Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory arthritis affecting up to 1% of the U.S. population that can lead to joint damage, functional disability, and reduced quality of life.1 In addition to articular involvement, systemic inflammation accompanying RA may lead to extra-articular manifestations and increase the risk of premature death.2 Cardiovascular disease (CVD), accounting for nearly half of all deaths among RA patients, is now recognized as a critical extra-articular manifestation of RA.2,3 As such, assessment and management of CVD risk is essential to the comprehensive care of the RA patient.
SCOPE OF THE PROBLEM
In a large meta-analysis of observational studies that included more than 111,000 RA patients, CVD-related mortality rates were 1.5 times higher among RA patients than among general population controls.4 The risk of overall CVD, including nonfatal events, is similar; a separate meta-analysis of observational studies that included more than 41,000 RA patients calculated a pooled relative risk (RR) for incident CVD of 1.48.5 Individual analyses identified heightened risk of acute coronary syndrome (ACS), cerebrovascular accident (CVA), and congestive heart failure (CHF).5 Perhaps more illustrative of the magnitude of the problem, the risk of CVD in RA approaches that observed among individuals with diabetes mellitus.6,7
Coronary artery disease (CAD) accounts for a significant portion of the CVD risk in RA, but its presentation may be atypical in RA patients. RA patients are at higher risk of suffering unrecognized myocardial infarctions (MI) and sudden cardiac death.8 The reasons for silent ischemia in RA are not fully known, but have been hypothesized to include imbalances of inflammatory cytokines, alterations in pain sensitization, or the female predominance of RA (with women more often presenting with atypical symptoms of myocardial ischemia).9 Alarmingly, a retrospective chart review study reported that RA patients admitted for an acute MI were less likely to receive appropriate reperfusion therapy as well as secondary prevention with beta-blockers and lipid-lowering agents.10 Even with appropriate therapy, long-term outcomes such as mortality and recurrent ischemic events are more likely to occur in RA patients after acute MI.11-13
Independent of ischemic heart disease, RA patients are at increased risk of CHF.14-16 RA patients are at particular risk for CHF with preserved ejection fraction,17 which may be a result of systemic inflammation causing left ventricular stiffening.18,19 Similar to CAD, patients with RA are less likely to present with typical CHF symptoms, are less likely to receive guideline-concordant care, and have higher mortality rates following presentation with CHF.17
Although accounting for a lower proportion of the excess CVD morbidity and mortality in RA, the risk of noncardiac vascular disease is also increased in RA patients. Large meta-analyses have identified positive associations between RA with both ischemic (odds ratio [OR], 1.64 [95% confidence interval CI, 1.32-2.05]) and hemorrhagic (OR, 1.68 [95% CI, 1.11-2.53]) stroke.20 Similarly, RA patients appear to have an approximately 2-fold higher risk of venous thromboembolic events.21 Less studied than other forms of CVD, peripheral arterial disease may be increased in RA patients independent of other CVD and CVD risk factors.22,23
ASSESSING CVD RISK IN RA
CVD RISK SCORES
In order to identify patients who may benefit from primary prevention interventions, such as lipid-lowering therapy, CVD risk estimation typically centers on the use of well-established CVD risk calculators (Table 1). CVD risk scores such as the Framingham Risk Score (FRS), Systematic Coronary Risk Evaluation (SCORE), and American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Equation incorporate traditional CVD risk factors including age, sex, smoking status, blood pressure, lipid levels, and presence of diabetes mellitus.24,25 However, CVD risk in RA patients appears to be inadequately explained by traditional CVD risk factors,26 with disease activity and inflammation being associated with higher CVD risk. Recognizing that inflammation may contribute to CVD risk even among non-RA patients, the Reynolds Risk Score includes high-sensitivity C-reactive protein (hsCRP) in its calculation.27 In contrast to more robust performance in the general population, these well-established CVD risk scores have had variable predictive potential of incident CVD in RA patients.28-30
Several models, or adaptations to existing models, have been proposed to improve CVD risk assessment in RA populations (Table 1). In 2009, the European League Against Rheumatism (EULAR) task force suggested that a correction factor of 1.5 be used with traditional CVD risk models in RA patients with 2 of the following criteria: disease duration > 10 years, rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibody positivity, or extra-articular manifestations of RA.31 An update to these recommendations in 2015 continued to propose the use of a 1.5 correction factor, but to apply this to all RA patients.32 QRISK2, a modification to QRISK1 which was developed to predict CVD in the UK general population, includes the diagnosis of RA as a risk factor and in early validation efforts more accurately discriminated patients in the general population at increased risk of CVD compared to the FRS.33 Additional disease-specific risk factors such as systemic lupus, steroid use, severe mental illness, and steroid and atypical antipsychotic use were incorporated in the QRISK3 algorithm, with model performance similar to the QRISK2.34 The Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) was specifically developed to assess CVD risk in RA patients by including RA disease activity, level of physical disability, RA disease duration, and prednisone use.35 Despite efforts to develop "RA-specific" risk scores, these have not consistently outperformed traditional CVD risk calculators.36-38 In one study involving more than 1700 RA patients, the ERS-RA performed similarly to the FRS and Reynolds Risk Score, with a net reclassification index of just 2.3% versus the FRS.36
Vivek Joseph, MD, Sayanika Kaur, MD, and Arundathi Jayatilleke, MD
From the Department of Medicine, Division of Rheumatology, Drexel University College of Medicine, Philadelphia, PA
DISCLOSURES: The authors have no financial relationships to disclose.
A 50-year-old Caucasian man with a past medical history significant for rheumatoid arthritis (RA) and hypertension presents to his primary care physician’s office for his yearly physical. He has a 10-year history of hypertension and is on lisinopril 10 mg daily. He has a 15-year history of seropositive RA with erosive changes on radiographs. He is taking methotrexate 20 mg weekly along with folic acid 1 mg daily with good control of his arthritic symptoms. On his most recent rheumatology visit, he was noted to have a clinical disease activity index (CDAI) of 6, suggestive of low disease activity.
On physical examination, his vital signs are: heart rate, 74 beats/min; blood pressure, 120/80 mm Hg; respiratory rate, 16 breaths/min. He is afebrile. Body mass index (BMI) is 25.6 kg/m2.
The results of the patient’s most recent lipid panel are: total cholesterol (TC), 150 mg/dL (reference, < 200); high-density lipoprotein (HDL) cholesterol, 45 mg/dL (reference, > 40); low-density lipoprotein (LDL) cholesterol, 100 mg/dL (reference, 100); triglycerides 130 mg/dL (reference, 150).
He does not have a history of diabetes and is a lifetime nonsmoker. His 10-year atherosclerotic cardiovascular disease (CVD) risk score is 3.1%.