Many patients with RA have concomitant diseases such as hypertension and hyperlipidemia, putting them at greater risk for cardiovascular disease (CVD). The inflammation associated with RA and other inflammatory diseases increases the risk for CVD above and beyond that attributed to the traditional factors included in the Framingham Risk Score. A 2008 study by Kremers and colleagues at the Mayo Clinic in Rochester, MN, found that the risk for developing CVD among patients with RA was similar to that of patients without RA who were 5 to 10 years older. Other studies have demonstrated that effective control of systemic inflammation with medications, such as anti–tumor necrosis factor (anti-TNF) agents, reduces the incidence of CVD among patients with RA. 

Atherosclerotic plaque can be conceptualized pathophysiologically as “synovitis of the artery.” These plaques are infiltrated by activated T cells and macrophages, which stimulate smooth muscle proliferation. Cardiologists now recognize that treatment with low-dose weekly methotrexate may be an appropriate approach to prevent recurrent CV events in individuals with a previous myocardial infarction (MI) or stroke. Paul M. Ridker, MD, MPH, of the Brigham and Women’s Hospital in Boston, MA, is conducting the large, randomized, double-blind, placebo-controlled, multicenter Cardiovascular Inflammation Reduction Trial (CIRT) to determine whether treatment with oral methotrexate 15 mg to 20 mg administered weekly and oral folate 1 mg administered daily for 6 days per week reduces rates of MI, stroke, and CV death among patients with stable coronary artery disease and type 2 diabetes or metabolic syndrome. The investigators anticipate completing this study in December 2019.

Reducing inflammation by inhibiting interleukin-1β (IL-1β) with canakinumab (a therapeutic monoclonal antibody targeting IL-1β) decreases the recurrence of CV events among patients with a prior MI and a high-sensitivity C-reactive protein (CRP) level greater than 2 mg/L. In the large, randomized, double-blind Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), treatment with subcutaneous canakinumab 150 mg every 3 months was superior to that with placebo in preventing MI, stroke, or death, despite it not lowering lipid levels. No reduction in mortality was observed; in fact, more deaths attributed to infection were reported among the canakinumab-treated patients. Nevertheless, this was the first prospective, controlled study to demonstrate that treatment with a biologic agent targeting a proinflammatory cytokine can reduce the incidence of CV events.

The contribution of obesity to CV risk in patients with RA may also involve inflammation. Adipose cells produce the proinflammatory cytokine interleukin 6, which stimulates CRP production by the liver. Elevated CRP levels increase the risk of developing CVD. By controlling disease activity, treatment with either methotrexate or anti-TNF agents decreases the risk of CV events among patients with RA. Of note, obesity reduces the likelihood of a patient with RA achieving remission when treated with either conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or an anti-TNF agent.

To summarize, the current approach to decreasing CV risk in patients with RA is to control disease activity effectively with csDMARDs, such as methotrexate, and targeted biological agents according to standard treatment algorithms. Ongoing discussion with our patients provides an excellent opportunity to reinforce the importance of smoking cessation and weight reduction and to address the other modifiable traditional Framingham risk factors, both to improve control of RA disease activity and to reduce CV risk.