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

Journal of Allergy and Clinical Immunolo.. - 3d ago Preview

 
 
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Publication date: Available online 24 May 2019

Source: Journal of Allergy and Clinical Immunology

Author(s): James G. Krueger, Keith A. Wharton, Thomas Schlitt, Maria Suprun, Rebecca I. Torene, Xiaoyu Jiang, Claire Q. Wang, Judilyn Fuentes-Duculan, Nicole Hartmann, Thomas Peters, Irina Koroleva, Rainer Hillenbrand, Martin Letzkus, Xiaojing Yu, Yue Li, Anton Glueck, Anke Hasselberg, Brian Flannery, Mayte Suárez-Fariñas, Wolfgang Hueber

Abstract

Background

Hyperactivity of the IL-23/IL-17-axis is central to plaque psoriasis pathogenesis. Secukinumab, a fully human monoclonal antibody 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 is lacking.

Objective / Methods

We performed a randomized, double-blinded, 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 histopathological 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 the upstream cytokine IL-23, drug target IL-17A, and downstream targets including beta-defensin2. Suppression of the IL-23/IL-17 axis by secukinumab at Week 4 was associated with clinical and histological responses at Week 12. Secukinumab did not affect ex vivo T-cell activation, consistent with its favorable long-term safety profile.

Conclusion

Our data suggest that IL-17A is the critical node within 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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