The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis

Davies, Ruth, Williams, Jessica, Sime, Katie, Jin, Hyun-Sun, Thompson, Charlotte, Jordan, Lauren, Lang, Derek, Halcox, Julian P, Ellins, Elizabeth ORCID: https://orcid.org/0000-0001-5164-6416, Jones, Gareth, Jones, Simon A. ORCID: https://orcid.org/0000-0001-7297-9711, Rose-John, Stefan, Williams, Anwen ORCID: https://orcid.org/0000-0001-6118-020X and Choy, Ernest ORCID: https://orcid.org/0000-0003-4459-8609 2021. The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis. Rheumatology 60 (6) , pp. 2852-2861. 10.1093/rheumatology/keaa725

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Abstract

Objectives Cardiovascular (CV) mortality in RA patients is 50% higher than in the general population. There is increasing recognition that systemic inflammation is a major driver of this. IL-6 is implicated in cardiovascular disease (CVD) in the general population but its role in CVD in RA is undefined. Of the two modes of IL-6 signalling, trans-signalling is pro-inflammatory whereas classical signalling is linked with inflammation resolution. This study examines the role of IL-6 trans-signalling in CVD in a mouse model and patients with RA. Methods Myography determined the effect of IL-6 trans-signalling blockade, using sgp130Fc, on aortic constriction in murine collagen-induced arthritis. Serum CCL2 and sVCAM-1 as soluble biomarkers of sIL-6R trans-signalling were investigated in a human cross-sectional study. An observational longitudinal study investigated the association between these biomarkers and progression of subclinical atherosclerosis in early RA by measuring carotid intima-media thickness (CIMT). Results sgp130Fc reduced arthritis severity, serum CCL2 and sVCAM-1 and restored vascular function in collagen-induced arthritis (CIA). In established RA, sVCAM-1 correlated with the 28-joint DAS (DAS28) and CV risk. In early RA, baseline DAS28 was associated with CIMT change at 6 months. CIMT ‘rapid progressors’ at 12 months had higher baseline sVCAM-1, haemoglobin A1c, cholesterol:high-density lipoprotein cholesterol ratio and LDL cholesterol. Conclusions IL-6 trans-signalling plays a pivotal role in vascular dysfunction in CIA. In early RA, sVCAM-1 was associated with progression of subclinical atherosclerosis. Inflammation from RA onset in CVD-susceptible individuals may accelerate atherosclerosis. IL-6 trans-signalling blockade may be beneficial to RA patients and perhaps for atherosclerosis in the general population.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Oxford University Press
ISSN:	1462-0324
Date of First Compliant Deposit:	6 January 2021
Date of Acceptance:	19 October 2020
Last Modified:	07 May 2023 03:22
URI:	https://orca.cardiff.ac.uk/id/eprint/137358

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