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- PATIENTS AND METHODS
The baseline characteristics of the 236 patients in ÓRALE and those of the SAHS cohort are shown in Table 1. The RA patients were older, with a slightly higher proportion of Hispanics. There was no difference between groups in the proportion of women. The mean systolic blood pressure and the BMI were higher in the RA cohort. Although diabetes mellitus was more frequent in the RA cohort, this was probably attributable to a difference in age, because the difference disappeared when we stratified by age. The probability of smoking cigarettes was equivalent in the 2 cohorts, and RA patients were significantly less likely to have hypercholesterolemia.
Table 1. Baseline characteristics of subjects compared in ÓRALE and SAHS*
|Individual characteristics||ÓRALE cohort (n = 236)||SAHS cohort (n = 4,635)||P|
|Age in years, median (range)||56 (22–80)||43.3 (25–65)||≤0.0001|
|Women||147 (62.3)||2,667 (58)||0.15|
| NonHispanic whites||49 (21)||1,668 (36)||≤0.0001|
| NonHispanic blacks||11 (5)||0||–|
| Asians||5 (2)||0||–|
| Hispanics||171 (72)||2,967 (64)||0.01|
|Diabetes mellitus||38 (16.1)||442 (9.5)||≤0.0001|
| Age <55||9/109 (8.3)||240/3,672 (6.7)||0.5|
| Age ≥55||29/127 (22.8)||202/963 (20.1)||0.7|
|Systolic blood pressure, mean ± SD mm Hg†||128.5 ± 17.9||116.4 ± 15.4||≤0.0001|
|Hypercholesterolemia||54 (22.9)‡||2,258 (48.7)§||≤0.0001|
| Age <55 years||24/109 (22)||1,626/3,672 (44)||≤0.0001|
| Age ≥55 years||30/127 (24)||632/963 (66)||≤0.0001|
|Cigarette smoking||57 (24.2)||1,276 (27.5)||0.25|
| Age <55 years||29/109 (27)||1,015/3,672 (28)||0.8|
| Age ≥55 years||28/127 (22)||261/963 (27)||0.2|
|Body mass index, mean ± SD kg/m2†||29.8 ± 7.4||27.4 ± 5.6||≤0.0001|
|Years with RA, median (range)||10 (0.2–52)||NA|
|Rheumatoid factor positive||201 (85)||NA|
|ESR, mm/hour median (range)||37 (2–115)||NA|
|Tender joints, median (range)||18 (0–48)||NA|
|Swollen joints, median (range)||3 (0–25)||NA|
|Deformed joints, median (range)||6 (0–38)||NA|
|Subcutaneous nodules||117 (49.5)||NA|
|Taking methotrexate||150 (64)||NA|
|Taking glucocorticoids||119 (50.4)||NA|
We obtained followup information on 234 (99%) of the ÓRALE patients. The mean length of time between the initial visit and the earliest of either 1) the followup visit, 2) CV death, or 3) the censoring date of December 31, 1997, was 1.07 years (range 2 months–1.9 years), for a total period at risk of 252 patient-years. During the period at risk, 67 of the 234 ÓRALE patients were hospitalized a total of 103 times. Of the 67 hospitalized patients, 16 attributed 19 hospitalizations to “chest pain,” “heart attack,” “stroke,” “loss of consciousness,” “shortness of breath,” “open heart surgery,” or “heart bypass,” which we considered potentially due to a CV cause. In addition, 1 patient was hospitalized for an amputation below the knee. We reviewed the records of these 20 hospitalizations and found that 2 of the patients had strokes and 1 underwent coronary angioplasty before the initial visit for the ÓRALE study. In 1 additional patient, the suspected CV-related hospitalization was due to pneumonia rather than a CV event. We thus did not include these 4 cases in our estimates of the rate of CV events, leaving 16 CV-related hospitalizations in 13 patients. In addition to the hospitalizations, 5 deaths occurred during the observation period, 2 of which we counted as CV related, because the death certificates listed MI as the cause of death.
In total, 15 persons in the ÓRALE cohort experienced CV events during the observation period: 7 MI (2 fatal), 2 strokes, 5 coronary revascularization procedures, and 1 occlusion of the popliteal artery due to atherosclerosis, requiring amputation (Table 2). Of the 15 events, 13 were in persons who had no history of CV events. The incidence of CV events in the ÓRALE cohort was 5.9 events per 100 person-years (95% CI 3.3–9.8) for all events, and 5.2 per 100 person-years (95% CI 2.7–8.8) for new events.
Table 2. Cardiovascular events occurring in members of the ÓRALE cohort during the period at risk*
|Patient||Age/sex/ethnic group||Outcome-defining event||Included in comparisons with SAHS?|
| 1||45/M/H||Coronary artery disease and coronary bypass||Yes|
| 2||48/F/H||Coronary artery disease and angioplasty||Yes|
| 3||56/M/W||Unstable angina and coronary bypass||Yes|
| 4||58/F/H||MI and angioplasty||Yes|
| 5||60/M/H||Coronary artery disease and angioplasty||Yes|
| 6||63/M/H||Coronary artery disease and angioplasty||Yes|
| 8||57/F/H||Popliteal artery occlusion||No†|
| 9||59/M/W||MI and coronary bypass||No‡|
In the SAHS cohort, followup information on CV events that occurred 7–8 years after the baseline assessment was available for 4,635 participants (90%). The total period at risk was 35,631 person-years. Compared with SAHS participants with followup information, those without followup information were older at baseline (44.7 ± 0.5 versus 43.3 ± 0.2 years; P = 0.01), had a higher BMI (28.0 ± 0.3 kg/m2 versus 27.4 ± 0.1 kg/m2; P = 0.03), a higher plasma cholesterol level (207 ± 2 mg/dl versus 202 ± 0.6 mg/dl; P = 0.03), and were more likely to be women (57.6% versus 52.3%; P = 0.04). There was no significant difference in ethnic background, baseline blood pressure, fasting blood sugar level, or history of smoking between SAHS participants with and without followup information.
Among SAHS cohort members, 269 cardiovascular events occurred, for an incidence rate of 0.75 events per 100 person-years (95% CI 0.66–0.85). Events recorded in the SAHS included 79 heart attacks, 73 strokes, 76 heart surgeries, and 54 CV deaths. Of these, 200 occurred among persons with no history of CV events, who contributed 33,881 person-years at risk, for a new-event incidence rate of 0.59 per 100 person-years. The types of new events included 70 heart attacks, 60 strokes, 53 heart surgeries, and 31 CV deaths (only the first event occurring during the observation period was used for calculating incidence rates). Subjects in the SAHS were recruited over a 9-year period. We compared the incidence of CV events in the SAHS according to year of recruitment, using logistic regression to adjust for age and sex, and found no significant difference. Specifically, participants recruited in the latter years did not have a higher rate of CV events than did early enrollees (odds ratio 1.02 per year of recruitment, 95% CI 0.98–1.07), nor was there a difference in the probability of heart surgery between participants enrolled early or late in the SAHS.
Because the SAHS was targeted to persons ages 25–65 years, we compared incidence rates between the 2 cohorts only among subjects who were in that age range at entry. We thus excluded 46 ÓRALE cohort members, among whom 6 CV events occurred during followup, and 3 SAHS participants, among whom no CV events occurred, because they were older than age 65 at the time of the baseline evaluation. We also excluded a CV event in 1 ÓRALE cohort member who was in the 25–65 age range but had experienced a CV event prior to the study period and 1 ÓRALE participant who had a popliteal artery occlusion, because we did not have an equivalent outcome in the SAHS. Table 3 shows the number of new events in each cohort, in strata defined by age and sex. The stratum-specific IRRs were higher in the RA cohort in all 4 age and sex strata but, because of the small number of events in each stratum, reached significance only in the stratum of men ages 55–65 years. The Mantel-Haenszel pooled age- and sex-adjusted IRR was nevertheless significantly increased (almost 4 times higher) in the RA cohort, with no significant heterogeneity among strata.
Table 3. Age- and sex-stratified incidence rates of new cardiovascular events in the ÓRALE and SAHS cohorts*
| ||ÓRALE cohort||SAHS cohort||Stratum-specific IRR||95% CI|
|Events||Patient-years||Incidence (per 100 patient-years)||Events||Person-years||Incidence (per 100 person-years)|
Because of the possibility that differences in the incidence of CV events between the 2 cohorts could be attributable to differences in the prevalence of CV risk factors, we modeled the incidence of CV events using Poisson regression. In this multivariate model, the predictor variables were 1) cohort membership (ÓRALE = 1, SAHS = 0), 2) age, 3) sex (men = 1, women = 0), 4) diabetes mellitus (yes = 1, no = 0), 5) cigarette smoking (yes = 1, no = 0), 6) systolic blood pressure, and 7) BMI. Risk coefficients associated with each of these predictor variables are shown in Table 4. This analysis revealed that the incidence of CV events in the RA cohort was more than triple that in the population-based cohort, independent of the influence of other cardiac risk factors. Because of the possibility that the increased rate of CV events in the ÓRALE cohort was explained by increased use of CV procedures, we fit a second Poisson model using only incident heart attacks or MI as the outcome, adjusting for CV risk factors. Although <1 primary MI was expected to occur during the 1-year period of observation among ÓRALE cohort members ages 25–65 years, we observed 2 such events. The IRR of primary MI associated with ÓRALE cohort membership was thus increased at 2.65, but the 95% CI did not exclude unity, at 0.64–7.19, because of the small number of events.
Table 4. Multivariate analysis of the incidence of new cardiovascular events in ÓRALE and SAHS participants ages 25–65 years*
|Predictor variables||IRR||95% CI|
|Cohort membership (ÓRALE = 1, SAHS = 0)||3.17||1.33–6.36|
|Age (per 10 years)||2.15||1.83–2.55|
|Sex (men = 1, women = 0)||1.99||1.50–2.66|
|Diabetes mellitus (yes = 1, no = 0)||2.28||1.65–3.12|
|Systolic blood pressure (per 15 mm Hg)||1.18||1.03–1.33|
|Body mass index (per 5 kg/m2)||1.13||0.99–1.28|
|Cigarette smoking (yes = 1, no = 0)||1.37||1.01–1.83|
|Hypercholesterolemia (yes = 1, no = 0)||1.35||1.01–1.82|
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- PATIENTS AND METHODS
That people with RA would have a high rate of CV morbidity and mortality may at first seem surprising. The predilection for RA to occur in women and its frequent treatment with aspirin and other nonsteroidal antiinflammatory drugs, with their well-known antiplatelet effect, could be expected to protect RA patients from CV disease. Yet, RA is not the only chronic inflammatory disease of women that is associated with CV disease. Systemic lupus erythematosus is also characterized by a high rate of coronary artery disease (33), mediated at least in part by chronic inflammation (18). Indeed, previous studies demonstrated excess CV mortality in RA (1, 11–15), a phenomenon not fully explained at present.
Perhaps because this high rate of CV mortality in RA has only recently been recognized, few studies have investigated the frequency of traditional risk factors in persons with RA, and their results were sometimes contradictory. For example, smoking, a factor strongly associated with atherosclerosis, had a protective influence on the susceptibility to RA in one study (34), while others found that smoking increased the risk of RA (35–37). The lipid profiles of patients with RA have also been investigated (38–41). One study showed that the levels of cholesterol, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein were reduced in RA patients (38), while others indicated that levels of lipoprotein(a) were increased (39–41). Diabetes mellitus, an important cardiac risk factor, has been found to occur with a similar frequency in patients with RA and controls (42). The above studies of CV risk factors in RA thus do not conclusively demonstrate that CV risk factors are increased in persons with RA.
The number of CV events we observed in RA patients was almost 4 times higher than what would be expected in persons without RA of the same age and sex. Because these findings could be attributable to a higher frequency of CV risk factors in RA, we adjusted our comparisons for the influence of traditional risk factors. Indeed, RA patients were older than persons without RA in our study, and the age-adjusted mean systolic blood pressure and BMI were also higher in the RA group. However, not all CV risk factors were more common in RA: although RA patients as a whole had diabetes mellitus more frequently, this was likely because they were older, since the age-stratified prevalence of diabetes did not differ between the 2 groups (Table 1). Similarly, RA patients were significantly less likely to have hypercholesterolemia than were the controls.
We adjusted our comparisons for the CV risk factors we measured and for the different periods of observation between the 2 cohorts, using Poisson regression. In our models, the higher incidence of CV events in RA was independent of the influence of CV risk factors. Therefore, traditional CV risk factors are not the sole explanation for high rates of CV events in RA.
Recent evidence suggests that systemic inflammation may play a role in the development of atherosclerosis (43–49). Fatty streaks, the earliest atherosclerotic lesions, contain macrophages and T lymphocytes and are rich in inflammatory cytokines such as tumor necrosis factor α (TNFα), interleukin-1 (IL-1) and IL-2, and adhesion molecules (50). Advanced atherosclerotic lesions, representing the fibrotic phase of inflammation, are also characterized by the expression of multiple cytokines and growth factors (43). In addition to the pathologic evidence, it has been recognized for some time that the level of acute-phase reactants rises during acute MI (51), and that coronary events are often temporally related to infections (47, 52, 53). Acute-phase reactants also predict myocardial ischemia in patients with angina, those with multiple risk factors, and even in apparently healthy male physicians (46, 54, 55, 57). It is also possible that RA and atherosclerosis share pathogenic mechanisms (19). In view of this evidence, accelerated atherosclerosis in RA should be expected.
How the inflammation that occurs in RA would lead to increased atherosclerosis is not clear, but evidence points toward an indirect effect of inflammation centered on the synovium, acting at a distance on the systemic vascular endothelium. Although inflammation in RA centers in synovial tissue, inflammation mediators spill into the systemic circulation, where they can easily interact with endothelial cells. IL-1 and TNFα, 2 of the central cytokines in RA that are found in high concentrations in the blood of RA patients (58–62), have profound effects on endothelial cells, up-regulating them to express adhesion molecules, increasing their permeability, and facilitating migration of inflammatory cells into vessel walls (63). C-reactive protein (CRP), the level of which rises in periods of RA disease activity, may also play a direct role in atherothrombosis. CRP stimulates macrophages to produce tissue factor, an important procoagulant that may be found in atherosclerotic plaques (64, 65). The localization of CRP in atheromatous lesions (66) also suggests a causative link between CRP and coronary events. From the above evidence, it is clear that a wide range of inflammatory mechanisms may explain accelerated atherosclerosis in RA and that further research is needed.
In addition to the inflammatory phenomena occurring in the joints, other factors may contribute to atherosclerosis in patients with RA. Corticosteroids have a recognized atherogenic effect, mediated through their effects on plasma lipids (17). However, these agents are used in only half of all RA patients and in low dosage, usually <10 mg per day. Some studies have not even been able to demonstrate an association between CV mortality and steroid use in RA (67, 68). Methotrexate is another drug used in RA that could cause atherosclerosis by inducing hyperhomocysteinemia, a novel factor recently associated with atherothrombosis (69). However, this effect is counterbalanced by the concomitant use of folic acid in methotrexate-treated RA (70). A sedentary lifestyle may also be more frequent among RA patients, secondary to the physical impairments caused by the disease.
Among the strengths of our study is its longitudinal design, with followup obtained on most members of both the ÓRALE and the SAHS cohorts. The availability of a comparison group of community-dwelling people from the general population of the same city, such as the SAHS cohort, in which CV risk factors and outcomes have been carefully ascertained, is an added strong point, because it enables inferences on the incidence of events observed in our RA patients. In addition, our analysis strategy allowed us to adjust our relative risk estimates for the competing effect of traditional cardiovascular risk factors, in effect isolating the contribution of RA itself to cardiovascular morbidity.
The main potential limitation of the present analysis is the possibility of differences in the methods used to ascertain outcomes and predictors in the 2 cohorts. In the case of predictor ascertainment, the measurement methods used in both studies were similar, with the possible exception of plasma cholesterol measurement. However, as has been the case in previous comparisons between RA patients and controls, we found that cholesterol levels in the ÓRALE patients were lower than those in the SAHS cohort (38). Thus, we believe the potential for differential ascertainment of hypercholesterolemia is small.
Determination of CV outcomes may also differ between the 2 cohorts. Patients in ÓRALE are followed up medically, and CV events in this cohort may be more likely to be recognized. We aimed to counterbalance this possibility by defining CV events more conservatively from a self-reported list of hospitalizations, confirmed by review records of those with potentially CV causes. By comparison, most SAHS outcomes are based on self-reported heart attack, heart surgery, or stroke. This could potentially lead to a higher frequency of outcomes falsely reported as CV-related compared with ÓRALE, which would be more likely to introduce bias toward the null hypothesis of no difference between the 2 cohorts.
Followup of the SAHS cohort began 7–16 years before and ended during the year in which we recruited the ÓRALE cohort. This nonconcurrency is a potential source of bias toward an increased rate of events in the ÓRALE cohort, which was followed up later than the SAHS cohort, because cardiac surgery may have become more commonplace in the interim. However, nonconcurrency could also bias toward the null hypothesis of no difference, because of the secular trend toward reduced CV mortality in the population. The lack of a significant trend in either direction in the incidence of CV events or heart surgery during the 8-year followup of the SAHS is evidence that neither of these 2 biases is operating to a significant degree in our study. Likewise, it is unlikely that the 10% of SAHS participants who were lost to followup would have had a sufficiently high rate of CV events to erase the increased rate in RA, given the small differences between respondents and those lost to followup in the SAHS.
In conclusion, we have shown that CV events occur more frequently than would be expected in RA, and that this increased incidence is not entirely explained by traditional CV risk factors. Physicians who provide medical care to patients with RA should recognize that this disease is characterized by a predisposition to atherosclerosis and CV disease and should implement appropriate prophylactic or therapeutic measures, as clinically indicated. Further research is needed to understand the mechanisms of increased atherogenesis in RA.