The Effect of Methotrexate on Cardiovascular Disease in Patients with Rheumatoid Arthritis: A Systematic Literature Review

Sarah L. Westlake; Alexandra N. Colebatch; Janis Baird; Patrick Kiely; Mark Quinn; Ernest Choy; Andrew J. K. Ostor; Christopher J. Edwards


Rheumatology. 2010;49(2):295-307. 

In This Article

Abstract and Introduction


Objectives. Patients with RA have an increased prevalence of cardiovascular disease (CVD). This is due to traditional risk factors and the effects of chronic inflammation. MTX is the first-choice DMARD in RA. We performed a systematic literature review to determine whether MTX affects the risk of CVD in patients with RA.
Methods. We searched Medline, Embase, Cochrane database, database of abstracts of reviews of effects, health technology assessment and Science Citation Index from 1980 to 2008. Conference proceedings (British Society of Rheumatology, ACR and EULAR) were searched from 2005 to 2008. Papers were included if they assessed the relationship between MTX use and CVD in patients with RA. Two reviewers independently assessed each title and abstract for relevance and quality.
Results. A total of 2420 abstracts were identified, of which 18 fulfilled the inclusion criteria. Two studies assessed the relationship between MTX use and CVD mortality, one demonstrated a significant reduction in CVD mortality and the second a trend towards reduction. Five studies considered all-cause CVD morbidity. Four demonstrated a significant reduction in CVD morbidity and the fifth a trend towards reduction. MTX use in the year prior to the development of RA decreased the risk of CVD for 3–4 years. Four studies considered myocardial infarction, one demonstrated a decreased risk and three a trend towards decreased risk with MTX use.
Conclusion. The current evidence suggests that MTX use is associated with a reduced risk of CVD events in patients with RA. This suggests that reducing the inflammation in RA using MTX not only improves disease-specific outcomes but may also reduce collateral damage such as atherosclerosis.


RA is a chronic inflammatory polyarthritis that often leads to joint destruction, deformity and loss of function.[1,2] In addition, patients with RA have a reduced life expectancy.[3,4] Early mortality is largely due to cardiovascular disease (CVD), which is the commonest cause of death in patients with RA.[5,6] In a recent UK-based study, the standardized mortality ratio for CVD in RA was 1.49 (1.21, 1.77).[7] In a large (n = 575) population-based study, the risk of RA patients developing chronic heart failure was approximately twice that of controls.[8] The increased prevalence of CVD is probably due to an increase in both the traditional risk factors for atherosclerosis and the presence of chronic inflammation.[9] Active systemic inflammation has multiple effects which accelerate atherosclerosis. These include changes to the endothelium by ICs, CRP and cytokines. Induction of secondary dyslipidaemia, altered glucose metabolism and creation of a hypercoagulable state due to platelet activation and increased production of clotting factors also play a role.[10] The importance of inflammation in the development of atherosclerosis is supported by the association of cardiovascular death with elevated levels of CRP in patients with inflammatory polyarthritis.[11] In the general population, raised levels of highly sensitive CRP (HsCRP) predicts CVD events.[12] Given the importance of inflammation in the development of CVD, therapies aimed at reducing disease activity in RA may also have a positive impact on CVD risk by reducing the burden of systemic inflammation.

MTX has become the most frequently used DMARD in RA and the cornerstone in most DMARD and biologic combinations.[13] Its mechanisms of action are diverse and complex but in the doses used to treat RA its actions are likely to be anti-inflammatory. Several studies have suggested a beneficial effect of MTX on CVD risk. As part of the 2007–08 international 3E initiative (Experts, Evidence and Exchange) to develop consensus guidelines on the use of MTX in rheumatic disorders, we performed a systematic literature review to determine whether the use of MTX in patients with RA affects the likelihood of developing CVD, the frequency of traditional risk factors and the presence of atherosclerosis.


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