline persisted despite treatment, but only in long-standing psoriasis. Baseline methylation differences were enriched for AP-1 transcription factor binding sites in long-standing disease and persistent methylation changes mapped to genes enriched for small GTPase pathways. Notably, AP-1 components were found to amplify IL-17A and TNF-α responses in keratinocytes, and a subset of these persistent methylation sites overlapped with accessible chromatin regions in psoriatic keratinocytes. CONCLUSIONS: Early secukinumab intervention may prevent formation of an epigenetic scar that persists in long-standing psoriasis even after clinical resolution. CLINICAL TRIAL REGISTRATION: NCT03020199.