Objectives Patients with rheumatoid arthritis (RA) have reduced serum low-density lipoprotein cholesterol (LDL-c), which increases following therapeutic IL-6 blockade. We aimed to define the metabolic pathways underlying these lipid changes.
Methods In the KALIBRA study, lipoprotein kinetic studies were performed on 11 patients with severe active RA at baseline and following three intravenous infusions of the IL-6R blocker tocilizumab. The primary outcome measure was the fractional catabolic rate (FCR) of LDL.
Results Serum total cholesterol (4.8 vs 5.7 mmol/L, p=0.003), LDL-c (2.9 vs 3.4 mmol/L, p=0.014) and high-density lipoprotein cholesterol (1.23 vs 1.52 mmol/L, p=0.006) increased following tocilizumab therapy. The LDL FCR fell from a state of hypercatabolism to a value approximating that of the normal population (0.53 vs 0.27 pools/day, p=0.006). Changes in FCR correlated tightly with changes in serum LDL-c and C-reactive protein but not Clinical Disease Activity Index.
Conclusions Patients with RA have low serum LDL-c due to hypercatabolism of LDL particles. IL-6 blockade normalises this catabolism in a manner associating with the acute phase response (and thus hepatic IL-6 signalling) but not with RA disease activity as measured clinically. We demonstrate that IL-6 is one of the key drivers of inflammation-driven dyslipidaemia.
- rheumatoid arthritis
- cardiovascular disease
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Handling editor Tore K Kvien
Contributors NS and IM conceived the study. IM, NS and CP wrote the study protocol. DM acted as principle investigator for the study. JR drafted and revised the manuscript. All authors reviewed the draft manuscript and provided feedback for the final version.
Funding This study was sponsored by Roche Products Ltd under contract with NHS Greater Glasgow & Clyde and the University of Glasgow. Funding for a clinical research fellow was provided through the University of Glasgow via an NHS endowment fund. Roche Products Ltd had no role in study design, patient recruitment, sample processing, data interpretation or the preparation of this manuscript.
Competing interests IM, NS, DM, CP and DP have received honoraria from or provided consultancy services for Roche / Chugai. JR has received personal fees from Janssen outside the submitted work. MC reports no relevant conflicts of interest.
Patient consent Consent for publication of results was included in the consent form signed by all subjects, as approved by West of Scotland Research Ethics Committee.
Ethics approval West of Scotland Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Full kinetic data for apoB-containing lipoproteins (VLDL-1, VLDL-2, IDL and LDL) may be available on discussion with study authors.