The inextricable link between atherosclerosis and prototypical inflammatory diseases rheumatoid arthritis and systemic lupus erythematosus

Abstract

The increased burden of cardiovascular disease in patients with rheumatoid arthritis and systemic lupus erythematosus has recently become the focus of intense investigation. Proatherogenic risk factors and dysregulated inflammation are the main culprits, leading to enhanced atherosclerosis in subgroups of patients with inflammatory diseases. Common molecular pathways shared by atherosclerosis and inflammatory disease may be involved. In this review we map the key determinants of the increased incidence of cardiovascular disease in patients with inflammatory diseases at each step of the atherogenesis.

Figure 1

Similarities between the atherosclerotic plaque and rheumatoid arthritis joint. The (a) atherosclerotic plaque has many features in common with (b) rheumatoid arthritic synovium. First, in both diseases, blood-borne mononuclear cells are recruited to sites that are devoid of any significant inflammation in physiological conditions. Second, upregulation of cytokines and matrix-degrading enzymes is central to the pathogenesis of both diseases. Third, both in rheumatoid arthritis and atherosclerosis, immune cells do not target resident cells in the same way that diabetogenic T cells directly destroy pancreatic islets. Instead, immune cells begin complex interactions with the resident cell types, which proliferate, change their properties and phenotype, and contribute to the inflammatory process and tissue destruction.

Figure 2

Formation and progression of atherosclerotic lesions. (a) Atherosclerosis disease initiation. Patients with rheumatoid arthritis and systemic lupus erythematosus present with clustering of traditional risk factors, notably low high-density lipoprotein (HDL) levels and pro-atherogenic lipid particles, leading to premature establishment of atherosclerotic lesions compared with age-matched and sex-matched control individuals. (b) Progression. Inflammatory disease activity and duration is emerging as a key determinant of the clinical association between cardiovascular disease (CVD) and inflammatory disease. Pro-inflammatory mediators and immune dysregulation features may enhance susceptibility to risk factors and establish chronic inflammation in vascular lesions. (c) Complications. Both inflammatory features and prothrombotic pathways may enhance the likelihood of acute events, increasing mortality. IFN, interferon; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); MCP, monocyte chemoattractant protein; MIF, macrophage migration inhibitory factor; MMP, matrix metalloproteinase; oxLDL, oxidized low-density lipoprotein; PG, prostaglandin; VCAM, vascular cell adhesion molecule; TF, tissue factor; TNF, tumour necrosis factor.