In a review1 of current literature and published guidelines by national health committees including the American College of Rheumatology (ACR), American College of Cardiology/American Heart Association (ACC/AHA), and European League Against Rheumatism (EULAR), there are three main steps to improve cardiovascular disease (CVD) risk in patients with rheumatoid arthritis (RA):
- Manage RA itself using treat-to-target and medication management
- Assess individual CVD risk and consider statin therapy
- Target traditional CVD risk factors (hyperlipidemia, hypertension, smoking, diabetes, healthy diet and physical activity)
Manage RA to Lower Cardiovascular Risk
The 2014 treat-to-target update from the ACR and EULAR recommends management of RA disease activity and targeting remission to lower CVD risk.1,2 In patients with RA who maintain tight control of RA (i.e. remission), CVD risk is lower compared to those with active disease.3,4 In a study conducted in Olmsted County in Minnesota, patients with RA had their CVD risk increase by 7% for each time they spent in an additional acute flare (hazard ratio [HR] 1.07 per 6-week flare, 95% confidence interval [CI] [1.01 to 1.15]).5 These studies demonstrated how RA disease activity contributes to the increased CVD risk observed in patients with RA. Del Rincon et al. showed that although a high erythrocyte sedimentation rate was associated with rapid progression of atherosclerosis, patients taking methotrexate (MTX) and anti-tumor necrosis factor (anti-TNF) medications were less affected by this relationship.6 Therefore, patients who follow their treatment regimen for rheumatoid arthritis will already be lowering their CVD risk. In another systematic review and meta-analysis of 10 observational studies, MTX was associated with 21% decrease in risk for CVD (relative risk [RR] 0.79, 95% CI [0.73 – 0.87], p<0.001).7 While there is a need for more research regarding the individual efficacy of RA medications, such as disease-modifying antirheumatic drugs (DMARDs), in lowering CVD risk, the current overall consensus is that one of the first approaches to lower CVD risk is to control RA disease activity.8-11 The one exception may be glucocorticoids, such as prednisone, which have been found to increase the risk of CVD12, myocardial infarction (MI)13, and mortality.14 Hence, the 2017 EULAR guidelines for CVD risk management in patients with RA recommend the termination and tapering of glucocorticoids as early as possible.15
Assessment of CVD Risk
According to the 2017 EULAR guidelines, CVD risk assessment and treatment for people with RA should follow the general population CVD guidelines.15 In the United States (US), this CVD risk calculation follows the ACC/AHA guidelines.16 Recent studies found that the US CVD risk calculators for the general population are adequate to use for patients with RA, as RA-specific CVD risk score calculators are not superior to those used in the general population.17
Statin use in patients with RA with and without history of CVD was shown to decrease all-cause mortality, regardless of DMARD use in a 2016 population-based cohort study of 2943 patients.18 There was a 21% lower risk of all-cause mortality (95% CI [0.68 – 0.91]) in patients taking a DMARD and statin and a 19% lower risk (95% CI [0.74 – 0.90]) in patients only taking a statin. When excluding patients with a history of CVD, statin use was associated with a 25% risk reduction in all-cause mortality (95% CI [0.61 0.92]). Based on the findings of meta-analyses19-22, including the Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis of 26 trials19, the ACC/AHA concluded statins reduce atherosclerotic CVD risk by about 30% for moderate-intensity statin therapy and about 45% for high-intensity statin therapy in the general population.23 The results of a randomized clinical trial using a high-intensity statin (atorvastatin 40 mg) suggested that this medication might be effective for the primary prevention of cardiovascular events compared to placebo in patients with RA.24 Although the result was not statistically significant, there was a trend towards an association of the use of atorvastatin and reduced number of cardiovascular events (HR 0.60, 95% CI [0.32 – 1.15], p=0.127). This is despite low adherence with atorvastatin in the intervention arm (39% of patients in the intervention arm were taking atorvastatin by the end of the study, 3 years later). This low adherence could have contributed to not achieving statistical significance in this study. Also, statin discontinuation in patients with RA has been reported to be associated with a 67% increased risk of acute MI (adjusted HR 1.67, 95% CI [1.24 – 2.25]).25 This emphasizes the beneficial effect that statins have in patients with RA in terms of reducing their CVD risk.26
Targeting Traditional CVD Risk Factors
Traditional CVD risk factors for the general population are shown to contribute to the increased CVD risk in patients with RA, but do not provide the full explanation of this increased risk.15,27 For the general population, the AHA developed the Life’s Simple 7® to help achieve ideal CV health: cholesterol, blood pressure, glucose, body mass index (BMI), physical activity, diet, and cigarette smoking.28 These biometric measurements and modifiable risk factors are the most important determinants of cardiovascular health. Diet, in particular the Mediterranean diet, is not only beneficial for CVD risk reduction but also for reduction of inflammation due to RA.29,30
A review by Zegkos et al. addressed these risk factors in the context of RA.27 They state that insulin resistance and metabolic syndrome are more prevalent in patients with RA than in the general population. The use of MTX and some biologic DMARDs by patients with RA seem to improve insulin resistance and sensitivity.31-33 In a cross-sectional study, patients with RA who used MTX had a significantly lower odds (odds ratio 0.517, 95% CI [0.33 – 0.81], p=0.004) of having metabolic syndrome and the authors suggested the “possibility of a drug-specific protective mechanism.”31 Anti-TNFα treatment has also been shown to decrease insulin resistance (measured by the Homeostasis Model Assessment of insulin resistance (HOMA)) and increase insulin sensitivity (measured by the Quantitative Insulin sensitivity Check Index (QUICKI)) within 6 months in normal weight patients with RA, but not obese patients with RA.33
The screening and treatment of hyperlipidemia is low among patients with RA.34-36 Multiple studies have found that only 22% – 51% of patients with RA undergo lipid screening. As noted previously, there is evidence for the use of lipid lowering medications such as statins as a strategy to decrease CVD risk and acute MI among patients with RA.25 This emphasizes the importance for patients with RA to obtain screening and, if necessary, treatment for hyperlipidemia.
Hypertension accounted for more CVD deaths in the US than any other modifiable risk factor in 2010.37 It is also important to keep blood pressure under control and use antihypertensive medications as necessary. The ACC/AHA recommends keeping blood pressure to under 120/80 mm Hg to reduce the risk of heart attack, stroke, and other complications of high blood pressure.38 The hazard ratios for CHD and stroke were between 1.1 and 1.5 for the comparison of SBP/DBP of 120 – 129/80 – 84 mm Hg versus <120/80 mm Hg and between 1.5 and 2.0 for the comparison of SBP/DBP of 130 – 139/85 – 89 mm Hg versus <120/80 mm Hg. This risk gradient was consistent across subgroups defined by sex and race/ethnicity. The relative increase in CVD risk associated with higher BP was attenuated but still present among older adults.
In population-based studies, increased BMI was associated with higher relative risk of CVD.39-41 Compared to those with normal weight (BMI 18.5 – 24.9), those who were overweight (BMI 25.0 – 29.9) had an increased HR for incident CVD of 1.21 (95% CI [1.14 – 1.28]) for men and 1.32 (95% CI [1.24 – 1.40]) for women. Patients who were obese (BMI 30.0 – 39.9) had even higher HR of 1.67 (95% CI [1.55 – 1.79]) for men and 1.85 (95% CI [1.72 – 1.99]) for women.40 Current ACC/AHA guidelines on primary prevention of CVD recommend caloric restriction, healthy diet, and physical activity to achieve weight loss.26
The ACC/AHA also recommends at least 150 minutes of moderate-intensity physical activity or 75 minutes of vigorous-intensity physical activity per week.26 Current evidence suggests that the physical activity recommendations for the general population are sufficient and beneficial for patients with RA.42-44
Cigarette smoking is associated with increased risk for CVD.26,45 In a meta-analysis studying the impact of smoking and smoking cessation on cardiovascular mortality, those who smoked had a significantly increased risk of cardiovascular death (HR 2.07, 95% CI [1.82 – 2.36]) and those who had stopped smoking still had an increased, but less dramatic, increased risk (HR 1.37, 95% CI [1.25 – 1.49]) compared to those who have never smoked.46 Smoking is also associated with the development of RA in its more severe seropositive form.38,47,48 In patients who have RA, smokers are less likely to achieve remission and have a lower response to some RA medications (anti-TNFs) due to the increase in inflammatory markers from smoking.49,50
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- Peters MJ, Symmons DP, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010; 69 (2): 325-331.
- Solomon DH, Reed GW, Kremer JM, et al. Disease activity in rheumatoid arthritis and the risk of cardiovascular events. Arthritis Rheumatol 2015; 67 (6): 1449-1455.
- Myasoedova E, Chandran A, Ilhan B, et al. The role of rheumatoid arthritis (RA) flare and cumulative burden of RA severity in the risk of cardiovascular disease. Annals of the rheumatic diseases 2016; 75 (3): 560-565.
- del Rincon I, Polak JF, O'Leary DH, et al. Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Ann Rheum Dis 2015; 74 (6): 1118-1123.
- Micha R, Imamura F, Wyler von Ballmoos M, et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol 2011; 108 (9): 1362-1370.
- Greenberg JD, Kremer JM, Curtis JR, et al. Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis. Ann Rheum Dis 2011; 70 (4): 576-582.
- Cho SK, Kim D, Won S, et al. Impact of anti-rheumatic treatment on cardiovascular risk in Asian patients with rheumatoid arthritis. Semin Arthritis Rheum 2018; 47 (4): 501-506.
- Day AL, Singh JA. Cardiovascular disease risk in older adults and elderly patients with rheumatoid arthritis: what role can disease-modifying antirheumatic drugs play in cardiovascular risk reduction? Drugs Aging 2019; 36 (6): 493-510.
- 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.
- del Rincón I, Battafarano DF, Restrepo JF, et al. Glucocorticoid dose thresholds associated with all‐cause and cardiovascular mortality in rheumatoid arthritis. Arthritis & Rheum 2014; 66 (2): 264-272.
- Aviña-Zubieta JA, Abrahamowicz M, De Vera MA, et al. Immediate and past cumulative effects of oral glucocorticoids on the risk of acute myocardial infarction in rheumatoid arthritis: a population-based study. Rheumatology 2012; 52 (1): 68-75.
- Ajeganova S, Svensson B, Hafström I. Low-dose prednisolone treatment of early rheumatoid arthritis and late cardiovascular outcome and survival: 10-year follow-up of a 2-year randomised trial. BMJ Open 2014; 4 (4): e004259.
- 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.
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- Crowson CS, Gabriel SE, Semb AG, et al. Rheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: a validation analysis of patients from seven countries. Rheumatology (Oxford) 2017; 56 (7): 1102-1110.
- Schoenfeld SR, Lu L, Rai SK, et al. Statin use and mortality in rheumatoid arthritis: a general population-based cohort study. Ann Rheum Dis 2016; 75 (7): 1315-1320.
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- Trialists CT. Efficacy of cholesterol-lowering therapy in 18 686 people with diabetes in 14 randomised trials of statins: a meta-analysis. The Lancet 2008; 371 (9607): 117-125.
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- De Vera MA, Choi H, Abrahamowicz M, et al. Statin discontinuation and risk of acute myocardial infarction in patients with rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis 2011; 70 (6): 1020-1024.
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- Tedeschi SK, Bathon JM, Giles JT, et al. Relationship between fish consumption and disease activity in rheumatoid arthritis. Arthritis Care Res (Hoboken) 2018; 70 (3): 327-332.
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