Methotrexate associated with reduced risk of cardiovascular disease in RA

Methotrexate-related mechanisms may modify cardiovascular risk in people with rheumatoid arthritis.

Rheumatoid arthritis is a chronic inflammatory disease that affects a person’s joints, and may cause pain and disability. Rheumatoid arthritis can affect people of all ages. It most often starts between the ages of 30 and 50 – although this can depend on where you live. Rheumatoid arthritis is more common in women than men.

People with rheumatoid arthritis have a higher risk of developing cardiovascular diseases. These affect the heart and blood vessels, and include heart attacks, heart failure or stroke. This is due to the inflammation present in rheumatoid arthritis that can also affect other systems in the body. Methotrexate is a common medicine that is often the first medicine given to people with rheumatoid arthritis.

Methotrexate has been shown to reduce the risk of cardiovascular disease in people with rheumatoid arthritis. However, the reasons for this so-called cardioprotective effect are poorly understood.


The authors wanted to find out whether the cardioprotective effects of methotrexate are caused primarily by improving people’s rheumatoid disease activity, or if there are other beneficial effects that relate to the drug itself.

The study looked at 2,044 people. Everyone taking part was a US veteran over the age of 18, and had been diagnosed with rheumatoid arthritis. Overall, 90% of the people taking part were male, and the average age was 64.

This was a prospective longitudinal study. This means that the people taking part were observed over a period of time and measurements were taken. However, there was no study intervention or medicine being tested. The study used data from the VARA registry, which collects information about US veterans diagnosed with rheumatoid arthritis.

The authors looked at information from the time of each person’s enrolment into the registry until they experienced a cardiovascular episode. These included being hospitalised for a heart attack, having a stroke, heart failure, or dying from cardiovascular disease. The underlying rheumatoid arthritis disease activity was assessed at each registry visit. The database collected information about medications dispensed, people’s weight, and cardiovascular risk factors such as having diabetes or high blood pressure (hypertension).

The authors first looked to see if there was any connection between methotrexate use and cardiovascular
episodes. Statistical methods were used to account for changes in other variables such as disease activity, age or weight that could influence both the likelihood of a person being treated with methotrexate, as well as their risk of cardiovascular disease. A second analysis was used to work out whether the association of methotrexate use with reduced cardiovascular risk was driven primarily through reductions in disease activity or other effects of the drug itself.

The main finding was that methotrexate use resulted in a 24% reduced risk of experiencing a cardiovascular event, including a 57% reduced risk of hospitalisation for heart failure. Analysis showed that the cardiovascular risk reduction was not due to the effect on rheumatoid disease activity, suggesting that there may be other beneficial cardioprotective properties that are specific to methotrexate.

Yes. The authors think that this is one of the very first studies to show that methotrexate reduces heart failure risk to a greater extent than heart attack or stroke. It is also the first to show that methotrexate-related properties apart from its ability to control disease activity offer cardiovascular protection to people with rheumatoid arthritis.

One limitation is that this study was done in an older, male-predominant group. This could mean that the findings may not apply to other groups of people with rheumatoid arthritis. Also, because this was an observational study, there is also a risk that unmeasured factors could have influenced the associations observed between methotrexate use and cardiovascular events. The authors found that effects other than disease activity reduction drove the cardiovascular risk reduction with methotrexate use in this cohort. Unfortunately they were unable to specifically determine those other mechanisms at this time.

The findings from this study suggest that there are factors beyond what can be assessed clinically with current disease activity measures that can influence cardiovascular risk in people with rheumatoid arthritis. Further studies are planned to investigate novel mediators of cardiovascular disease in rheumatoid arthritis, and to see whether these can be harnessed to better predict those at risk for cardiovascular disease, or serve as potential treatment targets for people with rheumatoid arthritis and cardiovascular disease.

If you have rheumatoid arthritis, you may have an increased risk of cardiovascular diseases such as heart attacks, heart failure or stroke. The findings of this study may be considered when making treatment decisions, especially if you are at high risk of – or already suffer from – cardiovascular disease. For example, if your rheumatoid arthritis is not under control on methotrexate alone and changes are being considered, continuing methotrexate along with a new drug may provide additional cardiovascular benefit.

If you have any concerns about your disease or its treatment, you should talk to your doctor.

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Date prepared: October 2021
Summary based on research article published on: 28 May 2021
From: Johnson TM, et al. Investigating changes in disease activity as a mediator of cardiovascular risk reduction with methotrexate use in rheumatoid arthritis. Ann Rheum Dis 2021;80:1385–1392. doi:10.1136/annrheumdis-2021-220125

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