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Objective  Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Systemic inflammation is proposed to play a fundamental role in the altered lipid metabolism associated with RA; however, the underlying mechanisms are unknown. We undertook this study to compare cholesterol and lipoprotein kinetics in patients with active RA with those in matched healthy volunteers.    Methods  This was a phase I open‐label mechanism‐of‐action study. Cholesterol and lipoprotein kinetics were assessed with  13 C‐cholesterol and  13 C‐leucine infusions. RA patients were reevaluated after receiving oral tofacitinib 10 mg twice daily for 6 weeks.    Results  Levels of high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, total cholesterol, and apolipoprotein A‐I (Apo A‐I) as well as HDL cholesterol particle number were lower in RA patients (n = 36) than in healthy volunteers (n = 33). In contrast, the cholesterol ester fractional catabolic rate was higher in RA patients, but no differences were observed in cholesterol ester transfer protein, cholesterol ester production rate, HDL‐associated Apo A‐I fractional catabolic rate, or LDL‐associated Apo B fractional catabolic rate. Following tofacitinib treatment in RA patients, the cholesterol ester fractional catabolic rate decreased and cholesterol levels increased. The decrease in cholesterol ester fractional catabolic rate correlated significantly with the increase in HDL cholesterol. Additionally, HDL cholesterol particle number increased and markers of HDL cholesterol function improved.    Conclusion  This is the first study to assess cholesterol and lipoprotein kinetics in patients with active RA and matched healthy volunteers. The data suggest that low cholesterol levels in patients with active RA may be driven by increases in cholesterol ester catabolism. Tofacitinib treatment reduced cholesterol ester catabolism, thereby increasing cholesterol levels toward those in healthy volunteers, and markers of antiatherogenic HDL function improved.

Potential Mechanisms Leading to the Abnormal Lipid Profile in Patients With Rheumatoid Arthritis Versus Healthy Volunteers and Reversal by Tofacitinib