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There have been significant advances in the management of rheumatologic disorders with the availability of newer disease-modifying drugs and biologic agents. However, cardiovascular disease (CVD) morbidity and mortality remain significantly increased in patients with rheumatologic disorders, especially rheumatoid arthritis (RA)1-4 and systemic lupus erythematosus (SLE).
There have been significant advances in the management of rheumatologic disorders with the availability of newer disease-modifying drugs and biologic agents. However, cardiovascular disease (CVD) morbidity and mortality remain significantly increased in patients with rheumatologic disorders, especially rheumatoid arthritis (RA)1-4 and systemic lupus erythematosus (SLE).5
Several factors may explain the increased CV risk in RA, including systemic inflammation, accelerated atherosclerosis, administration of medications (eg, long-term daily corticosteroids and NSAIDs), and a higher frequency of comorbidities (eg, dyslipidemia and hypothyroidism). However, the precise mechanism remains unclear.4
Primary care physicians taking care of patients with RA in conjunction with a rheumatologist should target CV risk factors aggressively and attempt to control inflammation resulting from chronic disease in an effort to decrease the CV morbidity and mortality in this patient population. Aggressive control of inflammation in RA is suggested in the same manner that tight control of diabetes mellitus (DM) is recommended to reduce the risk of CVD in patients with that condition.6 In this article, we focus on the epidemiology, proposed pathogenesis, evaluation, and management of CV risk in patients with RA.
The increased risk of premature death observed in patients with RA is attributed largely to an increased incidence of CVD, particularly coronary artery disease (CAD). The reported incidence of CAD varies among studies, but all have shown an increased risk.
In a population-based cohort study, patients with RA had a significantly higher risk of CVD than non-RA patients.7 More than half of the patients with a new diagnosis of RA aged 50 to 59 years and all of those older than 60 years had a more than 10% increased risk of CVD within 10 years of the onset of RA.
Of note, patients who have RA are less likely to report symptoms of angina than those who do not and more likely to experience unrecognized myocardial infarction (MI) and sudden cardiac death.8 The risk of CAD in patients with RA precedes the American College of Rheumatology criteria-based diagnosis of RA, and this risk cannot be explained by an increased incidence of traditional CAD risk factors in patients with RA.8
In the Nurses' Health Study, the incidence of the composite end point of fatal and nonfatal MI and stroke was evaluated in 527 women with a diagnosis of RA who were part of a prospective cohort study that included more than 100,000 women.9 The incidence of an adverse event was significantly higher in the women with RA (272 cases vs 96 cases per 100,000 person-years; relative risk, 3.1) whose duration of disease was longer than 10 years.
In a study that compared the incidence of CV-related hospitalizations, procedures, or deaths among patients with RA versus persons without RA from the same community, the incidence of CV events was significantly higher among those who did have RA (3.43 vs 0.59 per 100 person-years).4 Meta-analysis of observational studies showed that CVD mortality is increased by about 50% in patients who have RA compared with the general population.10
CVD is the main cause of the excess morbidity and mortality risk in patients with RA. However, traditional CV risk factors do not fully explain this risk.
Chronic inflammation is postulated to enhance the development of atherosclerosis in patients with RA. Recent studies that used carotid ultrasonography demonstrated an increased prevalence of atherosclerotic plaque in patients with RA and SLE compared with controls.11 Patients with a longer duration of RA have a greater prevalence of atherosclerosis than do patients with more recent disease onset.
Role of inflammatory cytokines
Proinflammatory cytokines, the levels of which are elevated in RA, have been found to play an important role in the development and progression of atherosclerosis. Now considered an inflammatory disease, atherosclerosis involves the production of proinflammatory cytokines by immune cells, such as monocytes, macrophages, and T cells, at sites of atherosclerotic lesions, as well as by endothelial and smooth muscle cells. The chronic systemic inflammation seen in RA and SLE may further amplify atherosclerosis through endothelial dysfunction and oxidative stress. Proinflammatory cytokines (eg, tumor necrosis factor α [TNF-α] and interleukin-1), expressed by affected joints in RA, may act on other tissues and organs and promote atherosclerosis.
Patients with RA have elevated levels of C-reactive protein (CRP), a marker of inflammation also associated with increased CV risk. The erythrocyte sedimentation rate (ESR) also increases linearly with increased carotid artery intima-medial thickness in both patients with RA and healthy persons. The rate of CV death is higher in patients with RA who have an elevated ESR than in those who do not.
Direct vascular injury
Vasculitic complications of SLE and RA could provoke an arterial healing response that accelerates atherosclerosis. Endothelial progenitor cells (EPCs) are now thought to be the most important cells in normal revascularization after endothelial damage; decreased levels of circulating EPCs and impaired function of EPCs may contribute to atherosclerosis.
RA is associated with increased plasma levels of fibrinogen, von Willebrand factor, and plasminogen activator inhibitor 1, producing a prothrombotic state. Recent data suggest that RA is a risk factor for venous thromboembolism (VTE) in hospitalized medical patients.12 A heightened awareness of the risks of VTE and a lower threshold for evaluation of patients for possible deep venous thrombosis or pulmonary embolism would be appropriate in the care of hospitalized patients with RA.12
Other factors may contribute to accelerated atherosclerosis and a higher incidence of ischemic heart disease. The additional factors include increased insulin resistance and impaired beta cell function resulting from inflammation.
EVALUATION OF CV RISK IN RA
Traditional and nontraditional factors may confer an increased risk of CVD in RA (Table). Risk factor assessment based on traditional risk factors alone is insufficient to capture the extent of CV risk in RA.13
Elevated markers of systemic inflammation confer a statistically significant additional risk of CV death among patients with RA, even after controlling for traditional CV risk factors and comorbidities.14 The magnitude and chronicity of the inflammatory response, as measured by the CRP level, correlates with carotid atherosclerosis development in RA.
Serum lipoprotein(a) level was found to be significantly increased and high-density lipoprotein significantly decreased in women who have RA compared with healthy women.15 In addition, high-density lipoprotein function appears to be abnormal in patients with RA, and it cannot protect low-density lipoprotein from oxidation.16
The prevalence and severity of coronary calcification are increased in established RA and are related, in part, to smoking and to elevated inflammatory markers.17 Levels of soluble vascular cell adhesion molecule–1 (VCAM-1), intercellular adhesion molecule, and endothelial-leukocyte adhesion molecule–1 are higher in RA; VCAM-1 levels are associated with carotid atherosclerosis.
In addition, patients with RA have impaired endothelial function and less favorable traditional CV risk factor profiles. A high-sensitivity CRP level and lower glomerular filtration rate were independently predictive of endothelial dysfunction in RA.18
Another study reported that endothelial dysfunction in patients who have RA with low-grade inflammation is associated with a reduced number and partial dysfunction of EPCs.19 In addition, reduced EPC numbers and abnormal EPC function clearly correlate with an increased incidence of atherosclerosis and impaired vasculogenesis after ischemia; they also predict future CV events.19
CV manifestations and diagnosis
In addition to an increased prevalence of atherosclerotic CAD, cardiac manifestations in RA include pericarditis, myocarditis, atrioventricular block, valvular regurgitation, embolic events, and rheumatoid nodules. The clinical manifestations of symptomatic CAD are similar to those in patients who do not have RA. However, patients with RA are more likely to have clinically silent CAD and are less likely to report chest pain during an acute coronary event.
A history of anginal equivalent symptoms, such as dyspnea on exertion, should be sought from these patients. In addition, patients who have chest wall pain on clinical examination may have coexistent underlying cardiac ischemia; therefore, the threshold for excluding CAD should be low.
Other causes of nonischemic chest pain also may be seen in patients with RA. They include the following:
•Sternoclavicular joint arthritis. Localized tenderness of the sternoclavicular joint may be evident. The diagnosis usually is not difficult once it is considered and tenderness is elicited on examination.
•Pericarditis. Up to 30% of patients with RA have pericarditis on autopsy; echocardiographic studies suggest that the rate may be as high as 50%.20,21 Only 2% to 4% of patients have symptoms, and fewer than 0.5% experience hemodynamic compromise. The major clinical manifestations of acute pericarditis are chest pain, pericardial friction rub, and the classic ECG changes. With the availability of modern treatment paradigms, however, extra-articular manifestations of RA, such as pleuritis and pericarditis, are much less common than they used to be.
•Pulmonary hypertension. This is a rare complication of interstitial lung disease in patients with RA. Manifestations may include exertional chest pain indistinguishable from angina pectoris. However, pulmonary artery dilatation on plain chest radiography or echocardiographic findings may help establish the diagnosis.
•Herpes zoster. Patients with RA who are receiving immunosuppressive drugs are at increased risk for herpes zoster. Diagnosis may be difficult before the appearance of the typical painful, unilateral vesicular rash in a dermatomal distribution.
•Aortitis. This is another rare complication of RA that may be accompanied by rheumatoid vasculitis in other vessels. Associated coronary vasculitis can cause MI. Aortic dissection or rupture also may occur. Imaging studies can confirm the diagnosis.
CV risk assessment and management are important in patients with RA, which along with ankylosing spondylitis and psoriatic arthritis is now being seen as an independent CV risk factor, having a risk comparable with that of type 2 DM. The key concept is that patients with RA have a higher risk of CVD because of both an increased prevalence of traditional risk factors and the inflammation inherent with the disease. Management recommendations include the following:
•Assess CV risk annually in all patients with RA.
•Maintain adequate control of inflammatory disease activity. Disease-modifying antirheumatic drugs and biologic agents are known to decrease the risk of CVD. Be sure to monitor the patient's CRP level and ESR to gauge the level of inflammation.
•Encourage patients to participate in a supervised exercise program within the limitations of their disease.
•Use lipid-lowering and antihypertensive medications appropriately per current guidelines. The use of statins may mediate modest anti-inflammatory effects with modification of vascular risk factors in the context of high-grade autoimmune inflammation.22
•Minimize corticosteroid dosages. Evidence is evolving in this area; some studies show increased CV risk, and other studies show the contrary.23
•Use selective cyclooxygenase-2–inhibiting NSAIDs with caution.
•Consider the CV risk profile of all agents used in the management of RA. For example, TNF-α antagonists are contraindicated in patients with RA who have congestive heart failure. Leflunomide may cause hypertension in a small percentage of patients. Also consider the effect of corticosteroids on blood pressure and lipids.23
•The use of low-dose aspirin is a reasonable consideration. When aspirin is combined with NSAIDs, however, there may be an increased incidence of GI adverse effects and decreased antiplatelet effects.
The authors suggest the following sources for readers seeking more information:
•Libby P. Rheumatic diseases and the cardiovascular system. In: Libby P, Bonow RO, Mann DL, Zipes DP, eds. Braunwald's Heart Disease:A Textbook of Cardiovascular Medicine. 8th ed. St Louis: WB Saunders; 2007:2094-2096. Cardiac involvement in rheumatoid arthritis is covered in this text.
•Sattar N, McInnes IB. Atherosclerosis in rheumatoid arthritis. In: Firestein GS, Budd RC, Harris ED Jr, et al, eds. Kelley's Textbook of Rheumatology. 8th ed. St Louis: WB Saunders; 2008:421-429. This text discusses the epidemiology and assessment of cardiovascular disease risk in patients with rheumatoid arthritis and the effects of various therapies.
References1. Turesson C, Jarenros A, Jacobsson L. Increased incidence of cardiovascular disease in patients with rheumatoid arthritis: results from a community based study. Ann Rheum Dis. 2004;63:952-955.
2. Van Doornum S, Brand C, King B, Sundararajan V. Increased case fatality rates following a first acute cardiovascular event in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:2061-2068.
3. Solomon DH, Goodson NJ, Katz JN, et al. Patterns of cardiovascular risk in rheumatoid arthritis. Ann Rheum Dis. 2006;65:1608-1612.
4. del RincÃ³n ID, Williams K, Stern MP, et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44:2737-2745.
5. Ippolito A, Petri M. An update on mortality in systemic lupus erythematosus. Clin Exp Rheumatol. 2008;26(5 suppl 51):S72-S79.
6. Pincus T, Gibofsky A, Weinblatt ME. Urgent care and tight control of rheumatoid arthritis as in diabetes and hypertension: better treatments but a shortage of rheumatologists. Arthritis Rheum. 2002;46:851-854.
7. Kremers HM, Crowson CS, Therneau TM, et al. High ten-year risk of cardiovascular disease in newly diagnosed rheumatoid arthritis patients: a population-based cohort study. Arthritis Rheum. 2008;58:2268-2274.
8. Maradit-Kremers H, Crowson CS, Nicola PJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 2005;52:402-411.
9. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107:1303-1307.
10. AviÃ±a-Zubieta JA, Choi HK, Sadatsafavi M, et al. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 2008;59:1690-1697.
11. Kumeda Y, Inaba M, Goto H, et al. Increased thickness of the arterial intima-media detected by ultrasonography in patients with rheumatoid arthritis. Arthritis Rheum. 2002;46:1489-1497.
12. Matta F, Singala R, Yaekoub AY, et al. Risk of venous thromboembolism with rheumatoid arthritis. Thromb Haemost. 2009;101:134-138.
13. Gonzalez A, Maradit-Kremers H, Crowson CS, et al. Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients? Ann Rheum Dis. 2008;67:64-69.
14. Gonzalez-Gay MA, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, et al. Endothelial dysfunction, carotid intima-media thickness, and accelerated atherosclerosis in rheumatoid arthritis. Semin Arthritis Rheum. 2008;38:67-70.
15. Dursunoglu D, EvrengÃ¼l H, Polat B, et al. Lp(a) lipoprotein and lipids in patients with rheumatoid arthritis: serum levels and relationship to inflammation. Rheumatol Int. 2005;25:241-245.
16. McMahon M, Grossman J, FitzGerald J, et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 2006;54:2541-2549.
17. Chung CP, Oeser A, Raggi P, et al. Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors. Arthritis Rheum. 2005;52:3045-3053.
18. Dessein PH, Joffe BI, Singh S. Biomarkers of endothelial dysfunction, cardiovascular risk factors and atherosclerosis in rheumatoid arthritis. Arthritis Res Ther. 2005;7:R634-R643.
19. Herbrig K, Haensel S, Oelschlaegel U, et al. Endothelial dysfunction in patients with rheumatoid arthritis is associated with a reduced number and impaired function of endothelial progenitor cells. Ann Rheum Dis. 2006;65:157-163.
20. Thadani U, Iveson JM, Wright V. Cardiac tamponade, constrictive pericarditis and pericardial resection in rheumatoid arthritis. Medicine (Baltimore). 1975;54:261-270.
21. MacDonald WJ Jr, Crawford MH, Klippel JH, et al. Echocardiographic assessment of cardiac structure and function in patients with rheumatoid arthritis. Am J Med. 1977;63:890-896.
22. McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004;363:2015-2021.
23. Nurmohamed MT, van Halm VP, Dijkmans BA. Cardiovascular risk profile of antirheumatic agents in patients with osteoarthritis and rheumatoid arthritis. Drugs. 2002;62:1599-1609.