Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications

Abstract

Rheumatoid arthritis is a systemic autoimmune disease characterized by excess morbidity and mortality from cardiovascular disease. Mechanisms linking rheumatoid arthritis and cardiovascular disease include shared inflammatory mediators, post-translational modifications of peptides/proteins and subsequent immune responses, alterations in the composition and function of lipoproteins, increased oxidative stress, and endothelial dysfunction. Despite a growing understanding of these mechanisms and their complex interplay with conventional cardiovascular risk factors, optimal approaches of risk stratification, prevention, and treatment in the context of rheumatoid arthritis remain unknown. A multifaceted approach to reduce the burden posed by cardiovascular disease requires optimal management of traditional risk factors in addition to those intrinsic to rheumatoid arthritis such as increased disease activity. Treatments for rheumatoid arthritis seem to exert differential effects on cardiovascular risk as well as the mechanisms linking these conditions. More research is needed to establish whether preferential rheumatoid arthritis therapies exist in terms of prevention of cardiovascular disease. Ultimately, understanding the unique mechanisms for cardiovascular disease in rheumatoid arthritis will aid in risk stratification and the identification of novel targets for meaningful reduction of cardiovascular risk in this patient population.

Fig 1

Overview of mechanisms of cardiovascular disease (CVD) in rheumatoid arthritis (RA). Several mechanisms interact to amplify risk of CVD in RA. Higher RA disease activity contributes to systemic inflammation and pro-inflammatory cytokine production. This inflammation causes quantitative and qualitative lipid modifications resulting in perturbations of cholesterol transport and enhanced foam cell formation. Post-translational modifications of proteins serve as targets of RA autoantibodies that may have deleterious effects on the cardiovascular system and enhance systemic/local inflammation. Oxidative stress, which results from inflammation, contributes to post-translational modifications of proteins and directly affects endothelial function. These RA related mechanisms exacerbate the pathogenicity of traditional CVD risk factors such as tobacco use, diabetes, hypertension, dyslipidemia, obesity, and chronic kidney disease. ACPA=anti-citrullinated protein antibodies; HDL=high density lipoprotein; IL=interleukin; LDL=low density lipoprotein; oxLDL=oxidized LDL; MAA=malondialdehyde-acetaldehyde; RF=rheumatoid factor; ROS=reactive oxygen species

Fig 2

Drugs used for treatment of rheumatoid arthritis and their cardiovascular risk. CHF=congestive heart failure; COX=cyclooxygenase; CVD=cardiovascular disease; DMARDs=disease modifying anti-rheumatic drugs; HCQ=hydroxychloroquine; LDL=low density lipoprotein; MI=myocardial infarction; NSAID=non-steroidal anti-inflammatory drug; RA=rheumatoid arthritis; RR=relative risk; TNF=tumor necrosis factor

Fig 3

Targeting cardiovascular disease (CVD) risk reduction in rheumatoid arthritis (RA). Targeting reduction of CVD in RA requires a multifaceted, team approach. Key areas to target are tobacco use cessation, treating comorbid conditions (diabetes, hypertension, chronic kidney disease), assessing cardiovascular risk, aggressively managing dyslipidemia, treating RA toward a goal of remission (or at least low disease activity), avoiding/limiting use of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, and potentially selecting disease-modifying antirheumatic drugs (DMARDs) with more favorable CVD risk profiles. HCQ=hydroxychloroquine; MTX=methotrexate; TNFi=tumor necrosis factor inhibitor