IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis
| Autor: | Anke Hasselberg, Claire Q.F. Wang, Rebecca I. Torene, Yue Li, Maria Suprun, Thomas Schlitt, Rainer Hillenbrand, Thomas Peters, Keith A. Wharton, Wolfgang Hueber, Anton Glueck, Mayte Suárez-Fariñas, Judilyn Fuentes-Duculan, Brian Flannery, Irina Koroleva, Xiaojing Yu, Nicole Hartmann, Xiaoyu Jiang, James G. Krueger, Martin Letzkus |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Immunology Antibodies Monoclonal Humanized Interleukin-23 Pathogenesis 030207 dermatology & venereal diseases 03 medical and health sciences Psoriatic arthritis 0302 clinical medicine Immune system Double-Blind Method Psoriasis Area and Severity Index Psoriasis medicine Humans Immunology and Allergy Skin Ankylosing spondylitis business.industry Interleukin-17 medicine.disease Treatment Outcome 030104 developmental biology Cytokine Secukinumab Transcriptome business |
| Zdroj: | Journal of Allergy and Clinical Immunology. 144:750-763 |
| ISSN: | 0091-6749 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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