As the overall prognosis for persons with systemic lupus erythematosus (SLE) has improved, arterial vascular disease, including coronary heart disease (CHD) (1–14), stroke (8, 9, 15–20), and peripheral vascular disease (21), has become an increasingly important cause of morbidity and fatality. Strokes are reported in 2.6–20% of SLE patients (9, 15–20) and have a high recurrence rate (20, 22) and result in greater mortality than in persons of similar age and sex but without SLE (22). The risk of myocardial infarction (MI) may be increased as much as 9-fold in SLE (9); a second study shows a 50-fold increase in MI in women with SLE ages 35–44 years (1). Cardiac involvement is also common in unselected patients with asymptomatic SLE (23–25).
SLE has features of accelerated atherosclerosis as seen in diabetes mellitus, in that vascular complications appear early in the course of the disease. The pathogenesis of this vascular disease is not understood. It remains unclear to what extent the excess risk of cardiovascular events observed reflects differences in the values of common risk factors. None of the reported studies has fully controlled for the effects of these risk factors. Manzi et al (1) adjusted only for age and sex, while Ward (26) did not take into account the effect of smoking and cholesterol. It is important to dissect the degree to which the disease, its treatment (i.e., corticosteroids), or coexistent “traditional” risk factors are involved, since the optimal prevention could differ correspondingly.
We have quantified the relative risks of developing stroke, nonfatal MI, CHD overall, and CHD death in SLE patients compared with the general population, while also taking into account the differences in vascular risk factors at the beginning of followup. Specifically, we tested the hypothesis that the rates of these outcomes among SLE patients, adjusted for their baseline risk profiles, are higher than the rates expected based on the risk factor effects estimated in the Framingham heart study (27). In addition, we have estimated 95% confidence intervals (95% CIs) for the identified relative risks, since the precision of the estimates is important given the relatively small sample sizes typical of SLE studies.
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- PATIENTS AND METHODS
We identified 204 SLE patients from the Montreal General Hospital and 92 SLE patients from the Notre-Dame Hospital. Of these patients, 21 at the Montreal General Hospital and 12 at the Notre-Dame Hospital had had a previous vascular event (nonfatal MI [n = 9], congestive heart failure [n = 3], angina [n = 12], and stroke [n = 12]) and were excluded. Fourteen of these 33 patients had had the vascular event after SLE diagnosis but prior to baseline assessment for the present study. Not unexpectedly, the 33 excluded subjects tended to have more abnormal levels for the Framingham risk factors at baseline (after the event) than did the remaining 263 SLE patients (183 from Montreal General Hospital, 80 from Notre-Dame Hospital) who had no clinical evidence of atherosclerotic vascular disease at the baseline visit. The 33 excluded subjects were significantly older and had significantly higher mean systolic and diastolic blood pressures as well as higher mean total serum cholesterol (Table 1). The risk factor distributions for the Montreal General and Notre-Dame patients were comparable, but the latter had significantly lower mean cholesterol (Table 1).
Table 1. Distributions of risk factors for patients with systemic lupus erythematosus, by center and for excluded patients*
|Risk factor||Montreal General Hospital (n = 183)||Notre-Dame Hospital (n = 80)||Excluded from the analyses (n = 33)†|
|Male, no. (%)||23 (13)||6 (8)||7 (21)|
|Age in years, mean ± SD||39 ± 14||35 ± 13||46 ± 16‡|
|Systolic BP in mm Hg, mean ± SD||122 ± 17||123 ± 21||129 ± 17‡|
|Diastolic BP in mm Hg, mean ± SD||76 ± 11||77 ± 11||81 ± 9‡|
|Current smoker, no. (%)||79 (59)§||43 (55)§||19 (61)§|
|Cholesterol in mmoles/liter, mean ± SD||5.2 ± 1.5||4.4 ± 1.0||5.5 ± 1.4‡|
|Diabetes mellitus, no. (%)||11 (6)||1 (1)||1 (3)|
|Left ventricular hypertrophy, no. (%)||3 (6)§||1 (2)§||3 (15)§|
The frequencies of outcome events were similar at the Montreal General and Notre-Dame Hospitals (Table 2). For 71 of the 263 SLE patients (27%), followup ended before the date of closure of the study, resulting in a total followup of 2,271.8 patient-years (mean ± SD 8.6 ± 4.9 years/patient). Among the 263 SLE patients, 34 had CHD events (12.9%), including 17 with angina (6.5%), 17 with nonfatal MIs (6.5%), 7 with CHF (2.7%), and 12 with a CHD death (4.6%). Sixteen of the 263 patients had a stroke (6.1%). Overall, 44 of the 263 patients (16.7%) had either a CHD event or a stroke (6 patients had both a CHD event and a stroke).
Table 2. Disease duration, followup, and numbers of patients with cardiovascular events, by center*
|Variable||Montreal General Hospital (n = 183)||Notre-Dame Hospital (n = 80)||Total (n = 263)||Overall yearly event rate, %|
|Duration of SLE from diagnosis to baseline in years, mean ± SD||4.2 ± 5.8||4.6 ± 5.4||4.3 ± 5.7||NA|
|Followup duration from baseline in years, mean ± SD||8.5 ± 5.0||9.0 ± 4.7||8.6 ± 4.9||NA|
|Angina, no. (%)||12 (6.6)||5 (6.3)||17 (6.5)||0.75|
|Nonfatal myocardial infarction, no. (%)||15 (8.2)||2 (2.5)||17 (6.5)||0.75|
|Congestive heart failure due to coronary heart disease, no. (%)||7 (3.8)||0 (0.0)||7 (2.7)||0.31|
|Death due to coronary heart disease, no. (%)||9 (5)||3 (3.8)||12 (4.6)||0.53|
|Overall coronary heart disease, no. (%)†||25 (13.7)||9 (11.3)||34 (12.9)||1.50|
|Stroke, no. (%)||11 (6.0)||5 (6.3)||16 (6.1)||0.70|
The 44 patients with a CHD or stroke event had higher baseline levels for most of the risk factors (Table 3). The levels were significantly higher for age, systolic and diastolic blood pressure, and cholesterol. The mean duration of SLE was on average 1 year longer in patients who had events, although the difference was not statistically significant and was reduced to 0.5 years after adjusting for age.
Table 3. Baseline risk factors in systemic lupus erythematosus (SLE) patients with and without subsequent outcome events*
|Risk factor||With outcome event (n = 44)||Without outcome event (n = 219)||P†|
|Male, no. (%)||7 (16)||22 (10)||0.300|
|Age in years, mean ± SD||44 ± 17||36 ± 13||0.003|
|Systolic BP in mm Hg, mean ± SD||129 ± 19||121 ± 18||0.003|
|Diastolic BP in mm Hg, mean ± SD||81 ± 10||76 ± 11||0.008|
|Current smoker, no. (%)||28 (68)‡||94 (55)‡||0.159|
|Cholesterol in mmoles/liter, mean ± SD||5.5 ± 1.2||4.8 ± 1.4||0.006|
|Diabetes mellitus, no. (%)||0 (0.0)||12 (5)||0.230|
|Left ventricular hypertrophy, no. (%)||1 (4.0)‡||3 (3)‡||1|
|Previous SLE duration in years, mean ± SD||5.8 ± 7.5||4.8 ± 5.6||0.326§|
The analysis, which took into account the patients' baseline risk factors, revealed a striking increase in the incidence rates for all 4 outcomes in SLE patients contrasted with those expected (Table 4). For individual patients, the probabilities of specific events ranged from a minimum below 0.01 for all 4 outcomes to a maximum of 0.09 for nonfatal MI, 0.17 for CHD overall, 0.07 for CHD death, and 0.27 for stroke.
Table 4. Relative risk of vascular outcomes in systemic lupus erythematosus compared with those expected based on Framingham models*
|Outcome||Observed number of events||Expected number of events||Observed:expected ratio||95% CI|
|Nonfatal myocardial infarction||17||1.7||10.1||5.8–15.6|
|Death due to coronary heart disease||12||0.7||17.0||8.1–29.7|
|Overall coronary heart disease||34||4.5||7.5||5.1–10.4|
One of the most striking findings was that among initially asymptomatic SLE patients, the risks of CHD or stroke were both >7-fold higher than what would be expected based on their individual vascular risk factors alone. The increased risk is most dramatic for particularly serious CHD events: 10-fold for nonfatal MI and 17-fold for CHD death. The relative risk estimates are systematically, but only marginally, higher using systolic blood pressure–based models (data not shown). The corresponding 95% CIs show that the presence of SLE inflates vascular risks at least 4-fold compared with the predictions based on the Framingham models (Table 4). For each outcome, even the lowest of the 10,000 estimates of the ratio was >1.0 (data not shown), further indicating very high statistical significance of the impact of SLE on vascular outcomes. Sensitivity analyses demonstrated the robustness of our relative risk estimates, since changes in imputing risk corresponding to age 30 years for patients who were under age 30 at the baseline visit did not change the observed:expected ratio estimates beyond the second decimal place (data not shown).
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- PATIENTS AND METHODS
The results of the present study demonstrate a significantly elevated risk for CHD and stroke in SLE. Most important, they show that the elevated risks cannot be fully explained by altered levels of the traditional Framingham risk factors considered in our analyses. The results are consistent with the increased risks noted in small case series and in uncontrolled studies as well as in several controlled studies. In a small population-based study of SLE in two health districts in southern Sweden, Jonsson et al (9) observed 8 MIs when 0.87 were expected. Although not tested statistically, this represented a 9-fold increase in risk. Using the California Discharge Database to evaluate hospitalization for acute MI, CHF, and cerebrovascular accident in persons with SLE, Ward (26) reported an ∼2-fold increase in these outcomes in those ages 18–44 years. Manzi et al (1) assessed angina and MI in 498 women with SLE who were seen over a 14-year period at the University of Pittsburgh Medical Center. These investigators reported a 52.4-fold increased risk of MI in women ages 35–44 years (95% CI 21.6–98.5) and a 4.2-fold increase in women ages 55–64 years (95% CI 1.7–7.9) compared with women in the Framingham Offspring Study. Although not statistically significant, angina was increased 2.3-fold in these same age ranges of 35–44 and 55–64 years, and for women ages 45–54 years, MIs took place with >2-fold the expected frequency.
The present results demonstrate that the risks of all relevant cardiovascular outcomes are increased even after accounting for all traditional Framingham risk factors (27) that were considered in our analyses. Thus, even when the baseline vascular risk factors are accounted for, nonfatal MI, death due to CHD, overall CHD, and stroke are increased 10.1-fold, 17.0-fold, 7.5-fold, and 7.9-fold, respectively, in patients with SLE.
The present study is not without limitations. While the traditional Framingham risk factors considered in our analyses include almost all those commonly taken into account in epidemiologic studies of CHD (34, 45), it is possible that some of the excess risk in SLE may be accounted for by factors such as family history, low levels of high-density lipoprotein cholesterol, obesity, or lack of exercise, for which data were not available in our study. However, even if these additional factors have been found in some studies to have statistically significant independent effects on cardiovascular risks, their reported effects seem far too weak to fully account for the dramatic risk increases revealed by our analyses.
The study was retrospective and therefore more open to error than if these same patients had been followed up prospectively with the specific hypothesis concerning CHD and stroke determined in advance. Nonetheless, the present study may have been more likely to miss mild outcome events than the Framingham study. This is particularly likely for mild angina, which may have been mistaken for pleuritis or pericarditis due to SLE (1). If this occurred, it would have biased the results conservatively.
Use of the Framingham models based on asymptomatic subjects required exclusion from the analysis of 33 patients with CHD or stroke events before their baseline evaluation. Among the 33 subjects excluded for this reason, there were 14 who had their first event before the baseline visit but after their first diagnosis of SLE. These subjects were eliminated because pre-event risk factor values were not available. Eliminating these patients probably reduced the risk estimates of the impact of SLE on the risks of cardiovascular events.
The explanation for the marked increase in risk for vascular outcomes in SLE is probably multifactorial and may differ for cardiovascular and cerebrovascular events. Immune complex–induced endothelial damage, vasculitis, antiphospholipid antibody–induced thrombosis, the effects of Libman-Sacks endocarditis, hypertension from renal involvement or corticosteroid therapy, and corticosteroid-induced central obesity, hyperglycemia, or hypercholesterolemia have all been suggested as causal factors and probably play a role.
The present study shows that the excess of cardiovascular events in SLE cannot be explained by the baseline values of the traditional Framingham risk factors that we considered in our analyses, and probably arises from the underlying disease and/or its treatment. Indeed, the fact that patients who had cardiovascular events during the followup period showed a slightly longer prebaseline duration of SLE than those without events, even after adjusting for the differences in age, seems to corroborate the hypothesis that at least some of the excess risk is due to SLE. The excess is sufficiently dramatic that clinicians should consider aggressive intervention to control known risk factors such as smoking, hypertension, and hypercholesterolemia pending the identification of SLE-specific risk factors and the results of SLE-specific intervention studies. However, it is not clear that even more aggressive application of what is currently recommended for traditional risk factor modification will affect the accelerated atherosclerosis observed.