Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis

Robertson, J., Porter, D., Sattar, N. , Packard, C. J. , Caslake, M., McInnes, I. and McCarey, D. (2017) Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis. Annals of the Rheumatic Diseases, 76(11), pp. 1949-1952. (doi: 10.1136/annrheumdis-2017-211708) (PMID:28916714)

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Abstract

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.

Item Type:Articles
Additional Information: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
Keywords:Cardiovascular disease, cytokines, lipids, rheumatoid arthritis.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Robertson, Dr Jamie and Caslake, Professor Muriel and Porter, Dr Duncan and McCarey, Dr David and Packard, Professor Chris and Sattar, Professor Naveed
Authors: Robertson, J., Porter, D., Sattar, N., Packard, C. J., Caslake, M., McInnes, I., and McCarey, D.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Annals of the Rheumatic Diseases
Publisher:BMJ Publishing Group
ISSN:0003-4967
ISSN (Online):1468-2060
Published Online:09 October 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Annals of the Rheumatic Diseases 76(11): 1949-1952
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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