Background/Purpose:  Patients with active rheumatoid arthritis (RA) have significantly increased cardiovascular (CV) morbidity and mortality, paradoxically in association with reduced circulating levels of total cholesterol (TC) and LDL-C. Tofacitinib (TOFA), an oral Janus Kinase inhibitor, improves systemic and joint inflammation in RA, increasing serum TC and LDL-C without affecting CV disease. Our aim was to study the effect of TOFA on the lipid profile of hyperlipidemic rabbits with chronic arthritis (CA) and to go deeper into the mechanisms associated to the regulation of reverse cholesterol transport (RCT) exerted by this treatment in chronic inflammation

Methods: Twenty-four male, New Zealand white rabbits fed with a high fat diet (HFD) were randomly assigned to two groups: control (n=6) and CA (n=18). CA was induced over six weeks via intra-dermal ovalbumin sensitization and four subsequent intra-articular injections. Nine CA rabbits were treated with TOFA (10mg/kg/day) for two weeks. Fully differentiated THP-1 cells were exposed to HFD rabbit serum or ox-LDL to become foam cells. Thereafter, cells were stimulated with IFNγ to reproduce the inflammatory milieu in the presence or absence of TOFA for 24 hours. Intracellular lipid accumulation was assessed by Oil Red-O staining and protein and RNA were isolated for molecular studies.

Results: CA rabbits showed lower levels of serum TC and LDL-C compared to controls (p=0.001 and p=0.012), while TC/HDL-C ratio was higher in CA+TOFA rabbits when compared with CA animals (150±15 vs. 230±17; p=0.004). Synovial inflammation and C-reactive protein (CRP) levels were increased in CA animals, and a significant reduction was shown in CA+TOFA rabbits in both parameters (p=0.015 and p=0.006). We observed an inverse correlation between serum TC and CRP (R=-0.454, p=0.029). An increased infiltration of lipid-loaded macrophages was found in the synovial membrane of CA and CA+TOFA rabbits. In vitro experiments confirmed that IFNγ further stimulates intracellular lipid accumulation in macrophages incubated with HFD rabbit serum or with oxLDL. INFγ inhibited the expression of the cellular ATP-binding cassette transporter (ABCA1) that mediates the first step of RCT. The impaired lipid accumulation was prevented in the presence of TOFA. Furthermore, TOFA restored the IFNγ-induced ABCA1 downregulation, both preventing STAT1 phosphorylation and increasing LXRα expression.

Conclusion: Our experimental model of CA perfectly replicated the lipid paradox observed in RA patients, and the increase in circulating lipids evoked by TOFA, together with an amelioration of joint and systemic inflammation. In vitro studies showed that TOFA prevented the inflammation-induced dysregulation of lipid transport in macrophages through a LXRα depending mechanism, counteracting the IFNg inhibition of RCT. Therefore, these results suggest that chronic inflammation would sequester lipids into macrophages -in the synovium and probably in other tissues- thus decreasing serum lipid levels. Taking together, our findings partially explain the effect of TOFA on the lipid profile in RA patients.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/tofacitinib-restores-reverse-cholesterol-transport-inhibition-induced-by-inflammation-understanding-the-lipid-paradox/