Article Text

Extended report
The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis
  1. D L Boyle1,
  2. K Soma2,
  3. J Hodge3,
  4. A Kavanaugh1,
  5. D Mandel4,
  6. P Mease5,
  7. R Shurmur6,
  8. A K Singhal7,
  9. N Wei8,
  10. S Rosengren1,
  11. I Kaplan2,
  12. S Krishnaswami2,
  13. Z Luo9,
  14. J Bradley2,
  15. G S Firestein1
  1. 1University of California, San Diego School of Medicine, San Diego, California, USA
  2. 2Pfizer Inc, Groton, Connecticut, USA
  3. 3Pfizer Inc, New York, New York, USA
  4. 4Office of David R Mandel MD, Inc., Mayfield Village, Ohio, USA
  5. 5Swedish Medical Center and University of Washington, Seattle, Washington, USA
  6. 6Bronson Internal Medicine and Rheumatology, Battle Creek, Michigan, USA
  7. 7Southwest Rheumatology Research LLC, Dallas, Texas, USA
  8. 8Arthritis Treatment Center, Frederick, Maryland, USA
  9. 9Pfizer Inc, Shanghai, China
  1. Correspondence to David L Boyle, Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA 92093, USA; dboyle{at}ucsd.edu

Abstract

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.

Trial registration number NCT00976599.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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