Pro-atherogenic lipid changes and decreased hepatic LDL receptor expression by tocilizumab in rheumatoid arthritis
Introduction
Rheumatoid arthritis (RA) has been widely acknowledged to increase cardiovascular morbidity and mortality, irrespective of established classical risk factors [1], [2]. Apart from the chronic inflammatory state as a driver of the excess cardiovascular risk [3], additional pro-atherosclerotic pathways including changes in the coagulation and fibrinolytic system and impaired endothelial regenerative capacity have been implicated [4]. Aggressive management of inflammatory activity in RA patients has been projected to reduce this augmented cardiovascular risk [5].
Tocilizumab (TCZ), a humanized monoclonal antibody blocking interleukin-6 (IL-6) signaling by binding both soluble and membrane bound IL-6 receptors (CD126), has been shown to effectively decrease RA disease activity [6], [7]. Upon treatment, TCZ has however been reported to increase total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), high-density cholesterol (HDLc) and triglycerides [8], [9], [10], [11], [12], [13], [14], [15]. It has been put forward that these modifications largely reflect a physiological adaptation following reversal of the chronic inflammatory state, in spite of a lack of studies addressing the underlying mechanisms of the lipid changes following TCZ administration [16]. These changes in lipid profile occur within a week after treatment initiation, which coincides with inhibition of inflammation [17]. The magnitude of the lipid changes associated with TCZ however generally exceed those following treatment with other potent anti-inflammatory regimens such as tumor necrosis factor (TNF) inhibition [18].
Together with the observation that IL-6 may impact on LDLr-mediated removal by the liver [19], we hypothesized that TCZ induced an adverse lipid profile by direct effects on hepatic clearance pathways. Therefore, we investigated the effect of 6 weeks TCZ treatment in RA patients on the fasting and non-fasting lipid profile. Changes in cholesterol synthesis, intestinal absorption, TG lipolysis and clearance, and HDL antioxidative capacity were measured. To validate hepatic changes, the direct effect of TCZ on LDLr expression was tested in HepG2 cells.
Section snippets
Patient selection
Twenty-one patients with RA were recruited from the outpatient clinic of the Academic Medical Center/University of Amsterdam (AMC) and enrolled in the study. The study protocol was approved by the institutional review board at the AMC. Written informed consent was obtained from all participants.
The first four recruited patients received TCZ as part of the ACT-RAY study: a phase IIIb study, designed to evaluate the efficacy and safety of TCZ in patients with RA who do not respond to methotrexate
Results
Of the 21 patients included in the study, one patient dropped out due to abdominal discomfort following oral fat ingestion at the first visit. No serious adverse events were observed during follow-up. After six weeks, TCZ treatment resulted in a substantial decrease in mean CRP from 13.23 (20.66) to 0.17 (0.42) (P < 0.0) (Table 1). Mean DAS28 after 12 weeks decreased from 4.65 (0.73) to 2.83 (1.30) (P < 0.001).
Plasma lipid profiles are depicted in Fig. 1. Following TCZ, TC increased by 22% (4.8
Discussion
TCZ administration in RA patients reduces disease activity as reflected by a reduction in DAS28 score and indices of systemic inflammation. Concomitantly, TCZ is associated with marked increases in LDLc, HDLc as well as in both fasting and postprandial TG levels. Since intestinal cholesterol absorption and whole-body cholesterol synthesis did not change, these changes are likely to reflect decreased clearance. In support, TCZ was found to reduce hepatic LDLr expression, which is expected to
Funding sources
Roche Pharmaceuticals funded this research with an unrestricted grant. Roche Pharmaceuticals had no role in the study design, the collection, analysis and interpretation of the data, and in the writing of the report. Authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. ESGS is supported by a grant from CVON Genius: Generating the best evidence-based pharmaceutical targets for atherosclerosis (GENIUS) (number CVON2011-19).
Acknowledgments and competing interests
We would like to thank all patients, the research nurses and consultant nurses of the Department of Clinical Immunology and Rheumatology, A.W.M. Schimmel, J. Peter and M.E. Doorenspleet for their excellent technical assistance. The LDL receptor promoter plasmid was kindly provided by Prof. Wilhelm Krone (Cologne, Germany).
Prof. Tak has served as consultant to Genentech and Roche, and became an employee of GlaxoSmithKline after completion of this study. Prof. Stroes has received cunsultancy fees
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