Preclinical Carotid Atherosclerosis in Patients with Rheumatoid Arthritis

Context Patients with rheumatoid arthritis are prone to premature death from coronary heart disease despite few risk factors. Researchers have wondered if chronic inflammation is a trigger. Content The authors measured inflammatory markers and risk factors for coronary heart disease in 98 matched case-patients and controls (mean age, 48 years). Carotid ultrasonography revealed that 44% of case-patients and 15% of controls had atherosclerotic plaque. Independent predictors of plaque were age, smoking, and rheumatoid arthritis. In patients with rheumatoid arthritis, inflammatory mediators did not predict plaque. Limitations This cross-sectional study cannot prove that rheumatoid arthritis accelerates atherosclerosis. Interpretation Carotid atherosclerotic plaque is much more common in patients with rheumatoid arthritis than in controls. The mechanism remains unknown. The Editors Compared with the general population, patients with rheumatoid arthritis die prematurely (1, 2), primarily because of cardiovascular disease (1-3). Women with this disease have high rates of nonfatal myocardial infarction (4-6), even in the absence of traditional risk factors for atherosclerosis (4, 5, 7). Although markers of disease severity have been linked to an increase in overall mortality rates (1), researchers have not been able to clearly identify specific aspects of rheumatoid arthritis or its treatment that might heighten the risk for cardiovascular disease. Use of corticosteroids or disease-modifying antirheumatic drugs does not appear to increase the risk for cardiovascular events (2). In fact, a large longitudinal study recently reported that death rates from myocardial infarction among North American patients with rheumatoid arthritis had declined to the level seen in the general population (thereby yielding a greater magnitude of decline) in the setting of increased methotrexate use (8). In another U.S. study, methotrexate use was associated with lower all-cause mortality rates in rheumatoid arthritis, mostly because cardiovascular mortality rates were decreased (9). Early diagnosis of atherosclerosis in this population might trigger more aggressive prophylaxis, but we have not determined the prevalence of preclinical atherosclerosis or identified markers for the disease. In this study, we examined the prevalence of atherosclerosis in patients with rheumatoid arthritis by using ultrasonogram-defined carotid artery plaque as a direct measure and proxy for generalized atherosclerosis and as a surrogate for coronary atherosclerosis; we also examined those features of rheumatoid arthritis that predict plaque presence. Previous studies reported that plaque prevalence in rheumatoid arthritis is statistically similar to that of control populations (10, 11). However, in systemic lupus erythematosus, another autoimmune disease characterized by chronic inflammation, cross-sectional studies that were conducted by us and by others showed a marked increase in plaque compared with that seen in carefully matched controls (12, 13). The increased plaque rate in systemic lupus erythematosus is associated with chronic inflammation (not with treatment or with traditional atherosclerosis risk factors), suggesting that similar factors may be at work in rheumatoid arthritis. Preclinical disease may also be identified by using ultrasonography to determine carotid intimamedia thickness, an indirect measure of atherosclerosis. Intimamedia thickness was increased in 2 studies of East Asian patients with rheumatoid arthritis (14, 15) but not in a U.S. study (11). Intimamedia thickness varied more with disease duration (14, 15), but an association with serum C-reactive protein levels and erythrocyte sedimentation rate (2 markers of inflammation) has not been established because of conflicting reports (11, 15). Intimamedia thickness does not always correlate with atherosclerosis, particularly in relatively young individuals with chronic inflammatory disease (12, 13), and it may measure other aspects of vascular disease. Discrete atherosclerotic plaque is a potent independent predictor of incident cardiovascular disease, whereas intimamedia thickness in areas free of discrete plaque has limited value as a marker after traditional risk factors for cardiovascular disease are considered (16-18). Because of conflicting data regarding premature preclinical atherosclerosis in rheumatoid arthritis, we chose to use the direct measure of plaque to examine the prevalence of carotid atherosclerosis in consecutive unselected, nonhospitalized patients with rheumatoid arthritis and matched controls. For our other primary outcome, we sought to determine those clinical and biological measures that best predict the presence of plaque. Methods Study Sample We consecutively recruited patients who met the American College of Rheumatology's classification criteria for a diagnosis (possessing at least 4 of 7 criteria) of rheumatoid arthritis (19) and who were enrolled in the Rheumatoid Arthritis Registry at the Hospital for Special Surgery in New York. Patients were recruited at regular visits with their rheumatologists during a 15-month period (participation rate, 94%). Exclusion criteria were age younger than 18 years, serum creatinine level of 270 mol/L or greater (3.0 mg/dL) or creatinine clearance of 0.50 mL/s or less (30 mL/min), or current or recent (within the past 3 months) pregnancy. We quantified extent of disease by recording extra-articular manifestations (for example, the Sjgren syndrome, leg ulcers, and evidence of vasculitis, such as nail fold infarcts, splinter hemorrhages, and motor neuropathy), active joint count (number of tender or swollen joints), number of joints irreversibly damaged (fixed deformity or surgical replacement) (20), and the patient's score on the Multidimensional Health Assessment Questionnaire (21). We recorded treatment by patient interview and chart review. Because treatment is often intermittent or at varying dosages, we tabulated medication use as never, former, or current. An 83-year-old woman had a previous stroke that was documented by magnetic resonance imaging, and a 45-year-old man had had coronary artery bypass surgery; we calculated our results both including and excluding these 2 patients. Patients were matched to controls on the basis of age (within 5 years), sex, and ethnicity. Controls were normotensive and hypertensive individuals who participated in longitudinal studies funded by the National Institutes of Health (22, 23) at the Hypertension Center of The New York Hospital and who underwent similar imaging protocols. We assessed patients for traditional cardiovascular disease risk factors: family history of myocardial infarction in first-degree male relatives younger than 55 years of age or first-degree female relatives younger than 65 years of age, smoking, hypertension (defined as blood pressure of 140/90 mm Hg or higher or the prescribed use of antihypertensive medications), diabetes mellitus (self-reported diagnosis), and fasting serum cholesterol levels. Hypertensive controls were studied after antihypertensive medications had been withheld for 3 or more weeks, whereas antihypertensive medications were not systematically withheld in hypertensive patients with rheumatoid arthritis. Brachial blood pressure was obtained at the end of the ultrasonographic studies after patients had remained in the supine position for 45 to 60 minutes in a quiet, darkened room. Of 100 patients with rheumatoid arthritis, a 74-year-old man was unable to be matched to a suitable control and a woman was excluded because she met diagnostic criteria for systemic lupus erythematosus. The institutional review board approved the study protocol, and all participants gave written informed consent. Carotid Ultrasonography All study participants underwent carotid ultrasonography, which was performed by experienced research sonographers who used an identical protocol. A single cardiologist, who was blinded to the identity of the study participants, interpreted the results. In brief, as previously described (22, 23), participants were studied in the supine position with slight hyperextension of the neck. Both extracranial carotid arterial systems were extensively scanned in multiple planes to optimize identification of atherosclerosis, which was defined as discrete plaque protruding into the lumen at least 50% beyond the diameter of the surrounding wall. Doppler interrogation was performed to evaluate the presence of significant (50% diameter reduction) obstruction. Intimamedia thickness was measured from end-diastolic (minimum dimension) M-mode images of the far wall of the distal common carotid artery. Intimamedia thickness was not measured in a location containing plaque. Mean values of right and left intimamedia thicknesses are presented. Reproducibility of intimamedia thickness and detection of plaque has been well documented (24-26). Carotid ultrasonographic studies were performed in the control group before 1999, whereas studies in the patients with rheumatoid arthritis were performed between 2000 and 2002. Laboratory Assessment Laboratory assessment of the patients with rheumatoid arthritis included routine chemistries and serum rheumatoid factor level. A high-sensitivity assay to determine serum levels of C-reactive protein was analyzed with a Cobas Integra system (Roche Diagnostics, Basel, Switzerland). Serum lipoprotein(a) levels were measured with an immunoturbidometric reagent (Diasorin, Stillwater, Minnesota) on a Roche Diagnostics Cobas Fara II system. Serum interleukin-6 levels were measured by automated enzyme immunoassay (Biosource International, Camarilo, California) on a Roche Diagnostics Cobas Core II analyzer. Serum levels of soluble intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 were measured by enzyme-linked immunosorbent assay (Caltag, Burlingame, California, and R&D Systems, Minneapolis, Minnesota,