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- PATIENTS AND METHODS
Patients with systemic lupus erythematosus (SLE) are significantly more likely to experience a myocardial infarction (MI) or a stroke than age-matched controls. Jonsson et al demonstrated a 9-fold increase in the MI rate in Swedish patients with SLE (1). Stroke may occur in up to 15% of patients with SLE, with some having multiple events (2, 3). Cardiovascular disease (CVD) currently accounts for between 20% and 30% of deaths in patients with SLE (1, 4, 5). As the antiinflammatory/immunosuppressive treatment of patients with SLE continues to improve (6), the contribution of CVD to morbidity and mortality is likely to increase.
Although there is an increased relative risk for atherosclerotic CVD in patients with SLE, it is not clear to what extent conventional risk factors, such as hypertension, diabetes, smoking, and hypercholesterolemia, contribute to this risk as opposed to lupus-specific risk factors. Although some studies have demonstrated an increased prevalence of conventional risk factors in patients with SLE (5, 7, 8), further research suggests that not all of the increased risk of CVD seen in patients with SLE is attributable to conventional risk factors (7, 9, 10). Esdaile et al (10) demonstrated that, after removing the effects of these known risk factors, there is still a 7.9-fold increase in the risk of stroke and a 10.1-fold increase in the risk of nonfatal MI in patients with SLE.
A critical management question at each clinic review of a patient with SLE is whether there are particular treatable clinical features that predict that the patient is likely to have coronary heart disease or stroke in the near future. It has been suggested that patients with SLE may be more sensitive to the effects of conventional risk factors than other persons (11). Therefore, one might be inclined to treat clinical problems such as hypertension or hypercholesterolemia in patients with SLE who have lower levels of these problems than healthy individuals, especially if any of these factors are known to be strongly predictive of MI or stroke in the near future in a patient with SLE. Case–control studies, such as that of Svenungsson et al (12), have suggested some possible predictive factors for CVD in patients with SLE. However, no case–control study has looked at the prevalence of risk factors at a time just before the cardiovascular event in the patient with SLE occurred. The prevalence of such risk factors at a time when patients are already known to have CVD may be affected by treatments such as antihypertensive drugs or statins introduced as a result of the cardiovascular event.
We therefore designed a case–control study to examine the prevalence of conventional and lupus-specific risk factors in patients with SLE at a time point just before they experienced a cardiovascular event. The controls were patients with SLE who had no CVD. Age is a known risk factor for CVD, and it has been suggested that chronic inflammatory disease may be a risk factor (13, 14). We therefore had 2 controls for each patient, 1 matched for age and 1 matched for duration of disease.
- Top of page
- PATIENTS AND METHODS
It is generally accepted that the risk of CVD is raised in patients with SLE. Furthermore, there is evidence that there is an increased prevalence of arterial disease in patients with SLE who have no symptoms of CVD, in comparison with age- and sex-matched controls. This increase has been demonstrated by a number of techniques, including carotid ultrasound and electron beam tomography (13, 19).
There is far less consensus about how to manage cardiovascular risk in patients with SLE. Both conventional and lupus-specific factors contribute to this risk, although the relative contributions made by these factors are not yet clear and may differ in different populations. A number of authors advocate active management of factors such as smoking, hypertension, and hypercholesterolemia in all patients with SLE, even where the absolute risk of coronary heart disease or stroke calculated from these factors is low (14, 20). In some cases, this policy would entail treating patients with drugs (such as statins) for many years without being sure whether those drugs are necessary.
It would be very useful to identify particular clinical features in patients with SLE that were readily identifiable in clinical practice and that were closely associated with increased risk of a cardiovascular event in the near future. The identification of such a feature in a patient with SLE might then help the patient's physician to decide when to take action to reduce cardiovascular risk. A number of different methods (10–13, 19) have been used to try to identify such features, but none of these studies has matched cases with controls on the basis of data from a time just before the CVD event occurred, as we have done. Our results suggest that high triglyceride levels, treatment for hypertension (a surrogate for the presence of persistent high blood pressure over a period of time), and elevated aPL are most likely to be predictive factors. Other factors such as current smoking and treatment with high doses of steroids may also be predictive factors, but our study was not large enough to confirm this for comparisons with both control groups.
A number of different methods have been used to address the question of which modifiable risk factors are most closely linked to the onset of CVD in patients with SLE (10–12, 21, 22). It is striking that many of these studies identify the same risk factors that we have identified (e.g., elevated triglyceride levels and hypertension).
Some authors have carried out cross-sectional studies on cohorts of patients with SLE to identify overall prevalence of particular risk factors in comparison with control groups. For example, in the Toronto Risk Factor Study, Bruce et al compared 250 women with SLE and 250 age-matched controls (11). Women with SLE were significantly more likely to have diabetes mellitus or hypertension. Body mass index, family history of coronary heart disease, and smoking rates did not differ between the groups, but patients with SLE were more likely to have a sedentary lifestyle. Although total cholesterol and LDL levels were similar in the 2 groups, triglyceride, VLDL, and homocysteine levels were significantly higher in the SLE group. This pattern of dyslipidemia had previously been noted in a Brazilian cohort that was rigorously selected to exclude influences on lipid levels other than SLE itself (21). This study found a correlation between increased disease activity and increased triglyceride levels. The authors argued that hypertriglyceridemia might enhance the creation of small dense LDL that would be susceptible to oxidation. In a later study by Nuttall et al (22), both increased triglyceride levels and small dense LDL were noted in the blood of female patients with SLE. This idea was supported by our results, which demonstrated that patients in the CVD group had significantly higher triglyceride levels than either control group.
Other studies have examined whether the presence of particular risk factors distinguishes patients with SLE who do experience CVD events from those who do not. Esdaile et al (10) followed 263 patients with SLE for a mean of 8.6 years each. Of these patients, 44 experienced coronary heart disease or stroke during the followup period; these patients were older and had significantly higher systolic and diastolic blood pressure and total cholesterol than the other 219 patients. However, these were values obtained at the baseline visit to the clinic and did not reflect the situation just prior to the CVD event. Neither the study by Esdaile et al (10) nor the study by Bruce et al (11) examined aPL.
Svenungsson et al (12) used a case–control method similar to ours, but with a number of important differences. They included a group of healthy controls as well as the 2 groups of patients with SLE (with and without CVD); they matched only for age and included only women in the study. Unlike us, they did not use the Rose questionnaire or any other validated method to screen negative controls for undiagnosed cardiac disease. Most importantly, they studied the patients after their CVD events, so that it is difficult to distinguish findings that might have been due to the management of CVD from those that were due to SLE. For example, their patients with SLE and CVD were more likely to be treated with statins than those with SLE only. Despite these differences in methodology, there are strong similarities between our findings and those of Svenungsson et al (12). They identified high triglyceride levels and increased aPL and lupus anticoagulant as markers of CVD in patients with SLE. They did not find a link to any particular manifestation of SLE or to current disease activity, but did find that CRP levels and erythrocyte sedimentation rates tended to be higher in patients with SLE and CVD than in those with SLE only. They did not find that treatment with antihypertensives was higher in the CVD group, but did find that cumulative steroid dose was higher. The possibility that use of higher doses of steroids could predispose to CVD, as also suggested by our comparisons between cases and age-matched controls, could be due to direct effects of steroids (such as raising blood pressure) or due to the fact that such patients have had higher disease activity over the course of their illness. In our study, however, we found no link between renal, cardiovascular, or vasculitis disease activity and risk of CVD.
The potential role of aPL in the development of atherosclerosis has been widely discussed (23, 24). Coronary disease and stroke are both common manifestations of antiphospholipid syndrome (APS). In a large retrospective study of 1,000 European patients with APS (primary and secondary), 19.8% experienced strokes and 5.5% experienced MI (25). Intraarterial thrombosis may play a role in the development of these arterial lesions, but a number of other mechanisms are also likely to be important. These include cross-reactivity of aPL with oxidized LDL and reduction in activity of paraoxonase, an enzyme that protects against oxidation of LDL (26).
The number of studied patients with CVD is a limitation of our study and of many other studies in this field. We identified 29 cases of CVD from 2 lupus units. This is comparable with the 26 patients from 2 units described by Svenungsson et al (12) and the 44 from 2 units described by Esdaile et al (10). It is important to stress that, both in this study and the others quoted above, the failure to discover a statistically significant correlation between the presence of CVD in patients with SLE and a number of traditional risk factors does not imply that those factors are irrelevant. The absolute frequency of CVD events in any cohort of patients with SLE is low and the prevalence of traditional risk factors (e.g., smoking or high cholesterol) is often high, so that it is difficult to obtain sufficient power to prove a correlation between occurrence of CVD and individual risk factors. For example, despite the abundant evidence that smoking increases the risk of CVD in the general population, only 1 study has previously shown a link between smoking and CVD in patients with SLE. This was the LUMINA study (Lupus in Minorities: Nature versus Nurture), in which 546 patients from 3 ethnic groups were followed for a median period of 73.8 months (27). CVD events occurred during this period in 34 patients, and the independent predictors of these events (measured at baseline) in multivariable analysis were older age, smoking, elevated CRP levels, longer followup time (but not disease duration), and the presence of aPL. This study differed from most others in that high triglyceride levels were not features of the group with CVD events.
Our finding that patients with CVD were significantly less likely to have been treated with hydroxychloroquine than those in the duration control group is interesting, particularly in view of recent data from the LUMINA study (28) demonstrating that patients who were taking hydroxychloroquine at baseline were less likely to develop damage over the next 2–5 years. A total damage score was measured using the Systemic Lupus International Collaborating Clinics Damage Index, which includes a domain for cardiovascular damage such as MI and stroke. However, the study did not have the power to detect effects of hydroxychloroquine on development of damage in the individual domains. Hydroxychloroquine has a number of actions, which might contribute to this apparent protective effect, including effects on the serum lipid profile and inhibition of platelet aggregation.
In conclusion, this study adds to the information from previous studies suggesting that hypertension, high triglyceride levels, and the presence of aPL may be risk factors for development of CVD in patients with SLE. Although there are no prospective controlled data, the physician may be inclined to add aspirin and hydroxychloroquine to the medications of SLE patients with these risk factors, especially if they are being treated for hypertension. Many doctors already advise aspirin for patients with persistently high aPL levels and no previous thrombosis. What is really needed, however, are much larger studies across multiple centers to compare far larger numbers of patients with SLE with and without CVD and to study inception cohorts for risk factors prospectively from the time of recruitment to each center. We are already involved in such studies.