Observational studies described an inverse association between high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular events [1]. Yet, genetic mutations and variants affecting HDL-C levels had no impact on cardiovascular risk [2] and HDL-C raising medications failed to lower it [3,4]. These observations suggested that HDL function, rather than levels, may preferentially underlie its cardioprotective benefits [5]. HDL removes cholesterol from foam cells in atherosclerotic lesions—a property known as cholesterol efflux capacity (CEC)—and may prevent formation and progression of atherosclerosis [5]. In recent meta-analyses, CEC inversely related with cardiovascular risk independently of HDL-C levels in general patients [6]. Additionally, CEC negatively associated with atherosclerotic lesion size and was a better predictor of plaque severity than HDL-C levels [7]. Furthermore, CEC inversely related with lipid-rich plaque burden and macrophage density in atherosclerotic lesions [8].

CEC is facilitated by several membrane transporter proteins on macrophages that export free cholesterol to various acceptor HDL particles according to their size, protein and lipid composition [5]. CEC through the aqueous diffusion and the scavenger receptor type B class 1 (SR-B1) pathways depend on free cholesterol gradient between cells and mature HDL particles [5]. The ATP-binding cassette A1 (ABCA1) membrane transporter actively and unidirectionally exports free cholesterol exclusively to lipid-free or lipid-poor apo-A1, discoidal HDL particles [5]. The ATP-binding cassette G1 (ABCG1) membrane transporter on the other hand actively promotes efflux predominantly to mature, spherical HDL particles [5]. Therefore, comprehensive assessment of HDL-CEC across these specific pathways individually may provide relevant details about HDL quality, maturation and function. ABCG1-CEC in particular, is specifically coupled with the elimination of 7-ketocholesterol [9], which induces apoptosis/necrosis in endothelial cells and macrophages [10] and is the most abundant oxysterol in oxidized LDL and in human atherosclerotic plaques [11]. Cell cholesterol efflux through the ABC transporters is also associated with lower plaque inflammation [10,12]. On the other hand, systemic inflammation induces HDL dysfunction [13]. ABCG1-CEC was shown to be lower in RA, inversely related with disease activity [14], and improving with treatment [15,16].

It is currently unknown whether CEC associates with cardiovascular event risk independently of HDL-C levels or with coronary atherosclerosis in RA. It is also unclear whether CEC at large-much less individual CEC pathways-themselves or their impact on such outcomes are influenced by disease activity, systemic inflammation or RA-specific therapies [16,17]. In recent reports, corticosteroids fostered cholesterol accumulation in macrophages in vitro [18] and independently promoted coronary atherosclerosis progression in RA [19]. In the present study we explored the link between ABCG1-CEC and coronary atherosclerosis burden, its progression and long-term incident cardiovascular risk in RA. We additionally explored whether inflammation and corticosteroid exposure influenced the relationship between ABCG1-CEC and atherosclerosis progression or cardiovascular risk.