Coronary artery disease in rheumatoid arthritis: Implications for prevention and management

INTRODUCTION — The prevalence of atherosclerotic coronary artery disease (CAD) is increased in patients with chronic inflammatory rheumatic diseases, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus [1]. Some differences exist in the presentation of CAD in this setting, and the increased risk of CAD has implications for drug therapy, although the clinical manifestations and diagnostic approach to CAD are generally similar in patients with or without RA.

The preventive and therapeutic implications specifically related to CAD in patients with RA will be reviewed here. The epidemiology, pathogenesis, risk factors, clinical manifestations, and diagnosis of CAD in patients with RA; and other cardiac manifestations of RA are presented separately. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications" and "Overview of heart disease in rheumatoid arthritis" and "Rheumatoid nodules", section on 'Cardiac nodules'.)

OVERALL APPROACH TO PREVENTION

Major elements — The key elements in the prevention of coronary artery disease (CAD) in patients with rheumatoid arthritis (RA) are aggressive management of traditional risk factors and optimization of antiinflammatory and immunomodulatory therapy to achieve effective disease control. (See 'General prevention measures' below and 'DMARDs for control of inflammation due to RA' below.)

This general approach is consistent with recommendations of the European Alliance of Associations for Rheumatology (EULAR; formerly the European League Against Rheumatism) [2]. The prevention (whether primary or secondary) and treatment of CAD are generally similar in patients with and without RA, but they are influenced by factors particular to RA and similar disorders. Efforts have been made to try to quantify the increase in risk in patients with RA, which results from multiple interacting factors. (See 'Risk estimation' below and "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Pathogenesis' and "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Risk factors'.)

Some issues of particular concern in RA that may affect cardiovascular disease (CVD) risk include:

●Effects of systemic inflammation on CAD. (See "Overview of established risk factors for cardiovascular disease", section on 'Inflammation' and "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Inflammation'.)

●Issues related to concomitant use of low-dose aspirin with nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), including both nonselective NSAIDs and cyclooxygenase (COX) 2 selective inhibitors. (See "NSAIDs: Adverse cardiovascular effects", section on 'Aspirin and other antithrombotic agents'.)

●Benefits and adverse effects of glucocorticoids and other RA therapies, including nonbiologic, biologic, and targeted synthetic disease-modifying antirheumatic drugs (DMARDs). (See 'Implications for RA therapeutic drug selection' below.)

Screening for cardiovascular disease is discussed separately. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Screening for CAD in RA'.)

Risk estimation — We use validated cardiovascular risk estimators, such as the American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic CVD risk calculator (calculator 1) to estimate CVD risk in RA, although it is important to note that the ACC/AHA calculator and other risk calculators underestimate risk in RA [3,4]. The use of multivariate risk models for the estimation of cardiovascular risk in individual patients is discussed in detail separately. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)

Qrisk2, a general-population cardiovascular risk calculator applied in the United Kingdom [5], was found to overestimate cardiovascular risk in a cohort of RA patients [6], and this will likely be the case with Qrisk3. There are insufficient data to guide tailoring of treatment targets based upon rheumatologic disease status, other than the evidence that patients with rheumatologic and inflammatory disorders, including RA, are at greater risk than the general population. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications".)

Other risk estimation methods have been proposed for patients with RA, but have different shortcomings. One recommendation has been an expert opinion based suggestion to use a multiplier of 1.5 for patients with RA [2] but in validation studies has not been shown to improve cardiovascular risk stratification beyond that of the population risk calculators [7,8].

Another method developed for cardiovascular risk estimation specifically for RA patients is the expanded cardiovascular risk prediction score for RA (ERS-RA). The score includes four RA-related variables that contributed, together with traditional risk factors, to more accurate risk estimation compared with the use of traditional risk factors alone [9]. External validation of ERS-RA has shown mixed results including findings of similar performance characteristics as existing cardiovascular risk estimators and has not been adopted in clinical care [7,10].

GENERAL PREVENTION MEASURES

General strategies also used in patients with RA — We recommend a primary prevention strategy in patients with rheumatoid arthritis (RA) that is comparable to that widely recommended in the general population to reduce the risk of cardiovascular events and cardiovascular deaths, consistent with expert guidelines [2]. These general preventive strategies are discussed in detail separately. (See "Overview of primary prevention of cardiovascular disease".)

Briefly, this involves identifying modifiable risk factors for coronary heart disease and employing interventions that include:

●Smoking cessation

●Lipid lowering

●Healthy diet

●Moderate exercise

●Weight control

●Blood pressure control

Special considerations in patients with RA influence several of these interventions. (See 'Blood pressure control' below and 'Exercise' below and 'Lipid lowering with statins' below and 'Low-dose aspirin' below.)

Blood pressure control — Particular attention to blood pressure control is important because blood pressure in patients with RA may be increased, although usually to a modest degree, by several of the medications used to treat the arthritis and related symptoms; these medications include nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs) (both nonselective and cyclooxygenase (COX)-2 selective), glucocorticoids, and leflunomide [11,12]. Thus, for those in whom these agents are necessary, monitoring blood pressure before and after starting such medications, with initiation or adjustment of antihypertensive therapy to maintain optimal blood pressure control, is suggested as a means of reducing the risk of cardiovascular disease (CVD). Early initiation of disease-modifying antirheumatic drugs (DMARDs) in most patients may avoid the need for regular use of NSAIDs and reduce the need for glucocorticoids. (See "Overview of hypertension in adults" and "NSAIDs: Adverse cardiovascular effects", section on 'Patients with hypertension' and "NSAIDs and acetaminophen: Effects on blood pressure and hypertension" and "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis", section on 'Adverse effects' and "Major adverse effects of systemic glucocorticoids", section on 'Cardiovascular effects'.)

Exercise — Exercise programs should be prescribed by a physical therapist and tailored for each patient’s disease severity, body build, and previous activity level. However, it may be difficult or impossible for patients with RA and either active synovitis or structural damage to joints of the lower extremities to perform the desired level of aerobic exercise. High-intensity weightbearing exercises may not be appropriate for patients with preexisting structural damage of lower extremity joints. Less intense or non-weightbearing exercises are alternatives for such patients. (See "Nonpharmacologic therapies for patients with rheumatoid arthritis", section on 'Physical activity and exercise' and "Nonpharmacologic therapies for patients with rheumatoid arthritis", section on 'Physical and occupational therapy' and "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease".)

Lipid lowering with statins

●Indications for use of statins – Primary and secondary prevention of CVD with statin therapy for the management of blood cholesterol is warranted in patients with RA using generally similar guidelines to those used in patients without RA; thus, for patients with intermediate or higher 10-year atherosclerotic CVD (ASCVD) risk (≥7.5 percent) we usually initiate statin therapy. The available data are insufficient, in our view, to warrant the use of statins in patients whose sole evidence of increased cardiovascular risk is the presence of RA. The use of statins for lipid management in the primary and secondary prevention of CVD is discussed separately. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach", section on 'How to assess ASCVD risk' and "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications".)

The ACC/AHA guidelines further suggest considering statin therapy for some patients with RA at borderline risk (≥5 to <7.5 percent). A coronary artery calcification (CAC) score can be used as a decision aid for RA patients who fall into this category. Patients with RA often receive non-gated noncardiac chest computed tomographies (CTs) for a variety of clinical indications; CAC detected on these CTs can be used to guide management with statins [13]. Presence of CAC either performed formally or present from prior testing may inform initiating a statin in a patient with RA, particularly in those with borderline risk. (See "Coronary artery calcium scoring (CAC): Overview and clinical utilization", section on 'Management based on CAC'.)

For patients with RA, the threshold for treatment is lower than the general population because RA is understood to be a risk-enhancing factor according to the ACC/AHA guidelines for the management of blood cholesterol, as are other chronic inflammatory diseases and persistently elevated inflammatory markers, including C-reactive protein (CRP) ≥2 mg/L [14-16].

Drawing conclusions regarding risk of CVD based upon lipid levels in RA is complicated by findings that higher levels of inflammation in patients with RA have been associated with lower lipid levels, perhaps explaining in part the observations that lipid levels may increase when patients are given treatments such as tocilizumab, tumor necrosis factor (TNF) inhibitors, and the Janus kinase (JAK) inhibitors [17,18]. (See 'DMARDs for control of inflammation due to RA' below.)

●Efficacy of statins for cardiovascular disease prevention – Some evidence suggests that statins are likely to reduce CVD in patients with RA, but this has not been well documented in randomized trials in such patients. The use of a statin (atorvastatin) for the primary prevention of cardiovascular events in RA has been evaluated in comparison with placebo in a randomized trial (referred to as the TRACE RA trial) involving 3002 patients with RA (with disease for >10 years or over age 50) without known cardiovascular disease requiring statins, diabetes mellitus, or myopathy [19]. Patients allocated to atorvastatin (40 mg daily) did not achieve a statistically significant reduction in cardiovascular risk (hazard ratio [HR] 0.66, 95% CI 0.39-1.11), and the trial was terminated prematurely (median follow-up of 2.5 years) due to a lower-than-anticipated number of cardiovascular events. However, despite the imprecision of this estimate, this degree of risk reduction with a statin (as reflected in the point estimate) was comparable to that in trials performed previously in individuals without RA [20]. Safety data were reassuring for use of statins in RA patients on typical DMARD therapy; no increased rate of adverse events for subjects on statins was observed compared with placebo. Additionally, levels of low-density lipoprotein cholesterol (LDL-C) were 29.8 mg/dL lower in patients receiving atorvastatin.

Results of observational studies further support the trend suggested in the randomized trial of a protective effect on cardiovascular risk with use of statins [21-23]. As an example, one population-based cohort study of patients with RA receiving DMARD therapy found that all-cause mortality was reduced by 21 percent in patients receiving statins compared with similar patients not on these agents (HR 0.79, 95% CI 0.68-0.91; absolute mortality risk of 32.6 versus 42.6/1000 patient-years) [21]. These benefits were similar to those seen in randomized trials in the general population. Another study demonstrating benefits for cardiovascular disease in patients with RA, as well as other inflammatory joint diseases, found that intensive statin therapy (with rosuvastatin) induced atherosclerotic regression in carotid plaque and significantly reduced LDL-C levels [22]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)

●Anti-inflammatory effects of statins – Statins have antiinflammatory properties in RA; however, the effect is modest. In the randomized TRACE RA trial [19], subjects receiving atorvastatin had lower CRP levels compared with those receiving placebo (median CRP 2.59 versus 3.60 mg/L) [19]. Another randomized trial involving 116 patients examined the lipid-lowering and antiinflammatory efficacy of atorvastatin in patients with active RA and also found a statistically significant but modest reduction in CRP [24]. Additional trials testing the effects of statins on cardiovascular endpoints in patients with RA are needed. These trials will need to address the relationship between disease activity, lipid levels, inflammation, and cardiovascular risk in RA [25].

Low-dose aspirin — Use of aspirin in patients with RA for cardiovascular prevention does not differ from patients in the general population without RA, but it may affect the use of NSAIDs employed for treating the arthritis. Low-dose aspirin is recommended for secondary prevention of cardiovascular events in patients with an established diagnosis of coronary heart disease. Based upon current guidelines, aspirin would not be appropriate for most RA patients, as many will have factors that increase bleeding risk, including age >70, and concurrent use of NSAIDs and glucocorticoids [26]. Aspirin use in primary and secondary prevention in the general patient population is discussed in detail elsewhere. (See "Overview of primary prevention of cardiovascular disease", section on 'Aspirin' and "Aspirin in the primary prevention of cardiovascular disease and cancer" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Among those with RA, the use of low-dose aspirin in primary or secondary prevention of coronary artery disease (CAD) may be complicated by the following:

●Interference by some nonaspirin NSAIDs with effects of ASA on platelets – Nonselective nonaspirin NSAIDs may interfere with the beneficial effects of low-dose aspirin when used for prevention of CVD. This interaction is discussed in more detail elsewhere. (See "NSAIDs: Adverse cardiovascular effects", section on 'Aspirin and other antithrombotic agents'.)

●COX-2 selective NSAID effects – The COX-2 selective NSAIDs do not appear to interfere with the antiplatelet effect of aspirin. In addition, the risk of coronary events appears to be less with celecoxib than with rofecoxib, the latter agent being no longer available. Because all NSAIDs, both nonselective and COX-2 selective, increase cardiovascular risk, it is prudent to also avoid the use of COX-2 selective drugs in patients without a diagnosis of CAD but with multiple risk factors. (See "NSAIDs: Adverse cardiovascular effects" and "NSAIDs: Adverse cardiovascular effects", section on 'Aspirin and other antithrombotic agents'.)

●Loss of benefit of COX-1 sparing by COX-2 selective drugs due to ASA effect – The potential gastroduodenal sparing effect with COX-2 selective agents may be counterbalanced by toxicity from concurrent low-dose aspirin therapy for primary or secondary prevention of cardiovascular or cerebrovascular disease, although this effect can be mitigated substantially by use of a proton pump inhibitor. (See "Overview of COX-2 selective NSAIDs", section on 'Coadministration with low-dose aspirin' and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity".)

Whether or not low-dose aspirin mitigates the cardiovascular risk in patients who use COX-2 selective agents is uncertain. Limited data from clinical trials of at least two COX-2 inhibitors, rofecoxib (subsequently withdrawn from the market), and lumiracoxib, suggest that concomitant low-dose aspirin may reduce the risk of cardiovascular events. (See "NSAIDs: Adverse cardiovascular effects", section on 'NSAID characteristics'.)

IMPLICATIONS FOR RA THERAPEUTIC DRUG SELECTION

Nonsteroidal antiinflammatory drugs — In patients with rheumatoid arthritis (RA) without known coronary artery disease (CAD), we use the same general approach to nonaspirin nonsteroidal antiinflammatory drug (NSAID) prescribing as in patients without RA, prescribing the lowest amount necessary for the shortest amount of time to achieve the desired clinical outcome. (See "NSAIDs: Adverse cardiovascular effects".)

The use of many, but not all, NSAIDs has been associated with an increased risk of cardiovascular disease (CVD) in the general population, particularly among patients with established CAD. Whether these drugs similarly increase risk in RA, where their antiinflammatory effects might reduce risk, is uncertain. The risks associated with these medications may have important implications for the selection of agents used to treat patients with RA.

Specific issues that influence the treatment decision include the presence or absence of CVD, the degree of risk for gastroduodenal damage, and/or the need for long-term oral anticoagulation. The optimal approach is uncertain in the patient with RA who is at high risk for gastroduodenal damage (ie, who has one or more risk factors for developing NSAID-associated gastroduodenal ulcer and complications). These issues are presented in detail separately. (See "NSAIDs: Adverse cardiovascular effects" and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "COX-2 inhibitors and gastroduodenal toxicity: Major clinical trials", section on 'Combined use of COX-2 inhibitors and PPIs' and "Risks and prevention of bleeding with oral anticoagulants", section on 'Other medications' and "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity".)

The effect of nonselective and selective NSAIDs on cardiovascular outcomes in patients with RA has not been extensively studied. While a few prior studies suggested that the CVD risk of NSAIDs may be less in patients with RA compared with the general population [27,28], there are a paucity of studies replicating those findings.

Limiting glucocorticoid exposure — When chronic therapy with glucocorticoids is required, we suggest trying to taper the dose as quickly as possible to the lowest effective dose, usually 5 to 10 mg/day of prednisone or its equivalent, based upon disease activity.

The use of supraphysiologic doses of glucocorticoids may be associated with increased rates of myocardial infarction, stroke, heart failure, and all-cause mortality. These effects may be mediated, at least in part, by elevated lipoprotein and glucose levels. Such adverse effects of chronic glucocorticoid therapy, including dyslipidemia, are typically seen at doses of 7.5 mg/day or higher and may be observed at lower doses as well. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis".)

The risk of CVD with use of systemic glucocorticoids is reviewed in detail separately. (See "Major adverse effects of systemic glucocorticoids", section on 'Cardiovascular effects'.)

DMARDs for control of inflammation due to RA — Effective control of disease activity in patients with RA appears to reduce CVD risk. Although the hypothesis has not been adequately tested in a prospective trial, observational data suggest that strict control of inflammation in RA by use of therapy that effectively decreases synovial inflammation may favorably affect some CVD risk factors and reduce the development and progression of CVD [29]. These data are strongest for methotrexate (MTX) and for tumor necrosis factor (TNF) inhibitors [2]. In addition, limited observational data suggest that biologic disease-modifying antirheumatic drugs (DMARDs) and MTX are associated with comparable risk of hospitalization for cardiovascular events in older patients with RA [30]. The potential benefit of treatment of joint inflammation with nonbiologic and biologic DMARDs, particularly MTX and the TNF inhibitors, is an additional factor that favors aggressive attempts to control synovitis.

One of the mechanisms that may contribute to reduction of risk is reduced atherogenicity of lipids associated with a reduction of inflammation after treatment with most DMARD therapies [31-33]. However, the relationship between chronic inflammation and lipid metabolism is complex and remains incompletely understood. In patients with RA and suboptimally controlled disease activity, total cholesterol and low-density lipoprotein (LDL) levels can be lower than in non-RA individuals [25,34]. Also, biologics targeting proinflammatory cytokines, such as TNF-alpha and interleukin (IL) 6, and the JAK inhibitors, which can suppress RA inflammation, appear to increase lipid levels [18,32,35]. Moreover, some agents, such as tocilizumab, may substantially increase total cholesterol, triglycerides, high-density lipoproteins (HDL), and LDL, while reducing some vascular risk surrogates [36]. In a prospective evaluation of 20 patients with active RA treated with tocilizumab, proatherogenic shifts in the lipid profile were unrelated to changes in disease activity [37]. The long-term impact on cardiovascular morbidity and mortality is unknown. Patients with abnormal lipid profiles should receive statin therapy as per national guidelines.

Reduction of inflammation may be beneficial for reducing cardiovascular risk in RA; however, the pathway targeted may be important as well, with some agents (eg, MTX, TNF inhibitors) affording benefit, while others (eg, tofacitinib) may increase cardiovascular risk:

●Methotrexate

•Several systematic reviews have found a reduction in cardiovascular risk associated with MTX, including metaanalyses in 2011 and 2015 that found a 21 to 28 percent reduction in all CVD events [38-40]. Subsequent studies from two independent cohorts confirmed these findings, with one suggesting that MTX itself has added benefit beyond reduction of RA disease activity [41,42]. These findings may be explained in part by in vitro data which suggest that MTX may limit foam cell transformation in monocytes and macrophages [43].

•A cohort study of 1240 patients with RA at one outpatient clinical center in North America addressed the question of a possible survival benefit among those treated with MTX [44]. After adjustment for possible confounding factors, the risk of death due to CVD was shown to be significantly lower among MTX-treated patients compared with those who did not receive MTX (HR 0.3, 95% CI 0.20.7).

●TNF-alpha inhibitors

•A 2015 meta-analysis found that TNF-alpha inhibitors were associated with reduced risk of all CVD events (risk ratio [RR] 0.70, 95% CI 0.54-0.90), as well as specific outcomes, including myocardial infarction (RR 0.59, 95% CI 0.36-0.97) and stroke (RR 0.57, 95% CI 0.35-0.92) [38].

As an example, one study included in the 2015 meta-analysis observed beneficial effects of TNF-alpha inhibitors on atherosclerotic CVD; in this retrospective study of 983 Swedish patients with RA, those who received a TNF inhibitor were compared with RA patients not treated with one of these drugs [45]. After controlling for age, sex, and disability, the incidence rates of new cardiovascular events for TNF inhibitor-treated and untreated patients were 1.4 and 3.5 per 100 patient-years, respectively (adjusted RR of 0.46, 95% CI 0.25-0.85). However, TNF inhibitors may be harmful to some patients with preexisting heart failure and should be used with caution in patients with heart failure or decreased left ventricular function; worsening and new-onset heart failure have been reported with these agents.

•The cardiovascular benefit of the TNF inhibitors may be limited to patients with RA whose synovitis responds to these agents. This was suggested by a study that used registry data on 10,840 patients with RA [46]. Rates of myocardial infarction were assessed in 8670 patients treated with TNF inhibitors and 2170 patients treated with traditional nonbiologic DMARDs. Overall, both groups had similar incidence rates of myocardial infarction. However, those patients whose disease activity was reduced by TNF inhibitor therapy within the first six months of treatment had a markedly decreased risk of myocardial infarction compared with those who continued to have active disease. Myocardial infarction rates per 1000 patient-years were 3.5 and 9.4, respectively (rate ratio 0.36 [95% CI 0.19-0.69]). A follow-up study from this cohort observed that exposure to TNF inhibitor therapy over time was associated with a lower incidence of myocardial infarction compared with those on conventional synthetic DMARD therapy [47]. (See "Overview of biologic agents in the rheumatic diseases", section on 'TNF inhibition'.)

●JAK inhibitors – Additional support for the view that the beneficial effects of antiinflammatory treatments may depend on the pathway targeted for treatment of RA comes from observations that some DMARDs, such as Janus kinase (JAK) inhibitors, particularly tofacitinib, may result in increased risk for cardiovascular adverse events when compared with TNF inhibitors in patients 50 years and older with cardiovascular risk factors. Overall data with JAK inhibitors demonstrated similar major adverse cardiovascular events as biologics [48]. These observations and the related warnings from regulatory agencies are described in more detail separately. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Cardiovascular'.)

TREATMENT OF ANGINA AND ACUTE CORONARY SYNDROMES — The medical management of patients with rheumatoid arthritis (RA) and with angina and/or acute coronary syndromes is the same as in patients without RA. (See "Chronic coronary syndrome: Overview of care", section on 'Antianginal therapy' and "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department" and "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction".)

Several additional points should be noted:

●Outcomes of acute coronary syndromes – Patients with RA who present with acute coronary syndromes may have poorer outcomes than other patients. (See 'Prognosis' below.)

●NSAID use in patients with cardiovascular disease – Issues related to the use of nonsteroidal antiinflammatory drugs (NSAIDs) in patients with cardiovascular disease (CVD) and the interference of some NSAIDs (eg, ibuprofen) with the beneficial antiplatelet effects of aspirin are described separately. (See 'Nonsteroidal antiinflammatory drugs' above and 'Low-dose aspirin' above.)

●Issues related to cardiac surgery – When cardiac surgery is needed, there are issues unique to patients with RA that must be addressed, including risk of cervical spine instability and preoperative and perioperative antirheumatic drug management. These issues are discussed separately. (See "Preoperative evaluation and perioperative management of patients with rheumatic diseases".)

PROGNOSIS — Cardiovascular disease (CVD) is a major contributor to the increased risk of premature death in patients with rheumatoid arthritis (RA). Risk is increased in patients with acute coronary syndromes, and overall risk is higher in patients with greater levels of systemic inflammation. Increased mortality risk in patients with RA is discussed in more detail separately. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Mortality'.)

Briefly, the following observations are pertinent:

●Acute coronary syndromes – Acute coronary syndromes may be more severe in patients with RA than in the general population and patients with RA who present with acute coronary syndromes may have poorer outcomes than other patients. As an example, in a retrospective study of 40 patients with RA and 40 age- and sex-matched controls, all with acute coronary syndromes, subsequent cardiovascular deaths were significantly more likely in those with RA (40 versus 15 percent) [49]. Patients with RA with acute coronary syndromes also have increased short-term mortality compared with controls from the general population who experience events of similar type and severity, even following adjustment for previous comorbidities, demographics, educational level, and acute coronary syndrome type (seven-day hazard ratio [HR] 1.44, 95% CI 1.14-1.82; 30-day HR 1.36, 95% CI 1.13-1.64) [50]. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Clinical manifestations'.)

●Mortality risk associated with systemic inflammation – The magnitude of the acute phase responses to inflammation, as indicated particularly by the erythrocyte sedimentation rate (ESR) and by the C-reactive protein (CRP) concentration, may be predictors of the risk of death due to CVD, supporting the view that aggressive disease-modifying antirheumatic drug (DMARD) therapy is indicated in patients with active joint inflammation. As examples of this association:

•One study evaluated the relationship between traditional and nontraditional cardiovascular risk factors and cardiovascular death in a cohort of 603 patients with RA followed for a mean period of 15 years [51]. When corrected for other risk factors for CVD death, patients with at least three measurements of sedimentation rates ≥60 mm/hour were twice as likely to die of CVD than other RA patients (HR 2.03, 95% CI 1.45-2.83).

•A study of 506 patients with newly diagnosed inflammatory polyarthritis (one-half with RA) found that elevated CRP levels at the time of diagnosis of RA were an independent risk factor for cardiovascular death [52]. After adjustment for other risk factors, a CRP level of ≥5 mg/L was associated with an increased risk of death due to CVD (HR 3.3, 95% CI 1.4-7.6).

•In addition, CRP levels >10 mg/mL predict all-cause mortality after standardization for traditional risk factors in patients with RA, psoriasis, or ankylosing spondylitis [53].

Although an elevated CRP level is recognized as a risk factor for coronary artery disease (CAD) in the general population, lower threshold levels for defining normal results are generally used than those present in patients with an inflammatory disease. Information is lacking regarding the effect of comorbid inflammatory illnesses, such as RA, on the discriminatory power of CRP in CVD risk stratification. (See "C-reactive protein in cardiovascular disease".)

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 AND RECOMMENDATIONS

●General approach and risk factor assessment – The key elements in the prevention of coronary artery disease (CAD) in patients with rheumatoid arthritis (RA) are aggressive management of traditional risk factors and optimization of antiinflammatory and immunomodulatory therapy. We use validated cardiovascular risk estimators, such as the American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic cardiovascular disease (CVD) risk calculator to estimate CVD risk in RA, although these risk calculators tend to underestimate risk in RA. (See 'Overall approach to prevention' above.)

●Standard primary prevention strategies – A primary prevention strategy should be undertaken in patients with RA that is comparable to that widely recommended in the general population to reduce the risk of cardiovascular events and cardiovascular deaths. This includes identifying modifiable risk factors for coronary heart disease and employing interventions that include smoking cessation, lipid lowering, healthy diet, moderate exercise, and weight control. (See 'General prevention measures' above.)

●Statins – Our approach to statin therapy for reduction of cardiovascular risk is generally consistent with ACC/AHA guidelines. Thus, we initiate statin therapy for patients with RA, which has been determined to be a risk-enhancer, at intermediate (>7.5 percent) or higher 10-year risk. Statin therapy reduces cardiovascular risk even in individuals with normal or elevated lipid levels and may have a beneficial effect on markers of inflammation in RA (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]). (See 'General prevention measures' above and 'Lipid lowering with statins' above.)

We do not use statins in patients whose sole evidence of increased cardiovascular risk is the presence of RA. For patients with a 10-year risk between 5 and 7.5 percent, we present the potential benefits and costs/risk and consider therapy in the presence of risk modifiers such as coronary artery calcification (CAC). (See 'Lipid lowering with statins' above.)

●Nonsteroidal antiinflammatory drugs – Nonsteroidal antiinflammatory drugs (NSAIDs) should be used with particular caution in patients with RA and CAD. (See 'Nonsteroidal antiinflammatory drugs' above and 'Low-dose aspirin' above.)

●Glucocorticoids – The risk of atherosclerosis associated with glucocorticoid use should be minimized by using the minimum effective dose of a glucocorticoid for the shortest possible time. (See 'Limiting glucocorticoid exposure' above.)

●DMARD risks and benefits – Strict control of inflammation due to RA with both nonbiologic disease-modifying antirheumatic drugs (DMARDs; eg, methotrexate [MTX]) and/or biologic DMARDs (eg, anti-tumor necrosis factor [TNF] therapy) may reduce the increased cardiovascular risk seen in patients with RA; however, this effect may not be evident in Janus kinase (JAK) inhibitors, which might increase risk. (See 'DMARDs for control of inflammation due to RA' above.)

●Effects of arthritis therapy on lipids – 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 of such changes is unknown. (See 'DMARDs for control of inflammation due to RA' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Peter Schur, MD, and Paul Cohen, MD, PhD, who contributed to an earlier version of this topic review.