Prevention of cardiovascular disease in systemic lupus erythematosusproposed guidelines for risk factor management
J. Wajed,
Y. Ahmad,
P. N. Durrington1 and
I. N. Bruce
The University of Manchester, Rheumatism Research Centre and 1Department of Medicine, Manchester Royal Infirmary, Central Manchester and Manchester Children's University Hospitals NHS Trust, Oxford Road, Manchester M13 9WL, UK.
Correspondence to: I. N. Bruce, University of Manchester, Rheumatism Research Centre, Central Manchester and Manchester Children's University Hospitals NHS Trust, Oxford Road, Manchester M13 9WL, UK. E-mail: Ian{at}fs1.ser.man.ac.uk
 |
Introduction
|
---|
In the past 23 decades it has become increasingly recognized that accelerated atherosclerosis and its sequelae are a major cause of morbidity and mortality in systemic lupus erythematosus (SLE) [1]. The consequences of this include an increased risk of cerebrovascular and coronary heart disease (CHD). To date there has been no formal attempt to devise and adapt population guidelines for prevention of CHD in the context of SLE, although several targets values have been suggested [2, 3]. Given the risk associated with SLE, it would seem important to identify potentially modifiable risk factors and introduce evidence-based guidelines that would aid clinicians in planning strategies that may help to reduce long-term cardiovascular morbidity in SLE. The aim of this review is to develop a firm rationale for risk factor management for patients with SLE, based on the approach we have initiated at the Manchester Royal Infirmary Lupus and Connective Tissue Disease Clinic.
 |
Evidence for an increased risk of CHD in SLE
|
---|
Overall, patients with SLE have 510 times the risk of CHD-related events compared with the background population [25]. In particular, Manzi et al. [4] found that women aged 3544 yr with SLE had a 50-times greater risk of myocardial infarction (MI) relative to healthy women in the Framingham Offspring Study cohort. In attempting to determine the absolute risk of developing CHD in SLE, two recent cohort studies have addressed this issue. In an inception cohort study, Bruce et al. [6] noted that over a mean of 12.4 yr of follow-up, 13.4% developed a new CHD-related event. Similarly, Esdaile et al. [7] in two Montreal hospital cohorts found that over a mean follow-up period of 8.6 yr, 12.9% developed CHD. The 10-yr risk of CHD-related events in SLE is therefore approximately 1315% [5, 6].
As a comparison, Haffner et al. [8] noted that patients with type II diabetes mellitus had a 20.2% risk of CHD over 7 yr of follow-up, a risk not dissimilar to that observed in non-diabetic subjects with pre-existing CHD (18.8%). As such, type II diabetes mellitus is now classified, by the Adult Treatment Panel III Guidelines (ATP III), as a CHD-equivalent condition for the purposes of CHD prevention [9]. Clearly these studies are not directly comparable and there are several important points to note regarding SLE. First, in contrast to CHD and type II diabetes mellitus, most patients with SLE are female. Women start with a much lower baseline risk of CHD [10]. Secondly, the mean ages of cohort entry in these two SLE studies were 35 and 39 yr, respectively [6, 7], compared with 58 and 56 yr, respectively, for the type II diabetes mellitus and CHD cohorts [8]. Since increasing age is associated with CHD risk in SLE [6, 7], it is highly likely that as patients with SLE get older, the incidence rate of new CHD events may continue to increase. As such, a 1315% 10-yr risk in a predominantly young female SLE population argues strongly for considering SLE also to be a CHD-equivalent condition. It is this approach that forms the rationale behind the individual guidelines we propose.
The reason for this increased risk of CHD is likely to be multifactorial. Established risk factors are important, but do not, however, fully explain the increased risk of CHD in SLE. Several studies of prevalent clinical or subclinical atherosclerotic disease have reported that factors such as hypercholesterolaemia, hypertension and obesity increase the risk of CHD. In a single centre cohort study, Bruce et al. [6] noted that of patients who had consistently elevated total cholesterol (>5.2 mmol/l), 26% developed new CHD events over a 12-yr follow-up period. Serum cholesterol independently predicted the risk of CHD in this cohort [6]. Similarly, in a study of carotid plaque development in a cohort of women with SLE, Manzi et al. [11] found that increasing age, hypertension and increased low-density lipoprotein (LDL) cholesterol were all significant predictors of plaque development. However, Rahman et al. [12] found that at the time of their coronary event, patients with SLE have on average one less conventional risk factor compared with a control cohort of patients with accelerated atherosclerosis, but without SLE. Esdaile et al. [7] also found that after adjusting for the baseline risk of CHD estimated using the predictive Framingham risk factor estimate, patients with SLE still had a 7- to 10-fold increased risk of CHD and stroke.
Additional metabolic, inflammatory and immunological factors as well as therapy with agents such as corticosteroids are therefore also likely to be of relevance. In particular, renal impairment and proteinuria are likely to have an adverse effect on cardiovascular risk in this population [2]. Furthermore, there is emerging evidence that additional factors such as endothelial dysfunction may also be more prevalent in SLE [13, 14] and recently, reduced paroxonase activity has been noted in SLE [15]. This may increase lipid peroxidation and further enhance atherogenesis in the context of chronic inflammation. The impact of such factors on future cardiovascular risk remains to be determined. Such additional factors are likely to have the effect of rendering patients with SLE more susceptible to the effects of conventional atherogenic factors (Fig. 1). For example, Rahman et al. [12] showed that the mean total cholesterol in patients with premature CHD in the general population was 6.9 mmol/l compared with 6.1 mmol/l in SLE patents with CHD. Established risk factors may therefore play an even more important role in the development of CHD in SLE than in the general population. Modification of classic risk factors is likely to have an impact on the risk of CHD in SLE. However, we recognize that additional studies are needed to identify other factors that will further impact the risk of CHD in SLE.

View larger version (10K):
[in this window]
[in a new window]
|
FIG. 1. Summary of the probable influence of classic risk factors on CHD risk in SLE. Patients with SLE may be more susceptible to the effects of risk factors than the general population.
|
|
 |
Individual risk factors
|
---|
Use of risk prediction formulae
Population screening and decisions on interventions for the primary and secondary prevention of cardiovascular disease is assisted by risk assessment charts or computer programs based on the Framingham risk equations [9, 16]. The Framingham risk equations, whilst predicting a higher CHD risk in patients with SLE [17], still underestimate the true CHD risk in these patients [7]. As such, SLE should be included in the group of conditions in which the use of these prediction charts are inappropriate. Individual targets for each risk factor in turn therefore need to be employed (Table 1).
Cholesterol
There is considerable evidence that dyslipidaemia occurs in SLE, partly related to inflammatory disease activity and partly to steroid therapy. Depending on the exact definition used, hypercholesterolaemia is found in 3451% of patients with SLE [17, 18]. Additional alterations in lipids seen in SLE patients include low high-density lipoprotein (HDL) cholesterol and raised triglycerides, which occur as a consequence of inflammatory disease activity and/or steroid therapy [19, 20]. Raised total cholesterol is predictive of future CHD events in SLE [6].
In recent guidelines regarding lipid modification in the general population, the Adult Treatment Panel III Guidelines (ATP III) point out that LDL cholesterol is the key lipid parameter on which lipid modification should be based [9]. This reflects the increasing evidence base to support LDL reduction as a key strategy for reducing future risk of CHD in the general population [9]. The target LDL cholesterol is determined by the overall predicted risk of CHD that the patient has once other factors are taken into consideration. A more stringent target is employed for patients with prevalent CHD than for patients with no other risk factors. It is therefore our view that since SLE can be viewed as a CHD-equivalent condition, the targets for LDL cholesterol should be derived from those used in diabetes mellitus.
As such we propose the following lipid targets for patients with SLE.
- Screening should involve measuring a fasting lipid profile, namely total, HDL and LDL cholesterol as well as triglyceride levels. This should be performed on at least an annual basis. LDL cholesterol can be directly measured or calculated from the lipid profile using the Friedwald formula (for measurements in mmol/l):
- For LDL cholesterol <2.6 mmol/l: no further action should be taken, but the lipid profile should be reviewed annually.
- For LDL cholesterol 2.63.4 mmol/l, therapeutic lifestyle changes should be introduced and the patient's progress on achieving the ideal target reviewed every 36 months. Such changes include dietary modification, i.e. saturated fat <7% of total calories, total fat 2535% of total calories and fibre 2030 g/day. Weight reduction and an increase in moderate physical activity is also suggested. In addition, plant stanols and increased soluble fibre intake may enhance LDL reductions [9]. It may be useful to attempt to review the steroid dose in this group as well as consider the introduction of an antimalarial drug, while controlling disease activity at a minimum [21, 22]. A cholesterol-lowering diet has been found to be of some benefit in SLE. Hearth-Holmes et al. [23] found that total and LDL cholesterol and triglyceride levels could be successfully reduced through dietary management.
- Drug therapy (statins) should be considered when LDL is >3.4 mmol/l with or without other risk factors, or when LDL is persistently >2.6 mmol/l even after therapeutic lifestyle changes [9, 16].
The overall aim of management is therefore to achieve a reduction in LDL cholesterol to <2.6 mmol/l.
Hypertension
Hypertension is a common risk factor in SLE patients [18, 24] and patients with SLE are more likely to be hypertensive than population controls [17]. It is associated with renal impairment, steroid therapy and a sedentary lifestyle. It is also more common with increasing age and in subjects of Afro-American ethnicity [18]. In a prospective study of patients with hypertension in SLE, Rahman et al. [24] observed that hypertension was associated with an increased risk of CHD events, and was associated with hypercholesterolaemia. Others have noted that hypertension is associated with clinical CHD [25] and subclinical atherosclerosis [11]. Given this strong association and a greater risk in patients with SLE, interventions to control blood pressure need to be instituted.
- Patients should have regular blood pressure assessments at every clinic visit and at least annually.
- As recommended for patients with diabetes, we suggest that the ideal target is to maintain the blood pressure at <130 mmHg systolic and <80 mmHg diastolic [26]. With a minimal acceptable level of <140 mmHg systolic and <90 mmHg diastolic [26].
- In patients with elevated blood pressure (>140 mmHg systolic or >90 mmHg diastolic), the blood pressure should be reviewed closely and lifestyle advice offered with an emphasis on approved non-pharmacological measures [26]. In the context of SLE, renal function should also be assessed and steroid therapy closely reviewed.
- If, despite these measures, the blood pressure is persistently found to be >140 mmHg systolic or >90 mmHg diastolic, then antihypertensive medication should be considered. The drug of choice will be determined by the patient's additional co-morbidities. While low-dose thiazide diuretics seem an effective first-line treatment [26], in many patients a second agent is likely to be necessary to achieve a target blood pressure. An angiotensin-converting enzyme (ACE) inhibitor would be a preferred agent since there is evidence that ACE inhibition may improve survival in at-risk patients [27]. Beta-blockers may precipitate Raynaud's phenomenon in some patients. For patients in whom a low-dose thiazide is not tolerated or indicated as a first-line agent, a calcium channel blocker is an acceptable alternative.
- Blood pressure should then be reviewed every 3 months, aiming ideally to keep levels <130 mmHg systolic and <80 mmHg diastolic [26].
ACE inhibitors
An ACE inhibitor is currently recommended as first-line therapy for patients with heart failure [28] and also has a role in left ventricular hypertrophy. Recent evidence suggests a wider role in prevention of CHD-related events. The recent HOPE study investigated the use of ramipril at 10 mg daily in a cohort of high-risk patients not known to have heart failure or a low ejection fraction [27]. Patients were considered to be high risk if they had a history of CHD, peripheral vascular disease, stroke or diabetes with an additional risk factor of either: hypertension, hypercholesterolaemia, microalbuminuria or smoking. This study found that ramipril use significantly reduced rates of stroke, MI and death in high-risk patients [27]. In the absence of a trial, it is impossible to extrapolate the results of the HOPE trial directly to all SLE patients, however patients with SLE and diabetes ought to be considered for ACE-inhibitor therapy. Also, as discussed above, if we consider SLE to be a high-risk condition like diabetes, and given the increased presence of renal manifestations, an ACE inhibitor should be given preference in the management of hypertension in SLE even when there is no left ventricular hypertrophy or heart failure. It is therefore our proposed second agent for hypertension. Therefore, for the present, we suggest that ACE inhibitors be employed in patients with SLE who also have:
- Prevalent CHD, stroke or peripheral vascular disease.
- Clinical chronic heart failure or impaired left ventricular function (ejection fraction <40%).
- Left ventricular hypertrophy.
- Patients with diabetes mellitus in the context of SLE.
- As the preferred second agent for the management of hypertension.
We suggest that specific screening should be undertaken to assess for the presence of left ventricular hypertrophy, an uncommon but important risk factor. This can be screened by standard voltage criteria on the electrocardiogram and confirmed by echocardiography [29].
Diabetes mellitus
Approximately 57% of patients with SLE develop diabetes mellitus [17, 18] and patients with SLE are more likely to have diabetes than a control population [17]. We therefore recommend the following.
- Testing for diabetes should be performed regularly in all patients with SLE. Screening assessment involves regular urine sampling at each clinic visit and random blood glucose at least annually, although when patients are on high-dose corticosteroids, this will need to be followed more closely. Diabetes mellitus [30] is diagnosed in the presence of: (i) fasting blood glucose
7.0 mmol/l or (ii) random blood glucose
11.1 mmol/l.
- In patients with a fasting glucose
6.1 mmol/l, this may indicate the presence of impaired glucose tolerance and a formal glucose tolerance test may be necessary. Referral to a dietician for advice regarding dietary modification is also suggested for such patients.
- A referral to a specialist in diabetes care is recommended for all patients with frank diabetes and where there is a concern regarding impaired glucose tolerance.
Smoking
Smoking is an important and established risk factor for CHD, as it causes platelet aggregation, reduced oxygenation of the blood and reduced HDL cholesterol levels. Stopping smoking may reduce the risk of subsequent CHD up to 50% [31]. Smoking may also be a risk factor for the development of SLE [32]. Interestingly, studies to date have not highlighted the contribution of smoking to the development of CHD in SLE. This is largely because of the low prevalence of smoking in some cohorts and the consequent limited power to identify this as a risk factor. However, it would seem important to advise smoking cessation in SLE given the strong risk associated with this potentially modifiable risk factor in the general population. Interventions are currently available to help stop smoking, involving advice by specialist nurses and clinicians, and referral to cessation clinics. Drug treatment is prescribed as either nicotine replacement therapy (NRT) or bupropion (Zyban) [33]. Current population guidelines recommend drug management for smokers who smoke >10 cigarettes per day, and express a strong desire to stop [33]. The smoker must show commitment to stop by a target date, and is offered support and advice. NRT or bupropion is prescribed for 2 weeks after this date, and repeat prescriptions are offered every 24 weeks, providing the smoker conveys a continued desire to quit. Personal motivation, specialist advice given by a clinician and other forms of social support will assist this process [33].
Obesity
Obesity, especially in a truncal distribution, is a risk factor for CHD events [31]. In SLE, obesity is frequently seen in the truncal distribution [34] and has been associated with the development of atheroma and CHD [11, 25]. In the general population, weight management has been found to influence several risk factors including blood pressure and lipid profiles.
- Screening for obesity should take place annually, involving weight measurement (kg) and calculation of target body mass index (BMI). If the patient is found to be overweight (>25 kg/m2), then secondary causes need to be considered, especially steroid treatment, which can cause truncal obesity and a cushingoid appearance. The initial therapy for such patients is therapeutic lifestyle changes, involving referral to a dietician and a multidisciplinary team, support and advice on diet, reducing alcohol intake, exercise programmes and behavioural support. Adjustment of steroid treatment, if applicable, should also be incorporated into the management programme. Weight should be monitored over a set time period.
- If the patient still remains obese, despite serious efforts to lose weight, then drug treatment should be considered [35, 36]. The current National Institute of Clinical Excellence (NICE) guidelines for the use of anti-obesity drugs suggest different thresholds for its use according to the baseline risk. Given the high-risk nature of SLE we suggest the use of drug therapy to control weight if the following three criteria are all met:
- BMI
27 kg/m2
- loss of >2.5 kg weight through diet and exercise, in the month before treatment
- aged 1875 yr.
Drug therapy is successful in causing weight loss, where a reduction of 5% initial body weight is aimed for by 3 months, and 10% by 6 months. The treatment should only be continued for 1 yr [35, 36]. There are no studies reporting the use of either currently recommended agent in the context of SLE, therefore such a therapy should be instituted under the guidance of a dietician and specialist in weight management. However, it is clear that successful weight reduction is associated with improvement in several risk factors including blood pressure, lipid profiles and glycaemic control [37].
Aspirin
Aspirin is of proven benefit in the primary and secondary prevention of CHD-related events in the general population. Daily aspirin decreases the risk of MI and is associated with a 25% reduction of CHD-related deaths [38]. Given the risk of CHD associated with SLE, decision analysis modelling suggests that all patients with SLE may potentially benefit from low-dose aspirin prophylaxis, the benefits being strongest in those who have the lupus anticoagulant (LAC) or antiphospholipid antibodies (aPL) [39]. A recent cohort study also suggests that low-dose aspirin may confer a survival advantage in patients with SLE [40]. However, there is no unequivocal proof that universal use of aspirin would be of clear benefit. In diabetes, current recommendations include the use of aspirin in patients with any additional conventional risk factor or with a history of prevalent CHD [41]. As a result, we suggest as a minimum standard that patients with SLE should receive low-dose aspirin prophylaxis if they have any of the following factors in the absence of a clear contraindication to aspirin:
- Previous history of myocardial infarction, angina, stroke or transient ischaemic attack.
- Positive aPL or LAC.
- Hypertension.
- Diabetes mellitus.
- Hypercholesterolaemia.
- Smokers.
It should be noted that many patients with the antiphospholipid syndrome already take warfarin therapy, often with an international normalized ratio (INR) >3.0. One retrospective study suggests that in this context, the addition of aspirin had no significant benefit [42], so aspirin therapy may not be necessary in this group.
 |
Summary
|
---|
CHD is a major cause of morbidity and mortality in SLE. While this has been recognized for many years there is no clear guidance on how cardiovascular risk in SLE should be managed. Indeed it has previously been noted that many risk factors for CHD can be detected prior to an event occurring in patients with SLE, although the management of these risk factors was somewhat variable [43]. We have attempted to review current guidelines used in the general population and adapted them for use in patients with SLE with a view to developing a minimum standard that can be implemented and subsequently audited. In particular, we have interpreted the currently available population guidelines as they apply to high-risk populations. We believe that there is good epidemiological evidence to include SLE in such a group of conditions, analogous to diabetes mellitus. These guidelines are clearly not the final word on this subject and with further studies both in the general population and within SLE populations these will be modified and revised.
A key point to emphasize is that in SLE there is likely to be increased scope to modify risk by adjustment of therapy, especially steroids, and by the introduction of antimalarials, where appropriate, in addition to therapeutic lifestyle changes. As such, particularly in patients who are deemed to be above their ideal weight, these measures may be beneficial in achieving several targets while avoiding the need for additional drug therapy. A proposed care pathway is therefore outlined that includes the pivotal role of considering the patient's initial body mass index (Fig. 2). There is clearly a need to maintain disease activity at a minimum while reducing steroid therapy. There is likely to be some scope for this, especially in patients with clinically quiescent disease, as suggested by the recent trial to evaluate the steroid-sparing effects of prasterone in SLE. This study found that in patients with a SLE disease activity index (SLEDAI) of zero at study entry, placebo-treated patients were able to achieve similar steroid reductions to the actively treated arm [44].

View larger version (27K):
[in this window]
[in a new window]
|
FIG. 2. A proposed care pathway for the management of cardiovascular risk in patients with SLE. *CHD, coronary heart disease.
|
|
Overall we expect that the way in which these guidelines will be implemented will vary according to local expertise and resources. Rheumatologists who manage the bulk of patients with SLE may not be expert in the area of risk-factor modification. They should nevertheless play a primary role in promoting awareness of this issue and recommending initial screening of SLE patients [43]. Our initial experience using these guidelines suggests that the incremental costs of introducing them are modest [45].
The authors have declared no conflicts of interest.
 |
References
|
---|
- Urowitz MB, Bookman AAM, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA. The bimodal mortality in systemic lupus erythematosus. Am J Med 1976;60:2215.[ISI][Medline]
- Bruce IN, Gladman DD, Urowitz MB. Premature atherosclerosis in SLE. Rheum Dis Clin North Am 2000;26:25778.[ISI][Medline]
- Salmon JE, Roman MJ. Accelerated atherosclerosis in systemic lupus erythematosus: implications for patient management. Curr Opin Rheumatol 2001;13:3414.[CrossRef][ISI][Medline]
- Manzi S, Meilahn EN, Rairie JE et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham study. Am J Epidemiol 1997;145:40815.[Abstract]
- Ward MM. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum 1999;42:33846.[CrossRef][ISI][Medline]
- Bruce IN, Urowitz MB, Gladman DD, Hallet DC. The natural history of hypercholesterolaemia in SLE. J Rheumatol 1999;26:213743.[ISI][Medline]
- Esdaile JM, Abrahamowicz M, Grodzicky T et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 2001;44:23317.[CrossRef][ISI][Medline]
- Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:22934.[Abstract/Free Full Text]
- Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Programme (NCEP) Expert Panel in Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). J Am Med Assoc 2001;285:248697.[Free Full Text]
- Volmink JA, Newton JN, Hicks NR, Sleight P, Fowler GH, Neil HA. Coronary event and case fatality rates in an English population: results of the Oxford myocardial infarction incidence study. Heart 1998;80:404.[Abstract/Free Full Text]
- Manzi S, Selzer F, Sutton-Tyrrell K et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum 1999;42:5160.[CrossRef][ISI][Medline]
- Rahman P, Urowitz MB, Gladman DD, Bruce IN, Genest J Jr. Contribution of traditional risk factors to coronary artery disease in patients with systemic lupus erythematosus. J Rheumatol 1999;26:23638.[ISI][Medline]
- Lima DS, Sato EI, Lima VC, Miranda F Jr, Hatta FH. Brachial endothelial function is impaired in patients with systemic lupus erythematosus. J Rheumatol 2002;29:2927.[ISI][Medline]
- El-Magadmi M, Bodill H, Ahmad Y, Bernstein RM, Walker MG, Bruce IN. Impaired endothelium dependent-flow mediated dilatation of the brachial artery in patients with systemic lupus erythematosus (SLE). Ann Rheum Dis 2002;61(Suppl. 1):97.
- Delgado Alves J, Ames PR, Donohue S et al. Antibodies to high-density lipoprotein and beta2-glycoprotein I are inversely correlated with paroxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome. Arthritis Rheum 2002;46: 268694.[CrossRef][ISI][Medline]
- Wood D, Durrington P, Poulter N, McInnes G, Rees A, Wray R. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 1998;80(Suppl. 2):S1S29.
- Bruce IN, Gladman DD, Ibanez D, Steiner G, Urowitz MB. The prevalence of Framingham risk factors in women with SLE: a cohort control study. Arthritis Rheum 2000;43:S246.[CrossRef]
- Petri M, Spence D, Bone LR, Hochberg MC. Coronary artery disease risk factors in the Johns Hopkins Lupus cohort: prevalence, recognition by patients and preventive practices. Medicine 1992;71:291302.[ISI][Medline]
- Borba EF, Bonfa E. Dyslipoproteinemias in systemic lupus erythematosus: influence of disease activity and anticardiolipin antibodies. Lupus 1997;6:5339.[ISI][Medline]
- MacGregor AJ, Dhillon VB, Binder A et al. Fasting lipids and anticardiolipin antibodies as risk factors for vascular disease in systemic lupus erythematosus. Ann Rheum Dis 1992;51:1525.[Abstract]
- Wallace DJ, Metzger AL, Stecher VJ, Turnbull BA, Kern PA. Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids. Am J Med 1990;89:3226.[ISI][Medline]
- Rahman P, Gladman DD, Urowitz MB, Yuen K, Hallett D, Bruce IN. The cholesterol lowering effect of antimalarial drugs is enhanced in patients with lupus taking corticosteroid drugs. J Rheumatol 1999;26:32530.
- Hearth-Holmes M, Baethge BA, Broadwell L, Wolf RE. Dietary treatment of hyperlipidemia in patients with systemic lupus erythematosus. J Rheumatol 1995;22:4504.[ISI][Medline]
- Rahman P, Aguero S, Gladman DD, Hallett D, Urowitz MB. Vascular events in hypertensive patients with SLE. Lupus 2000; 9:6725.[ISI][Medline]
- Petri M, Perez-Gutthan S, Spence D, Hochberg MC. Risk factors for coronary artery disease in patients with systemic lupus erythematosus. Am J Med 1992;93:5139.[ISI][Medline]
- Ramsay LE, Williams B, Johnston GD et al. Guidelines for the management of hypertension: report of the third working party of the British Hypertension Society. J Hum Hypertens 1999;13:56992.[CrossRef][ISI][Medline]
- Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342:14553.[Abstract/Free Full Text]
- Remme WJ, Swedberg K. Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:152760.[Free Full Text]
- Rowlands DJ. The electrocardiogram. In: Weatherall DJ, Ledingham JGG, Warrell DA eds. The Oxford textbook of medicine, 3rd edn. Oxford: Oxford Medical Publishers, 1996.
- Anonymous. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20: 118397.[ISI][Medline]
- Kannel WB, Wilson PW. An update on coronary risk factors. Med Clin North Am 1995;79:95171.[ISI][Medline]
- Hardy CJ, Palmer BP, Muir KR, Sutton AJ, Powell RJ. Smoking history, alcohol consumption, and systemic lupus erythematosus: a casecontrol study. Ann Rheum Dis 1998;57:4515.[Abstract/Free Full Text]
- National Institute for Clinical Excellence. Guidance on the use of nicotine replacement therapy (NRT) and bupropion for smoking cessation. Technology Appraisal Guidance No. 39. www.nice.org.uk March 2002.
- Bruce IN, Gladman DD, Ibanez D, Steiner G, Urowitz MB. Lipid subfractions and metabolic risk factors associated with coronary artery disease (CAD) in women with SLE: a cohortcontrol study. Arthritis Rheum 2000;43:S244.
- National Institute for Clinical Excellence. Guidance on the use of orlistat for the treatment of obesity in adults. Technology Appraisal Guidance No. 22. www.nice.org.uk March 2001.
- National Institute for Clinical Excellence. Guidance on the use of sibutramine for the treatment of obesity in adults. Technology Appraisal Guidance No. 31. www.nice.org.uk October 2001.
- Ballinger A, Peikin SR. Orlistat: its current status as an anti-obesity drug. Eur J Pharmacol 2002;440:10917.[CrossRef][ISI][Medline]
- Lauer MS. Clinical practice aspirin for the primary prevention of coronary events. N Engl J Med 2002;346:146873.[Free Full Text]
- Wahl DG, Bounameaux H, de Moerloose P, Sarasin FP. Prophylactic antithrombotic therapy for patients with SLE, with or without antiphospholipid antibodies. A decision analysis. Arch Intern Med 2000;160:20428.[Abstract/Free Full Text]
- Leung M-H, Heaton S, Skan J et al. Mortality and malignancy in the multi-ethnic Birmingham Lupus Cohortaspirin use is beneficial and non-Caucasian origin is not associated with poor outcome. Rheumatology 2002;41(Suppl. 1):S17.
- Anonymous. Aspirin treatment in diabetes (Diabetes UK). Guidelines 2002;18:214.
- Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995;332:9937.[Abstract/Free Full Text]
- Bruce IN, Gladman DD, Urowitz MB. Detection and modification of risk factors for coronary artery disease in patients with systemic lupus erythematosus: a quality improvement study. Clin Exp Rheumatol 1998;16:43540.[ISI][Medline]
- Petri MA, Lahita RG, Van Vollenhoven RF et al. Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2002;46:18209.[CrossRef][ISI][Medline]
- Wajed J, Ahmad Y, El-Magadmi M, Shelmerdine J, Bruce IN. Guidelines for the primary prevention of coronary heart disease in SLE: A needs assessment. Rheumatology 2003;42(Suppl. 1):76.
Submitted 24 March 2003;
Accepted 14 May 2003