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BACKGROUND AND PURPOSE Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The Janus kinase (Jak) inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analyzed the effect of tofacitinib on the lipid profile of hyperlipidemic rabbits with chronic arthritis (CA) and on the regulation of reverse cholesterol transport (RCT) during chronic inflammation. EXPERIMENTAL APPROACH CA was induced in previously immunized rabbits fed with a high-fat diet (HFD) by administering four intra-articular injections of ovalbumin. A group of rabbits received tofacitinib (10 mg kg-1 day-1) for two weeks. Systemic and synovial inflammation and lipid content were evaluated. For in vitro studies, THP-1-derived macrophages were exposed to high lipid concentrations, and then stimulated with interferon gamma (IFNγ) in the presence or absence of tofacitinib in order to study RCT mediators. KEY RESULTS Tofacitinib decreased systemic and synovial inflammation and increased circulating lipid levels. Although it did not modify synovial macrophage density, it was able to reduce the lipid content within synovial macrophages. In foam macrophages in culture, IFNγ further stimulated intracellular lipid accumulation, while Jak/STAT inhibition provoked by tofacitinib induced lipid release by increasing cellular liver X receptor alpha (LXRα) and ATP-binding cassette transporter (ABCA1) synthesis. CONCLUSION AND IMPLICATIONS Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. Jak inhibition induced lipid release though RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients.

Background Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced serum lipid levels. In fact, an inverse relationship between C-reactive protein (CRP) and circulating lipid levels has been observed [1,2]. The Jak inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids [3]. Objectives Our aim was to analyze the effect of tofacitinib on the lipid and inflammatory profile of hyperlipidemic rabbits with chronic arthritis (CA), and on the regulation of reverse cholesterol transport (RCT) during chronic inflammation. Methods New Zealand male rabbits were randomly assigned to three groups: control group (n=6), chronic arthritic rabbits (CA, n=9) and CA rabbits receiving tofacitinib (CA+TOFA, n=9). All animals were fed ad libitum with a high-fat diet (0.5% cholesterol, 4% peanut oil). CA was induced in previously immunized rabbits by administering four intra-articular injections of ovalbumin. A group of rabbits received tofacitinib (10mg/kg/day) for two weeks. All animals were euthanized 6 weeks after challenge, when synovial and serum samples were collected. For in vitro studies, vehicle and ABCA1 siRNA-treated THP-1-derived macrophages were exposed to high lipid concentrations, and then stimulated with interferon gamma (IFNγ) in the presence or absence of tofacitinib, in order to assess their cholesterol efflux capacity and the involved mediators. Results CA rabbits showed lower levels of serum TC and LDL-C compared to controls (p=0.001, p=0.012), while TC/HDL-C ratio was higher in CA+TOFA rabbits when compared to CA animals (150±15 vs 231±17, p=0.004). Synovial inflammation and CRP levels were increased in CA animals, and a significant reduction was shown in CA+TOFA rabbits in both parameters. We also observed an inverse correlation between serum TC and CRP (R=-0.454, p=0.029). Tofacitinib was able to reduce the lipid content within synovial macrophages up to a 58% (p=0.041), although it did not modify synovial macrophage density. In foam macrophages in culture, an inflammatory milieu induced by IFNγ further stimulated the intracellular lipid accumulation (p=0.041) along with a decrease in the protein levels of the nuclear factor LXRα (liver X receptor α) and the cholesterol transporter ABCA1 (ATP-binding cassette transporter 1) (p=0.002 and p=0.0047, respectively). Tofacitinib prevented the lipid accumulation within macrophages (p=0.029) by increasing LXRα (p=0.047) and ABCA1 synthesis (p=0.004) in a Jak/STAT-dependent manner, while it was unable to reduce lipid accumulation in ABCA1 silenced macrophages. Conclusions Our results suggest that active inflammation could be associated with lipid accumulation within macrophages – in the synovium and probably in other tissues – thus inducing a decrease in serum lipid levels. Tofacitinib may prevent this phenomenon, at least partially, by increasing RCT pathways in macrophages. Taken together, these findings further explain how serum lipid levels are diminished in RA and partially justify the effect of tofacitinib on the lipid profile in RA patients. References Choy E, Sattar N. Ann Rheum Dis 2009;68:460–9. Johnsson H et al. Ann Rheum Dis 2013;73:1495–9. van Vollenhoven RF et al. N Engl J Med 2012;367:508–19. Disclosure of Interest None declared

Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The JAK inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analysed the effect of tofacitinib on the lipid profile of hyperlipidaemic rabbits with chronic arthritis (CA) and on the changes in reverse cholesterol transport (RCT) during chronic inflammation.CA was induced in previously immunized rabbits, fed a high-fat diet, by administering four intra-articular injections of ovalbumin. A group of rabbits received tofacitinib (10 mg·kgTofacitinib decreased systemic and synovial inflammation and increased circulating lipid levels. Although it did not modify synovial macrophage density, it reduced the lipid content within synovial macrophages. In foam macrophages in culture, IFNγ further stimulated intracellular lipid accumulation, while the JAK/STAT inhibition provoked by tofacitinib induced lipid release by increasing the levels of cellular liver X receptor α and ATP-binding cassette transporter (ABCA1) synthesis.Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. JAK inhibition induced lipid release through RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients.

Background Tofacitinib (TOFA) is a Janus Kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis (RA) in different countries. TOFA treatment has recently been shown to selectively inhibit the expression of several chemokines from synovial biopsies from RA patients that were treated over 28 days (1). However, TOFA did not modify the expression of various pro-inflammatory cytokines, nor histopathological synovial inflammation, including macrophage infiltration. In this regard, animal models may allow a better understanding of the consequences of JAK inhibition in chronic arthritis (CA). Our group developed a model of CA in rabbits that mimics severe human RA, thereby allowing investigation of TOFA and its consequences in synovial tissue. Objectives We have analyzed the early treatment effect of TOFA in a model of CA, aiming to evaluate early tissue changes rather than the final therapeutic effect. Methods A well-established model of antigen-induced CA was induced in 20 rabbits via four, weekly intra-articular injections of ovalbumin in previously immunized rabbits (CA group). After two intra-articular injections, 10 CA rabbits were treated with TOFA (10mg/kg/day, orally) for two weeks (CA+TOFA) and 10 healthy rabbits were used as controls. Animals were euthanised four weeks after intra-articular challenge, when we collected serum and synovial samples for different studies. Results CA animals showed reduced weight gain compared to controls, which was partially prevented by TOFA (weight gain, kg; Control: 0.8±0.05; CA: -0.09±0.06*; CA+TOFA: 0.18±0.1*#; *p Conclusions In synovial tissue with intense inflammatory activity, TOFA treatment mainly inhibited the expression of MMPs and, to a lesser extent, the expression of other pro-inflammatory mediators. These data suggest that this drug could act as an immunomodulator of the chronic inflammatory response. TOFA does not induce a fast or drastic reduction in cellular recruitment within synovial tissue, but a moderate and generalized decrease of cytokines with a stronger effect on MMPs. References Boyle DL et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis. 2014 [epub ahead of print] Disclosure of Interest None declared