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The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signaling in rheumatoid arthritis

Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. A randomised, double-blind, phas... Full description

Journal Title: Annals of the Rheumatic Diseases 2015-06, Vol.74 (6), p.1311-1316
Main Author: Boyle, D L
Other Authors: Soma, K , Hodge, J , Kavanaugh, A , Mandel, D , Mease, P , Shurmur, R , Singhal, A K , Wei, N , Rosengren, S , Kaplan, I , Krishnaswami, S , Luo, Z , Bradley, J , Firestein, G S
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: England: British Medical Association
ID: ISSN: 0003-4967
Link: https://www.ncbi.nlm.nih.gov/pubmed/25398374
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4431345
title: The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signaling in rheumatoid arthritis
format: Article
creator:
  • Boyle, D L
  • Soma, K
  • Hodge, J
  • Kavanaugh, A
  • Mandel, D
  • Mease, P
  • Shurmur, R
  • Singhal, A K
  • Wei, N
  • Rosengren, S
  • Kaplan, I
  • Krishnaswami, S
  • Luo, Z
  • Bradley, J
  • Firestein, G S
subjects:
  • 1506
  • Adult
  • Aged
  • Antirheumatic Agents - pharmacology
  • Antirheumatic Agents - therapeutic use
  • Arthritis, Rheumatoid - drug therapy
  • Arthritis, Rheumatoid - metabolism
  • Basic
  • Basic and Translational Research
  • Chemokines - drug effects
  • Chemokines - genetics
  • Chemokines - metabolism
  • Dosage and administration
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Gene expression
  • Genetic aspects
  • Humans
  • Janus Kinase 1 - drug effects
  • Janus Kinase 1 - metabolism
  • Male
  • Matrix Metalloproteinase 1 - drug effects
  • Matrix Metalloproteinase 1 - genetics
  • Matrix Metalloproteinase 1 - metabolism
  • Matrix Metalloproteinase 3 - drug effects
  • Matrix Metalloproteinase 3 - genetics
  • Matrix Metalloproteinase 3 - metabolism
  • Methotrexate - therapeutic use
  • Middle Aged
  • Piperidines - pharmacology
  • Piperidines - therapeutic use
  • Protein Kinase Inhibitors - pharmacology
  • Protein Kinase Inhibitors - therapeutic use
  • Pyrimidines - pharmacology
  • Pyrimidines - therapeutic use
  • Pyrroles - pharmacology
  • Pyrroles - therapeutic use
  • Research
  • Rheumatoid arthritis
  • Risk factors
  • RNA, Messenger - drug effects
  • RNA, Messenger - metabolism
  • Signal Transduction - drug effects
  • STAT Transcription Factors - drug effects
  • STAT Transcription Factors - metabolism
  • Synovial Membrane - drug effects
  • Synovial Membrane - metabolism
  • Tofacitinib
  • Translational Research
  • Treatment Outcome
ispartof: Annals of the Rheumatic Diseases, 2015-06, Vol.74 (6), p.1311-1316
description: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p
language: eng
source:
identifier: ISSN: 0003-4967
fulltext: no_fulltext
issn:
  • 0003-4967
  • 1468-2060
url: Link


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titleThe JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signaling in rheumatoid arthritis
creatorBoyle, D L ; Soma, K ; Hodge, J ; Kavanaugh, A ; Mandel, D ; Mease, P ; Shurmur, R ; Singhal, A K ; Wei, N ; Rosengren, S ; Kaplan, I ; Krishnaswami, S ; Luo, Z ; Bradley, J ; Firestein, G S
creatorcontribBoyle, D L ; Soma, K ; Hodge, J ; Kavanaugh, A ; Mandel, D ; Mease, P ; Shurmur, R ; Singhal, A K ; Wei, N ; Rosengren, S ; Kaplan, I ; Krishnaswami, S ; Luo, Z ; Bradley, J ; Firestein, G S
descriptionTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. NCT00976599.
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languageeng
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subject1506 ; Adult ; Aged ; Antirheumatic Agents - pharmacology ; Antirheumatic Agents - therapeutic use ; Arthritis, Rheumatoid - drug therapy ; Arthritis, Rheumatoid - metabolism ; Basic ; Basic and Translational Research ; Chemokines - drug effects ; Chemokines - genetics ; Chemokines - metabolism ; Dosage and administration ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Gene expression ; Genetic aspects ; Humans ; Janus Kinase 1 - drug effects ; Janus Kinase 1 - metabolism ; Male ; Matrix Metalloproteinase 1 - drug effects ; Matrix Metalloproteinase 1 - genetics ; Matrix Metalloproteinase 1 - metabolism ; Matrix Metalloproteinase 3 - drug effects ; Matrix Metalloproteinase 3 - genetics ; Matrix Metalloproteinase 3 - metabolism ; Methotrexate - therapeutic use ; Middle Aged ; Piperidines - pharmacology ; Piperidines - therapeutic use ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; Pyrimidines - pharmacology ; Pyrimidines - therapeutic use ; Pyrroles - pharmacology ; Pyrroles - therapeutic use ; Research ; Rheumatoid arthritis ; Risk factors ; RNA, Messenger - drug effects ; RNA, Messenger - metabolism ; Signal Transduction - drug effects ; STAT Transcription Factors - drug effects ; STAT Transcription Factors - metabolism ; Synovial Membrane - drug effects ; Synovial Membrane - metabolism ; Tofacitinib ; Translational Research ; Treatment Outcome
ispartofAnnals of the Rheumatic Diseases, 2015-06, Vol.74 (6), p.1311-1316
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0Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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9Rosengren, S
10Kaplan, I
11Krishnaswami, S
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13Bradley, J
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0The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signaling in rheumatoid arthritis
1Annals of the Rheumatic Diseases
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descriptionTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. NCT00976599.
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12Dosage and administration
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16Gene expression
17Genetic aspects
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19Janus Kinase 1 - drug effects
20Janus Kinase 1 - metabolism
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22Matrix Metalloproteinase 1 - drug effects
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29Middle Aged
30Piperidines - pharmacology
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32Protein Kinase Inhibitors - pharmacology
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38Research
39Rheumatoid arthritis
40Risk factors
41RNA, Messenger - drug effects
42RNA, Messenger - metabolism
43Signal Transduction - drug effects
44STAT Transcription Factors - drug effects
45STAT Transcription Factors - metabolism
46Synovial Membrane - drug effects
47Synovial Membrane - metabolism
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49Translational Research
50Treatment Outcome
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titleThe JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signaling in rheumatoid arthritis
authorBoyle, D L ; Soma, K ; Hodge, J ; Kavanaugh, A ; Mandel, D ; Mease, P ; Shurmur, R ; Singhal, A K ; Wei, N ; Rosengren, S ; Kaplan, I ; Krishnaswami, S ; Luo, Z ; Bradley, J ; Firestein, G S
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5Arthritis, Rheumatoid - drug therapy
6Arthritis, Rheumatoid - metabolism
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8Basic and Translational Research
9Chemokines - drug effects
10Chemokines - genetics
11Chemokines - metabolism
12Dosage and administration
13Double-Blind Method
14Drug Therapy, Combination
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16Gene expression
17Genetic aspects
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20Janus Kinase 1 - metabolism
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32Protein Kinase Inhibitors - pharmacology
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42RNA, Messenger - metabolism
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44STAT Transcription Factors - drug effects
45STAT Transcription Factors - metabolism
46Synovial Membrane - drug effects
47Synovial Membrane - metabolism
48Tofacitinib
49Translational Research
50Treatment Outcome
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atitleThe JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signaling in rheumatoid arthritis
jtitleAnnals of the Rheumatic Diseases
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date2015-06
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volume74
issue6
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abstractTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. NCT00976599.
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pubBritish Medical Association
pmid25398374
doi10.1136/annrheumdis-2014-206028
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