Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study - 06/04/16
for the
A3921147 Study Investigators∗
Abstract |
Background |
Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.
Objective |
We sought to elucidate the molecular mechanisms underlying the clinical efficacy of tofacitinib in patients with psoriasis.
Methods |
Twelve patients with plaque psoriasis were randomized (3:1) to receive 10 mg of tofacitinib or placebo twice daily for 12 weeks. Biopsy specimens were taken from nonlesional (baseline) and lesional (baseline, days 1 and 3, and weeks 1, 2, 4, and 12) skin. Biopsy specimens were examined for psoriatic epidermal features (thickness, Ki67+ keratinocytes and keratin 16 [KRT16] mRNA expression, and phosphorylated signal transducer and activator of transcription [pSTAT]+ nuclei) and T-cell and dendritic cell (DC) subsets by using immunohistochemistry, and mRNA transcripts were quantified by using a microarray.
Results |
In lesional skin keratinocyte pSTAT1 and pSTAT3 staining was increased at baseline but reduced after 1 day of tofacitinib (baseline, median of 1290 pSTAT1+ cells/μm2; day 1, median of 332 pSTAT1+ cells/μm2; and nonlesional, median of 155 pSTAT1+ cells/μm2). Epidermal thickness and KRT16 mRNA expression were significantly and progressively reduced after days 1 and 3 of tofacitinib administration, respectively (eg, KRT16 decreased 2.74-fold, day 3 vs baseline, P = .016). Decreases in DC and T-cell numbers were observed after weeks 1 and 2, respectively. At week 4, significant decreases in IL-23/TH17 pathways were observed that persisted through week 12. Improvements in clinical and histologic features were strongly associated with changes in expression of psoriasis-related genes and reduction in IL-17 gene expression.
Conclusions |
Tofacitinib has a multitiered response in patients with psoriasis: (1) rapid attenuation of keratinocyte Janus kinase/STAT signaling; (2) removal of keratinocyte-induced cytokine signaling, leading to reductions in pathologic DC and T-cell numbers to nonlesional levels; and (3) inhibition of the IL-23/TH17 pathway.
Le texte complet de cet article est disponible en PDF.Key words : IL-17, IL-22 family, IL-23, inflammation, Janus kinase, keratinocyte, psoriasis, phosphorylated signal transducer and activator of transcription, TH17 cell, tofacitinib
Abbreviations used : AMP, DC, DEFB4A, FDR, JAK, KRT16, MAD3, PASI, pSTAT, STAT, TLDA, TPSS
Plan
| This study was sponsored by Pfizer Inc. Both Pfizer Inc and non-Pfizer Inc authors have participated in the study design, data collection, data analysis, and open scientific discussion of the data; its interpretation; and the development of the associated manuscript. The views and opinions expressed within the manuscript are those of all authors and do not necessarily represent those of the funding organization. Medical writing support was funded by Pfizer Inc. |
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| Disclosure of potential conflict of interest: J. Krueger received research funding from Novartis, Pfizer Inc, Janssen, Lilly, Merck, Kadmon, Dermira, Boehringer, BMS, and Paraxel during the conduct of the study; grants paid to institutions from Amgen, Innovaderm and Kyowa; and personal fees from Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Xenoport, and Kineta. M. Suárez-Fariñas receives research funding and speakers' fees from Pfizer. J. D. Clark, H. Tan, R. Wolk, S. T. Rottinghaus, M. Z. Whitley, H. Valdez, D. von Schack, S. P. O'Neil, P. S. Reddy, and S. Tatulych are employees of Pfizer Inc. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 137 - N° 4
P. 1079-1090 - avril 2016 Retour au numéro
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