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

Abstract

ObjectiveTofacitinib 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.MethodsThis was a phase I open‐label mechanism‐of‐action study. Cholesterol and lipoprotein kinetics were assessed with 13C‐cholesterol and 13C‐leucine infusions. RA patients were reevaluated after receiving oral tofacitinib 10 mg twice daily for 6 weeks.ResultsLevels 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.ConclusionThis 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.

Cardiovascular comorbidity in rheumatic diseases

“…38 A potential explanation for the abnormal lipid profile observed in RA is that the low cholesterol levels detected in patients with active RA are driven by high cholesterol ester fractional catabolic rates. 39 In support of this hypothesis, in patients with RA, treatment with a Janus-kinase inhibitor reduces cholesterol ester catabolism, thereby increasing levels of HDL chol esterol and LDL cholesterol relative to pretreatment levels. 39 In the context of cardiovascular risk assessment in patients with RA, measurement of the ratio of total cholesterol to HDL cholesterol is recommended in clinical practice, and it might be reasonable to suggest that lipid measure ments during inactive stages of the disease are the most representative of the overall situation in a given patient.…”

Janus kinase inhibitors for autoimmune disorders

“…[29][30][31] This effect is more frequent than with methotrexate or adalimumab but is not associated with a change in the LDL/HDL ratio or, so far (up to eight years for tofacitinib), an increase in cardiovascular events; similar findings have been reported in patients with psoriasis treated with tofacitinib. 29,31,32 Tofacitinib and baricitinib have been associated with anaemia, lymphopenia or neutropenia (and with thrombocytopenia in patients with myelofibrosis treated with ruxolitinib), 33 and with abnormal liver function tests; prescribing cautions require …”

Editorial: Lipid Changes With Different Antiinflammatory Regimens in Rheumatoid Arthritis: Developing a Pragmatic Approach to Complex Data

“…Scavenger receptors are dysregulated on leukocytes in patients with active inflammatory arthritis. Moreover, in a mechanism-of-action study in RA patients, tofacitinib treatment reduced peripheral cholesterol ester catabolism, thereby increasing cholesterol levels toward those observed in comparator healthy volunteers (4). Such data suggest that the rise in levels of LDL cholesterol upon reduction of inflammation may be driven not by increased hepatic synthesis, but rather largely via modulation of its catabolism and clearance.…”