Lipids, cardiovascular disease and atherosclerosis in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus is commonly associated with early onset cardiovascular disease and is often associated with hyperlipidaemia. This review examines the evidence for an increased prevalence of both CHD and hyperlipidaemia in SLE and mechanisms by which autoimmunity in SLE could accelerate the progression of atheroma. It postulates how lipid lowering therapies used in cardiological disease might help reduce the incidence of CHD in SLE.

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DOI: 10.1191/096120300678828235
2000 9: 194Lupus
As Wierzbicki
Lipids, cardiovascular disease and atherosclerosis in systemic lupus erythematosus
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REVIEW
Lipids, cardiovascular disease and atherosclerosis in systemic
lupus erythematosus
AS Wierzbicki
1
*
1
Department of Chemical Pathology, Guy's, King's and St. Thomas' Medical School (King's College London), St. Thomas' Hospital
Campus, London, UK
Systemic lupus erythematosus is commonly associated with early onset cardiovascular disease and
is often associated with hyperlipidaemia. This review examines the evidence for an increased
prevalence of both CHD and hyperlipidaemia in SLE and mechanisms by which autoimmunity in
SLE could accelerate the progression of atheroma. It postulates how lipid lowering therapies used
in cardiological disease might help reduce the incidence of CHD in SLE.
Lupus (2000) 9, 194±201
Keywords: systemic lupus erythematosus; atherosclerosis; cardiovascular disease; lipids;
apolipoproteins
Introduction
Systemic lupus erythematosus (SLE) is a moderately
common autoimmune disorder affecting 1 in 500 ±
1000 females. It is commonly associated with renal
disease and death has been considered to result from
the complications of renal disease or sepsis. However,
improvements in immunosuppression and antibiotic
therapy have reduced the incidence of these compli-
cations from 80% in 1973 ± 85 to 56% in 1985 ± 1995
whilst cardiovascular disease and stroke have in-
creased from 5% to 22%.
1±4
Epidemiological Studies of CHD in SLE
Whilst cardiac involvement with myocarditis and
steroid-induced cardiomyopathy are well recognised
in SLE, coronary heart disease was only noted as an
incidental ®nding in many studies.
5±8
It has, however,
been recognised as an increasing problem in the
management of SLE.
9
There are relatively few studies
of the epidemiology of atheroma-related disease in
SLE and these are 1imited in their follow-up. A
survey of 378 patients between 1971 and 1985 showed
5% died of cardiovascular complications with 60%
having strokes.
10
In this study the age at death was 34
years, 2 years after diagnosis and the primary cause of
mortality was renal disease and related sepsis.
Improvements in antibiotic therapy and immunosup-
pression over the next 10 years meant that in a survey
of 408 patients for the period 1984 ± 95, mortality
from sepsis declined to 25% whilst atheroma related
disease increased to 24% with 33% having strokes.
11
The patients in this study were older (42 years at
entry) and the risk of CHD tended to be concentrated
in older patients but the relative risk of death was high
as 25% of women in the cohort had a myocardial
infarct prior to age 50. This is the level of relative risk
seen in studies of women with familial hypercholes-
terolaemia. One study has examined the cardiac
complications of SLE in 75 Swedish patients and
noted that pericarditis occurred in 48%, valvular
disease in 27% and previous myocardial infarction,
left ventricular dysfunction or angina was detected in
19%.
5
In contrast to the previous studies in American
Blacks
3
this Caucasian study showed no association
with anti-cardiolipin antibodies though a strong
association with the use of steroids was noted. The
most recent study in 175 women from America
12
showed evidence of previous myocardial infarction in
15%, with 50% having had a stroke, but was designed
to look for evidence of atherosclerosis as measured by
*Correspondence: Dr AS Wierzbicki, Senior Lecturer, Department of
Chemical Pathology, St. Thomas' Hospital, Lambeth Palace Road,
London SEl 7EH, UK Tel: (44)17l 928 9292X2027;
Fax: (44)17l 928 4226; E-mail: anthony.wierzbicki@kcl.ac.uk
Lupus (2000) 9, 194±201
ß 2000 Macmillan Publishers Ltd All rights reserved 0961
-
2033/00 $15.00
www.nature.com/lup

carotid plaques. Focal plaques were found in 40% and
associations were noted with age, duration of disease,
blood pressure, LDL-cholesterol, ®brinogen and CRP
and use of steroids. Levels of cardiovascular risk were
increased 10 ± 50-fold compared to age- and sex-
matched women from the Framingham epidemiologi-
cal study.
13
Carotid intimal medial thickness was
grossly increased in the majority of patients and this is
known to bear a close relationship to the presence of
coronary atheroma.
14,15
These studies are intriguing,
suggesting a great increase in the risk of atheromatous
disease in SLE (650) and a further pre-disposition to
peripheral vascular manifestations (stroke) rather than
coronary disease.
16,17
The disadvantage of the studies
is that they are retrospective small scale cohort studies
in dissimilar populations. Prospective multi-centre
cohort studies are required and a model could be
provided by the Simon Broome Register which has
monitored mortality in familial hypercholesterolaemia
in 2900 patients for the last 15 years.
18
Mechanisms predisposing to atherosclerosis in
SLE
A basic scheme of mechanisms
19
pre-disposing to
atherosclerosis is shown in Figure 1. Most interest has
centred on the lipid and coagulation sides of the risk
graph but there is increasing recognition that in¯amma-
tion plays a major role in atherogenesis. In SLE
hyperlipidaemia, hypertension, in¯ammation and im-
mune-related coagulopathies are common features. SLE
is often associated with renal disease and surveys in
patients with renal disease show atheroma-related
events can account for 40% of mortality.
20-22
Renal
disease is associated with hypertension, insulin resis-
tance, secondary dyslipidaemias of which the hyperch-
olesterolaemia of nephrotic syndrome and the mixed
hyperlipidaemia associated with chronic ambulatory
peritoneal dialysis are most common. In addition,
carbamylation of apolipoproteins occurs in renal disease
and increased oxidative stress both of which are known
to predispose to cardiovascular disease.
20 ± 22
Aortic stenosis is known to be associated with both
chronic renal failure and SLE.
23
It predisposes to left
ventricular hypertrophy, a known cardiovascular risk
factor, and shows many histological features of
atheroma.
24
Thus it may be another manifestation of
atheroma requiring similar treatment.
25
Insulin resistance and SLE
Insulin resistance is a strong cardiovascular risk factor
independent of LDL-cholesterol.
26,27
Populations with
increased insulin resistance, e.g. Indian Asians or
women with previous polycystic ovaries, are known to
have higher rates of cardiovascular disease. Insulin
resistance can be induced by drug therapy, particularly
steroids. Insulin resistance pre-disposes to hyperten-
sion and is associated with obesity, hypertriglycer-
idaemia, low-HDL and hyperuricaemia, which have
all been described as independent risk factors for
cardiovascular disease. It is associated with hypercoa-
gulability through increases in ®brinogen and plasmi-
nogen-activator inhibitor-1 (PAI-1) levels. In SLE
anticardiolipin antibodies would predispose to further
proacoagulant changes in macrophage function
27
independent of the use of steroids. In lipoprotein
metabolism insulin resistance predisposes to the
formation of the atherogenic small dense lipoproteins
(e.g. LDL and intermediate density lipoprotein) and
retention of apoC3 on the LDL particles, reducing
their af®nity for the LDL apoB=E receptor. Insulin
resistance is a common feature of renal disease and
occurs secondary to steroid therapy. Studies in renal
transplantation recommend the minimisation of ster-
oid use to retard the rogression of atheroma.
20 ± 22
Lipids and SLE
Lipid pro®les in SLE are often abnormal compared to
the normal population due to exacerbations of disease
and renal involvement where they tend to follow
patterns in acute phase reaction with an increase in
triglycerides and often a fall in cholesterol due to
Figure 1 A schematic placing of biochemical risk factors and protective
factors (in parentheses) and their interactions in causing or protecting
against atheroma. Abbreviations: PAI-1  plasminogen activator inhibitor-
1; PDGF  platelet-derived growth factor; Lp(a)  lipoprotein (a);
TAGs  triglycerides; oxLDL  oxidised LDL-cholesterol; CRP 
C-reactive protein; ICAMs  intercellular adhesion molecules;
Hcy  homocysteine; Il  interleukin; vWF  von Willebrand factor;
NKk-B  nuclear factor-kappa-B; p21
ras
 Ras oncogene product; TGF-
b  tranforming growth factor-beta. Emboldened factors have been
implicated in SLE.
Lipids, cardiovascular disease and atherosclerosis
AS Wierzbicki
195
Lupus

cytokine activation and stress hormone production.
28
However, these pro®les underestimate the effects of
SLE on lipids as many of the agents used to treat SLE
have independent effects on lipids. Steroids promote
insulin resistance, hypertriglyceridaemia and in-
creased fatty acid ¯ux to the liver throughout the
development of central obesity. Azathioprine is
hepatotoxic and thus promotes the formation of a
fatty liver with over¯ow secretion of VLDL and, in
susceptible patients, a secondary mixed hyperlipidae-
mia. Similarly, obesity and insulin resistance promote
the occurrence of fatty liver and steatosis. Immuno-
suppressants such as cyclosporine and tacrolimus
(FK506) have direct effects in increasing LDL
cholesterol (especially cyclosporine) and may predis-
pose to accelerated atheroma.
20 ± 22
Thus SLE may
resemble patients with established renal transplants in
the mechanisms predisposing to atheroma (Table 1).
Indeed non-speci®c immune suppression may itself
predispose to atheroma through mechanisms as yet
unclear as is now being seen in patients with HIV
infection, albeit in the context of therapy with
protease inhibitors.
29
In¯ammation and atherosclerosis
Immune activation is a cardinal feature of SLE and
has been associated with atheroma in polygenic
CHD.
30 ± 32
Chronic in¯ammation with in®ltration of
leukocytes, macrophages and some lymphocytes are
clear features of atheroma and it is suspected that cell-
mediated immunity as is seen in SLE is a major factor
in promoting the differentiation and migration of
smooth muscle cells as well as maintaining macro-
phage activation.
33
Antibodies to lipoproteins in SLE
Yet this underestimates the role of the immune
response in SLE. Antibodies to lipoproteins are
consistently found in SLE particularly to B-2
glycoprotein-l (apolipoprotein H), an HDL associated
protein, which has been noted to have prognostic
signi®cance for the process of in¯ammation in
SLE.
34-37
Yet antibodies also occur to other HDL-
associated proteins including its principal components
apoA-1 and apoA-2. These may induce macrophage
induced immunoglobulin Fc receptor mediated clear-
ance of HDL reducing the functional role in reverse
cholesterol transport from apoE-associated cholesterol
particles secreted by macrophages (Figure 2) by
recycling the cholesterol to foam cells.
38-40
Yet the
antibody production in SLE is more diverse and
includes antibodies to the apoB series of particles
including oxidised LDL and possibly others as well.
37
Thus much of the LDL and HDL in SLE may circulate
as immune complexes which have been postulated as
atherogenic particles themselves given their enhanced
clearance via the reticuloendothelial system and
increased retention in atheroma plaques. Immunisa-
tion with apoH can be used to induce atherosclerosis
in LDL-receptor de®cient mouse model.
41
Anti-apoH
antibodies have been shown to increase VCAM-1
levels and thus may predipose to increased macro-
phage binding to endothelium and initiation of foam
cell formation and may be associated with elevations
in Lp(a).
42
The evidence for these mechanisms in
Table 1 Factors involved in hyperlipidaemia and atheroma in
transplant recipients compared with patients with SLE
Renal patient SLE Renal patient SLE
1. Age + 1. Insulin resistance +
2. Diet + 2. Small dense LDL +
3. Renal function + 3. Modi®cation of LDL +
4. Pre-existing
hyperlipidaemia
+ 4. Lipoprotein (a) metabolism +
5. Weight gain + 5. Homocysteine metabolism +
6. Glucose intolerance + 6. Immune complex formation +
7. Hypertension +
8. Use of diuretics
9. Proteinuria +
10. Steroids +
11. Cyclosporine 
12. Number of rejection
episodes Flares
Figure 2 Schematic representation of mechanisms involved in athero-
sclerosis in SLE. Abbreviations: ICAMs  intercellular adhesion mole-
cules; IC  immune complex; FcR  Gamma-globulin Fc receptor;
ScR  lipoprotein scavenger receptor.
Lipids, cardiovascular disease and atherosclerosis
AS Wierzbicki
196
Lupus

polygenic CHD or familial hypercholesterolaemia is
relatively weak but present but this process may only
achieve full signi®cance in disorders associated with
immune activation such as SLE and renal disease.
Antibodies to apoH (cardiolipin) have been detected
in type I diabetes and at levels which were higher in
patients with vascular complications
43
but levels are
normal in patients with familial hypercholesterolae-
mia.
44
Immune complexes containing LDL have been
found to be multiply modi®ed with greater densities,
mobilities, be de-sialated and have a higher oxy-sterol
content and induce greater accumulation of cholester-
ol and its esters in cultured human aortic explant
cells
45
However, the signi®cance of these ®ndings
in polygenic CHD
46
and SLE remain to be deter-
mined.
Lipoprotein(a), renal disease, SLE and
atherosclerosis
The role of lipoprotein (a) as a risk factor for
atherosclerosis in SLE is unclear
47
but this strange
particle of unknown physiological function plays a
signi®cant role in atherogenesis in other areas of the
vasculature.
48,49
Structurally it consists of a particle of
LDL with apolipoprotein B covalently attached to
apolipoprotein (a), a molecule whose structure
resembles plasminogen.
50
Its role in atherogenesis is
unclear except as an independent risk factor but in
vitro it competes for the plasminogen thrombolysis
pathway, reducing its effectiveness and inactivates
transforming-growth factor beta.
51
Though the gene
for apolipoprotein (a) has interleukin-6 response
elements it does not seem to behave as an acute
phase reactant except in some patients post-myocar-
dial infarction and in renal disease.
50
Lipoprotein(a) is
associated with coronary disease and progression of
stenosis both in the coronary and carotid circulations
and has been shown to be one of the ®rst molecules
that enter the intima following disruption of the
endothelial barrier.
48 ± 50
Again the affects of apoli-
poprotein (a) genotype and phenotype on the pre-
valence and progression of SLE need further
investigation.
In¯ammatory markers and atherosclerosis
Though lipids accumulate in atherosclerotic plaques
in¯ammation plays a key part of atherogenesis (Figure
2). The role of in¯ammation in atherosclerosis extends
beyond infection as modest elevations in C-reactive
protein or serum amyloid A identi®es a group of
patients with a worse prognosis from coronary heart
disease.
30,31,52,53
Lipid lowering drugs and in parti-
cular statins (HMG-CoA reductase inhibitors) have
anti-thrombotic and anti-in¯ammatory actions as well
as reducing and modifying LDL cholesterol.
54 ± 56
Endothelial function in SLE
Few studies exist of endothelial function in SLE.
However, in polygenic CHD endothelial function is
determined by classical risk factors including LDL,
oxidised or modi®ed lipoproteins, smoking, insulin
resistance or diabetes, and homocysteine.
57 ± 59
Little
is known about whether antibodies affect endothelial
function in polygenic coronary heart disease but
recent studies have show that anti-endothelial cell
antibodies are present in SLE.
60
These are associated
with endothelial cell activation with increased expres-
sion of von Willebrand factor and other intercellular
cellular adhesion molecules (ICAMs) and later anti-
body induced apoptosis.
60,61
The expression of
ICAMS seems to be a standard response of endothe-
lial cells to injury and may be related to atheroma load
in CHD.
62
All of these would predispose to increased
rates of atherosclerosis by increasing rates of
lipoprotein entry to, and retention in, the subendothe-
lial space.
63,64
In addition any hypertension
65,66
present due to associated renal disease or steroid
therapy would exacerbate the effects
62
by causing
endothelial cell apoptosis
60,61,66,67
as occurs in mouse
models of SLE
65
or in human renal disease.
68
Similarly LDL and Lp(a), particularly if oxidised,
induce apoptosis in the atherosclerotic plaque and in
endothelial cells and promote the formation of
amorphous cholesterol deposits and crystals.
66
Thus
the combination of oxidised lipoproteins and anti-
bodies favours accelerated atherosclerosis.
Stroke and SLE
Atheroma can occur in all circulatory beds though
lipoprotein involvement is prominent in epidemio-
logical studies of coronary heart disease rather than
stroke. Yet the processes of atheroma occur in both
low pressure (cardiac) and high pressure vessels and
are similar in their pathogenesis.
12,14
Though initial
meta-analyses did not suggest a role for cholesterol in
stroke)more recent subgroup studies of lipid-lowering
trials in patients with coincident strokes and cardio-
vascular disease have shown a 30% reduction in
Lipids, cardiovascular disease and atherosclerosis
AS Wierzbicki
197
Lupus

strokes and transient ischaemic attacks.
55
Trials of
anti-hypertensive therapy have shown similar reduc-
tions with a l0 mmHg fall in systolic blood pressure.
Trials are now underway in patients with strokes to
determine whether lipid-lowering drugs can reduce
stroke as a primary endpoint. Stroke occurs commonly
in SLE and its greater incidence has been ascribed to
the presence of anti-cardiolipin antibodies.
1± 4,9,12
Yet
studies of the association of stroke and anti-cardioli-
pin (anti-apoH) antibodies have been con¯icting with
the general consensus that their role is slight if
signi®cant.
69 ± 71
Less is known about peripheral
vascular disease though again its incidence is
increased in SLE.
16
The area is complicated by
reports of interactions between other cardiovascular
risk factors including homocysteine
72
with poly-
morphisms in clotting proteins (e.g. factor V Leiden)
but de®nitive studies are still awaited.
Similarly,although homocystinuria is associated
with early stroke, hyperhomocysteinaemia associated
with the G677T polymorphism causing a thermolabile
mutation in 5,l0-,methylene tetrahydrofolate reductase
only seems to be a risk factor for atherosclerosis in
some populations.
72
Homocysteine levels are in-
creased further in patients with renal dysfunction but
its role in renal disease-related atherosclerosis remains
unclear. De®nitive trials using folate supplementation
to correct hyperhomocysteinaemia in patients with
coronary heart disease are now underway.
Lipid lowering therapy and cardiovascular
disease
Older trials of lipid-lowering therapy in cardiovascu-
lar disease were generally unsuccessful in reducing
mortality but did show reductions in cardiovascular
events. The ®eld has been revolutionised by the recent
series of statin trials (Table 2).
73,74
This series of 3
statin secondary prevention trials (Scandinavian
Simvastatin Survival Study-4S
75
; the Long-term
Intervention with Pravastatin in Ischemic Disease Ð
LIPID
76
and Coronary atheroma and Recurrent
Events Ð CARE
77
) have shown convincing bene®ts
for LDL reduction to levels of 3 mmol=L. In
saphenous vein coronary bypass graft (CABG)
patients the post-CABG study
78
has shown further
bene®ts in in-graft atheroma formation with additional
LDL reduction to 2.5 mmol=L and a ®brate trial
(Veterans Administration HDL Intervention study
79
)
has shown bene®ts in patients with both HDL and low
LDL.
Large trials of aggressive LDL reduction in
secondary prevention are now underway. Sub-studies
of these group of trials have shown additional bene®ts
of statins in reducing events in the elderly, women,
diabetics and reducing events of cardiac failure (30%),
stroke or transient ischaemic attacks (30%)
80
or
peripheral vascular disease (28%). Similar bene®ts
have been shown in patients without established
coronary heart disease (Table 3) in the West of
Scotland Coronary Prevention Study (WOSCOPS)
81
and the Air Force ± Texas Coronary Atheroma Pre-
vention Study (AF=TexCAPS).
82
Though as yet trial
evidence is lacking, early studies suggest major
bene®ts in both renal and cardiac transplant patients
with statin therapy with possibly a direct effect
synergistic with cyclosporine on reducing rejection
episodes.
20 ± 22
The speed of action of statins in
preventing CHD events after 6 ± 12 months compared
to 24 ± 36 months seen with other modalities of
reducing only LDL such as ileal bypass surgery in the
Program on Surgical Correction of Hyperlipidaemia
(POSCH) has suggested these drugs may have
additional actions
54,55,83
and also stabilise athero-
sclerotic plaques.
84
Certainly by reducing cholesterol
and reducing triglycerides they improve platelet
function and reduce plasminogen activator inhibitor-
l (PAI-1) levels and hence improve haematorheol-
ogy.
54,55
Their effects on other clotting factors
Table 2 Summary of evidence from clinical trials in patients
with established heart disease (secondary prevention)
Trial Units 4S
75
CARE
77
LIPID
76
VA-HIT
79
Drug Simvastatin Pravastatin Pravastatin Gem®brozil
Dose mg 20-40 40 40 1200
Number 4444 4159 9014 2531
% female 19 14 17
%MI 70 100 64 100
Mean TC mmol/L 6.8 5.4 5.7 4.70
Mean LDL mmol/L 4.9 3.6 3.9 2.87
± DLDL % 35 28 25 +3(TG: 722)
± DCHD events % 34 24 24 22
± Dmortality % 32 18 23 11
Table 3 Summary of evidence from trials in patients without
overt coronary heart disease (primary prevention trials)
Trial Units WOSCOPS
81
AF/TexCAPS
82
Drugs Pravastatin Lovastatin
Dose mg 40 20 ± 40
Number 5955 6605
% female Ð 13
% angina and PVD 8 0
Framingham risk %/year 1.5 1.2
Mean TC mmol/L 7.0 5.7
Mean LDL mmol/L 4.8 3.9
± DLDL % 25 25
± HDL mmol/L 1.3 0.9
± DCHD events % 28 34
± Dmortality % 23 N/A
Lipids, cardiovascular disease and atherosclerosis
AS Wierzbicki
198
Lupus

including ®brinogen are controversial.
55
They also
may have direct effects on lymphocyte differentiation
and reduce markers of in¯ammation including C-
reactive protein (CRP) and serum amyloid A (SAA)
where their relative ef®cacy seems to have prognostic
consequences.
56
Large scale trials of statin therapy are
underway in reducing chronic rejection and in
reducing cardiovascular events in renal transplant
patients and these should report by 2003. In polygenic
CHD treatment is now advised after calculation of
cardiovascular risk rather than any individual para-
meter
85 ± 87
with treatment with statins as ®rst line
drugs and ®brates reserved for patients with low HDL
or high triglycerides
88,89
Little data exists on the
safety and ef®cacy of these drugs in patients with SLE
apart from anecdotal reports. Only chloroquine and
other anti-malarials have been used in the treatment of
SLE-related hyperlipidaemia with a modest reduction
in triglycerides.
90
Further work is needed to investi-
gate whether stains and ®brates can reduce the CHD
burden in SLE.
Conclusion
This review has summarised the evidence that
atherosclerotic disease is a major factor in SLE. Yet,
there is little epidemiological or cross-sectional data
on the signi®cance or relative importance of risk
factors for atherosclerosis in SLE. It remains to be
proven in large cross-sectional prospective studies
that all the factors mentioned have a clear impact on
the progression of atherosclerosis in SLE. Also it is
unclear whether any of the current anti-thrombotic or
lipid lowering therapies so successful in preventing
coronary heart disease and stroke in the general
population might retard the progression of athero-
sclerosis in SLE.
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