Effects of One-Year Tofacitinib Therapy on Lipids and Adipokines in Association with Vascular Pathophysiology in Rheumatoid Arthritis

Abstract

Background: Cardiovascular (CV) morbidity, mortality and metabolic syndrome are associated with rheumatoid arthritis (RA). A recent trial has suggested increased risk of major CV events (MACE) upon the Janus kinase (JAK) inhibitor tofacitinib compared with anti-tumor necrosis factor α (TNF-α) therapy. In our study, we evaluated lipids and other metabolic markers in relation to vascular function and clinical markers in RA patients undergoing one-year tofacitinib therapy. Patients and methods: Thirty RA patients treated with either 5 mg or 10 mg bid tofacitinib were included in a 12-month follow-up study. Various lipids, paraoxonase (PON1), myeloperoxidase (MPO), thrombospondin-1 (TSP-1) and adipokine levels, such as adiponectin, leptin, resistin, adipsin and chemerin were determined. In order to assess flow-mediated vasodilation (FMD), common carotid intima-media thickness (IMT) and arterial pulse-wave velocity (PWV) ultrasonography were performed. Assessments were carried out at baseline, and 6 and 12 months after initiating treatment. Results: One-year tofacitinib therapy significantly increased TC, HDL, LDL, APOA, APOB, leptin, adipsin and TSP-1, while significantly decreasing Lp(a), chemerin, PON1 and MPO levels. TG, lipid indices (TC/HDL and LDL/HDL), adiponectin and resistin showed no significant changes. Numerous associations were found between lipids, adipokines, clinical markers and IMT, FMD and PWV (p < 0.05). Regression analysis suggested, among others, association of BMI with CRP and PWV (p < 0.05). Adipokines variably correlated with age, BMI, CRP, CCP, FMD, IMT and PWV, while MPO, PON1 and TSP-1 variably correlated with age, disease duration, BMI, RF and PWV (p < 0.05). Conclusions: JAK inhibition by tofacitinib exerts balanced effects on lipids and other metabolic markers in RA. Various correlations may exist between metabolic, clinical parameters and vascular pathophysiology during tofacitinib treatment. Complex assessment of lipids, metabolic factors together with clinical parameters and vascular pathophysiology may be utilized in clinical practice to determine and monitor the CV status of patients in relation with clinical response to JAK inhibition.

Effect of the JAK/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism

“…In this context, tofacitinib might impact the serum lipoprotein levels, serum lipoprotein functions, and vascular macrophage cholesterol handling. The data on serum lipoproteins indicate that tofacitinib induces increased levels that are not necessarily harmful, as the LDL/HDL ratio is unchanged [ 17 ]; tofacitinib use is also associated with an increase in the HDL capacity to promote cell cholesterol efflux [ 18 ]. In this study, we explored the direct effect of tofacitinib on macrophage functions controlling intracellular cholesterol homeostasis in vitro.…”

“…As with many anti-rheumatic treatments, tofacitinib use is associated with increased serum lipid levels, but this finding is not “per se” suggestive of increased atherosclerotic risk [ 16 ]. In fact, the anti-atherosclerotic properties of circulating lipoproteins usually improve in patients treated with anti-rheumatic treatments [ 4 ], including tofacitinib [ 17 , 18 ].…”