Centre for Rheumatology, Department of Medicine, University College London, London, UK
Correspondence to: D. Isenberg, Centre for Rheumatology, Department of Medicine, University College London, Arthur Stanley House, 4050 Tottenham Street, London W1T 4NJ, UK.
As we write this editorial, snow flurries are swirling around the country. Falling snow restricts visibility but once settled and on a clear day the bright reflected light often seems to increase visual acuity. By analogy, we will explore whether a recent flurry of papers on atherosclerosis in patients with systemic lupus erythematosus (SLE) has helped to shed light on this challenging clinical problem or whether we are still stuck in a period of reduced visibility.
Attention was first drawn to the increased risk of atherosclerosis and, in particular, death due to atherosclerosis in patients with SLE by Murray Urowitz and his colleagues in 1976 [1]. Subsequent studies have confirmed these findings, with reports of up to 30% of deaths in SLE patients being due to coronary artery disease [2, 3]. Despite the fact that survival has improved significantly over the past 50 yr, SLE remains a condition with significant morbidity. Although many effective treatments are now available for the severe organ-threatening manifestations, SLE has become a chronic disease entity. A large proportion of this burden of chronic disease is due to atherosclerotic vascular disease, even in young women. In 1997, Manzi et al. [4] compared women with SLE with age-matched controls in the Framingham cohort: not only was the incidence of myocardial infarction five times as high, but, in premenopausal women, the age-specific incidence was increased by a factor of 50.
Traditional risk factors for atherosclerotic vascular disease, including hypertension, obesity, diabetes mellitus, smoking, hyperlipidaemia, hyperhomocysteinaemia and sedentary lifestyle, do appear to explain the increased risks for patients with SLE [57]. However, there is consensus that, even after these factors are controlled for, the diagnosis of SLE remains the strongest risk factor for cardiovascular disease [4, 8]. One of the principal culprits has been presumed to be corticosteroid therapy, a treatment which nearly all patients with SLE will receive at some time: numerous studies found that longer steroid use resulted in poorer outcome [3, 4, 9, 10]. Corticosteroids may be directly atherogenic (via actions on plasma lipoproteins) or may serve to augment classical risk factors, such as hypertension, hyperlipidaemia and diabetes mellitus [5]. Furthermore, it has been suggested that, as it is the patients with more aggressive disease who receive larger cumulative doses of corticosteroids, disease severity may be the greater determinant of atherosclerosis [5].
The last decade has seen a burgeoning of interest in the field of atherosclerosis, to the extent that it has become a science itself. It is now recognized that atherosclerosis is an inflammatory disease: plaque formation requires complex interplay between components of the immune system and the expression of different patterns of genes rather that the simple accumulation of lipids [11, 12]. C-reactive protein (CRP) has been shown to be both a marker and, when elevated, a risk factor for cardiovascular disease independent of other classical risk factors [13]. This phenomenon has also been demonstrated in patients with lupus [14].
Much of the original work on atherosclerotic vascular disease in patients with SLE has relied on the recording of clinical events. Despite a relatively high frequency, the absolute number of such events is low and underestimates the actual prevalence of atherosclerosis in this population. In the last few years, there has been more focus on attempts to screen for preclinical disease rather than relying on clinical events. This may be especially pertinent in view of the need to develop other surrogate markers of atherosclerosis beyond the traditional (Framingham) markers. B-mode carotid ultrasonography has been found to be a reliable non-invasive method of detecting carotid atherosclerosis, which correlates strongly with the presence of coronary artery disease [14]. The original paper of Manzi et al. found that traditional cardiovascular risk factors, along with cumulative prednisolone dose, were the most important predictors of carotid plaque formation. Electron beam tomography (EBT) has also been found to be useful in identifying patients with carotid artery calcification, implying subclinical coronary artery disease [15]. High rates of abnormal myocardial perfusion, another potential surrogate for coronary artery disease, were recorded when myocardial perfusion scintigraphy was performed on patients with SLE [16]. The anklebrachial index is also more frequently abnormal in SLE than in the normal population (37 vs <4%) [17]. These techniques have suggested prevalence rates of between 28% [15, 16] and 40% [14, 17], often in patients with no other classical risk factors for atherosclerosis.
Chronic endothelial dysfunction plays a vital role in atherogenesis and may be the earliest demonstrable abnormality [12]. In the general population, factors such as hyperlipidaemia, smoking, diabetes, hypertension and hyperhomocysteinaemia are contributory. Endothelial dysfunction is measured using flow-mediated dilatation and is frequently abnormal in patients with SLE compared with normal controls [18]. Although traditional cardiovascular risk factors appear to play a role, these results are often observed in patients without such risk factors. Pulse wave velocity analysis, a measure of vascular stiffness and a probable marker of early vascular disease, is also more frequently abnormal in patients with SLE [19]. Furthermore, anti-endothelial cell antibodies have been demonstrated in the sera of SLE patients and seem to be related to disease activity: a pathogenic role has been suggested but not yet proven [20].
A proatherogenic lipid profile has been observed in SLE that has long been presumed to be secondary to corticosteroid therapy. This profile is characterized by high plasma triglycerides, low-density lipoproteins (LDL) and very-low-density lipoproteins and low high-density lipoproteins (HDL) [21]. It has, however, been reported that patients with SLE produce antibodies against plasma lipoproteins and their constituents that may augment this dyslipidaemic state. As long ago as 1993, antibodies to oxidized LPL (oxLDL) were identified and found to cross-react with anticardiolipin antibodies (ACL) in SLE [22]. Antibodies to oxLDL are considered a marker of atherosclerosis and a predictor of future coronary events [23]. Recently, antibodies to both apolipoprotein A-I (a major component of the HDL complex) and to HDL itself have been identified and also found to cross-react with ACL [24]. As these lipoproteins are increasingly considered to be protective against atherosclerosis, the presence of such antibodies may contribute to the accelerated atherosclerosis observed both in SLE and the antiphospholipid syndrome [25]. HDL contains an antioxidant enzyme, paraoxonase, which acts to prevent the oxidation of LDL. In patients with lupus, a significant reduction in paraoxonase activity has been observed which correlates with titres of anti-HDL antibodies [26]. Since paraoxonase regulates the oxygenation of lipoproteins (it is oxygenated lipoproteins which help to form foam cells), any interference in its action, for example by antibodies to it, is likely to be proatherogenic. Furthermore, levels of tumour necrosis factor (TNF-
) have also been found to be correlated to plasma triglycerides in patients with lupus and a history of coronary artery disease. It is postulated that TNF-
may be implicated in lupus-related atherogenesis by promoting hypertriglyceridaemia and vascular inflammation [27].
These recent insights into the possible pathogenesis of atheroma in SLE are contributing pieces to a complex puzzle. Two recent articles in the New England Journal of Medicine make further contributions and question what has been widely believed thus far [28, 29]. These independent studies used surrogate markers of vascular disease (carotid ultrasound and EBT) to study the prevalence of atherosclerosis in women with SLE. Both studies reported higher rates of atherosclerosis at all ages (rates of 3137% compared with 915% of controls). Independent associations were observed with age, hypertension and SLE itself. However, both studies found no correlation with cumulative corticosteroid dose. In fact, the study of Roman et al. [28] recorded lower rates of atherosclerosis in the patients with higher mean doses of steroid and immunosuppressant medication (hydroxychloroquine and cyclophosphamide) [28]. This implies that more aggressive disease control may serve to prevent atherogenesis. The negative correlation with the use of hydroxychloroquine has been reported previously and attributed to its lipid-lowering potential [3]. However, this study reported no association between lipid levels and treatment with hydroxychloroquine. Furthermore, the autoantibody profile of patients without plaque appeared to differ from that of patients with plaque: lower rates of anti-Sm, anti-RNP and ACL antibodies were observed in the women without plaque. The authors went on to postulate that these differences may represent two patterns of SLE: a more chronic, less aggressive disease which potentiates atherogenesis via continual low-grade inflammation, compared with a more autoimmune, aggressive disease state in which atherosclerosis is less likely. The latter would be the more likely to be treated with potent immunosuppression.
These new findings have implications for both screening and preventing atherosclerosis in our patients with lupus. Thus far, there has been emphasis on screening for and treating conventional cardiovascular risk factors. However, there are no data to suggest that this affects the prevalence of atherosclerosis or cardiovascular events in patients with SLE. The evidence to suggest that other factors are contributory is strengthening, especially with new insights into the pathogenesis of atheroma in SLE. Clearly, further work is needed to elucidate these pathogenetic mechanisms; however, randomized controlled clinical trials are required to reveal the utility of conventional cardiovascular screening in our patients before such costly and time-consuming measures are fully embarked upon. Another point worthy of investigation is the possible effect of statins on the disease manifestations of SLE. In addition to their lipid-lowering activity, these agents have also been found to have pleiotropic effects on the immune system, inflammatory pathways and vascular endothelium [12]. Such effects suggest that they may have the potential to modify disease activity in patients with SLE.
In conclusion, when considering atherosclerosis in patients with SLE, it seems to us that while it may still be snowing, the storm is passing, dawn is breaking and visibility is definitely improving.
The authors have declared no conflicts of interest.
References
|