Therapy Insight: systemic lupus erythematosus as a risk factor for cardiovascular disease
Sahena Haque and Ian N Bruce* About the authors
Correspondence *Arthritis Research Campaign Epidemiology Unit, Stopford Building, Oxford Road, Manchester M13 9PT, UK
Email ian.bruce@manchester.ac.uk
Summary
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with a strong female predilection. Cardiovascular morbidity and mortality is a frequent complication, particularly in females aged 35–44 years, in whom the risk of myocardial infarction is raised 50-fold. The mechanisms underlying this increased risk are not fully understood. Certain traditional risk factors, such as hypertension and diabetes mellitus, are more common in SLE patients than in the general population. These factors do not, however, completely account for the increased cardiovascular risk; factors such as renal impairment, increased homocysteine levels and early menopause probably have a role. In addition, several factors more-specifically related to lupus are proposed to be of importance, including chronic inflammation, antiphospholipid antibodies and therapy, especially corticosteroid use. Thus, we need to be proactive in our approach to risk-factor management in SLE patients. Here, we propose that, like diabetes mellitus, SLE should be considered a coronary heart disease equivalent condition for baseline risk and that assessment of cardiovascular risk should be done routinely. In addition to lifestyle modifications, blood pressure and cholesterol levels should be stringently controlled, and administration of aspirin should be considered in selected patients. The increased use of certain interventions, such as statins, also needs to be more-widely investigated in this population.
Review criteria
We searched Medline from 1975 to the present for English-language papers using the keywords "systemic lupus erythematosus", "atherosclerosis", "coronary heart disease", "inflammation", "chronic kidney disease", "mannose-binding lectin", "homocysteine", "chloroquine" and "corticosteroids". The first three terms were crossreferenced with the other terms. We also manually searched for relevant abstracts from the American College of Rheumatology and British Society for Rheumatology annual scientific meetings for the last 5 years.
Introduction
Systemic lupus erythematosus (SLE) is a complex multisystem inflammatory disease caused by autoimmune dysregulation. There is a marked female predominance (female-to-male ratio between 9:1 and 13:1) and the disease is more prevalent in African Americans, Afro-Caribbeans and Asians from the Indian subcontinent.1, 2 The recognition and management of SLE has improved over the past few decades and survival rates have improved since the 1950s. There remains, however, a significantly higher mortality in patients with SLE than in the general population, with the 10–15 year survival rate estimated to be 85%. As the longevity of patients with SLE improves, the long-term sequelae of this disease are becoming increasingly apparent.3, 4
In 1976, Urowitz et al.5 observed a bimodal pattern of death among patients with SLE: those who died early in the course of disease had active disease and a high incidence of infection associated with treatment with high doses of corticosteroids, whereas those patients who died later in the course of the disease all suffered a myocardial infarction (MI) at the time of death. Several studies have since confirmed this observation. Patients with SLE are five to six times more likely to have a significant coronary event than people in the general population.6, 7 In particular, when compared with rates of cardiovascular events in the Framingham Offspring Study,7 it was determined that patients with SLE aged between 35 and 44 years from the Pittsburgh cohort were over 50 times more likely to have an MI.
Traditional risk factors, such as hypertension, diabetes mellitus and obesity, have a significant role in atherogenesis and in the development of premature atherosclerosis in patients with SLE. As discussed in this review, however, these factors alone do not fully account for the increased risk observed. We review the additional risk factors that should be included in risk assessments for SLE patients and discuss how these should impact on our management decisions if we are to reduce the rates of cardiovascular morbidity and mortality seen in these patients.
Subclinical disease
The premature atherosclerosis that occurs in patients with SLE does not only affect patients with clinically apparent disease. Several studies have attempted to determine the prevalence of subclinical atherosclerosis in SLE by different methods. Hosenpud et al.8 studied 26 nonselected patients with SLE and found that 38% of patients with no prior history of clinical atherosclerosis and who were younger than 50 years of age had abnormalities on exercise 201Tl myocardial imaging, consistent with cardiac ischemia. Similarly, in another uncontrolled study of 130 patients with SLE, 35% of patients without clinically evident atherosclerosis were found to have evidence of subclinical disease on SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY–DUAL ISOTOPE MYOCARDIAL PERFUSION IMAGING (SPECT–DIMPI).9 Subclinical disease detected by this method has also been found to correlate with abnormalities in the anatomy of coronary vessels, and with future significant cardiovascular events. Sella et al.10 demonstrated myocardial perfusion abnormalities in 30 of 90 patients (33%) studied. Coronary angiography was performed in 21 of these patients (mean age 42 years), of whom 8 (38%) were found to have significant coronary-artery stenosis. One subsequently died from acute MI complicated by a cerebrovascular accident and four underwent revascularization procedures. Studies using a control group also confirm that the prevalence of subclinical disease is higher in SLE patients. A case-controlled study of 197 patients with SLE and age-matched controls (mean age 44 years) demonstrated that carotid plaques, as detected by B-MODE DOPPLER ULTRASOUND, were significantly more prevalent in SLE patients than in controls (37.1% versus 15.2%; P <0.001).11
Taken together, the data derived from these studies, which predominantly included women with a mean age of over 50 years, confirm the burden of atherosclerosis in patients with SLE and support the notion that premature atherosclerosis contributes to cardiovascular disease in this group of patients. The reason for this vulnerability remains unclear, although several lines of evidence suggest that it arises because of complex interactions between traditional cardiovascular risk factors with other SLE-specific factors.
Traditional risk factors
The importance of classic risk factors for cardiovascular disease in the general population is well established; however, the impact of these factors on cardiovascular disease in patients with SLE is less clear and has been the subject of several studies. The prevalence of some risk factors, such as age, hypertension and in particular hypercholesterolemia, has been linked with both subclinical and clinical atherosclerosis.10, 11, 12, 13 SLE has been associated with adverse lipid profiles, including increased serum levels of total cholesterol, triglycerides and LDL cholesterol.14 In a cross-sectional study of the prevalence of classic risk factors in the Baltimore lupus cohort, a high proportion of SLE patients (53%)15 were found to have three or more classic risk factors, the most prevalent being a sedentary lifestyle (70%), obesity (56%) and hypercholesterolemia (56%). A cohort-controlled study in Toronto assessed the prevalence of traditional risk factors in 250 women with SLE in comparison with age-matched, healthy control women.16 Women with SLE had a significantly higher prevalence of hypertension (33% versus 13%; P <0.01) and diabetes mellitus (5% versus 1%; P <0.01), and significantly higher serum levels of VLDL cholesterol and total triglycerides than the controls. Also, despite being matched for age, women with SLE were more likely to be postmenopausal (38% versus 19%, P <0.01) and experienced the menopause on average 4 years earlier than women in the control group. Therefore, patients with SLE do have a higher prevalence of traditional risk factors. Esdaile et al.17 noted, however, that the Framingham risk factors do not fully account for the disease burden seen in patients with SLE. They observed that patients with SLE still had a 10-fold higher risk of nonfatal MI and a 17-fold higher risk of death related to coronary heart disease than would be expected taking into account the traditional risk factors present. Similar results were also obtained in a retrospective longitudinal study of 47 SLE patients with clinically evident cardiovascular events over a 10-year period. The observed rate of cardiovascular events in this group was significantly greater than the 10-year risk-prediction calculation using the Framingham data model.18
Lupus-specific risk factors
Steroid therapy
Manzi et al.7 established in the Pittsburgh cohort that certain risk factors were more common in SLE patients with cardiovascular events than in those without events, including older age at diagnosis, longer disease duration, hypercholesterolemia, postmenopausal status and longer duration of corticosteroid therapy. Petri et al.19 also showed an association between risk factors and steroid exposure in the Baltimore cohort. The association between atherosclerosis and corticosteroid use in this group of patients is perhaps not surprising, given the adverse effects of this drug on the development of hypertension, dyslipidemia and diabetes mellitus. Indeed, as early as 1975, Bulkley et al.20 found evidence of atherosclerosis in over 50% of autopsy specimens from patients with SLE who had been treated with corticosteroids for more than 12 months. With regard to specific risk factors, in a study comparing 46 SLE patients with healthy controls, the SLE patients had significantly raised triglyceride and LDL cholesterol levels, and significantly lower HDL cholesterol levels.21 This profile was further exaggerated in those patients from this group who were treated with steroids (n = 14). Leong et al.14 found similar results in SLE patients treated with more than 30 mg prednisolone daily.14
The association between atherosclerosis and steroid therapy might, however, be more complicated than at first thought. Roman et al.11 noted that SLE patients with carotid plaques were less likely to have been treated with prednisolone or cyclophosphamide than patients without such plaques, indicating perhaps that improved disease control with immunosuppressants would be protective against the development of atherosclerosis, or that reduced steroid exposure indicates a subgroup of patients with low-grade grumbling disease activity and inflammation who are not clinically considered for steroid therapy. In addition, MacGregor et al.22 showed that SLE patients treated with prednisolone at a daily dose of greater than 10 mg (or an equivalent regimen) 6 months before testing had significantly higher levels of triglyceride and apolipoprotein B than controls. By contrast, lipid profiles in SLE patients taking less than 10 mg prednisolone daily did not differ significantly from controls.22
Steroid exposure is clearly an important factor. Since it is, however, also a surrogate for the underlying inflammatory disease severity, as well as perhaps patients' longevity, its exact role is difficult to determine. In addition, the effects of prior therapy can be hard to ascertain retrospectively for a variety of reasons. Comparisons are difficult because measures to quantify exposure (e.g. cumulative doses or duration of exposure) have differed between studies. In practice, therefore, judicious use of steroids to control inflammation is probably beneficial. Excessive dosing may exacerbate metabolic factors. Achieving the correct balance, therefore, remains a major clinical challenge.
Inflammation
The concept of atherosclerosis as an inflammatory condition has gained increased acceptance over the past decade (Figure 1).23 The process is thought to be driven by activation of mononuclear cells triggered by various factors, including free radicals caused by cigarette smoking.23 This finding is supported by observations of a correlation between infections and atherosclerosis, for example the association between strokes and MI in respiratory-tract infections.24, 25 Activation of monocytes and T lymphocytes are believed to lead to the release of chemotactic factors, which promote further accumulation of mononuclear cells and subsequent migration into the vessel wall early in the formation of the atherosclerotic plaque.23, 26 Furthermore, in a case-control study of 34 patients with unstable angina compared to a group with stable angina, clonally expanded T cells were found in association with unstable atherosclerotic plaques.27 In this study, similar T-cell receptor sequences were found in different patients, implying that chronic antigenic stimulation by a common antigen, possibly caused by inflammation or infection, contributes to plaque instability and rupture.
Figure 1 Schematic summary of atherosclerosis development emphasizing the inflammatory nature of the process.
(A) Early in the process LDL cholesterol is oxidatively modified, which promotes endothelial dysfunction (reduced nitric oxide synthase activity) and expression of adhesion molecules, both of which have been observed in patients with systemic lupus erythematosus. (B) Circulating monocytes and lymphocytes migrate to the subendothelial space, where, under the influence of several factors, oxidised LDL cholesterol is taken up by macrophages to form foam cells. Antibodies to 
2-glycoprotein I might facilitate this process in systemic lupus erythematosus. (C) Macrophage secretion of growth factors promotes migration of vascular-smooth-muscle cells to the intima, as well as their proliferation. The T cells are chiefly of the T-helper-1 phenotype and produce several cytokines that can promote a systemic inflammatory response by stimulating production of interleukin-6 and C-reactive protein. Arrows denote positive effects; blocking arrows denote negative effects. 2GPI, 2-glycoprotein I; CRP, C-reactive protein; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; FcRs, Fc receptors; IL-6, interleukin 6; IFN-
, interferon gamma; SR, scavenger receptor; SLE, TH1, T helper 1 cells; VSMC, vascular-smooth-muscle cell.
A clinical correlation can be made between the inflammatory phenotype in SLE and coronary events, for example the increased occurrence of previous pericarditis in patients with atherosclerosis.8 In addition, increased levels of serum C-reactive protein were found to correlate with clinical cardiovascular disease in SLE patients.12 This inflammatory marker has also been shown to be predictive of future coronary events in postmenopausal women in the general population.28 This concept is particularly interesting and relevant, given that inflammation is the hallmark of SLE.
Antiphospholipid antibodies
When considering factors involved in the development of arterial disease in patients with SLE, obvious culprits for consideration are ANTIPHOSPHOLIPID ANTIBODIES (aPL). The prothrombotic nature of these antibodies is well established in the context of the ANTIPHOSPHOLIPID SYNDROME (APS).29 Antiphospholipid antibodies are found in 30–40% of patients with SLE.30 The association between these antibodies and cardiovascular disease is, however, unclear: studies have reported a positive correlation,12, 31 no correlation13 or a negative correlation11 between these factors. In addition, small controlled studies have shown conflicting findings with regard to the presence of atherosclerosis on carotid Doppler imaging as a surrogate marker in primary APS.32, 33 Importantly, a prospective case-control study of the general population nested within the Helsinki Heart Study34 demonstrated significantly higher baseline levels of anticardiolipin antibodies (aCL) in patients with MI or cardiac death, independent of other traditional risk factors.34 Crossreactivity between aCL and antibodies to oxidized LDL has also been reported.35 Serum lipoproteins contain phospholipids and modified LDL. Therefore, it is conceivable that these serum lipoproteins might be a target for aPL. In this context, oxidized LDL has been found in atherosclerotic plaques.36 Although the possible association between aPL and oxidized LDL is interesting, the exact nature and function of these antibodies is unknown. The key antigenic target for aPL is 2-GLYCOPROTEIN I. In vitro studies have found that 2-glycoprotein I inhibits uptake of oxidized LDL by MACROPHAGE SCAVENGER RECEPTORS, but that in the presence of antibodies to 2-glycoprotein I, uptake of oxidized LDL by FC RECEPTORS is increased.37 In addition, complexes of 2-glycoprotein I and oxidized LDL, and antibodies recognizing these complexes, are frequently found in sera of patients with SLE and APS, and are associated with the presence of arterial thrombosis.38 Another study showed that healthy men with aCL and oxidized LDL had a higher frequency of future cardiovascular mortality.39
Lahita et al.40 found that SLE patients who had aCL and who were not treated with steroids had reduced triglyceride, HDL cholesterol and apolipoprotein A-I levels compared with aCL-negative SLE patients.40 Of relevance, Delgado et al.41 demonstrated that patients with SLE and primary APS have significantly higher titers of antibodies to both apolipoprotein A-I and HDL cholesterol than controls. In vitro studies of sera from these patients demonstrated crossreactivity between HDL antibodies and aCL, and between apolipoprotein A-I antibodies and aCL.41 Again, the role of these antibodies is not clear. Interestingly, a mouse model using LDL-receptor-deficient animals demonstrated that PASSIVE ADMINISTRATION of aCL to these mice resulted in significantly reduced plaque formation, suggesting a protective role for these antibodies.42 Further studies are clearly required to further clarify the function of aPL, as current evidence is conflicting. It is likely that certain subtypes of aPL are proatherogenic whereas others are atheroprotective. The prothrombotic role of these antibodies might not, therefore, be the only mechanism of relevance in SLE patients.
Other risk factors
Renal disease
In addition to the factors discussed previously, renal disease, which is common in patients with SLE, is a potential risk factor for the development of arterial disease. The importance of renal disease in the pathogenesis of dyslipidemia, hypertension and atherosclerosis is well documented,43 and impaired renal function has been associated with subclinical atheroma in SLE.44 This association is not, however, consistently seen in all studies: for example, Roman et al.11 did not find any significant association between carotid plaque formation and renal disease in SLE patients. The methods used to measure renal disease need to be considered. The extent of renal function is usually based on plasma creatinine levels, but a more refined assessment using estimated creatinine clearance might provide a greater insight into the role of renal impairment in SLE patients.
Homocysteine levels
Raised levels of homocysteine have been shown to correlate with atherosclerosis in SLE in some studies, and have previously been shown to be a significant factor in cardiovascular events in SLE.12, 16 Studies by Petri et al.45, 46 have shown an association between homocysteine levels and the development of stroke and arterial thrombotic events in patients with SLE. Whether intervening to reduce homocysteine levels in SLE will have a role in primary or secondary prevention remains unclear.
Mannose-binding lectin
Mannose-binding lectin is a protein capable of activating the COMPLEMENT CASCADE by the lectin pathway. The frequency of polymorphisms in the mannose-binding lectin genes that result in reduced levels of mannose-binding lectin protein is higher in patients with SLE than in controls.47 Deficiency in mannose-binding lectin is associated with increased risk of infections and atherosclerosis. A small prospective study showed that six of seven SLE patients with homozygous mannose-binding lectin gene mutations subsequently developed an arterial thrombosis (two patients had cerebral infarction and four had acute MI) with a hazard ratio of 7 (95% CI 1.9–25.2). In contrast, there was no increased risk for venous thrombosis.48 The interaction between mannose-binding lectin and the complement cascade is interesting. The complement system has a role in immune complex and antigenic clearance, and individuals who are deficient for the C1q component of complement present with early-onset, severe SLE. Complement-cascade dysfunction is clearly central to the pathogenesis of SLE and its precise role in the pathogenesis of atherosclerosis development in this condition is a subject of ongoing study.
Potential for risk modification
Given the nature of the risk and the population affected, it is apparent that we not only need to be aware of the risks to SLE patients but we also need to be proactive in our approach to their management. There are no clinical trials on which to base such recommendations, but given the magnitude of the cardiovascular risks associated with SLE, we propose that (like diabetes mellitus) SLE should be considered a 'coronary heart disease-equivalent' condition for baseline risk.49, 50 A holistic approach to patients with SLE should include assessment of their risk. Advice regarding lifestyle measures, including weight loss, smoking cessation and exercise, should be offered and there is evidence that diet control may help improve dyslipidemia in this context.51 The need for stringent control of active disease and associated factors such as proteinuria is further advocated by the above findings, but iatrogenic risks, such as corticosteroid therapy, should also be minimized. In this context, antimalarial drugs such as hydroxychloroquine are commonly used in the management of mild SLE. The use of these drugs is further merited by their beneficial effect on lipid profiles particularly in the setting of corticosteroid therapy.52 The use of statins is of particular interest in this group of patients, as patients with SLE are known to have a high prevalence of dyslipidemia. This class of drug not only has a favorable effect on lipoprotein metabolism but also has an increasingly recognized immunomodulatory role.53 Our view is that statin therapy should be used more widely in SLE patients, specifically to achieve a stringent LDL cholesterol target of below 2.6 mmol/l (100 mg/dl)49 The use of aspirin is well established in patients with aPL. Recent decision-analysis modeling has suggested that primary prophylaxis with aspirin is beneficial to all patients with SLE.54 In support of this finding, Leung et al.55 have reported the beneficial effect of low-dose aspirin in a cohort study of SLE patients. The argument could be made, therefore, that most patients with SLE should be given aspirin, although this approach needs to be further studied. Finally, blood-pressure control should be a high priority in SLE patients, among whom the prevalence of hypertension is increased compared with the general population. A blood pressure target of <130/80 mmHg should be aimed for, and, as in the general population, combination antihypertensive therapy should be used if necessary. We have suggested that angiotensin-converting-enzyme inhibitors should be the favored second-line antihypertensive agent in this context and that they may also have a wider role in patients with known diabetes mellitus, left-ventricular hypertrophy or proteinuria.49 We have made these recommendations because there is good evidence that physicians have not appropriately addressed cardiovascular risk factors in SLE patients.56
Conclusions
Despite it being nearly 30 years since the fascinating link between SLE and coronary heart disease was first reported, many questions remain unanswered. Further research is required to identify and clarify the role of risk factors and to enable risk stratification for these patients. For the time being, the following facts are clear: there is a significantly increased risk of coronary heart disease in patients with SLE and some risk factors that have been identified are modifiable. Nevertheless, there are no large-scale clinical trials of interventions on which to base any firm recommendations for primary prevention. Multinational trials of this kind are vital in order to provide a rational basis on which to build sound evidence-based strategies that will hopefully enable us to continue to improve the morbidity and mortality of patients with SLE over the next few decades.
Acknowledgments
We acknowledge the support of the Ontario Lupus Association (Geoff Carr Lupus Fellowship), The Heart and Stroke Foundation of Ontario, The Arthritis Research Campaign (UK), Lupus UK, The Wellcome Trust and the charitable funds of Central Manchester and Manchester Children's University Hospital NHS Trust.
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Competing interests
The authors declared no competing interests.
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Subject areas under which this article appears: Vascular disease | Concomitant disease
