Risk Factors for Cardiovascular Disease
in Systemic Lupus Erythematosus
Elisabet Svenungsson, MD; Kerstin Jensen-Urstad, MD, PhD; Mikael Heimbürger, MD, PhD;
Angela Silveira, PhD; Anders Hamsten, MD, PhD; Ulf de Faire, MD, PhD;
Joseph L. Witztum, MD; Johan Frostegård, MD, PhD
Background—Cardiovascular disease (CVD) is overrepresented in patients with systemic lupus erythematosus (SLE). We
determined the prevalence of traditional and nontraditional risk factors for CVD in SLE patients with and without CVD
compared with controls.
Methods and Results—Twenty-six women (aged 52?8.2 years) with SLE and a history of CVD (SLE cases) were
compared with 26 age-matched women with SLE but without manifest CVD (SLE controls) and 26 age-matched
population-based control women (population controls). Common carotid intima-media thickness (IMT) was measured
by B-mode ultrasound as a surrogate measure of atherosclerosis. SLE cases had increased IMT compared with SLE
controls (P?0.03) and population controls (P?0.001), whereas IMT of SLE controls did not differ from population
controls. SLE cases had raised plasma concentrations of circulating oxidized LDL (OxLDL; P?0.03), as measured by
the monoclonal antibody EO6, and autoantibodies to epitopes of OxLDL (P?0.001); dyslipidemia with raised
triglycerides (P?0.001) and lipoprotein(a) (P?0.002) and decreased HDL-cholesterol concentrations (P?0.03); raised
?-1-antitrypsin (P?0.002), lupus anticoagulant (P?0.007), and homocysteine levels (P?0.03); more frequent
osteoporosis (P?0.03); and a higher cumulative prednisolone dose (P?0.05) compared with SLE controls. Disease
duration, smoking, blood pressure, body mass index, and diabetes mellitus did not differ significantly between the
Conclusions—A set of distinct CVD risk factors separate SLE cases from SLE controls and population controls. If
confirmed in a prospective study, they could be used to identify SLE patients at high risk for CVD in order to optimize
treatment. (Circulation. 2001;104:1887-1893.)
Key Words: cardiovascular diseases ? risk factors ? atherosclerosis ? ultrasonics
treatment has improved during recent decades, patients with
SLE appear to have increased morbidity and mortality from
cardiovascular disease (CVD).1
ystemic lupus erythematosus (SLE) is a systemic inflam-
matory disease that mainly affects women. Although
See p 1876
Among established risk factors for atherosclerosis, only
dyslipoproteinemia has been demonstrated in SLE, in which
enhanced plasma triglycerides and decreased HDL levels
have been described while the LDL concentration is similar
to that of controls in most patients.2Lipoprotein(a) [Lp(a)]
has also been reported to be elevated in SLE.3Hypertension
is not generally present in SLE, although it may be a feature
of SLE nephritis. Comparatively little is known about diabe-
tes mellitus in SLE, although both chronic inflammation4and
steroid treatment may be associated with diabetes.
Inflammation is a prominent feature of atherosclerotic
lesions,5and systemic inflammation, as reflected by a
raised serum concentration of C-reactive protein (CRP), is
associated with enhanced risk of CVD.6Oxidized LDL
(OxLDL) plays an important role in atherogenesis and may
contribute to the immune activation and inflammation
present in the atherosclerotic lesions, because it has
chemotactic, immune-stimulatory, and toxic properties and
is taken up by macrophages and other cells in the athero-
sclerotic plaque, which develop into foam cells.7,8To
elucidate the relationship between SLE and arterial disease
and possible causes of the increased risk of CVD present in
SLE, we studied the prevalence of traditional and nontra-
Received April 30, 2001; revision received August 6, 2001; accepted August 9, 2001.
From the Department of Rheumatology and Centre for Molecular Medicine (E.S., J.F.), Department of Clinical Physiology (K.J.-U.), Department of
Cardiology and King Gustaf V Research Institute (A.S., A.H.), Karolinska Hospital, Stockholm, Sweden; Department of Rheumatology (M.H.), Huddinge
University Hospital, Huddinge, Sweden; Division of Cardiovascular Epidemiology (U.d.F.), Institute of Environmental Medicine and Cardiovascular
Laboratory, Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden; and Department of Medicine (J.L.W.), University
of California, San Diego.
Correspondence to Dr Elisabet Svenungsson, Department of Rheumatology, Karolinska Hospital, 17176 Stockholm, Sweden. E-mail Elisabet.Svenungsson@
© 2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
Clinical Investigation and Reports
ditional risk factors for CVD in SLE cases with CVD,
age-matched SLE controls free of CVD, and population
The study group consisted of 26 women with SLE surviving 1 or
more manifestations of CVD, defined as a history of myocardial
infarction (MI; n?7), angina (n?9), cerebral infarction (n?15), or
claudication (n?4). The SLE cohort at the Karolinska Hospital
comprises 206 SLE patients. Of these, 24 women had a history of
arterial disease, 1 of whom declined to participate in the study. Three
SLE cases were also selected from Huddinge University Hospital.
Twenty-six age-matched women with SLE but without manifest
CVD were included from the cohort at Karolinska Hospital, and 26
control women were recruited randomly from the population regis-
try; none of the control women had arterial disease or SLE. All
patients fulfilled the 1982 revised criteria of the American Rheuma-
tism Association for classification of SLE.9CVD was defined as
thromboembolic and not hemorrhagic or vasculitic stroke (confirmed
by computed tomography or MRI), MI (confirmed by electrocardi-
ography and a rise in creatine kinase), angina pectoris (coronary
insufficiency confirmed by exercise stress test), or intermittent
claudication (peripheral atherosclerosis confirmed by angiogram).
Of the 35 CVD events, 27 occurred before menopause.
The study was approved by the local Ethics Committee of the
Karolinska Hospital. All subjects gave informed consent before
entering the study.
The investigation included a written questionnaire, an interview, and
a physical examination by a rheumatologist; laboratory determina-
tions; and blinded ultrasound examination of the carotid arteries.
SLE disease activity was determined with the Systemic Lupus
Activity Measure (SLAM).10Organ damage was determined with
the Systemic Lupus International Collaborating Clinics (SLICC)
damage index.11Osteoporosis was considered present if osteoporotic
fractures had occurred or bone mineral density measurement was
clinically indicated and showed ?2.5 SD (T-score) as determined by
dual-energy x-ray absorptiometry.
Routine Laboratory Tests
Anti–double-stranded DNA (dsDNA) antibodies were determined
by immunofluorescence with Crithidia lucillae kinetoplast assay.
Anticardiolipin antibodies (aCLs) were measured by ELISA with
ethanol-fixed cardiolipin (Sigma) and horseradish peroxidase–con-
jugated fractionated rabbit immunoglobulins against human IgG and
IgM, respectively (Dako). Lupus anticoagulant was determined by a
modified Dilute Russel Viper Venom method (Biopool) with Bioclot
lupus anticoagulant. ?2-Glycoprotein I (?2GPI) antibodies were
determined with ELISA (R&D Systems).
Plasma lipoprotein concentrations were determined by a combina-
tion of preparative ultracentrifugation followed by lipid analyses of
the lipoprotein fractions as described previously.12Lp(a) was deter-
mined by use of ELISA [TintELIZE Lp(a), Biopool Int]. LDL was
isolated from pooled plasma of healthy donors by sequential prepar-
ative ultracentrifugation under conditions to minimize oxidation and
proteolysis and subsequently oxidized by copper or modified by
malondialdehyde (MDA) as described previously.13
Chemiluminescent Immunoassay for Autoantibody
Binding to OxLDL
The chemiluminescent assay was performed with modifications as
described previously14on plasma dilutions of 1:250. Data are
TABLE 1.Basic Characteristics
102 572?75 043
38 255?35 105
91 502?125 135
25 680?24 985
Disease duration, y
? ? ?
Estimated cigarettes consumed, n104 096?107 733
Any history of smoking
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
Total prednisolone equivalent dose, mg
? ? ?
Diabetes mellitus 1/26
BMI indicates body mass index.
Values are given as mean?SD (median); SLAM is a measure of disease activity and is given as median (see
*P?0.06 vs population controls.
†P?0.05 vs SLE controls.
October 16, 2001
expressed as relative light units per millisecond (RLU/ms). Each
determination was done in triplicate, and all samples were measured
in a single assay. The coefficients of variation for low and high
standards were 6% to 8%.
Determination of OxLDL Epitopes
The EO6 epitope concentration on apolipoprotein (apo) B-100–
containing particles was measured by a chemiluminescent modifica-
tion of a previously described assay.14,15This sandwich assay uses an
anti-human apoB-100 monoclonal antibody, MB47, to capture apoB-
containing lipoproteins and a biotin-labeled anti-OxLDL antibody,
EO6, to measure the amount of the EO6 epitope present on the
apoB-containing lipoproteins captured. The number of apoB-
containing particles should saturate the binding capacity of the plated
MB47. To verify this, in parallel wells, we determined the binding of
biotinylated MB24, another apoB-specific monoclonal antibody that
binds to a distinct apoB epitope on apoB apart from that recognized
by MB47, as described previously.15
Data are expressed as a ratio of the amount of EO6 bound per well
normalized by the number of apoB particles per well, eg, the ratio of
EO6/MB24.15All samples were measured in a single assay, and the
intra-assay coefficients of variation of low and high standards were
6% to 8%.
The right and left carotid arteries were examined with a duplex
scanner (Acuson Sequoia), and the intima-media thickness (IMT)
was determined as described previously.16A plaque was defined as
a local intimal-medial thickening, with a thickness ?1 mm.17
For skewed variables, nonparametric tests were used for compari-
sons between groups (Friedman test), whereas ANOVA was used for
normally distributed variables, with paired t test used as post hoc
analysis. McNemar’s test was used for comparison of nominal
variables between study groups. Nonparametric continuous variables
were logarithmically or reciprocally transformed. The significance
level was put at P?0.05.
Basic Characteristics of Study Groups
Disease duration and present disease activity (SLAM) did not
differ significantly between the SLE groups (Table 1). Organ
damage (SLICC) was higher in SLE cases than in controls
(median value of 4 and 1, respectively), but SLICC includes
CVD and is therefore biased when SLE cases and SLE
controls are compared.
SLE manifestations including nephritis, vasculitis, serosi-
tis, skin involvement, and central nervous system affections
did not differ between SLE groups. Osteoporosis was more
frequent in SLE cases than in SLE controls (P?0.027).
Both SLE groups were subject to long-term prednisolone
treatment. The cumulative dose (evaluated through interview
and retrospective review of patient charts) was significantly
higher in SLE cases and was also significantly associated
with the plasma triglyceride concentration (P?0.01) in the
whole SLE group. Exposure time (months of prednisolone
use) and current dosage did not differ significantly between
the 2 SLE groups (data not shown).
Medication with cyclophosphamide, chloroquine, azathio-
prine, or antihypertensive drugs did not differ between SLE
groups (data not shown). However, lipid-lowering com-
pounds were taken by 9 SLE cases, 1 SLE control, and 1
IMT and Traditional Risk Factors
There were no differences in blood pressure, smoking habits,
body mass index, or prevalence of diabetes mellitus between
groups. SLE cases had a greater common carotid IMT than
SLE controls and population controls, whereas SLE controls
did not differ from population controls in this respect. SLE
cases had significantly more plaques than population con-
trols, and a similar trend was present in relation to SLE
controls. Furthermore, SLE controls had significantly more
plaques than population controls (Table 2).
Plasma concentrations of major lipoproteins and lipids are
presented in Table 3. A dyslipoproteinemia was present in
SLE cases but not in SLE controls that comprised signifi-
cantly decreased HDL cholesterol and increased triglyceride
concentrations in both VLDL and LDL fractions. LDL
cholesterol did not differ between the SLE groups. The
plasma Lp(a) concentration was significantly higher in SLE
patients than in SLE controls or population controls (Table 1).
Nontraditional Risk Factors
The erythrocyte sedimentation rate and plasma concentra-
tions of orosomucoid, ?1-antitrypsin, and CRP were signifi-
cantly higher in SLE cases than in SLE controls (Table 4).
aCLs, anti-?2GPI antibodies, and lupus anticoagulant were
more common in SLE cases than in population controls
(Table 4). In addition, lupus anticoagulant was significantly
higher in SLE cases than in SLE controls (Table 4). Homo-
cysteine levels discriminated strongly between groups, with
SLE cases having significantly higher levels than either SLE
controls or population controls.
IgG and IgM autoantibodies to OxLDL and MDA-LDL were
increased in both SLE groups. Both anti-OxLDL and anti-
MDA-LDL antibodies of the IgG subclass discriminated
between SLE cases and SLE controls (Table 5). ApoB-
containing lipoproteins (mainly LDL) from SLE cases ex-
pressed significantly higher levels of EO6-specific epitopes
(oxidized phospholipid) than SLE controls. This also tended
to be true for population controls (Table 5).
In this study, we sought to determine the prevalence of risk
factors in SLE patients who developed CVD compared with
those who did not. The common carotid IMT of SLE cases
Ultrasound Measurements of Common Carotid
SLE CasesSLE Controls Population Controls
Values are given as mean?SD (median).
*P?0.03 vs SLE controls.
†P?0.001 vs population controls.
‡P?0.07 vs SLE controls.
§P?0.002 vs population controls.
?P?0.02 vs population controls.
Svenungsson et al CVD Risk Factors in Systemic Lupus Erythematosus
was greater than that of SLE controls and population controls,
a finding that validates our selection of patients and also
indicates that atherosclerosis plays an important role in
arterial disease in SLE. The IMT of the SLE controls was not
different from that of population controls. SLE cases tended
to have more plaques than SLE controls, and both SLE cases
and SLE controls had significantly more plaques than popu-
Despite a more common use of hypolipidemic drugs,
dyslipidemia (elevated triglycerides and decreased HDL cho-
lesterol) was more common in SLE cases than in either SLE
controls or healthy controls. In contrast, the LDL-cholesterol
concentration did not differ between groups. Dyslipidemia
was present only in SLE cases with manifest CVD, whereas
the lipoprotein pattern in SLE controls was identical to that of
In line with recent findings3,18our data indicate that the
plasma concentration of Lp(a) is significantly enhanced in SLE
the latter 2 groups do not differ. aPLs predict an increased risk
for MI, and their levels are increased in young survivors of
MI.19,20?2GP1 is a cofactor for antibody binding to cardiolip-
in,17and recent studies indicate that many aCLs recognize
oxidized CL (OxCL) and/or adducts of OxCL with ?2GP1.21
The antiphospholipid antibody syndrome is characterized
by both arterial and venous thrombosis and is common in
SLE.22In the present study, lupus anticoagulant showed a
significant association with CVD in SLE. In addition, both
aCLs and anti-?2GPI antibodies tended to be associated with
arterial disease in SLE. It is possible, therefore, that the
increased risk of CVD in SLE is to some extent caused by
Homocysteine is increasingly recognized as a risk factor in
the general population23and in SLE.24How homocysteine is
related to arterial disease is not completely clear, but one
interesting possibility is an association with increased LDL
Steroid treatment is often believed to be atherogenic, due to
effects on plasma lipoproteins. Because inflammation is
implicated in atherosclerosis, cortisone could actually prevent
atherosclerosis as well. Indeed, one animal study supports
this notion.26In spite of high cumulative prednisolone doses,
the SLE control group did not have increased common
carotid IMT. SLE cases, on the other hand, had higher total
prednisolone consumption than SLE controls, which most
likely reflects a raised cumulative disease activity among
SLE cases. Clearly, the role of prednisolone treatment in
development of arterial disease in SLE deserves further study.
TABLE 3.Plasma Lipid and Lipoprotein Concentrations
SLE Cases: 1 SLE Controls: 2 Population Controls: 3Significance
Lp(a), mg/L1?2 P?0.05
Values are given as mean?SD (median).
October 16, 2001
Of note, no association between disease duration and arterial
disease was found.
Recently, an association between increased bone loss and
progression of atherosclerotic calcification in women was
reported.27We found that osteoporosis was more frequent in
SLE cases than in SLE controls. Whether this is related to
prednisolone treatment only or to other underlying mecha-
nisms remains to be shown.
We confirm previous observations that autoantibodies
related to OxLDL are elevated in SLE.21,28,29We also report
that anti-MDA-LDL and anti-OxLDL antibodies of IgG type
appear to discriminate between SLE cases and SLE controls.
Such autoantibodies could be mere markers of disease or
could play an important role in SLE-associated arterial
disease. In one previous report,29anti-MDA-LDL antibodies
were found not to be associated with arterial disease in an
SLE cohort of 118 patients, in contrast to our findings. Apart
from methodological differences, this discrepancy may be
related to differences in populations tested, because our
selection procedure allowed us to match both SLE controls
and population controls with SLE cases on the basis of age.
CRP and other markers of inflammatory activity were
elevated in SLE cases. Another novel observation was that
oxidized phospholipid epitopes were significantly more fre-
quent on apoB particles from SLE cases than on those from
SLE controls. OxLDL has proinflammatory and atherogenic
properties.8It is thus possible that OxLDL may contribute to
arterial disease in SLE.
In the present study, we selected women with SLE who did
and did not have clinical evidence of CVD, even though they
all had evidence of SLE for a considerable period of time.
Because of this selection process, it is not possible to reach
any conclusions about the prevalance of atherosclerosis in our
cohort of SLE patients. The design is aimed at studying
survivors of CVD and does not allow any conclusions about
risk factors for mortality in CVD among SLE patients.
TABLE 4. Inflammatory Markers, SLE-Related Laboratory Tests, and Plasma Homocysteine Concentrations
SLE Cases: 1SLE Controls: 2Population Controls: 3Significance
ESR, mm 30.1?20.2
?-1-antitrypsin, g/L 1.67?0.24
Fibrinogen, g/L 4.20?1.30
Orosomucoid, g/L 1.02?0.25
Lupus anticoagulant ratio 1.33?0.43
Cardiolipin IgG11/268/26 1/26
Cardiolipin IgM8/264/26 2/26
?2GPI IgG 11/26 6/262/26
History of positive anti-ds
Values are given as mean?SD (median).
Svenungsson et alCVD Risk Factors in Systemic Lupus Erythematosus
Nevertheless, it is interesting to observe that women with
SLE of close to 20 years’ duration without CVD had risk
factors that distinguished them from SLE patients with CVD
and furthermore had an IMT that did not differ from that of
healthy women. Thus, it could be hypothesized that having
SLE does not inherently predispose an individual to an
enhanced risk of CVD.
Taken together, this study identifies a variety of risk factors
for CVD in SLE patients, not only traditional factors such as
dyslipidemia and Lp(a) but also a range of factors reflecting
acute and chronic inflammation, including indices of en-
hanced LDL oxidation. It will be important to determine in a
prospective study whether these factors can predict future
CVD. If so, they can be used to identify a high-risk group that
would be eligible for intense intervention, for example, with
potent antioxidants and anti-inflammatory agents.
This work was supported by the King Gustaf V 80th Birthday Fund,
the Swedish Society of Medicine, the Swedish Rheumatism Associ-
ation, Soderberg Foundation, the Swedish Heart-Lung Foundation,
Margaretha Rheumatology Research Foundation, and NIH grants
HL-64833 and -56989 (SCOR). We are grateful to Jill Gustafsson,
Kerstin Personne, Britt-Marie Forsberg, and Eva Jemseby for their
help with management of patient cohorts and blood sampling and to
Elizabeth Miller for determinations of OxLDL and anti-OxLDL
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TABLE 5.Antibodies Against OxLDL and Oxidation Epitopes in LDL
SLE Cases: 1SLE Controls: 2Population Controls: 3 Significance
aMDA-LDL IgG 31 583?20 551
20 747?11 916
12 435?6 113
aMDA-LDL IgM 43 014?24 101
46 248?25 778
31 278?14 217
aOxLDL IgG16 411?14 949
aOxLDL IgM 24 214?18 230
25 149?22 201
Values are given as mean?SD (median). aMDA-LDL indicates anti-MDA LDL antibodies; aOxLDL,
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October 16, 2001
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Svenungsson et al CVD Risk Factors in Systemic Lupus Erythematosus