Background/Purpose: Tofacitinib is a novel oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The specific JAK-STAT (signal transducer and activator of transcription) pathways affected by tofacitinib in different tissues and the downstream effects on gene expression in situ are unknown. Phase 3 studies ORAL Scan¹ (A3921044 NCT00847613) and ORALStart² (A3921069 NCT01039688) have shown that tofacitinib reduces the progression of joint destruction; however, the underlying mechanisms are unknown. The effects of tofacitinib on synovial histopathology, gene expression, and signaling were studied and correlated with clinical response. We also evaluated the relationship of synovial, blood and urine biomarkers with inflammation and structural damage.

Methods:

A randomized, double-blind, Phase 2a clinical trial (A3921073; NCT00976599) of seropositive RA patients (pts) with inadequate response to methotrexate compared tofacitinib 10 mg twice daily for 28 days (15 pts) with placebo (PBO; 14 pts). Synovial biopsies were performed on Days -7 and 28. Biopsies were analyzed by immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (qPCR), and synovial tissue extracts by enzyme-linked immunosorbent assay. Clinical response was determined by disease activity score (DAS)28-4 ESR and EULAR response criteria on Day 28 in study A3921073 and at 4 months in an open label long term extension study (A3921024; NCT00413699).

Results:

Tofacitinib led to EULAR moderate to good responses (11/14 pts), while PBO was ineffective (1/14 pts) on Day 28. Tofacitinib significantly reduced synovial gene expression of the matrix metalloproteases MMP1 and MMP3 (p<0.05) and chemokines CCL2, CXCL10, and CXCL13 (p<0.05). Changes in synovial phosphorylation of STAT1 and STAT3 predicted 4-month clinical responses (correlations of 0.755 and 0.874, respectively), significantly (p=0.0018 and p<0.0001).  Tofacitinib significantly decreased plasma IP-10 (p<0.005) which is a mediator of osteoclastogenesis³. Urine CTX-II, an indicator of MMP-mediated type II collagen turnover and cartilage damage⁴, was reduced by tofacitinib (LS mean change -122.93) compared to PBO (LS mean change -6.2) (p=0.08). No changes were observed in synovial inflammation scores or immune cell lineages using IHC, e.g. CD20, CD3, CD68, or qPCR.

Conclusion:

The data suggest that tofacitinib modulates synovial immune and inflammatory responses.  Modulation of certain JAK STAT pathways correlates with clinical response, e.g. STAT1 and STAT3-dependent IL-6, and interferon signaling. Biomarkers including MMP-3⁴, IP-10³ and urinary CTX-II⁴ which are associated with an increased risk of joint damage in RA are reduced by tofacitinib. This study provides insights into the mechanism of tofacitinib’s clinical efficacy and preservation of cartilage and bone.

References:

1. Van dr Heijde D, Arthritis Rheum. 2013 65(3):559-70
2. Lee E.B et al. American College of Rheumatology 2012;64(Suppl. 10:1063)
3. Lee E.Y et al. Arthritis Res Ther. 2011:13(3):R104
4. Carrasco R et al. Arthritis research UK, 2010, 2:26-38

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-jak-inihibitor-tofacitinib-suppresses-synovial-jak-stat-signalling-in-rheumatoid-arthritis/