Potential mechanisms leading to the abnormal lipid profile in patients with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib

Christina Charles-Schoeman, Roy Fleischmann, Jean Davignon, Howard Schwartz, Scott M Turner, Carine Beysen, Mark Milad, Marc K Hellerstein, Zhen Luo, Irina V Kaplan, Richard Riese, Andrea Zuckerman, Iain B McInnes, Christina Charles-Schoeman, Roy Fleischmann, Jean Davignon, Howard Schwartz, Scott M Turner, Carine Beysen, Mark Milad, Marc K Hellerstein, Zhen Luo, Irina V Kaplan, Richard Riese, Andrea Zuckerman, Iain B McInnes

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01262118.

© 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Figures

Figure 1
Figure 1
Diagram of reverse cholesterol transport. Reverse cholesterol transport starts with the transfer of free cholesterol (FC) and phospholipid to a lipid‐poor pre–β high‐density lipoprotein (pre–β‐HDL) particle. Esterification of free cholesterol to cholesterol ester (CE) by lecithin:cholesterol acyltransferase (LCAT) then generates a mature HDL particle. From this mature HDL particle, cholesterol ester may be transferred to low‐density lipoprotein (LDL) via cholesterol ester transfer protein (CETP) and then delivered to the liver via the LDL receptor (LDLr). Alternatively, selective cholesterol ester uptake via scavenger receptor class B type I (SR‐BI) can deliver cholesterol ester directly to the liver from HDL, regenerating a lipid‐poor apolipoprotein (Apo) A‐I–containing particle. Once delivered to the liver, cholesterol can leave the body via biliary secretion.
Figure 2
Figure 2
Correlation of change in cholesterol ester fractional catabolic rate (FCR) with change in HDL cholesterol levels (A) and change in large HDL cholesterol particle levels (B) following treatment. See Figure 1 for other definitions.

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