The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.
OBJECTIVE
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
NCT00976599.
University of California, San Diego School of Medicine, San Diego, California, USA.
D L
DL
Boyle
Pfizer Inc, Groton, Connecticut, USA.
K
K
Soma
Pfizer Inc, New York, New York, USA.
J
J
Hodge
University of California, San Diego School of Medicine, San Diego, California, USA.
A
A
Kavanaugh
Office of David R Mandel MD, Inc., Mayfield Village, Ohio, USA.
D
D
Mandel
Swedish Medical Center and University of Washington, Seattle, Washington, USA.
P
P
Mease
Bronson Internal Medicine and Rheumatology, Battle Creek, Michigan, USA.
R
R
Shurmur
Southwest Rheumatology Research LLC, Dallas, Texas, USA.
A K
AK
Singhal
Arthritis Treatment Center, Frederick, Maryland, USA.
N
N
Wei
University of California, San Diego School of Medicine, San Diego, California, USA.
S
S
Rosengren
Pfizer Inc, Groton, Connecticut, USA.
I
I
Kaplan
Pfizer Inc, Groton, Connecticut, USA.
S
S
Krishnaswami
Pfizer Inc, Shanghai, China.
Z
Z
Luo
Pfizer Inc, Groton, Connecticut, USA.
J
J
Bradley
University of California, San Diego School of Medicine, San Diego, California, USA.
G S
GS
Firestein
D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D018925:Chemokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D053613:Janus Kinase 1 / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D050791:STAT Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism; D016896:Treatment Outcome
D018501:Antirheumatic Agents; D018925:Chemokines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; D050791:STAT Transcription Factors; C479163:tofacitinib; D053613:Janus Kinase 1; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D008727:Methotrexate