Assessing Cardiovascular Disease Risk in Rheumatoid Arthritis

Reducing the cardiovascular disease (CVD) risk with nonpharmacologic and pharmacologic interventions may improve both rheumatoid arthritis (RA) disease activity and cardiovascular (CV) outcomes, according to study results published in Physiotherapy Research International and results published in Rheumatology and Therapy.

The risk for CVD attributed to traditional factors such as hypertension, diabetes, obesity, and physical inactivity has been estimated in the general population using risk calculators such as the Reynolds Risk Score, the Framingham Risk Score, the systematic coronary risk evaluation, and the American College of Cardiology/American Heart Association Cardiovascular Risk Calculator. Compared with the general population, patients with RA have a 50% higher risk for CVD-related morbidity and mortality, primarily from silent ischemic heart disease, heart failure, and sudden death.^1,2 The increased risk suggests that RA is in and of itself a CVD risk factor. The current CVD risk scores, however, do not capture RA as a risk factor and RA-specific risk tools do not assess CVD-related mortality.³ Consequently, CVD risk in patients with RA is grossly underestimated and may account for the disproportionately high CVD-related deaths in this population.

“Since patients with RA suffer from an increased morbidity and mortality in CVD, a risk score that better predicts this risk is of interest,” said Lars Ångström, MD lead investigator and researcher in the department of public health and clinical medicine/rheumatology at Umeå University in Sweden. It has been demonstrated that RA and atherosclerosis are closely linked, influenced by the same genetic and environmental factors that contribute to activation of endothelial cells to increase permeability^4,5 and elevated levels of proinflammatory cytokines that collectively contribute to physiologic changes.^6,7 The evidence that RA is a risk factor for CVD independent of traditional risk factors comes from the increased carotid intima-media thickness associated with an elevated erythrocyte sedimentation rate and C-reactive protein.⁵

The close link between CVD and traditional risk factors, as well as the additional risks from inflammatory markers and cytokines associated with RA disease activity, suggests that reducing these risks with nonpharmacologic and pharmacologic interventions may improve both RA disease activity and CV outcomes. Indeed, aerobic exercise has been shown to have an inverse relationship with atherosclerotic processes, and significantly reduce the production of adipokines — bioactive molecules known to increase inflammatory cytokines including interleukin-1, interleukin-6, and tumor necrosis factor (TNF)-α.⁸ These changes have been associated with a reduction in classic CVD risk factors such as hypertension in patients with and without RA.⁸ Low aerobic capacity has been identified as an independent risk factor for CVD and all-cause mortality in the general population.^9,10

Although limited large-scale studies have focused on the effect of aerobic exercise on CVD risk factors in patients with RA, the study by Ångström, et al investigated aerobic capacity and its association with disease activity and CVD in a population of 67 patients with early RA.³ The study found that patients with higher aerobic capacity had more favorable disease activity and CVD risk factors.³ Furthermore, the inverse association between aerobic capacity and the systematic coronary risk evaluation suggest that aerobic capacity may be a useful indicator for CVD risk, at least in patients with early RA.

“From studies on the general population, we can note that the addition of aerobic capacity in risk scores may improve the CVD risk prediction,” said Dr Ångström, adding that “patients with RA are often less physically active and present lower aerobic capacity than healthy controls and aerobic capacity may be even more important for this population. Therefore, aerobic capacity may be a good surrogate indicator for CVD risk in patients with RA.”

The positive effect of exercise on CV outcomes among patients with and without RA and with risk factors for CVD have led to recommendations from the European League Against Rheumatism (EULAR) that frontline healthcare practitioners include physical activity as a routine component of RA patient treatment.¹¹

In addition to physical activity, the EULAR guidelines recommend pharmacologic therapy to achieve tight RA disease control. Although the guidelines provide general recommendations for pharmacologic therapy, the precise treatment choice in order to achieve sustained remission or low disease activity is less clear.¹² A review by Daniel DeMizio, MD, of the division of rheumatology, department of medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York,  and colleagues, however, suggests that the choice of treatment should be taken into consideration, given their finding of the differential effect of RA treatment classes on CVD.⁷ For example, their study found no beneficial effects of nonsteroidal anti-inflammatory drugs and glucocorticoids on CV risk; in fact, nonsteroidal anti-inflammatory drugs were found to significantly increase the risk for all CV events.⁷

Nonbiologic disease-modifying antirheumatic drugs were associated with a 20% reduction in CV events (stroke, myocardial infarction, and congestive heart failure), and abatacept was associated with an approximate 20% greater reduction in CV risk compared with TNF inhibitors. Similar rates of myocardial infarction were seen in patients with RA treated with rituximab compared with patients treated with methotrexate, and improved vascular and left ventricular function in patients with RA treated with anakinra, especially patients with prior documented coronary artery disease.⁷ Currently, the TARGET trial (NCT02374021) is comparing 2 common RA treatments: triple therapy (sulfasalazine, methotrexate, and hydroxychloroquine) vs TNF inhibitor (etanercept or adalimumab) for reducing vascular and joint inflammation in patients with RA.¹³ The results from this trial will better clarify the effect of RA treatments on CVD risk reduction.

The disproportionately high number of CVD-related deaths in patients with RA supports the EULAR recommendations that rheumatologists be actively involved in the assessment and coordination of CVD risk management in this patient population. Given that none of the available CVD risk scores include RA as a risk factor or aerobic capacity as a component of the determination of CVD risk, there is lack of clarity on how rheumatologists should assess and manage risks.

“Based on our paper,³ we cannot conclude a causal effect from aerobic capacity on disease activity, only associations,” said Dr Ångström, “[h]owever, based on current research, exercise (aerobic/strength) seem[s] to be beneficial, not only on inflammation, joint damage and symptoms, but also general health, in patients with inflammatory rheumatic diseases in general, and more specific in patients with RA.”

These findings suggest that incorporating aerobic capacity in routine patient assessment may be a strategy to screen CVD risk in patients with early RA. It is also necessary that rheumatologists are fully cognizant of the relative CVD benefits of the different RA treatment options so they can make appropriate treatment selections according to the patient’s traditional and RA-associated CVD risk in order to achieve best outcomes.

References

1. 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.

2. Gabriel SE. Cardiovascular morbidity and mortality in rheumatoid arthritis. Am J Med. 2008;121(10 Suppl 1):S9-S14.

3. Ångström L, Hörnberg K, Sundström B, Jonsson SW, Södergren A. Aerobic capacity is associated with disease activity and cardiovascular risk factors in early rheumatoid arthritis. Physiother Res Int. 2020:e1833.

4. Chodara AM, Wattiaux A, Bartels CM. Managing cardiovascular disease risk in rheumatoid arthritis: clinical updates and three strategic approaches. Curr Rheumatol Rep. 2017;19(4):16.

5. Khanna NN, Jamthikar AD, Gupta D, et al. Rheumatoid arthritis: atherosclerosis imaging and cardiovascular risk assessment using machine and deep learning-based tissue characterization. Curr Atheroscler Rep. 2019;21(2):7.

6. Fang Q, Ou J, Nandakumar KS. Autoantibodies as diagnostic markers and mediator of joint inflammation in arthritis. Mediators Inflamm. 2019;2019:6363086.

7. DeMizio DJ, Geraldino-Pardilla LB. Autoimmunity and inflammation link to cardiovascular disease risk in rheumatoid arthritis [published online December 18, 2019]. Rheumatol Ther.

8. Metsios GS, Moe RH, van der Esch M, et al. The effects of exercise on cardiovascular disease risk factors and cardiovascular physiology in rheumatoid arthritis. Rheumatol Int. 2020;40(3):347-357

9. Berry JD, Willis B, Gupta S, et a. Lifetime risks for cardiovascular disease mortality by cardiorespiratory fitness levels measured at ages 45, 55, and 65 years in men. The Cooper Center Longitudinal Study. J Am Coll Cardiol. 2011;57(15):1604-1610.

10. Kodama S, Saito K, Tanaka S, et al. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA. 2009;301(19):2024-2035.

11. Rausch Osthoff AK, Niedermann K, Braun J, et al. 2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis. Ann Rheum Dis. 2018;77(9):1251-1260.

12. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis.

13. ClinicalTrials.gov. Treatments against RA and effects on FDG-PET/CT [NCT 02374021]. https://clinicaltrials.gov/ct2/show/NCT02374021. Accessed February 6, 2020.