Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor PF-06700841 Reveal Reduction of Skin Inflammation in Plaque Psoriasis.
Adult
Biopsy
Female
Follow-Up Studies
Gene Expression Profiling
Humans
Interleukin-12 Subunit p40
/ metabolism
Interleukin-17
/ metabolism
Janus Kinase 1
/ antagonists & inhibitors
Male
Middle Aged
Protein Kinase Inhibitors
/ administration & dosage
Psoriasis
/ drug therapy
Pyrazoles
/ administration & dosage
Pyrimidines
/ administration & dosage
Signal Transduction
/ drug effects
Skin
/ drug effects
TYK2 Kinase
/ antagonists & inhibitors
Th17 Cells
/ drug effects
Treatment Outcome
Young Adult
Journal
The Journal of investigative dermatology
ISSN: 1523-1747
Titre abrégé: J Invest Dermatol
Pays: United States
ID NLM: 0426720
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
23
05
2019
revised:
16
11
2019
accepted:
21
11
2019
pubmed:
24
1
2020
medline:
9
3
2021
entrez:
24
1
2020
Statut:
ppublish
Résumé
The IL-23/T helper type 17 cell axis is a target for psoriasis. The TYK2/Janus kinase 1 inhibitor PF-06700841 will directly suppress TYK2-dependent IL-12 and IL-23 signaling and Janus kinase 1-dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n = 30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n = 14) or 100 mg (n = 7) PF-06700841 or placebo (n = 9) for 28 days. Biopsies were taken from nonlesional and lesional skin at baseline and weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and reverse transcriptase-PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and approximately 70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3
Identifiants
pubmed: 31972249
pii: S0022-202X(20)30027-0
doi: 10.1016/j.jid.2019.11.027
pii:
doi:
Substances chimiques
IL12B protein, human
0
IL17A protein, human
0
IL17F protein, human
0
Interleukin-12 Subunit p40
0
Interleukin-17
0
Protein Kinase Inhibitors
0
Pyrazoles
0
Pyrimidines
0
PF-06700841
3X8387Q25N
JAK1 protein, human
EC 2.7.10.2
Janus Kinase 1
EC 2.7.10.2
TYK2 Kinase
EC 2.7.10.2
TYK2 protein, human
EC 2.7.10.2
Banques de données
ClinicalTrials.gov
['NCT02310750']
Types de publication
Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1546-1555.e4Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.