Short-term transcriptional response to IL-17 Receptor-A antagonism in the treatment of Psoriasis

Abstract Background IL-17 antagonists induce impressive clinical benefit in psoriasis, but it is unknown to what extent cellular and molecular psoriasis characteristics are suppressed by a clinically relevant dose/schedule of any IL-17-receptor antagonist. Objective Examine the effects of the IL-17-receptor-A antagonist brodalumab, on clinical and molecular psoriasis features over a 12-week period. Methods A subset of patients (n=116) enrolled in three Phase-3 randomized clinical trials (AMAGINE-1,2,3) participated in a mechanistic sub-study where punch biopsies were collected (lesional and non-lesional skin) between baseline and 12-weeks. This cohort included moderate-to-severe psoriasis patients treated with 140mg (n=46), 210mg (n=41) brodalumab or placebo (n=29). Key epidermal psoriatic features, including T-cell and dendritic cell subsets, were examined using immunohistochemistry. Treatment-induced changes in lesional skin gene expression profiles were evaluated using Affymetrix arrays. Results IL-17RA antagonism caused extensive improvements in clinical, histological and transcriptomic features of psoriasis. Cellular infiltrates (CD3+, CD8+, CD11c+, CD163+), markers of keratinocyte proliferation (Ki67+, KRT16) and inflammatory cytokines (IL-17A/C/F, IL-23A, IL-12B) decreased progressively, reaching close to non-lesional levels, paralleled by decreases in epidermal thickness. Psoriasis transcriptome gene expression improved ∼85-95% in PASI75 responders (n=63), compared with ∼30-65% in non-responders (n=12), whilst the “residual disease genomic profile” was 10% of the psoriasis transcriptome, less than earlier generation drugs. IL-17-dependent gene expression, including keratinocyte genes, improved earlier and more extensively following brodalumab treatment compared with ustekinumab (anti-IL-23/IL-12). Conclusions The clinically approved dose and schedule for brodalumab leads to near complete resolution of clinical, histological and transcriptomic features of psoriasis. Evidently, IL-17-induced release of keratinocyte-derived inflammatory mediators is a key driver of psoriasis pathogenesis.