Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study
James Krueger, James D Clark, Mayte Suárez-Fariñas, Judilyn Fuentes-Duculan, Inna Cueto, Claire Q Wang, Huaming Tan, Robert Wolk, Scott T Rottinghaus, Maryann Z Whitley, Hernan Valdez, David von Schack, Shawn P O'Neil, Padmalatha S Reddy, Svitlana Tatulych, A3921147 Study Investigators, James Krueger, James D Clark, Mayte Suárez-Fariñas, Judilyn Fuentes-Duculan, Inna Cueto, Claire Q Wang, Huaming Tan, Robert Wolk, Scott T Rottinghaus, Maryann Z Whitley, Hernan Valdez, David von Schack, Shawn P O'Neil, Padmalatha S Reddy, Svitlana Tatulych, 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/μm(2); day 1, median of 332 pSTAT1(+) cells/μm(2); and nonlesional, median of 155 pSTAT1(+) cells/μm(2)). 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.
Trial registration: ClinicalTrials.gov NCT01710046.
Keywords: IL-17; IL-22 family; IL-23; Janus kinase; T(H)17 cell; inflammation; keratinocyte; phosphorylated signal transducer and activator of transcription; psoriasis; tofacitinib.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed