Short-term transcriptional response to IL-17 receptor-A antagonism in the treatment of psoriasis

Lewis E. Tomalin, Chris B. Russell, Sandra Garcet, David Adrian Ewald, Paul Klekotka, Ajay Nirula, Hanne Norsgaard, Mayte Suàrez-Fariñas, James G. Krueger

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Background: IL-17 antagonists induce impressive clinical benefits 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: We sought to 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 3 phase-3 randomized clinical trials (AMAGINE -1 [Efficacy, Safety, and Withdrawal and Retreatment With Brodalumab in Moderate to Severe Plaque Psoriasis Subjects], -2 [P3 Study Brodalumab in Treatment of Moderate to Severe Plaque Psoriasis], and -3 [Efficacy and Safety of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis in Subjects]) participated in a mechanistic substudy where punch biopsies were collected (lesional and nonlesional skin) between baseline and 12 weeks. This cohort included moderate-to-severe psoriasis patients treated with 140 mg (n = 46), 210 mg (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-17 receptor-A antagonism caused extensive improvements in clinical, histologic, 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 nonlesional levels, paralleled by decreases in epidermal thickness. Psoriasis transcriptome gene expression improved ∼85% to 95% in responders whose psoriasis area severity index improved by 75% from baseline by week 12 (n = 63), compared with ∼30% to 65% in nonresponders (n = 12), while the residual disease genomic profile was 10% of the psoriasis transcriptome, which is less than for earlier generation drugs. IL-17–dependent gene expression, including keratinocyte genes, improved earlier and more extensively following brodalumab treatment compared with ustekinumab treatment (anti-IL-23/-IL-12). Conclusions: The clinically approved dose and schedule for brodalumab leads to nearly complete resolution of clinical, histologic, and transcriptomic features of psoriasis. Evidently, IL-17–induced release of keratinocyte-derived inflammatory mediators is a key driver of psoriasis pathogenesis.

Original languageEnglish
Pages (from-to)922-932
Number of pages11
JournalJournal of Allergy and Clinical Immunology
Volume145
Issue number3
DOIs
StatePublished - Mar 2020

Keywords

  • IL-12
  • IL-17
  • IL-23
  • brodalumab
  • inflammatory cytokines
  • keratinocytes
  • psoriasis
  • transcriptomic profiling
  • ustekinumab

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