Background/Purpose: Tofacitinib (TOFA) is a Janus Kinase (Jak) inhibitor approved for the treatment of rheumatoid arthritis (RA) ¹. It has recently been shown to selectively inhibit the expression of several chemokines in the synovium of RA patients that were treated over 28 days, without modifying the expression of various pro-inflammatory cytokines, nor the histopathological synovial inflammation, including macrophage infiltration ². Despite being the synovium the main articular tissue affected by RA, to date there are very limited data regarding the early modulation of synovial cytokines by this Jak inhibitor. In this sense, animal models may allow a better understanding of the consequences of Jak inhibition in chronic arthritis (CA). Our aim was to develop a rabbit model of CA which mimicked severe human RA in early phases of treatment, in order to evaluate early tissue changes rather than the final therapeutic effect.

Methods: Twenty-four male, New Zealand white rabbits were randomly assigned to two groups: control (n=8) and CA (n=16). CA was induced over six weeks via intra-dermal ovalbumin sensitization and four subsequent intra-articular injections on a weekly basis. After the second intra-articular injection, eight CA rabbits were treated with TOFA (10mg/kg/day).

Results: CA animals showed reduced weight gain compared to controls, which TOFA tended to increase (weight gain, kg; Control: 0.8±0.05; CA: -0.09±0.06*; CA+TOFA: 0.18±0.1*#; *p<0.05 vs Control; #p=0.07 vs CA). A substantial increase in serum C-reactive protein (CRP) was found both in CA and CA+TOFA animals. CA animals showed a severe synovitis that was partially prevented by TOFA (Krenn Score; Control: 0.9±0.3; CA: 7.6±0.2*; CA+TOFA: 6.6±0.2*#; p<0.05 *vs. control; # vs. CA), and exhibited an augmented macrophage infiltration which was not modified by this inhibitor. TOFA effectively reduced the synovial expression of matrix metalloproteinases MMP-1 (93% inhibition, p<0.05) and MMP-3 (83% inhibition p<0.05), the C-C Motif Chemokine Ligand 2 (CCL2, 74% inhibition, p<0.05) as well as the pro-inflammatory cytokines Interleukin-6 (IL-6, 42% inhibition, p<0.05) and Tumor Necrosis Factor-α (TNFα, 55% inhibition, p<0.05). However, IL-1β was not modified with this Jak inhibitor. Signal Transducer and Activator of Transcription (STAT) -1 and -3, and Nuclear Factor-κB (NF-κB) were activated during CA, but TOFA was only able to diminish STAT-1 phosphorylation.

Conclusion: In a synovial tissue with an intense inflammatory activity, TOFA treatment initially blocked STAT-1 phosphorylation, whereas phospho-STAT-3 levels remained unchanged. This Jak inhibitor induced a partial decrease in the synovitis score along with a marked reduction of the expression of MMPs and, to a lesser extent, other pro-inflammatory mediators. These data suggest a key role of STAT-1 in the initial changes occurring in the synovium after TOFA treatment.

References: 1. Elkan, A. C. et al. Arthritis Res. Ther. 11, R37 (2009); 2. Boyle, D.L. et al. Ann Rheum Dis 74, 1311–1316 (2015)

ACR Meeting Abstracts - https://acrabstracts.org/abstract/phospho-stat1-inhibition-is-the-initial-step-after-tofacitinib-treatment-in-rabbits-with-severe-chronic-synovitis/