Methotrexate and Cardiovascular Disease in Patients With Rheumatoid Arthritis: Insights and Novel Speculations

Rheumatoid arthritis (RA) increases the risk for cardiovascular disease (CVD) and the risk is related to disease activity1,2,3,4. Groundbreaking studies on the etiology of CVD have shown that there is a strong relationship with inflammation5,6. Given that a core therapeutic goal in RA is to control inflammation, it is appropriate to determine if therapeutic interventions for disease activity may also favorably affect the incidence of CVD. Because of the association of inflammation with CVD, a large therapeutic trial was conducted to determine if methotrexate (MTX) treatment in patients with a history of CVD could actually prevent new vascular events. The Cardiovascular Inflammation Reduction Trial (CIRT) was conducted in patients with a history of CVD (without RA or any other inflammatory disease) to determine if weekly MTX was associated with a decrease in new cardiovascular (CV) events7. The study was discontinued due to the lack of benefits of MTX on CVD reduction in this population. However, there has been much speculation regarding the reason(s) for the absence of MTX effect, including the fact that these patients did not have systemic inflammation with elevated C-reactive protein (CRP)8. Given the inflammatory nature of RA, it is certainly logical to posit that therapeutic interventions directed at the treatment of the underlying disease would also favorably affect the incidence of CVD in that population. Indeed, studies have shown that inhibition of both tumor necrosis factor (TNF)9,10 and MTX11,12,13,14,15 significantly diminishes the incidence of CVD in patients with RA. In this issue of The Journal of Rheumatology , Xie and colleagues have demonstrated that MTX is also incrementally beneficial for the prevention of CVD when used in combination … Address correspondence to Dr. J. Kremer, 521 Sir Charles Way, Albany, NY 12203, USA. Email: jkremer{at}corrona.org.