title: Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study.
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.
authors.affiliation: Rockefeller University, New York, NY.
authors.forename: James
authors.initials: J
authors.lastname: Krueger
authors.affiliation: Pfizer Inc, Cambridge, Mass.
authors.forename: James D
authors.initials: JD
authors.lastname: Clark
authors.affiliation: Rockefeller University, New York, NY.
authors.forename: Mayte
authors.initials: M
authors.lastname: Suárez-Fariñas
authors.affiliation: Rockefeller University, New York, NY.
authors.forename: Judilyn
authors.initials: J
authors.lastname: Fuentes-Duculan
authors.affiliation: Rockefeller University, New York, NY.
authors.forename: Inna
authors.initials: I
authors.lastname: Cueto
authors.affiliation: Rockefeller University, New York, NY.
authors.forename: Claire Q
authors.initials: CQ
authors.lastname: Wang
authors.affiliation: Pfizer Inc, Groton, Conn.
authors.forename: Huaming
authors.initials: H
authors.lastname: Tan
authors.affiliation: Pfizer Inc, Groton, Conn.
authors.forename: Robert
authors.initials: R
authors.lastname: Wolk
authors.affiliation: Pfizer Inc, Groton, Conn.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Rottinghaus
authors.affiliation: Pfizer Inc, Cambridge, Mass.
authors.forename: Maryann Z
authors.initials: MZ
authors.lastname: Whitley
authors.affiliation: Pfizer Inc, New York, NY.
authors.forename: Hernan
authors.initials: H
authors.lastname: Valdez
authors.affiliation: Pfizer Inc, Cambridge, Mass.
authors.forename: David
authors.initials: D
authors.lastname: von Schack
authors.affiliation: Pfizer Inc, Cambridge, Mass.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: O'Neil
authors.affiliation: Pfizer Inc, Cambridge, Mass.
authors.forename: Padmalatha S
authors.initials: PS
authors.lastname: Reddy
authors.affiliation: Pfizer Inc, Groton, Conn. Electronic address: svitlana.tatulych@pfizer.com.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Tatulych
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D015398:Signal Transduction; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib
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