Increased cardiovascular disease (CVD) risk in patients with rheumatoid arthritis (RA) has been established in numerous studies to date, prompting the European League Against Rheumatism (EULAR) in 2016 to publish updated recommendations and reinforce the adjusted risk score for patients with RA, calculated by multiplying the total CVD risk by a factor of 1.5 if 2 or 3 disease-specific criteria are fulfilled.1 The EULAR guidelines also urge clinicians to conduct CVD risk assessment using national guidelines or the SCORE CVD risk prediction model for all patients with RA, ankylosing spondylitis, and psoriatic arthritis, and to establish adequate control of disease activity early in the disease process to lower the risk.2

Studies have estimated that patients with RA have an approximately 50% higher CVD risk2 and a 1.6 times higher rate of acute myocardial infarction and ischemic stroke.3 This increased risk has been attributed to the presence of traditional risk factors, such as smoking, obesity, hypertension, and type 2 diabetes; underlying chronic inflammatory processes4,5 and anti-rheumatic medication-related toxicity have also been implicated as risk factors for CVD.6 Emerging studies aim to better understand the therapeutic interventions that may mitigate this increased CVD risk in patients with RA.

In an interview with Rheumatology Advisor, Laura Geraldino-Pardilla, MD, MSc, clinical researcher/rheumatologist and Assistant Professor of Medicine at the Columbia University Medical Center, Division of Rheumatology, in New York, discussed the latest insights pertaining to the link between chronic inflammation and CVD risk in RA.

Rheumatology Advisor: Which factors contribute to increased CVD risk in patients with RA?


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Laura Geraldino-Pardilla, MD, MSc: Both traditional CV risk factors and intrinsic RA features contribute to the overall excess CVD-related morbidity and mortality in RA patients. Conventional CVD risk factors, such as hypertension, smoking, type 2 diabetes mellitus, and hyperlipidemia are well-defined CVD risk factors in the general population and in RA,7 yet patients with RA have a higher atherosclerotic burden with up to a 2.5-fold increase in coronary and aortic calcifications, with the chronic systemic and/or vascular inflammation of RA being an independent CVD risk factor.8

Rheumatology Advisor: Which pro-inflammatory molecules have been implicated in the promotion of atherosclerotic plaque formation and cardiac remodeling in RA?

Dr. Geraldino-Pardilla: Atherosclerosis is an inflammatory process, reflected directly in plaque by the presence of infiltrating macrophages and T cells, and systemically, by mildly elevated levels of inflammatory cytokines such as tumor necrosis factor, interleukins-1 and -6, and metalloproteases.9 In the general population, mild elevations in these cytokines are independent risk factors for CVD, particularly [myocardial infarction], presumably through promotion of plaque rupture.10 In RA, patients have much higher serum levels of the same molecules and these are independent predictors of CV events in RA.11 Additionally, the presence of anti-citrullinated peptide antibodies, anti-malondialdehyde-acetaldehyde adducts, and antibodies against carbamylated proteins have been associated with an increased risk for CV-related death in patients with RA through their potential for promoting atherosclerotic plaque formation and cardiac remodeling.12-14

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Rheumatology Advisor: Have specific anti-inflammatory or disease-modifying antirheumatic drug (DMARD) therapies shown a differential effect on CV risk in RA?

Dr. Geraldino-Pardilla: Data suggest a differential impact of different DMARDs on CVD risk in RA. Conventional DMARDs such as methotrexate,15 sulfasalazine, and hydroxychloroquine have been shown to improve CV risk in RA; further decrease in this risk is also seen with biologic DMARDs.16,17 While the comparative effect of different classes of biologic DMARDs has not been optimally studied by direct head-to-head assessment, observational studies suggest fewer [CV] events associated with abatacept and tocilizumab.18,19

Rheumatology Advisor: How can clinicians make the best assessment of individual CVD risk in patients with RA?

Dr. Geraldino-Pardilla: It is important for rheumatologists to play an active role in the assessment and coordination of CVD risk management in patients with RA. This implies regularly monitoring not only traditional [CV] risk factors, but also closely observing and promptly evaluating those patients known to have autoantibodies associated with higher atherosclerotic burden and overall increased CVD risk.

Rheumatology Advisor: What types of studies are still needed to more closely examine the association between CVD and RA, and how should the increased CV risk in patients with RA be mitigated?

Dr. Geraldino-Pardilla: Further research is required into the relative effects of specific DMARDs on CVD risk in RA with direct head-to-head trials. In an era of increasing therapeutic options and precision medicine, the results from such trials will allow [for the consideration of] a patient’s unique subset of traditional CV risk factors and intrinsic RA features in order to guide treatment choices that best mitigate the risk of CVD and mortality in patients with RA.

References

1. 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.

2. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 2008;59(12):1690-1697.

3. Semb AG, Kvien TK, Aastveit AH, et al. Lipids, myocardial infarction and ischaemic stroke in patients with rheumatoid arthritis in the Apolipoprotein-related Mortality RISk (AMORIS) Study. Ann Rheum Dis. 2010;69(11):1996-2001.

4. Mason JC, Libby P. Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur Heart J. 2015;36(8):482-489.

5. DeMizio DJ, Geraldino-Pardilla LB. Autoimmunity and inflammation link to cardiovascular disease risk in rheumatoid arthritis [published online December18, 2019]. Rheumatol. Ther. doi:10.1007/s40744-019-00189-0.

6. Zegkos T, Kitas G, Dimitroulas T. Cardiovascular risk in rheumatoid arthritis: assessment, management and next steps. Ther Adv Musculoskelet Dis. 2016;8(3):86-101.

7. Boyer JF, Gourraud PA, Cantagrel A, Davignon JL, Constantin A. Traditional cardiovascular risk factors in rheumatoid arthritis: a meta-analysis. Joint Bone Spine. 2011;78(2):179-183.

8. Giles JT, Szklo M, Post W, et al. Coronary arterial calcification in rheumatoid arthritis: comparison with the Multi-Ethnic Study of Atherosclerosis. Arthritis Res Ther. 2009;11(2):R36.

9. Libby P. History of discovery: Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(9):2045-2051.

10. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101(15):1767-1772.

11. Myasoedova E, Crowson CS, Kremers HM, et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis. 2011;70(3):482-487.

12. Geraldino-Pardilla L, Russo C, Sokolove J, et al. Association of anti-citrullinated protein or peptide antibodies with left ventricular structure and function in rheumatoid arthritis. Rheumatology (Oxford). 2017;56(4):534-540.

13. Anderson DR, Duryee MJ, Shurmur SW, et al. Unique antibody responses to malondialdehyde-acetaldehyde (MAA)-protein adducts predict coronary artery disease. PLoS One. 2014;9(9):e107440.

14. Spinelli FR, Pecani A, Ciciarello F, et al. Erratum to: Association between antibodies to carbamylated proteins and subclinical atherosclerosis in rheumatoid arthritis patients. BMC Musculoskelet Disord. 2017;18:263.

15. Widdifield J, Abrahamowicz M, Paterson JM, et al. Associations between methotrexate use and the risk of cardiovascular events in patients with elderly-onset rheumatoid arthritis. J Rheumatol. 2019;46(5):467-474.

16. Barnabe C, Martin BJ, Ghali WA. Systematic review and meta-analysis: Anti-tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2011;63(4):522-529.

17. Ljung L, Rantapää-Dahlqvist S, Jacobsson LT, Askling J. Response to biological treatment and subsequent risk of coronary events in rheumatoid arthritis. Ann Rheum Dis. 2016;75(12):2087-2094.

18. Zhang J, Xie F, Yun H, et al. Comparative effects of biologics on cardiovascular risk among older patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75(10):1813-1811.

19. 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 [published online March 15, 2019]. Arthritis Care Res (Hoboken). doi:10.1002/acr.23875.