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Objective Excess cholesterol loading on arterial macrophages is linked to foam cell formation, atherosclerosis and cardiovascular risk in rheumatoid arthritis (RA). However, the effect of changes in cholesterol loading on coronary plaque trajectory and the impact of RA therapies on this relationship are unknown. We investigated the association between variations in cholesterol loading capacity (CLC) over time and atherosclerosis progression.Methods In a prospective observational cohort study, coronary CT angiography evaluated atherosclerosis (non-calcified, partially calcified or fully calcified plaques and coronary artery calcium (CAC) score) in 100 patients with RA without cardiovascular disease at baseline and 6.9±0.4 years later. The presence of ≥5 plaques and lesions rendering >50% stenosis was considered an extensive and obstructive disease, respectively. Serum CLC was measured on human THP-1 monocyte-derived macrophages with a fluorometric assay.Results Mean CLC change (follow-up CLC−baseline CLC) was 1.54 (SD 3.69) μg cholesterol/mg protein. In models adjusting for atherosclerotic cardiovascular disease risk score, baseline plaque and other relevant covariates, CLC change (per SD unit increase) is associated with a higher likelihood of progression of non-calcified (OR 2.55, 95% CI 1.22 to 5.35), fully calcified plaque (OR 3.10, 95% CI 1.67 to 5.76), CAC (OR 1.80, 95% CI 1.18 to 2.74) and new extensive or obstructive disease (OR 2.43, 95% CI 1.11 to 5.34). Exposure to prednisone unfavourably influenced, while biologics and statins favourably affected the relationship between CLC change and atherosclerosis progression (all p-for-interactions ≤0.048).Conclusion CLC change is associated with atherosclerosis progression in a dose-dependent manner, including lipid-rich non-calcified plaques and extensive or obstructive disease that yield the greatest cardiovascular risk.

Objectives Cholesterol loading capacity (CLC) describes the ability of serum to deliver cholesterol to cells. It is linked to foam cell formation, a pivotal step in atherosclerotic plaque development. We evaluate the associations of CLC with coronary atherosclerosis presence, burden and cardiovascular risk in patients with rheumatoid arthritis (RA).Methods Coronary atherosclerosis (any, high-risk low-attenuation plaque and obstructive plaque) was evaluated with CT angiography in 141 patients. Participants were prospectively followed for 6.0±2.4 years and cardiovascular events including cardiac death, myocardial infarction, unstable angina, stroke, claudication, revascularisation and hospitalised heart failure were recorded. CLC was quantified as intracellular cholesterol in human macrophages after incubation with patient serum.Results CLC was not linked to overall plaque presence or burden after adjustments for atherosclerotic cardiovascular disease (ASCVD) score, statin use and low-density lipoprotein cholesterol. However, CLC associated with presence and numbers of any, low-attenuation and obstructive plaques exclusively in biologic disease-modifying antirheumatic drugs (bDMARD) non-users (p for interaction ≤0.018). CLC associated with cardiovascular event risk overall after adjustments for ASCVD and number of segments with plaque (HR=1.76 (95% CI 1.16 to 2.67) per 1 SD increase in CLC, p=0.008). Additionally, bDMARD use modified the impact of CLC on event risk; CLC associated with events in bDMARD non-users (HR=2.52 (95% CI 1.36 to 4.65) per 1SD increase in CLC, p=0.003) but not users.Conclusion CLC was linked to long-term cardiovascular event risk in RA and associated with high-risk low attenuation and obstructive coronary plaque presence and burden in bDMARD non-users. Its prospective validation as a predictive biomarker may be, therefore, warranted.