clinical topic updates

Comparative Risk of Cardiovascular Events With Disease-Modifying Antirheumatic Drugs in Patients With Rheumatoid Arthritis

by Leonard H. Calabrese, DO


Controlling disease activity in rheumatoid arthritis (RA) appears to reduce cardiovascular (CV) risk, with risk reduction extending to the non–tumor necrosis factor (non-TNF) biologics and targeted synthetic agents. Still, distinct mechanisms involved in this risk may have greater relative importance in one patient population vs another.

Expert Commentary

Leonard H. Calabrese, DO

Professor of Medicine
RJ Fasenmyer Chair of Clinical Immunology
Director, RJ Fasenmyer Center for Clinical Immunology
Vice Chair, Department of Rheumatic and Immunologic Diseases
Cleveland Clinic Foundation
Cleveland, OH

“The MBDA test appears to accurately predict CV risk in RA, and I think that it can be game changing in how we are following patients.”

Leonard H. Calabrese, DO

Over the last 15 to 20 years, ample evidence has demonstrated that disease control in RA with methotrexate and/or TNF inhibitors is associated with a decreased risk of CV disease (CVD). The question arises as to whether the newer non-TNF biologics and targeted synthetic agents also reduce the risk of CV end points. Agents such as interleukin-6 inhibitors and Janus kinase inhibitors have mixed effects on biomarkers for CVD, producing a decrease in C-reactive protein but also increasing low-density lipoprotein cholesterol and total cholesterol. Because of this, the US Food and Drug Administration mandated a head-to-head trial comparing the effects of tocilizumab vs etanercept on CV safety. The results indicated no significant difference in the time to first major adverse CV events between agents. 

The consensus among key opinion leaders seems to be that control of RA disease activity, however you can accomplish it with any of the available drugs, will likely lessen CV risk. The one caveat is that, while there is no evidence that Janus kinase inhibitors increase the risk of myocardial infarction or stroke, there is a small but reproducible signal of increased venous thromboembolism risk; I think that most rheumatologists are screening patients for venous thromboembolism risk and that these are not the agents that people are going to gravitate to when patients are at high risk. The physiologic pathways contributing to inflammation and CVD in RA are not well understood and there may be different mechanisms in different patient populations. For example, low-dose methotrexate did not reduce inflammatory cytokines or CV events in patients with stable atherosclerosis but without RA. 

The multi-biomarker disease activity (MBDA) test is the only biomarker test that has been included in the American College of Cardiology recommendations for routine use in the clinical evaluation of patients with RA. The MBDA test appears to accurately predict CV risk in RA, and I think that it can be game changing in how we are following patients. It is a useful tool for those patients who have indeterminate presentations, such as increasing pain and fatigue but with modest tender joints and no swollen joints. Since it is challenging to know the contributing importance of comorbid factors, the MBDA test can provide reassurance regarding our clinical assessment. I often use the MBDA test during the initial evaluation to assess prognosis and therapeutic decision making, and I will also often use it when I am initiating or changing therapy. I will repeat the test to make sure that the results are in concordance with my clinical appraisal.  


Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2017;76(1):17-28.

Calabrese LH. MBDA: a valuable tool for medical decision making. J Rheumatol. 2019;46(12):1642.

Curtis JR, Xie F, Chen L, Saag KG, Yun H, Muntner P. Biomarker-related risk for myocardial infarction and serious infections in patients with rheumatoid arthritis: a population-based study. Ann Rheum Dis. 2018;77(3):386-392.

England BR, Tiong BK, Bergman MJ, et al. 2019 update of the American College of Rheumatology recommended rheumatoid arthritis disease activity measures. Arthritis Care Res (Hoboken). 2019;71(12):1540-1555.

Giles JT, Sattar N, Gabriel S, et al. Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol. 2020;72(1):31-40.

Myasoedova E, Davis J, Roger V, Achenbach S, Crowson C. Improved incidence of cardiovascular disease in patients with incident rheumatoid arthritis in 2000s: a population-based cohort study [abstract 922]. Arthritis Rheumatol. 2019;71(suppl 10). Accessed March 17, 2020.

Roubille C, Richer V, Starnino T, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74(3):480-489.

Singh S, Fumery M, Singh AG, et al. Comparative risk of cardiovascular events with biologic and synthetic disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2019 Mar 15. doi: 10.1002/acr.23875. [Epub ahead of print]

Voelker R. Higher dose of tofacitinib for rheumatoid arthritis poses risks. JAMA. 2019;321(13):1245.

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