CVD Risks, Management in Patients With Rheumatoid Arthritis

Risk for atherosclerotic cardiovascular disease (CVD) is approximately doubled in patients with rheumatoid arthritis (RA).¹ The 2 disorders share inflammatory etiologies, and despite the known connection, studies have indicated a lack of sufficient primary and secondary CVD preventive care measures in patients with RA.^1,2

Cardiovascular Morbidity and Mortality

The development of CVD occurs at an earlier age in patients with confirmed RA compared with the general population, and is responsible for as much as 50% of mortality in this patient group.¹ The inflammatory pathophysiology of RA has demonstrated the formation of rheumatoid factor (RF) and anticitrullinated protein antibodies in the blood that promotes joint swelling and stiffness of the hands and feet, as well as other major joints.¹ The chronic inflammation from RA can also lead to formation of atherosclerotic lesions and has been implicated in the development of all forms of CVD. Likewise, CVD mortality is higher in the presence of RA. Results of 2 large-scale meta-analyses reported an increase of 50% to 60% in CVD mortality in patients with RA, and a third reported a 45% higher mortality in women with RA.^3-6

CVD Risk Reduction in RA

Myocardial Infarction (MI) – The rate of silent MI in patients with RA is twice that of the general population, and the plaque burden is greater in patients with RA, even when no clinical signs of coronary artery disease (CAD) are present.³ Some studies have found that that the CVD risk preceded the onset of RA symptoms, with a 3-fold increase in hospitalization for MI occurring up to 2 years before the first signs of RA.¹ The latter was not replicated however, in 2 large Scandinavian cohorts.^1,7

Hypertension – The reported prevalence of hypertension in patients with RA varies in the literature, ranging from 3.8 to 73%. The effect of hypertension is far more evident; a 2015 meta-analysis showed an 84% increase in MI in patients who had comorbid RA and hypertension.⁸ Outcomes studies suggest that hypertension is both under-recognized and suboptimally treated in the RA population. A study from the UK revealed that only 23% of patients were treated with antihypertensive drugs, and of those who were, less than 50% achieved the target systolic BP of  > 140 mmHg.⁹

Heart Failure (HF) – The risk of HF is 2.5 times higher in patients with RA, compared with the general population, as a direct result of RA disease activity, measured by elevated RF levels in the blood. Outcomes tend to be poor in RA-associated HF, and left ventricular dysfunction is common.¹

Metabolic Syndrome – Metabolic syndrome (defined as 3 of the 5 signs of obesity, glucose intolerance, elevated triglycerides, low HDL, and hypertension) increases CVD risks 2-fold in general, but a 37% higher prevalence has been reported in the RA population.^3,10

Complications to CVD Management Approaches in RA

Rheumatoid arthritis has lipid modifying effects that can complicate achieving targets for these patients, as traditional CVD risk calculation matrices grossly and consistently underestimate CVD risk.¹ This may be due to the presence of chronic inflammation, but is also attributed to other factors. Serum LDL-C and triglyceride levels are both lower in patients with RA than among age- and sex-matched control patients studied, skewing scores when applied to standard risk calculators; application of specific risk factors in RA and even recommended multiplication factors do not improve the accuracy of these predictions.¹ A recent review by Semp et al¹ discussed the use of carotid ultrasound as an adjunct to detecting risk for CVD. This modality can measure carotid intima-media thickness (CIMT) and detect the presence of existing carotid plaques, but results are highly operator-dependent, and there was no added value in the prediction of future events or CVD risk.

In addition, DMARD treatments for RA often substantially raise lipid levels. Tumor necrosis factor inhibitor (TNFi) may increase both TC and LDL-C levels by as much as 30%, while studies have indicated similar increases with the use of tocilizumab and tofacitinib, along with variations in HDL-C.²

Although RA inflammation is a primary mechanism leading to the development of CVD, the use of glucocorticoids (GCs) to reduce inflammation also paradoxically increases rates of individual risk factors for CVD, such as insulin resistance, diabetes, obesity, hypertension, and hyperlipidemia.³ NSAIDs commonly used to manage pain and inflammation in RA also increase risks for cardiovascular events in general.¹⁰ Given all of these challenges, CVD risk management strategies begin with traditional targets as recommended in EULAR guidelines,¹¹ while balancing against potential RA-mitigated effects.^1-3

No specific guidelines for assessment and management of CVD risk in RA patients exist, and so prevention follows general guidelines. Traditional cardiovascular risk factors such as smoking, hypertension, and hyperlipidemia are still important, and represent modifiable risk factors in both patients with RA and those without RA.¹⁰ Standard preventive therapies should include lifestyle modifications such as improvements in diet and exercise, and smoking cessation to achieve CVD targets, along with pharmacologic management of blood pressure, serum cholesterol levels, and glycemic control.

Optimum targets are the same for RA as the general population^1,11:

• LDL cholesterol : <3.0 mmol/l (<116 mg/dl)
• HDL cholesterol: No target; recommended levels of >1.0 mmol/l (>40 mg/dl) in men and >1.2 mmol/l (>45 mg/dl) in women
•  Triglyercides: No target; recommended  level <1.7 mmol/l (<150 mg/dl) indicates lower risk

Summary

Management of CVD risk in patients with RA is especially important, as the RA disease course tends to hide standard markers of CVD while also elevating serum levels that are predictive of cardiovascular events. Aggressive preventive management of CVD is recommended along with that of RA, and treatments need to be monitored for potential influences on CVD markers.

References

1. Semb AG, Ikdahl E, Wibetoe G, Crowson C, Rollefstad S. Atherosclerotic cardiovascular disease prevention in rheumatoid arthritis. Nat Rev Rheumatol. 2020 Jul;16(7):361-379. doi:10.1038/s41584-020-0428-y
2. Liao KP. Cardiovascular disease in patients with rheumatoid arthritis. Trends Cardiovasc Med. 2017 Feb;27(2):136-140. doi:10.1016/j.tcm.2016.07.006
3.   Jagpal, A., Navarro-Millán, I. Cardiovascular co-morbidity in patients with rheumatoid arthritis: a narrative review of risk factors, cardiovascular risk assessment and treatment. BMC Rheumatol. 2018 Apr 11;2:10. doi:10.1186/s41927-018-0014-y. eCollection 2018.
4. Avina-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):1690–7.
5.  Meune C, Touze E, Trinquart L, Allanore Y. Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 2009;48(10):1309–13. Abstract.
6.  Sparks JA, Chang SC, Liao KP, Lu B, et al. Rheumatoid arthritis and mortality among women during 36 years of prospective follow-up: results from the Nurses’ health study. Arthritis Care Res (Hoboken). 2016;68(6):753–62.
7. 7. Holmqvist, M., Ljung, L. & Askling, J. Acute coronary syndrome in new-onset rheumatoid arthritis: a population-based nationwide cohort study of time trends in risks and excess risks. Ann Rheum. Dis. 76, 1642–1647 (2017). Abstract.
8. Baghdadi LR, Woodman RJ, Shanahan EM, Mangoni AA. The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis. PLoS One. 2015;10(2):e0117952.
9. van Breukelen-van der Stoep DF, van Zeben D, et al. Marked underdiagnosis and undertreatment of hypertension and hypercholesterolaemia in rheumatoid arthritis. Rheumatology (Oxford). 2016;55(7):1210–6. Abstract.
10.  Rawla P. Cardiac and vascular complications in rheumatoid arthritis. Reumatologia. 2019;57(1):27-36. doi:10.5114/reum.2019.83236
11.   Agca R, Heslinga SC, Rollefstad S, Heslinga M, McInnes IB, Peters MJ, 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.