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The role of sIL-6R mediated trans-signaling in cardiovascular morbidity in Rheumatoid Arthritis

Davies, Ruth 2018. The role of sIL-6R mediated trans-signaling in cardiovascular morbidity in Rheumatoid Arthritis. PhD Thesis, Cardiff University.
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Cardiovascular mortality in patients with RA is 50% higher than the general population. Although well established that the incidence of CVD is increased, the precise cause is unclear. There is increasing recognition that systemic inflammation is a major driver of increased CV risk. IL-6 is implicated in CVD in the general population but its role in CVD in RA is undefined. Of the two modes of IL-6 signaling, evidence demonstrates that trans-signaling is pro-inflammatory whereas classical signaling has regenerative or anti-inflammatory effects. The aim of this thesis is to examine the role of IL-6 trans-signaling in CVD in RA by experimental and translational studies. Methods Myography was used to determine the effect of IL-6 trans-signaling blockade, using sgp130Fc, on aortic constriction in mice with CIA. Serum CCL2 and VCAM-1 were measured. The effect of IL-6 trans-signaling, using Hyper-IL-6, on atherosclerotic plaque size and fibrous cap thickness was assessed in ApoE-/- mice. Arterial and plaque VCAM-1 expression was assessed. The relationship between sIL-6R-regulated CVD Candidate Proteins (SCCPs) and CVD in established RA was investigated in a cross-sectional study. An observational longitudinal study investigated whether SCCPs were associated with presence and progression of subclinical atherosclerosis in early RA, using carotid ultrasound to measure CIMT. Results Sgp130Fc reduced arthritis severity and restored vascular dysfunction in CIA. This was associated with reduced serum CCL2 and VCAM-1. In ApoE-/- mice, Hyper-IL-6 increased plaque size and VCAM-1 expression in the brachiocephalic artery. In established RA, VCAM-1 correlated with disease activity and CV risk. In early RA, baseline RA disease activity was associated with CIMT change at 6 months. Patients that were ‘rapid progressors’, in terms of CIMT change at 12 months, had higher baseline VCAM-1, HbA1c, total cholesterol:HDL ratio and LDL cholesterol. Discussion IL-6 trans-signaling appears to play a pivotal role in vascular dysfunction and atherosclerosis in mouse models. In early RA, proteins regulated by IL-6 trans-signaling are associated with progression of subclinical atherosclerosis. Inflammation from RA onset in CVD susceptible individuals may accelerate atherosclerosis. Findings suggest that IL-6 trans-signaling blockade may be beneficial to RA patients, and perhaps for atherosclerosis in the general population.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Funders: Arthritis Research UK: Grant number 20760
Date of First Compliant Deposit: 11 July 2018
Last Modified: 12 Apr 2021 15:18

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