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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:
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
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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1Soma, K
2Hodge, J
3Kavanaugh, A
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7Singhal, A K
8Wei, N
9Rosengren, S
10Kaplan, I
11Krishnaswami, S
12Luo, Z
13Bradley, J
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title
0The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signaling in rheumatoid arthritis
1Annals of the Rheumatic Diseases
addtitleAnn Rheum Dis
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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5Arthritis, Rheumatoid - drug therapy
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9Chemokines - drug effects
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11Chemokines - metabolism
12Dosage and administration
13Double-Blind Method
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15Female
16Gene expression
17Genetic aspects
18Humans
19Janus Kinase 1 - drug effects
20Janus Kinase 1 - metabolism
21Male
22Matrix Metalloproteinase 1 - drug effects
23Matrix Metalloproteinase 1 - genetics
24Matrix Metalloproteinase 1 - metabolism
25Matrix Metalloproteinase 3 - drug effects
26Matrix Metalloproteinase 3 - genetics
27Matrix Metalloproteinase 3 - metabolism
28Methotrexate - therapeutic use
29Middle Aged
30Piperidines - pharmacology
31Piperidines - therapeutic use
32Protein Kinase Inhibitors - pharmacology
33Protein Kinase Inhibitors - therapeutic use
34Pyrimidines - pharmacology
35Pyrimidines - therapeutic use
36Pyrroles - pharmacology
37Pyrroles - therapeutic use
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
48Tofacitinib
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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2Aged
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4Antirheumatic Agents - therapeutic use
5Arthritis, Rheumatoid - drug therapy
6Arthritis, Rheumatoid - metabolism
7Basic
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
18Humans
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20Janus Kinase 1 - metabolism
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22Matrix Metalloproteinase 1 - drug effects
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28Methotrexate - therapeutic use
29Middle Aged
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32Protein Kinase Inhibitors - pharmacology
33Protein Kinase Inhibitors - therapeutic use
34Pyrimidines - pharmacology
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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
48Tofacitinib
49Translational Research
50Treatment Outcome
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1Soma, K
2Hodge, J
3Kavanaugh, A
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7Singhal, A K
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9Rosengren, S
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9Rosengren, S
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atitleThe JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signaling in rheumatoid arthritis
jtitleAnnals of the Rheumatic Diseases
addtitleAnn Rheum Dis
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date2015-06
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volume74
issue6
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pages1311-1316
issn0003-4967
eissn1468-2060
notesHandling editor Tore K Kvien
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.
copEngland
pubBritish Medical Association
pmid25398374
doi10.1136/annrheumdis-2014-206028
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