Tumor Necrosis Factor-Alpha Inhibitors and Cardiovascular Risk in Rheumatoid Arthritis: A Systematic Review

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that, if untreated or poorly controlled, can cause significant morbidity in terms of loss of physical function and higher mortality due to higher cardiovascular risk. The standard of care for this disease is the use of disease-modifying antirheumatic drugs (DMARDs). However, patients unable to reach low disease activity or remission and patients unable to tolerate conventional DMARDs will be switched to biologic therapy, a subset of which includes anti-tumor necrosis factor-alpha inhibitors. Since tumor necrosis factor-alpha inhibitors (TNFi) inhibit the inflammatory cascade, they also play an essential role in dampening the progression of atherosclerosis and altering the risk of cardiovascular outcomes in RA. In this study, we assessed the risk of cardiovascular diseases, namely, congestive heart failure, nonfatal myocardial infarction, cerebrovascular disease, and coronary artery disease. We carried out the analysis by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and conducted a literature search utilizing the following databases: PubMed, Science Direct, and Cochrane Library. Using the search strategy, we found a total of 19 articles that fit the inclusion and exclusion criteria, in addition to passing the risk of bias assessment. This is composed of three systematic reviews with meta-analyses, three randomized control studies, four narrative reviews, and nine cohort studies. In this systematic review, it was found that treatment with TNFi causes a corresponding reduction in the risk of cardiovascular events. This review encourages further dissection into the inner workings of TNFi in reducing the risk of cardiovascular disease among patients with RA.

Keywords: cerebrovascular diseases; congestive heart failure; myocardial ischemia and infarction; reduce the risk of coronary artery disease in rheumatoid arthritis; rheumatoid arthritis; risk of cardiovascular diseases; tumor necrosis factor-alpha (tnf-α) inhibitors.

Figure 1. Identification of studies via databases and registers

CCRBT: Cochrane Collaboration Risk of Bias Tool; NOS: Newcastle-Ottawa Scale; AMSTAR 2: Assessment of Multiple Systematic Reviews 2; SANRA 2: Scale for the Assessment of Narrative Review Articles 2.

Figure 2. Inflammatory events outlined in atherosclerosis

Monocytes pass through the arterial wall and then express the CCR3 chemokine receptor and bind chemokines. Monocytes then differentiate into macrophages and then foam cells, which are the main components in atherosclerotic plaque formation. T lymphocytes also move into the vessel wall, where they express chemokine receptors and differentiate into TH1 and TH2 cells. Both macrophages and TH1 cells release, among other inflammatory mediators, TNF. Therefore, TNFi biologic agents may be effective in controlling atherosclerosis related to rheumatoid arthritis. CCR3: CC‑chemokine receptor 3; CXCR3: CXC‑chemokine receptor 3; HSP: heat shock proteins; IFN: interferon; IL: interleukin; oxLDL: oxidized low‑density lipoprotein; TH: T‑helper lymphocyte; TNF: tumor necrosis factor; vCAM‑1: vascular cell adhesion molecule 1. Adapted from and used with permission from Professor Dr. Szekanecz Zoltan [22].