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

作者：Christina Charles‐Schoeman, Roy Fleischmann, Jean Davignon, Howard J. Schwartz, Scott Turner, Carine Beysen, Mark A. Milad, Marc K. Hellerstein, Zhen Luo, Irina V Kaplan, Richard J. Riese, Andrea Zuckerman, Iain B. McInnes · 发表于：Arthritis & Rheumatology · 年份：2014 · DOI：10.1002/art.38974 · 被引用次数：188 · 研究领域：Rheumatoid Arthritis Research and Therapies、Autoimmune and Inflammatory Disorders Research、Spondyloarthritis Studies and Treatments

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. Additi...