Preclinical vascular disease in systemic lupus erythematosus and primary antiphospholipid syndrome

Sònia Jiménez1, M. Angels García-Criado2, Dolors Tàssies3, Joan Carles Reverter3, Ricard Cervera1, M. Rosa Gilabert2, Daniel Zambón4, Emilio Ros4, Concepció Bru2 and Josep Font1

1 Department of Autoimmune Diseases, Institut Clínic de Medicina i Dermatologia, 2 Department of Radiology, Centre de Diagnòstic per la Imatge, 3 Department of Hemotherapy and Hemostasis, Centre de Diagnòstic Biomèdic and 4 Lipid Unit, Institut Clínic de Malalties Digestives i Metabolisme, Hospital Clínic, Barcelona, Spain.

Correspondence to: Josep Font, Servicio de Enfermedades Autoinmunes, ICMiD, Hospital Clínic, C/Villaroel 170, 08036 Barcelona, Spain. E-mail: jfont{at}clinic.ub.es


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To determine the prevalence of preclinical vascular disease and associated risk factors in patients with systemic lupus erythematosus (SLE) or primary antiphospholipid syndrome (APS).

Methods. We consecutively studied 70 SLE patients and 25 primary APS patients without clinical coronary artery disease. The control group included 40 healthy women. Carotid ultrasound was performed and the intima-media wall thickness (IMT) and presence of plaque was investigated in all patients and controls. Traditional vascular risk factors and SLE-disease and treatment related factors were also analysed.

Results. SLE patients had a higher prevalence of traditional atherosclerosis risk factors: hypertension (P<0.005) and dyslipidaemia (P<0.05) and higher levels of total cholesterol (P = 0.03), triglycerides (P = 0.004) and apolipoprotein B (P = 0.04). The prevalence of carotid plaque was higher and appeared earlier in SLE patients than in the primary APS patients or controls (P<0.001). The IMT was similar in the three groups. SLE patients with secondary APS had a higher prevalence of carotid plaque than patients with primary APS (37.5% vs 8%, P = 0.03). The presence of plaque in SLE patients was associated with a higher SLICC score (2.40 ± 1.78 vs 1.02 ± 1.18, P = 0.002), higher ECLAM score (3.10 ± 2.32 vs 1.84 ± 1.59, P = 0.02) and older age (47.3 ± 8.44 vs 37.38 ± 11.28, P = 0.003) at the time of carotid ultrasound study.

Conclusion. Plaque prevalence in patients with primary APS is similar to that of controls and inferior to that of SLE patients with secondary APS. SLE patients have a high prevalence of early carotid atherosclerosis that is associated with cumulative disease damage and disease activity.

KEY WORDS: Atherosclerosis, Systemic lupus erythematosus, Antiphospholipid syndrome, Carotid ultrasound


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The description of late-stage morbidity and mortality has contributed to the understanding of systemic lupus erythematosus (SLE) [1]. In 1974, Urowitz et al. [2] described the bimodal pattern of mortality in SLE and found a second mortality peak in the long-term outcome of SLE patients related to cardiovascular disease. Epidemiological studies have suggested a precocious, accelerated atherosclerosis in these patients. In large series of SLE patients described since 1970, 6–75% of deaths were due to cardiovascular disease, with many occurring in premenopausal women [1, 3–7]. SLE patients have a high prevalence of traditional risk factors for atherosclerosis, related to clinical conditions and treatment received [8]. However, there is increasing evidence that traditional risk factors do not fully explain the atherosclerotic process in SLE. Recent studies have implicated new aetiopathogenic factors such as chronic inflammation or endothelial cell injury [9–17], suggesting a multifactorial pathogenesis of cardiovascular disease in SLE. The real prevalence of preclinical atheromatosis is unknown. The diagnosis of asymptomatic atherosclerotic disease in SLE may lead to early, effective treatment of potential complications.

Various studies have attempted to evaluate the frequency of preclinical cardiovascular disease using different imaging techniques [18–26]. Extracranial carotid artery disease is related to cardiovascular morbidity and mortality and the extent of coronary atherosclerosis [26]. The high-resolution duplex technique provides accurate and reliable measurements of atherosclerosis in its preclinical stage [26]. In recent years, several studies have assessed the prevalence of carotid atherosclerosis in SLE patients. However, the prevalence of preclinical atherosclerosis in SLE and primary antiphospholipid syndrome is little studied.

The aim of the present study was to determine the prevalence of preclinical vascular disease and associated risk factors in patients with SLE or primary antiphospholipid syndrome (APS) evaluated by carotid ultrasound study.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients and controls
Seventy consecutive patients with a diagnosis of SLE and 25 patients with primary APS according to the revised criteria of the American College of Rheumatology [27] and 1999 Sapporo criteria [28], respectively, were included. All patients were seen at our department between January 2000 and January 2002. No patient had a previous history of clinical coronary artery disease. The control group included 40 healthy women. Patients and controls gave written informed consent before entering the study. The study design was approved by the Hospital Ethics Committee.

Assessment of risk factors for atherosclerosis
Traditional cardiovascular risk factors
Family history of cardiovascular disease was defined as a myocardial infarction, stroke, peripheral vascular disease or sudden death in a first-degree relative before the age of 65 years in men and 55 years in women. Hypertension was defined as systolic blood pressure greater than 140 mmHg and/or diastolic blood pressure greater than 90 mmHg on two or more prospective visits or prior antihypertensive medication. Smoking was defined as current consumption of more than one cigarette per day. Diabetes was defined as a physician diagnosis of diabetes requiring insulin or hypoglycaemic agents. Follicle-stimulating hormone levels were determined when menopausal status was uncertain; the use of estrogen replacement therapy was also ascertained. The body mass index was calculated using the formula: weight (kg)/height2 (m). Hypercholesterolaemia was defined as a total serum cholesterol level greater than 6.39 mmol/l on two or more prospective visits or current use of lipid lowering agents. Hypertriglyceridaemia was defined as a serum triglyceride level greater than 1.69 mmol/l on two or more prospective visits. Total cholesterol (reference range 3.83–6.39 mmol/l), low-density lipoprotein (LDL) cholesterol (reference range 0–4.66 mmol/l), high-density lipoprotein (HDL) cholesterol (reference range >1.03 mmol/l), triglycerides (reference range 0.56–1.69 mmol/l), apolipoprotein A1 (reference range 1.02–2.15 mmol/l) and apolipoprotein B levels (reference range 0.59–1.55 mmol/l) were measured in fasting blood samples using standardized laboratory tests at the time of carotid ultrasound. All reference ranges were those habitually used in our centre.

SLE-related disease factors
SLE disease activity and cumulative damage were measured at the time of the carotid ultrasound in all SLE patients, using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) [29], the European Consensus Lupus Activity Measurement (ECLAM) [30] and the Systemic Lupus International Collaborating Clinics (SLICC) [31] damage index, respectively. Cumulative clinical manifestations of SLE were recorded. Renal disease was defined as the presence, at any time, of lupus nephritis, nephrotic syndrome or renal insufficiency due to lupus nephritis. Renal failure was defined as a serum creatinine level greater than 1.5 mg/dl on two or more prospective visits. Data on corticosteroid therapy included current therapy, cumulative dose and duration of use. Information on chloroquine, immunosuppressive agents (such as cyclophosphamide and azathioprine) and antiaggregant agents were also recorded. Various laboratory tests were performed at the time of carotid ultrasound, including: markers of chronic inflammation such as C-reactive protein (CRP) (reference range 0–0.008 g/l) or erythrocyte sedimentation rate (ESR) (reference range 1–15 mm/h); antibodies to native DNA (measured by Farr ammonium sulphate precipitation technique and indirect immunofluorescence with Crithidia lucillae as substrate); IgG and IgM anticardiolipin antibodies (measured by an ELISA technique as described by Gharavi et al. [32]); lupus anticoagulant was measured by coagulation assays following the recommendations of the subcommittee on lupus anticoagulant of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis [33].

Carotid ultrasound
Carotid ultrasound was performed with a Toshiba scanner (Power Vision) using a multifrequency duplex doppler transductor of 7.5–10 MHz for the real time imaging and 3.75 MHz for the doppler study. The scanning was performed at right and left carotid territories. The common carotid artery (1 cm proximal to bifurcation), carotid bifurcation and internal carotid artery (1–2 cm distal to the junction) were examined. For each location, the sonographer imaged the vessel in longitudinal and transverse planes, with 45° of neck rotation to the contralateral side. For each study the following parameters were assessed: (1) Intima-media wall thickness (IMT) in all territories. (2) The presence of plaque, defined as a focal or diffuse thickness of 1.2 mm or more. Plaque analysis included location, number and maximal height.

Statistical analysis
The statistical analysis was performed with SPSS/Windows statistical software (version 10.0). Mean values are reported with standard deviation (S.D.). Mean values of continuous variables were compared using the Student t-test or non-parametric Mann-Whitney U-test. The chi-square test and Fisher's exact test were performed to evaluate differences between categorical data in patients and controls. Multiple logistic regression analysis was performed. All statistical tests were two-tailed and only associations with P<0.05 were considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The traditional cardiovascular risk factors and lipid profile of SLE patients, primary APS patients and controls are shown in Table 1. SLE patients had a significantly higher prevalence of hypertension (P<0.005) and hypercholesterolaemia (P<0.05) than primary APS patients and controls, and higher hypertriglyceridaemia (P<0.05) than controls. SLE patients had higher total cholesterol (P = 0.03), triglycerides (P = 0.003) and apolipoprotein B (P = 0.04) levels than controls at time of ultrasound study. Seven SLE patients (5%) were receiving lipid lowering agents. In the multivariate analysis, hyperlipidaemia and hypertension in SLE patients were associated with the presence of renal disease (P = 0.004 and P = 0.01, respectively), greater SLICC score (P = 0.01 and P = 0.03, respectively) and ECLAM score (P = 0.02 and ns, respectively). In contrast, we found no relationship between hypertension, hypercholesterolaemia or hypertriglyceridaemia and the accrued dose of prednisone or the duration of prednisone treatment. Menopausal status, smoking and familial history of cardiovascular disease were similar in the three groups.


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TABLE 1. Profile of traditional cardiovascular risk factors, plasma lipid and lipoprotein concentrations

 
The sonographic findings are summarized in Table 2. The three groups presented a similar IMT. Twenty SLE patients (28.6%) had carotid plaque. SLE patients had greater prevalence of plaque than patients with APS or controls. In addition, SLE patients presented a greater number of plaques. The prevalence of plaque increased with age, with a third of SLE patients in the 35 to 44 years age group having plaque.


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TABLE 2. Ultrasound features of carotid artery

 
Sixteen SLE patients had a secondary APS. The prevalence and number of carotid plaque in SLE patients with secondary APS was greater than in primary APS patients (Table 3). Four of the sixteen SLE patients with secondary APS presented a history of arterial thrombosis (small vessel stroke) and were taking aspirin (300 mg/day) or anticoagulant therapy with acenocumarol. The remaining patients had only obstetric manifestations. Primary APS patients with arterial thrombotic events (small vessel stroke, n = 9) had a greater IMT than APS patients without arterial thrombotic events (0.60 vs 0.50, P = 0.03).


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TABLE 3. Ultrasound features in patients with secondary APS versus primary APS

 
SLE patients with plaque were older (47.3 ± 8.4 vs 37.3 ± 11.2, P<0.005), had greater age at diagnosis (31.9 ± 6.5 vs 26.8 ± 10.2, P = 0.04) and had a longer disease evolution (175.05 ± 91.85 vs 124.22 ± 66.96 months, P = 0.01) than SLE patients without plaque. Table 4 compares traditional cardiovascular risk factors in SLE patients with and without plaque. The presence of plaque was not associated with any of the clinical and serological SLE features analysed and we found no relationship between the presence of plaque and prednisone, immunosuppressive or chloroquine treatment (Table 5). SLE patients with plaque had higher levels of CRP and ESR than SLE patients without plaque; however, the levels of CRP for both groups were within hospital reference ranges. SLE patients with plaque also had higher ECLAM score (3.10 ± 2.32 vs 1.84 ± 1.59, P = 0.01) and greater SLICC score (2.40 ± 1.78 vs 1.02 ± 1.18, P<0.0005) than SLE patients without carotid plaque. Using logistic regression analysis, that included age, total cholesterol, apolipoprotein B, age at diagnosis, SLE duration, CRP and ESR levels, ECLAM and SLICC, the presence of plaque was associated with a greater age at study entry (P = 0.003), a higher ECLAM score (P = 0.02) and a higher SLICC score (P = 0.002).


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TABLE 4. Traditional cardiovascular risk factors, plasma lipids and lipoproteins in SLE patients according to the presence or not of carotid plaques

 

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TABLE 5. Disease and treatment related factors in SLE patients according to the presence or not of carotid plaques

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results of this study indicated a higher prevalence of preclinical atherosclerosis in SLE patients compared with primary APS patients or controls and this prevalence was associated with disease activity and chronicity.

Unlike other recent studies analysing the prevalence of carotid atherosclerosis in SLE patients [34–39], none of our patients had a previous history of coronary artery disease. Only in two previous studies [37, 39] SLE patients with previous coronary artery disease were also excluded, but neither was controlled.

This is the first study that compares preclinical atherosclerosis in SLE patients, patients with primary APS and age-matched controls. The number of primary APS patients included was halted at 25 as these patients were showing similar results to those of controls. We found a higher prevalence of carotid plaque in SLE patients with secondary APS compared with primary APS. In a recent study of patients with primary APS, the IMT correlated with the anticardiolipin antibody titre and was greater in thrombotic than in non-thrombotic subjects [40]. In another study of 28 patients with primary APS [41], patients with arterial thrombosis had a higher IMT than those without arterial thrombotic events, as in the present study, although we found no correlation between IMT and the different antiphospholipid antibodies (aPL) or their titres.

Our SLE patients had a greater prevalence of some traditional risk factors (hypertension, hypercholesterolaemia, hypertriglyceridaemia) than APS patients or controls, and were directly associated with disease-related factors. However, the presence of plaque in SLE patients was not associated with these traditional cardiovascular risk factors or with corticosteroid therapy. Hypertension, hyperlipidaemia and obesity may be present in SLE patients as a consequence of the disease or the treatment. Corticosteroid therapy has been implicated in the development of vascular disease in SLE patients [42–44]. Patients with more active, severe SLE will receive higher doses of corticosteroid therapy for a longer time, although the relationship between corticosteroids and vascular disease in SLE patients remains controversial. Most ultrasound studies in SLE patients have found an association between carotid plaque and corticosteroid therapy. Our SLE patients had a higher prevalence of hypertension and hyperlipidaemia related to SLE, which are associated with renal damage, greater chronicity and disease activity. Other independent cardiovascular risk factors such as smoking, family history, body mass index or postmenopausal status had a similar prevalence in the three groups.

In most previous studies, both the prevalence of carotid plaque and the IMT was higher than in our series. This might be because our patients were younger. Manzi et al. [34] and Svenungsson et al. [35] also found an association between the presence of plaque and chronicity, but in these studies the SLICC included cardiovascular disease, as patients with coronary events were included. In our series, six out of seventy SLE patients had arterial thrombotic events; in two, arterial thrombosis was related to vasculitis, and in four, to APS (small vessel cerebral vascular disease). We found carotid plaque in two of these six patients. Doria et al. [37] found no association between carotid abnormalities and age and cumulative prednisone dose. Selzer et al. [39] found that determinants of plaque included older age, higher systolic blood pressure, lower levels of LDL and antidepressant use. In the recent study by Roman et al. [38], independent predictors of plaque were longer disease duration, a higher damage-index score and a lower incidence of cyclophosphamide use. We found a higher prevalence of carotid plaque in the 35–44 years age group (33%), similar to that observed by Roman et al. [38] and superior to that observed by Manzi et al. [34] and in our control group. This confirms the early, accelerated atherosclerosis in SLE patients reported in various epidemiological studies, some of which found that SLE women in the 35–44 years age group were over 50 times more likely to have a myocardial infarction than controls [45].

The pathogenesis of cardiovascular disease in SLE is multifactorial, involving an interaction between inflammation-induced and aPL-mediated vascular injury/thrombosis from the underlying disease as well as traditional cardiovascular risk factors. Various factors, such as those that can produce endothelial injury (immune complexes, complement activation, CD40-CD40 ligand interactions) seen in SLE or inherent to the disease mechanism, may contribute to atherogenesis. SLE patients with more active, longstanding disease accumulate more damage and have more risk of developing atherosclerosis. Our patients with carotid artherosclerotic plaque had longer disease duration, a higher number of flares and a higher SLICC than patients without carotid plaque. The higher prevalence of carotid artherosclerotic plaque in SLE patients with secondary APS compared with primary APS patients suggests that, although the presence of aPL may contribute to atherogenesis, the participation of other factors (traditional cardiovascular risk factors, inflammatory and immune factors) which are present in SLE patients but not in patients with primary APS, is necessary.

In conclusion, our study confirms the existence of an accelerated, early atherosclerosis in some SLE patients. This early atherosclerosis is associated with cumulative disease damage and disease activity. A strict approach, including more aggressive control of traditional cardiovascular risk factors, intensive suppression of disease activity and early detection of preclinical vascular disease, is necessary in these patients.


    Acknowledgments
 
Supported in part by grants from FIS 2003/0280, FIS 2002/0711, FIS 2002/0696 and FIS 2000/1048 from Fondo de Investigaciones Sanitarias of Spain and Grant G03/181 from Instituto de Salud Carlos III, Spanish Ministry of Health.

The authors have declared no conflicts of interest.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 29 July 2004; revised version accepted 26 January 2005.