IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis

IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis

Background: Hyperactivity of the IL-23/IL-17 axis is central to plaque psoriasis pathogenesis. Secukinumab, a fully human mAb that selectively inhibits IL-17A, is approved for treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. Secukinumab improves the complete spectrum of psoriasis manifestations, with durable clinical responses beyond 5 years of treatment. In the feed-forward model of plaque chronicity, IL-17A has been hypothesized as the key driver of pathogenic gene expression by lesional keratinocytes, but in vivo evidence in human subjects is lacking.

Methods: We performed a randomized, double-blind, placebo-controlled study (NCT01537432) of patients receiving secukinumab at the clinically approved dose up to 12 weeks. We then correlated plaque and nonlesional skin transcriptomic profiles with histopathologic and clinical measures of efficacy.

Results: After 12 weeks of treatment, secukinumab reversed plaque histopathology in the majority of patients and modulated thousands of transcripts. Suppression of the IL-23/IL-17 axis by secukinumab was evident at week 1 and continued through week 12, including reductions in levels of the upstream cytokine IL-23, the drug target IL-17A, and downstream targets, including β-defensin 2. Suppression of the IL-23/IL-17 axis by secukinumab at week 4 was associated with clinical and histologic responses at week 12. Secukinumab did not affect ex vivo T-cell activation, which is consistent with its favorable long-term safety profile.

Conclusion: Our data suggest that IL-17A is the critical node within the multidimensional pathogenic immune circuits that maintain psoriasis plaques and that early reduction of IL-17A–dependent feed-forward transcripts synthesized by hyperplastic keratinocytes favors plaque resolution.


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