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Keywords:

  • Systemic lupus erythematosus;
  • SLE;
  • Risk factors;
  • Cardiovascular disease

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Objective

Patients with systemic lupus erythematosus (SLE) are significantly more likely to experience a myocardial infarction or a stroke than age-matched controls. We compared the prevalence of conventional and lupus-specific risk factors in patients with SLE just before a cardiovascular event and in matched controls with SLE but no cardiovascular disease (CVD).

Methods

Twenty-nine patients with SLE and CVD were enrolled. For each patient, 2 ethnically- and sex-matched controls were obtained, 1 matched for age and 1 for SLE duration. Data regarding risk factors were collected for the time immediately preceding the relevant cardiovascular event, or at an equivalent time for controls.

Results

Patients' median age at event was 49 years (interquartile range 43–54 years) and mean disease duration was 12.0 ± 7.1 years. Patients with SLE and CVD were more likely than both age and duration controls to be treated for hypertension (P = 0.01 and P = 0.001, respectively) and to have elevated triglyceride levels (P = 0.05 and P = 0.01, respectively). Compared with duration controls, CVD patients were more likely to have lupus anticoagulant (P = 0.03), but less likely to be receiving treatment with hydroxychloroquine (P = 0.003). Compared with age controls, patients were more likely to be current smokers (P = 0.03), to have taken a mean dosage >7.5 mg/day of prednisolone (P = 0.04), and to have been treated with pulsed methylprednisolone (P = 0.03). In multivariable analysis, only hypertension treatment was an independent risk factor for CVD.

Conclusion

We identified significantly increased prevalence of some conventional and lupus-specific risk factors in patients with SLE immediately before a CVD event compared with controls matched for age or disease duration.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

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.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Patients.

The study group consisted of 29 patients with SLE who were attending 1 of 2 specialist SLE centers (16 from University College London Hospitals and 13 from the University of Birmingham lupus cohort) and who had survived at least 1 episode of CVD (CVD patients). Previous studies have demonstrated very similar clinical parameters in patients with SLE enrolled from these 2 centers (15). The total numbers of patients in each cohort during the period of the study were 300 at London and 380 at Birmingham. CVD was defined as an MI (confirmed by serial electrocardiography and a rise in cardiac enzymes), angina (confirmed by exercise stress test or thallium scanning), cerebral infarction (confirmed by computed tomography or magnetic resonance imaging), or peripheral vascular disease (confirmed by angiography).

For each CVD patient, 2 ethnically- and sex-matched patients with SLE were obtained as controls from the same hospital clinic, 1 matched for age (age controls) and 1 for duration of SLE (duration controls). Controls and patients were matched to within 3 years of age and duration. The absence of CVD in controls was determined by clinical history and examination and use of the questionnaire developed by Rose (16). All patients and controls fulfilled the revised American College of Rheumatology criteria for the classification of SLE (17). Local ethics committees approved the study and all patients gave their informed consent before entering the study.

Data collection.

Data regarding conventional and lupus-specific risk factors were collected for the visit to the clinic immediately preceding the relevant cardiovascular event, or at an equivalent time for the controls. Equivalent time means a time point when the age controls were the same age that the patient had reached when he or she experienced a cardiovascular event, or a time point when the duration controls had had SLE for the same length of time that the patient had experienced SLE at the time of his or her event. In both the London and Birmingham cohorts, standard practice is to review all patients routinely every 3–6 months, so that data for most patients will have been obtained at a point within 3–6 months of the cardiovascular event. Antiphospholipid antibodies (aPL) and lupus anticoagulant are an exception, because they are not measured at each visit. These tests are usually carried out once at inception into the cohort and repeated every 1–2 years only if the first result is abnormal. In this study, values for aPL and lupus anticoagulant are from the nearest available time point before the cardiovascular event, or an equivalent time point for controls. The risk factors that we studied are detailed in Tables 1, 2, and 3.

Table 1. Prevalence of conventional risk factors between the 3 groups*
 CVD patientsAge controlsDuration controls
  • *

    P values and ORs were calculated as described in the Patients and Methods section. CVD = cardiovascular disease; IQR = interquartile range; OR = odds ratio; 95% CI = 95% confidence interval.

  • OR could not be calculated due to small numbers of patients positive for the factor being studied in the control groups.

Age at event, years   
 Mean ± SD47.7 ± 10.648.0 ± 11.341.06 ± 11.6
 Median (IQR)49 (43–54)48 (41–50)39 (32–48)
Disease duration at event, mean  ± SD years12.0 ± 7.110.6 ± 7.212.18 ± 7.35
Any history of smoking   
 No./total no. (%)14/29 (48.3)10/27 (37.0)15/29 (51.7)
 OR (95% CI) 2 (0.29, 22.1)0.86 (0.24, 2.98)
 P value 0.690.78
Current smokers   
 No./total no. (%)11/29 (37.9)4/27 (14.8)7/29 (24.1)
 OR (95% CI) 1.8 (0.54, 6.84)
 P value 0.030.42
Hypertension   
 No./total no. (%)11/29 (37.9)5/29 (17.2)6/29 (20.7)
 OR (95% CI) 4 (0.80, 38.7)2.25 (0.63, 10.0)
 P value 0.060.17
Hypertension prescription   
 No./total no. (%)17/29 (58.6)8/29 (27.6)5/29 (17.2)
 OR (95% CI) 5.5 (1.20, 51.1)13 (1.95, 552)
 P value 0.010.001
Family history of CVD   
 No./total no. (%)14/28 (50)7/23 (30.4)8/29 (27.6)
 OR (95% CI) 1.75 (0.44, 8.15)2.2 (0.70, 8.08)
 P value 0.370.13
Table 2. Plasma lipid concentrations*
 CVD patientsAge controlsDuration controls
  • *

    Plasma lipid concentrations are in mmoles/liter. P values and 95% CIs were calculated using paired t-tests. HDL = high-density lipoprotein; LDL = low-density lipoprotein; see Table 1 for additional definitions.

Triglycerides   
 Mean ± SD1.77 ± 0.891.28 ± 0.601.22 ± 0.61
 Difference (95% CI) 0.49 (0.01, 0.96)0.64 (0.15, 1.13)
 P value 0.050.01
Total cholesterol   
 Mean ± SD5.46 ± 1.085.10 ± 1.035.10 ± 0.80
 Difference (95% CI) 0.26 (−0.31, 0.84)0.38 (−0.19, 0.95)
 P value 0.360.18
HDL   
 Mean ± SD1.57 ± 0.431.59 ± 0.521.62 ± 0.47
 Difference (95% CI) 0.07 (−0.15, 0.30)−0.1 (−0.40, 0.20)
 P value 0.510.49
LDL   
 Mean ± SD3.04 ± 0.912.99 ± 0.893.09 ± 0.70
 Difference (95% CI) 0.06 (−0.66, 0.78)−0.04 (−0.63, 0.55)
 P value 0.870.88
Total cholesterol − (HDL + LDL)   
 Mean ± SD0.84 ± 0.410.64 ± 0.330.54 ± 0.31
 Difference (95% CI) 0.19 (−0.07, 0.46)0.29 (0.01, 0.71)
 P value 0.140.04
Table 3. Lupus-specific risk factors*
 CVD patientsAge controlsDuration controls
  • *

    P values and odds ratios were calculated as described in the Patients and Methods section. Anti-dsDNA = anti–double-stranded DNA; BILAG = British Isles Lupus Assessment Group index; see Table 1 for additional abbreviations.

  • OR could not be calculated due to small numbers of patients positive for the factor being studied in the control groups.

Elevated anti-dsDNA   
 No./total no. (%)12/24 (50)19/27 (70.4)16/22 (72.7)
 OR (95% CI) 0.33 (0.03, 1.86)0.43 (0.07, 1.88)
 P value 0.290.21
Elevated antiphospholipid IgG   
 No./total no. (%)9/25 (36)3/28 (10.7)4/28 (14.3)
 OR (95% CI) 7 (0.90, 315)2.67 (0.64, 15.6)
 P value 0.070.13
Elevated antiphospholipid IgM   
 No./total no. (%)3/18 (16.7)0/24 (0)4/25 (16)
 OR (95% CI) 1 (0.13, 7.47)
 P value 0.251.00
Lupus anticoagulant   
 No./total no. (%)7/17 (41.2)1/14 (7.1)1/14 (7.1)
 OR (95% CI) 7 (0.90, 315)
 P value 0.070.03
Steroid use   
 No./total no. (%)24/28 (85.7)21/29 (72.4)20/29 (69.0)
 OR (95% CI) 2 (0.43, 12.4)3.5 (0.67, 34.5)
 P value 0.510.18
Steroid dose >7.5 mg/day   
 No./total no. (%)11/28 (39.3)4/29 (13.8)7/29 (24.1)
 OR (95% CI) 8 (1.07, 355)2.25 (0.63, 10.0)
 P value 0.040.17
Pulsed methylprednisolone   
 No./total no. (%)14/28 (50)7/29 (24.1)14/28 (50)
 OR (95% CI) 4.5 (0.93, 42.8)1.2 (0.31, 4.97)
 P value 0.030.76
Hydroxychloroquine   
 No./total no. (%)6/29 (20.7)13/29 (44.8)18/29 (62.1)
 OR (95% CI) 0.36 (0.08, 1.23)0.14 (0.02, 0.62)
 P value 0.070.003
Ever active in renal system (BILAG score A or B)   
 No./total no. (%)7/23 (30.4)8/21 (38.1)3/20 (15)
 OR (95% CI) 2 (0.10, 118)1.5 (0.17, 18.0)
 P value 1.001.00
Ever active in cardiovascular system (BILAG score A or B)   
 No./total no. (%)4/20 (20)2/22 (9.1)3/25 (12)
 OR (95% CI) 
 P value 0.500.25
Ever active in vasculitis system (BILAG score A or B)   
 No./total no. (%)2/15 (13.3)3/22 (13.6)3/23 (13.0)
 OR (95% CI) 
 P value 0.500.50

Because this was a retrospective analysis using data available from the clinical records of the patients, we were not able to examine the effects of some potentially interesting variables that are not measured routinely in our clinics. Examples include homocysteine levels and high-sensitivity C-reactive protein (CRP) assay. Elevated aPL (IgG or IgM) levels were defined as >20 IgG phospholipid units or IgM phospholipid units. Elevated anti–double-stranded DNA (anti-dsDNA) antibodies were defined as >50 IU/ml (as measured using the assay provided by Shield Diagnostics, Sheffield, UK). The aPL and anti-dsDNA antibody levels were measured by standard enzyme-linked immunosorbent assay tests as part of the routine clinical management of these patients. The British Isles Lupus Assessment Group (BILAG) index was used to determine clinical disease activity in each patient (18). The BILAG index is designed to determine activity in each organ or system separately. Although a global BILAG activity score can be calculated, that is not the purpose of the index and we did not use global scores in this study. We looked at activity in the renal, cardiovascular, and vasculitis domains of BILAG specifically, postulating that activity in these systems would most likely be related to development of CVD. The ancillary hypothesis being tested was that active disease in any of these systems would predispose to later development of CVD.

Statistical analysis.

Initially we analyzed each binary risk factor separately (univariable analyses) using either McNemar's chi-square test or an exact test, depending on the sample size. The 95% confidence intervals were calculated for odds ratios (ORs) using exact methods. Continuous risk factors were analyzed using paired t-tests. Two analyses were performed for each factor, 1 for each set of controls. A limitation of our approach was that we could not exclude the possibility that comparisons between cases and age-matched controls were confounded by duration or that comparisons between cases and duration-matched controls were confounded by age.

We then sought to determine the independent risk factors for CVD using conditional logistic regression (multivariable analyses). Because the sample size was small, we only investigated factors that had P values less than 0.05 in the univariable analyses. These factors were combined in a model and backwards elimination was applied using P values equal to 0.05 to find the strongest factors. This strategy was applied separately using the age- and duration-matched controls.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

Basic characteristics of study groups.

We included all patients in each cohort who had experienced CVD, with 3 exceptions. One patient from the London cohort had been lost to followup and could not be contacted to give consent. Two patients from the Birmingham cohort were excluded. One had experienced CVD before the onset of SLE. The other had experienced CVD 4 years before coming under the care of the Birmingham physicians and clinical notes from that period were not available. Of the 29 CVD patients, 24 were women and 5 were men. Twenty-one CVD patients were white, 5 were Asian, and 3 were of African Caribbean ethnic origin. Eleven had MIs, 11 had strokes, 6 had angina, and 1 had peripheral vascular disease. The median age at the time of cardiovascular event of these patients was 49 years (interquartile range 43–54 years) and mean disease duration at the time of event was 12.0 ± 7.1 years. The control groups were well matched for age and duration, respectively (Table 1).

Conventional risk factors.

The CVD patients were more likely (37.9%) to be current smokers than the controls (14.8% and 24.1% for age and duration controls, respectively), but this difference was significant at the 5% level for the age controls only (Table 1). CVD patients were also more likely to be hypertensive (defined as a systolic blood pressure >140 mm Hg or a diastolic pressure >90 mm Hg) and were significantly more likely to be receiving treatment for hypertension than both age controls (OR = 5.5, P = 0.01) and duration controls (OR = 13, P = 0.001).

Plasma concentrations of lipids are presented in Table 2. CVD patients had significantly elevated triglyceride levels compared with both age controls (P = 0.05) and duration controls (P = 0.01). Concentrations of total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol did not differ significantly between groups. There was, however, a tendency for the remaining cholesterol fraction (principally very low-density lipoprotein [VLDL]), measured as total cholesterol minus (HDL + LDL), to be increased in the CVD patients (P = 0.04 compared with duration controls).

Lupus-specific risk factors.

Lupus anticoagulant was present in 7 (41.2%) of 17 tested CVD patients compared with only 1 (7.1%) of 14 patients in each of the 2 control groups. This difference was significant at the 5% level between CVD patients and duration controls (P = 0.03) but not compared with age controls (P = 0.07). There was some evidence of an association between raised IgG aPL and the presence of CVD when cases were compared with age controls (P = 0.07). It should be noted, however, that because aPL and lupus anticoagulant are not measured routinely at every visit in the London and Birmingham lupus cohorts, data on these factors were only available for approximately half the patients. ORs could not be calculated where very small numbers of patients were positive for elevated aPL or lupus anticoagulant in the control groups. There was no convincing evidence of a difference in the prevalence of raised anti-dsDNA antibodies between the study groups.

CVD patients were more likely to have been treated with a high mean steroid dose (>7.5 mg/day; OR 8, P = 0.04) for the duration of their disease and to have received pulsed methylprednisolone (OR 4.5, P = 0.03) than age-matched controls, but CVD patients did not differ significantly from duration controls in these respects. To compare SLE disease activity, the proportions of patients in the case and control groups who had ever experienced activity in the renal, cardiovascular, and/or vasculitis domains of BILAG were compared. There was no significant difference between the CVD group and either of the control groups in any of these comparisons (see Table 3).

Significantly fewer CVD patients (20.7%) than duration controls (62.1%) were receiving treatment with hydroxychloroquine (OR 0.14, P = 0.003). CVD patients were also less likely than age controls to be receiving treatment with hydroxychloroquine (OR 0.36), but this was not significant at the 5% level (P = 0.07). Medication with azathioprine, cyclophosphamide, aspirin, and statins did not differ between study groups (data not shown).

Multivariable analyses.

For the age-matched controls, we investigated 5 risk factors: current smoker, treatment for hypertension, elevated triglyceride levels, treatment with high mean steroid dose, and received pulsed methylprednisolone. After applying backwards elimination, only treatment for hypertension remained in the model (P = 0.03), although treatment with high mean steroid dose had a P value that just exceeded 0.05 (P = 0.065).

For the duration-matched controls, we considered treatment for hypertension, elevated triglyceride levels, total cholesterol minus (HDL + LDL), and received pulsed methylprednisolone. Lupus anticoagulant was omitted because it caused numerical difficulties due to missing data. After applying backwards elimination, only treatment for hypertension remained in the model (P = 0.01).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES

We would like to thank Ada Franklin-Stevens, Veronica Toescu, Stephanie Heaton, Janet Skan, Simon Bowman, Deva Situnayake, and all our colleagues who have worked in the lupus clinics for their help with acquisition of data.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES