INTRODUCTION — The prevalence of atherosclerotic coronary artery disease (CAD) is increased in patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus.
The epidemiologic evidence, possible pathogenetic mechanisms, and clinical relevance of CAD in RA will be reviewed here. The impact of CAD on the management of RA; other cardiac manifestations of RA, including pericarditis, myocarditis, atrioventricular block, valvular regurgitation, embolic events, and rheumatoid nodules; and the general clinical manifestations of RA are presented separately. (See "Coronary artery disease in rheumatoid arthritis: Implications for prevention and management" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis", section on 'Cardiac disease' and "Clinical manifestations of rheumatoid arthritis" and "Rheumatoid nodules", section on 'Cardiac nodules'.)
EPIDEMIOLOGY — An increased risk of premature death is observed in patients with rheumatoid arthritis (RA). This is largely due to cardiovascular disease, particularly coronary artery disease (CAD). (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Impact of comorbidities'.)
The reported incidence and prevalence of CAD in patients with RA varies based upon the specific manifestations of the disease, the population evaluated, and/or the screening and diagnostic methods utilized [1-7]. A meta-analysis of 24 observational studies comprising 111,758 patients concluded that the risk of CAD mortality was 59 percent higher in patients with RA than in the general population [8]. Risk may be increased once symptoms develop and before patients meet formal classification criteria for the diagnosis of RA [9-11].
PATHOGENESIS — Many of the underlying mechanisms of pathogenesis of atherosclerosis are shared in patients with and without rheumatoid arthritis (RA). Among the general population, it is increasingly clear that inflammation has a significant role in the development of coronary artery disease (CAD) and that the innate and adaptive immune systems play an important role in the initiation and progression of atherosclerosis.
Inflammation — The results of a number of studies are consistent with the notion that inflammation plays an important role in myocardial infarction (MI) among patients with RA. It is postulated that, in patients with RA, chronic inflammation may accelerate the progression of atherosclerosis, perhaps via the effects of cytokines; abnormal effector functions of T lymphocytes, macrophages, and dendritic cells; immune complexes; coagulation abnormalities; oxidative stress; or a combination of these factors. Some of these mechanisms may be [12-18]:
●Changes in the endothelium associated with circulating immune complexes and cytokines.
●Direct vascular injury, with depletion of circulating endothelial cell progenitors [15,19,20].
●A hypercoagulable state due to increased plasma levels of fibrinogen, von Willebrand factor, plasminogen activator inhibitor-1, and/or other acute phase reactants (eg, C-reactive protein [CRP]) that correlate with the erythrocyte sedimentation rate (ESR).
●Inflammation in the synovium, which is also occurring in the vascular wall [21], with the strongest association among anti-citrullinated protein antibody (ACPA)-positive RA patients [22]. Abnormal adaptive immune responses, which involve T cells and dendritic cells, have been described for the inflamed atherosclerotic plaque; these abnormalities are similar to those encountered in the inflamed synovial membrane [23,24].
Inflammation may worsen insulin resistance and impair pancreatic beta cell function [25,26]. These metabolic changes may contribute to accelerated atherosclerosis and to the higher incidence of ischemic heart disease characteristic of patients with diabetes mellitus (see "Overview of established risk factors for cardiovascular disease", section on 'Diabetes mellitus'). Additionally, coronary microvascular dysfunction, a manifestation of endothelial dysfunction, was associated with similar risk of mortality in RA as in patients with diabetes [27].
The constellation of abdominal obesity, hyperglycemia, dyslipidemia, and hypertension (referred to variously as the metabolic syndrome, syndrome X, and "the deadly quartet") is associated with a higher risk of CAD and of cardiovascular morbidity and mortality (see "Metabolic syndrome (insulin resistance syndrome or syndrome X)"). The prevalence of the metabolic syndrome may be increased in patients with RA. This was illustrated in a study of 88 patients with early RA, 66 with longstanding RA, and 85 controls [28,29]. The metabolic syndrome was present in 31 percent of patients with early RA, in 42 percent of those with longstanding RA, and in 11 percent of controls. In addition, those with the metabolic syndrome were more likely to have higher coronary calcification scores as detected by computed tomography (CT).
In a study from the British Society for Rheumatology Biologics Register (BSRBR), the rates of MI were examined in 8670 RA patients treated with tumor necrosis factor (TNF)-alpha inhibitors and were compared with the rate of MI among 2170 patients with active RA treated with disease-modifying antirheumatic drugs (DMARDs) [30]. The following findings were observed:
●Following adjustment for baseline cardiovascular risk factors, there was no reduction in the rate of MI in the TNF inhibitor cohort: incidence rate ratio 1.44 (95% CI 0.56-3.67).
●In the subset of TNF inhibitor-treated patients who responded to therapy within six months compared with those who did not, MI rates were lower in responders compared with non-responders (3.5 versus 9.4 MIs per 1000 patient-years).
●The adjusted incidence rate ratio for MI in responders versus non-responders was 0.36 (95% CI 0.19-0.69).
Subsequently, longer-term follow-up data have become available from the BSRBR for Rheumatoid Arthritis, in which it was observed that the reduced risk of MI among patients on TNF inhibitors compared with those using nonbiologic DMARDs remains after adjusting for potential confounders (hazard ratio [HR] 0.61, 95% CI 0.41-0.89) [31].
That inflammation plays an important role in MI among patients with RA is also supported by an autopsy study that compared coronary artery pathology of 41 deaths among patients with RA with 82 controls. Less atherosclerosis was present in those with RA, but more inflammation and unstable plaque were noted in those with RA versus the controls [32]. These findings are also consistent with the observation that elevated levels of TNF-alpha and interleukin (IL)-6 in patients with RA were associated with the severity of subclinical atherosclerosis as measured by coronary artery calcification, and were independent of the Framingham risk score and diabetes mellitus [17].
Ongoing, persistent disease activity may be necessary to induce acceleration of atherosclerosis. In a study in Northern Sweden involving 79 patients with very early RA and 44 controls, prematurity of atherosclerosis was evaluated by measuring endothelial-dependent flow-mediated dilation and intima media thickness [33]. There were no signs of atherosclerosis in patients with newly diagnosed RA when compared with controls, although serum markers suggestive of endothelial activation were significantly elevated in the patients.
Autoantibodies to oxidized low-density lipoprotein (anti-oxLDL) have also been proposed as a factor in the cardiovascular risk seen in RA, but their overall clinical impact remains uncertain [34].
Vasculitis — Coronary arteritis is a rare complication of rheumatoid vasculitis and is unlikely to be the cause of MI in the absence of other organ involvement. (See "Etiology and pathogenesis of rheumatoid vasculitis" and "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
RISK FACTORS — Traditional risk factors for coronary artery disease (CAD) in the general population include hypertension, cigarette smoking, diabetes, older age, and dyslipidemia. One study suggests that, with the exception of former cigarette smoking, these risk factors are not more prevalent in women with rheumatoid arthritis (RA) than in women without RA. This was best shown in an analysis of the Nurses' Health Study in which the clinical risk factors for cardiovascular disease were compared in women with and without RA [35]. No significant differences between the two groups were observed for diabetes, hypertension, concurrent smoking, or dyslipidemia.
In studies that included both males and females, differences have been reported in the prevalence of hypertension, diabetes, and dyslipidemia between RA and the general population, although the evidence is conflicting [36]. Other studies noted an increased prevalence of traditional risk factors in patients with RA, particularly in those with longstanding disease [29,37]. These data suggest that traditional risk factors do play a role, but may only explain a small portion of the increased risk of cardiovascular morbidity and mortality in RA.
Exercise of even moderate degree has a protective effect against coronary heart disease and all-cause mortality. For a variety of reasons, many patients with RA exercise less than recommended amounts, thereby possibly enhancing the risk of heart disease. As an example, a study of 298 Swedish patients with RA identified 47 percent whose physical activity did not comply with public health recommendations [38].
Markers of increased systemic inflammation are also associated with an increased risk of CAD. The best studied of these markers in the general population and in those with RA is the acute phase reactant C-reactive protein (CRP). In the Nurses' Health Study, for example, CRP levels were significantly higher in women with RA and heart disease versus those with heart disease but without RA (average CRP levels of 0.87 versus 0.34 mg/dL, respectively) [35].
There are many other factors that may be associated with an increased risk of atherosclerosis in the general population. A few of these have also been evaluated in patients with RA. As examples:
●Patients with RA appear to have a significantly greater burden of atherosclerotic carotid plaques, suggesting the presence of generalized atherosclerosis [5,39]. The prevalence of carotid plaques as detected ultrasonographically correlates with the duration of RA [3,39].
●Conflicting data exist concerning an increase in arterial intima-media thickness in patients with RA [5,39,40]. (See "Overview of possible risk factors for cardiovascular disease", section on 'Arterial intima-media thickness'.)
●Coronary artery calcification noted on ultrafast computed tomography (CT) scanning, a finding that is correlated with an increased risk of clinical and angiographic coronary atherosclerosis, is more prevalent in patients with established RA than in patients with early RA or healthy controls [29,41,42]. (See "Coronary artery calcium scoring (CAC): Overview and clinical utilization".)
●Glucocorticoid use is associated with increased cardiovascular risk in patients with RA, with use of higher doses being associated with greater risk [43,44]. This effect appears to be more pronounced among rheumatoid factor-positive RA patients. In a study of 603 adults with RA, those with rheumatoid factors receiving glucocorticoids appeared to be at greater risk for cardiovascular events than those patients who were seronegative [45]. The mechanism of this effect is unknown. Others have proposed that the administration of glucocorticoids increases the risk of CAD via its effects on lipoprotein levels. (See "Major side effects of systemic glucocorticoids".)
●Chronic use of selective cyclooxygenase (COX)-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of myocardial infarction (MI), stroke, and sudden cardiac deaths. The adverse cardiovascular effects of COX-2 selective inhibitors and NSAIDs are discussed in more detail elsewhere. (See "NSAIDs: Adverse cardiovascular effects".)
●The function of high-density lipoprotein (HDL) as an antiatherogenic particle is impaired or altered. A form of HDL cholesterol that is not protective against cardiovascular disease may be found in some patients with RA [46,47]. HDL with proinflammatory activity in vitro is found in patients with coronary heart disease and elevated HDL levels and is increased in patients with RA compared with healthy controls [46]. In a cross-sectional observational study, this form of HDL was significantly associated with active disease and joint injury in patients with RA and was inversely associated with use of methotrexate [47]. Furthermore, the ability of HDL to extract cholesterol from lipid-laden atherosclerotic plaques is impaired in patients with active RA and improves when inflammation is reduced [48,49]. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'High-density lipoprotein'.)
●There is mounting evidence that RA patients with the lowest low-density lipoproteins (LDL) cholesterol levels have higher cardiovascular risk than those with moderate LDL cholesterol levels (generally <160 mg/dL) [50-52]. In line with these findings, a pooled cohort study of RA patients observed that coronary artery calcium (CAC) scores were highest among patients with LDL cholesterol <70 mg/dL [53].
●Some of the newer antiinflammatory and disease-modifying agents used in patients with RA (eg, the anti-interleukin [IL] 6 receptor antibody tocilizumab, Janus kinase [JAK] inhibitors) can change the lipoprotein profile (increase in total cholesterol, triglycerides, LDL, HDL, etc), thus possibly impacting cardiovascular risk adversely. However, the net effect on cardiovascular-related morbidity remains unclear, given the antiinflammatory efficacy of these agents. Findings suggest that the cardiovascular risk may be more strongly related to the treatment rather than changes in lipid levels. A randomized trial compared tocilizumab with etanercept, observing higher lipid levels in the tocilizumab arm; the higher lipid levels were not associated with higher risk of cardiovascular events [54].However, a preliminary description of a postmarketing surveillance study comparing tofacitinib with tumor necrosis factor (TNF) inhibitors described a likely increased risk of myocardial infarction (MI) in the tofacitinib arm [55]; the full report with details on lipid levels and cardiovascular events is pending.
There is also evidence for an interaction between traditional cardiovascular risk factors and the level of inflammation in RA. In a longitudinal study of 487 patients with RA, a subset of patients experienced rapid progression of carotid intima-media thickness (cIMT), a marker for elevated cardiovascular risk, over a three-year period [56]. As expected, the predictors for rapid cIMT progression included both traditional cardiovascular risk factors and the baseline level of the erythrocyte sedimentation rate (ESR). In addition, there was a significant interaction between the number of cardiovascular risk factors and the ESR, as the risk of rapid progression was higher than would be expected by simply adding the risk from the traditional cardiovascular risk factors to that from the higher levels of inflammation alone. In a separate study, it was estimated that 30 percent of cardiovascular disease events in RA were driven by RA-specific clinical factors, such as disease activity and seropositivity [57].
CLINICAL MANIFESTATIONS — The clinical manifestations of symptomatic coronary artery disease (CAD) in patients with rheumatoid arthritis (RA) are typically similar to those without RA. However, a larger proportion of patients with RA have clinically silent CAD than do demographically similar individuals in the general population [9]. Patients with RA are also less likely than those without RA to report chest pain during an acute coronary event [58]. (See "Angina pectoris: Chest pain caused by fixed epicardial coronary artery obstruction".)
Patients with RA may experience more severe acute coronary syndromes compared with patients without RA. In a Swedish cohort study involving 1135 patients with RA and acute coronary syndrome identified in a nationwide database, the patients with RA presented more often with sudden cardiac death, ST-segment elevation myocardial infarction (MI), higher levels of troponin, and higher frequencies of inpatient complications, compared with patients in the general population [59].
It is uncertain why patients with RA and CAD are less likely to report chest pain prior to or during a cardiovascular event. Possible explanations are that patients with active arthritis or those with structural joint damage may be less physically active, less likely to place sufficient demand on the heart to elicit angina, and more likely to attribute pain to RA, or it may be that use of nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, or disease-modifying antirheumatic drugs (DMARDs) alters pain perception.
DIAGNOSIS AND SCREENING
Diagnosis of CAD in RA — The approach to the diagnosis of coronary artery disease (CAD) is generally similar in patients with and without rheumatoid arthritis (RA). (See "Outpatient evaluation of the adult with chest pain" and "Stress testing for the diagnosis of obstructive coronary heart disease" and "Diagnosis of acute myocardial infarction".)
Screening for CAD in RA — Given the enhanced incidence of CAD in this patient population, we suggest the performance of a yearly cardiovascular evaluation, focused history and physical examination, as well as electrocardiography in patients ≥50 years of age. There should also be a low threshold for proceeding to exercise or pharmacologic stress testing in those with symptoms or electrocardiographic findings suggestive of CAD. (See "Screening for coronary heart disease".)
Estimation of cardiovascular risk in patients with RA is described in detail separately. (See "Coronary artery disease in rheumatoid arthritis: Implications for prevention and management", section on 'Risk estimation'.)
Differential diagnosis — The differential diagnosis of chest pain in the general population is broad. This is presented in detail elsewhere.
There are some causes of chest pain other than ischemic heart disease that are relatively unique to patients with rheumatoid arthritis (RA). These include the following:
●Sternoclavicular joint arthritis – Painful sternoclavicular joint involvement with localized tenderness may be present in up to 7 percent of patients with established, generalized RA. Rarely, involvement of the sternoclavicular joint is the initial manifestation of RA. Establishing the diagnosis is usually not difficult, once considered, since point tenderness favors local inflammation. (See "Major causes of musculoskeletal chest pain in adults", section on 'Rheumatoid arthritis'.)
●Pericarditis – Acute painful pericarditis occurs in less than 10 percent of patients with RA during their lifetimes. Since small pericardial effusions are relatively common in patients without symptoms of pericarditis, caution is required in attributing chest pain to pericarditis based solely upon echocardiographic findings of an effusion. The major clinical manifestations of acute pericarditis are chest pain, pericardial friction rub, and the classic finding of widespread saddle-shaped or concave-up ST segment elevation on the electrocardiogram (ECG). Increasingly, cardiac magnetic resonance imaging (MRI) is used to identify acute pericardial inflammation [60]. (See "Acute pericarditis: Clinical presentation and diagnosis".)
●Herpes zoster – The likelihood of herpes zoster infection is increased in patients with RA receiving immunosuppressive medications, such as biologics, azathioprine, cyclosporine, or high doses of glucocorticoids. It is characterized by a painful, unilateral vesicular eruption in a restricted dermatomal distribution. The diagnosis may be difficult prior to the appearance of the rash. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)
●Pulmonary hypertension – Exertional chest pain indistinguishable from that of angina pectoris may be a manifestation of pulmonary hypertension, a rare complication of interstitial lung disease in patients with RA. Clinical evidence suggesting right ventricular dysfunction, such as pulmonary artery dilation on plain chest radiography and characteristic echocardiographic findings, may help distinguish chest pain symptoms related to pulmonary hypertension from angina pectoris. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)
●Aortitis – Aortitis is a rare complication of RA, which, when present, is typically accompanied by rheumatoid vasculitis in other vessels [61]. Disease at the coronary ostia or associated coronary vasculitis can cause myocardial infarction (MI). Dilatation of the ascending aorta is a common initial finding. Thoracic aortic dissection or rupture could cause chest pain. A "ripping" or "tearing" quality to the pain, associated back pain, pulse deficits, a difference in limb blood pressure of more than 10 mmHg, and hemodynamic compromise are suggestive of aortic dissection. An imaging study such as transthoracic or transesophageal echocardiography, MR angiography, or contrast computed tomography (CT) is necessary to confirm the diagnosis. (See "Clinical manifestations and diagnosis of thoracic aortic aneurysm".)
●Chest wall pain – Musculoskeletal pain in the chest wall is the most common cause of precordial chest pain in patients with RA and should be considered in the differential diagnosis of the RA patient with chest pain.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)
SUMMARY
●There is an increased incidence of cardiovascular events, including myocardial infarctions (MI) and cardiac deaths, in patients with rheumatoid arthritis (RA) compared with the populations in which they live. (See 'Epidemiology' above.)
●It is postulated that the presence of chronic inflammation in RA may enhance the development of atherosclerosis. This may be the result of effects mediated by cytokines, immune complexes, endothelial dysfunction, or, rarely, coronary vasculitis. Abnormal functions of T cells, dendritic cells, and macrophages have been implicated in promoting inflammation and progression of atherosclerotic plaque formation, and similarities may exist between synovial and vascular inflammation. (See 'Pathogenesis' above.)
●The increased risk of coronary artery disease (CAD)-related events does not appear to be mediated entirely through traditional risk factors for atherosclerosis. Use of antiinflammatory drugs such as glucocorticoids, nonsteroidal antiinflammatory drugs (NSAIDs), and cyclooxygenase (COX)-2 selective inhibitors may contribute to increased risk for coronary thrombosis. (See 'Risk factors' above.)
●Some medications used in RA can adversely impact the lipoprotein profile, while simultaneously reducing vascular risk surrogates, including inflammatory markers. The net effect on cardiovascular morbidity/mortality may differ by therapy. (See 'Risk factors' above.)
●Despite an increased incidence of ischemic cardiac events in patients with rheumatoid arthritis (RA), the prevalence of clinical angina pectoris in RA patients is lower than in the general population. Aside from this point, the clinical manifestations and diagnosis of coronary artery disease (CAD) are generally similar in patients with or without RA, but tend to be more severe in the patients with RA. (See 'Clinical manifestations' above.)
●For patients with RA ≥50 years of age, we suggest yearly history, physical examination, and electrocardiogram (ECG) to periodically assess for the presence of symptomatic CAD or electrocardiographic evidence of a silent MI. Exercise or pharmacologic stress testing is suggested for those with symptoms (eg, angina, atypical chest pain, exertional dyspnea) or electrocardiographic findings suggestive of CAD. (See 'Screening for CAD in RA' above.)
●As in the general population, the differential diagnosis of chest pain in a patient with RA is broad. Some disorders that may be of particular interest are chest wall pain, pericarditis, Herpes zoster, pulmonary hypertension, and thoracic aortic aneurysm or dissection. (See 'Differential diagnosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier version of this topic review.
