Clinical Investigation and Reports

Risk Factors for Cardiovascular Disease

in Systemic Lupus Erythematosus
Elisabet Svenungsson, MD; Kerstin Jensen-Urstad, MD, PhD; Mikael Heimbrger, MD, PhD;
Angela Silveira, PhD; Anders Hamsten, MD, PhD; Ulf de Faire, MD, PhD;
Joseph L. Witztum, MD; Johan Frostegrd, MD, PhD
BackgroundCardiovascular 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 ResultsTwenty-six women (aged 528.2 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 (P0.03) and population controls (P0.001), whereas IMT of SLE controls did not differ from population
controls. SLE cases had raised plasma concentrations of circulating oxidized LDL (OxLDL; P0.03), as measured by
the monoclonal antibody EO6, and autoantibodies to epitopes of OxLDL (P0.001); dyslipidemia with raised
triglycerides (P0.001) and lipoprotein(a) (P0.002) and decreased HDL-cholesterol concentrations (P0.03); raised
-1-antitrypsin (P0.002), lupus anticoagulant (P0.007), and homocysteine levels (P0.03); more frequent
osteoporosis (P0.03); and a higher cumulative prednisolone dose (P0.05) compared with SLE controls. Disease
duration, smoking, blood pressure, body mass index, and diabetes mellitus did not differ significantly between the
groups.
ConclusionsA 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

ystemic lupus erythematosus (SLE) is a systemic inflammatory disease that mainly affects women. Although
treatment has improved during recent decades, patients with
SLE appear to have increased morbidity and mortality from
cardiovascular disease (CVD).1

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.2 Lipoprotein(a) [Lp(a)]
has also been reported to be elevated in SLE.3 Hypertension
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 inflammation4 and

steroid treatment may be associated with diabetes.
Inflammation is a prominent feature of atherosclerotic
lesions,5 and systemic inflammation, as reflected by a
raised serum concentration of C-reactive protein (CRP), is
associated with enhanced risk of CVD.6 Oxidized 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 atherosclerotic plaque, which develop into foam cells.7,8 To
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@
medks.ki.se
2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

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TABLE 1.

Basic Characteristics
SLE Cases
(n26)

SLE Controls
(n26)

Age, y

52.28.2

52.28.2

Disease duration, y

20.09.9

(54.3)

Estimated cigarettes consumed, n

Any history of smoking
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
BMI, kg/m2

(54.4)

Diabetes mellitus

(54.7)

(19)

(16)

102 57275 043

91 502125 135

104 096107 733

(117 165)

(66 065)

(93 440)

20/26

17/26

17/26

12816

12922

12425
(120)

(125)

(127)

799

7611

8112

(74)

(78)
24.03.6

(81)
24.05.0

(22.5)

(25.0)

(23.2)

0.860.08

0.860.09

0.810.09

(0.85)*

(0.85)

(0.79)

38 25535 105

25 68024 985

(35 825)

(19 275)

3/26

1/26

SLAM
Total prednisolone equivalent dose, mg

52.38.2

18.59.5

23.83.6

Waist/hip ratio

Population Controls
(n26)

1/26

BMI indicates body mass index.

Values are given as meanSD (median); SLAM is a measure of disease activity and is given as median (see
Methods).
*P0.06 vs population controls.
P0.05 vs SLE controls.

ditional risk factors for CVD in SLE cases with CVD,

age-matched SLE controls free of CVD, and population
control women.

Methods
Study Group
The study group consisted of 26 women with SLE surviving 1 or
more manifestations of CVD, defined as a history of myocardial
infarction (MI; n7), angina (n9), cerebral infarction (n15), or
claudication (n4). 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 registry; none of the control women had arterial disease or SLE. All
patients fulfilled the 1982 revised criteria of the American Rheumatism Association for classification of SLE.9 CVD was defined as
thromboembolic and not hemorrhagic or vasculitic stroke (confirmed
by computed tomography or MRI), MI (confirmed by electrocardiography 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.

tions; and blinded ultrasound examination of the carotid arteries.

SLE disease activity was determined with the Systemic Lupus
Activity Measure (SLAM).10 Organ damage was determined with
the Systemic Lupus International Collaborating Clinics (SLICC)
damage index.11 Osteoporosis 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 conjugated 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 Lipoproteins
Plasma lipoprotein concentrations were determined by a combination of preparative ultracentrifugation followed by lipid analyses of
the lipoprotein fractions as described previously.12 Lp(a) was determined by use of ELISA [TintELIZE Lp(a), Biopool Int]. LDL was
isolated from pooled plasma of healthy donors by sequential preparative ultracentrifugation under conditions to minimize oxidation and
proteolysis and subsequently oxidized by copper or modified by
malondialdehyde (MDA) as described previously.13

Study Protocol

Chemiluminescent Immunoassay for Autoantibody

Binding to OxLDL

The investigation included a written questionnaire, an interview, and

a physical examination by a rheumatologist; laboratory determina-

The chemiluminescent assay was performed with modifications as

described previously14 on plasma dilutions of 1:250. Data are

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Svenungsson et al

CVD Risk Factors in Systemic Lupus Erythematosus

TABLE 2. Ultrasound Measurements of Common Carotid

Artery Atherosclerosis

IMT, mm
Plaque occurrence

SLE Cases

SLE Controls

Population Controls

0.660.15*

0.600.14

0.590.12

(0.66)

(0.57)

(0.58)

17/26

10/26

3/26

Values are given as meanSD (median).

*P0.03 vs SLE controls.
P0.001 vs population controls.
P0.07 vs SLE controls.
P0.002 vs population controls.
P0.02 vs population controls.

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 modification of a previously described assay.14,15 This sandwich assay uses an
anti-human apoB-100 monoclonal antibody, MB47, to capture apoBcontaining 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 apoBcontaining 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/MB24.15 All samples were measured in a single assay, and the
intra-assay coefficients of variation of low and high standards were
6% to 8%.

1889

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 (P0.01) 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, azathioprine, or antihypertensive drugs did not differ between SLE
groups (data not shown). However, lipid-lowering compounds were taken by 9 SLE cases, 1 SLE control, and 1
healthy control.

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 controls, 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 significantly 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

Carotid Ultrasound
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.16 A plaque was defined as
a local intimal-medial thickening, with a thickness 1 mm.17

Statistical Methods
For skewed variables, nonparametric tests were used for comparisons between groups (Friedman test), whereas ANOVA was used for
normally distributed variables, with paired t test used as post hoc
analysis. McNemars 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 P0.05.

Results
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, serositis, skin involvement, and central nervous system affections
did not differ between SLE groups. Osteoporosis was more
frequent in SLE cases than in SLE controls (P0.027).

The erythrocyte sedimentation rate and plasma concentrations of orosomucoid, 1-antitrypsin, and CRP were significantly 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). Homocysteine levels discriminated strongly between groups, with
SLE cases having significantly higher levels than either SLE
controls or population controls.

Oxidation-Associated Factors
IgG and IgM autoantibodies to OxLDL and MDA-LDL were
increased in both SLE groups. Both anti-OxLDL and antiMDA-LDL antibodies of the IgG subclass discriminated
between SLE cases and SLE controls (Table 5). ApoBcontaining lipoproteins (mainly LDL) from SLE cases expressed significantly higher levels of EO6-specific epitopes
(oxidized phospholipid) than SLE controls. This also tended
to be true for population controls (Table 5).

Discussion
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

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TABLE 3.

Plasma Lipid and Lipoprotein Concentrations

SLE Cases: 1

SLE Controls: 2

Population Controls: 3

Significance

4.990.95

5.091.14

5.060.93

(4.85)

(4.96)

(4.85)

0.570.51

0.260.16

0.260.16

12 P0.007

(0.37)

(0.22)

(0.26)

13 P0.006

LDL

2.740.81

2.820.91

2.820.91

(2.71)

(2.75)

(2.85)

HDL

1.510.53

1.780.45

1.780.77

(1.51)

(1.67)

(1.49)

Cholesterol, mmol/L
Plasma
VLDL

NS

23 NS
NS
12 P0.03
13 NS
23 NS
Triglycerides, mmol/L
Plasma

1.641.00

0.960.37

1.010.37

12 P0.001

(1.26)

(0.94)

(0.96)

13 P0.005
23 NS

VLDL

1.150.93

0.600.32

0.640.34

12 P0.004

(0.75)

(0.55)

(0.53)

13 P0.02

0.310.11

0.210.08

0.220.11

12 P0.001

(0.30)

(0.20)

(0.20)

13 P0.001

0.230.05

0.200.06

0.200.05

(0.21)

(0.18)

(0.20)

352351

177212

159208

(239)

(113)

(74)

23 NS
LDL

23 NS
HDL
Lp(a), mg/L

NS
12 P0.05
13 P0.02
23 NS

Values are given as meanSD (median).

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 population controls.
Despite a more common use of hypolipidemic drugs,
dyslipidemia (elevated triglycerides and decreased HDL cholesterol) 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
healthy controls.
In line with recent findings3,18 our data indicate that the
plasma concentration of Lp(a) is significantly enhanced in SLE
cases compared with SLE controls and healthy controls, whereas
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 cardiolipin,17 and 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.22 In 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
thrombosis.
Homocysteine is increasingly recognized as a risk factor in
the general population23 and in SLE.24 How homocysteine is
related to arterial disease is not completely clear, but one
interesting possibility is an association with increased LDL
oxidation.25
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.26 In 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.

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TABLE 4.

CVD Risk Factors in Systemic Lupus Erythematosus

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Inflammatory Markers, SLE-Related Laboratory Tests, and Plasma Homocysteine Concentrations

ESR, mm

SLE Cases: 1

SLE Controls: 2

Population Controls: 3

Significance

30.120.2

18.015.1

7.93.2

12 P0.006

(25.0)

(11.5)

(7.0)

13 P0.001
23 P0.003

CRP, mg/L

7.07.3

3.64.2

1.91.8

(4.4)

(1.65)

(1.2)

12 P0.05
13 P0.002
23 P0.07

-1-antitrypsin, g/L

1.670.24

1.450.30

1.290.20

(1.60)

(1.40)

(1.20)

12 P0.002
13 P0.001
23 P0.03

Fibrinogen, g/L

4.201.30

3.501.25

3.010.77

(4.10)

(3.45)

(2.85)

1.020.25

0.910.28

0.730.23

(1.0)

(0.82)

(0.66)

12 NS
13 P0.001
23 P0.06

Orosomucoid, g/L

12 P0.05
13 P0.0002
23 P0.04

Lupus anticoagulant ratio

1.330.43

1.090.22

0.980.09

(1.18)

(1.04)

(0.98)

12 P0.02
13 P0.0003
23 P0.04

Cardiolipin IgG

11/26

8/26

1/26

12 NS
13 P0.001
23 P0.05

Cardiolipin IgM

8/26

4/26

2/26

12 NS
13 NS
23 NS

2GPI IgG

11/26

6/26

2/26

12 NS
13 P0.03
23 NS

History of positive anti-ds

DNA antibody
Homocysteine, mol/L

18/26

14/26

0/26

19.29.6

15.05.1

11.63.8

(16.0)

(14.5)

(11.0)

12 NS
12 P0.01
13 P0.001
23 P0.03

Values are given as meanSD (median).

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.27 We 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 mechanisms remains to be shown.
We confirm previous observations that autoantibodies
related to OxLDL are elevated in SLE.21,28,29 We 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,29 anti-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 frequent on apoB particles from SLE cases than on those from
SLE controls. OxLDL has proinflammatory and atherogenic
properties.8 It 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.

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TABLE 5.

Antibodies Against OxLDL and Oxidation Epitopes in LDL

aMDA-LDL IgG

SLE Cases: 1

SLE Controls: 2

Population Controls: 3

31 58320 551

20 74711 916

12 4356 113

(26 026)

(16 441)

(11 076)

Significance
12 P0.02
13 P0.001
23 P0.002

aMDA-LDL IgM

43 01424 101

46 24825 778

31 27814 217

(42 803)

(41 527)

(27 294)

12 NS
13 P0.07
23 P0.019

aOxLDL IgG

16 41114 949

80444244

67362895

(13 026)

(7471)

(6148)

12 P0.005
13 P0.0004
23 NS

aOxLDL IgM

24 21418 230

25 14922 201

(21 306)

(18 055)

13 7318620
(10 263)

12 NS
13 P0.08

0.1350.097

0.1130.095

0.1140.085

12 P0.03

(0.087)

(0.066)

(0.078)

23 P0.01
E06/apoB

13 P0.07
23 NS

Values are given as meanSD (median). aMDA-LDL indicates anti-MDA LDL antibodies; aOxLDL,
anti-Ox LDL antibodies. E06/apoB is an index of the content of E06 epitopes per apoB100 particle (see
Methods).

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 enhanced 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.

Acknowledgments
This work was supported by the King Gustaf V 80th Birthday Fund,
the Swedish Society of Medicine, the Swedish Rheumatism Association, 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
antibody levels.

References
1. 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;145:408 415.
2. Borba EF, Bonfa E. Dyslipoproteinemias in systemic lupus erythematosus: influence of disease, activity, and anticardiolipin antibodies. Lupus.
1997;6:533539.

3. Borba EF, Santos RD, Bonfa E, et al. Lipoprotein(a) levels in systemic

lupus erythematosus. J Rheumatol. 1994;21:220 223.
4. Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate
immune system? Diabetologia. 1998;41:12411248.
5. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;
340:115126.
6. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other
markers of inflammation in the prediction of cardiovascular disease in
women. N Engl J Med. 2000;342:836 843.
7. Frostegard J, Wu R, Giscombe R, et al. Induction of T-cell activation by
oxidized low density lipoprotein. Arterioscler Thromb. 1992;12:
461 467.
8. Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet. 1994;
344:793795.
9. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:
12711277.
10. Liang MH, Socher SA, Roberts WN, et al. Measurement of systemic
lupus erythematosus activity in clinical research. Arthritis Rheum. 1988;
31:817 825.
11. Gladman D, Ginzler E, Goldsmith C, et al. The development and
initial validation of the Systemic Lupus International Collaborating
Clinics/American College of Rheumatology. Arthritis Rheum. 1996;
39:363369.
12. Carlson K. Lipoprotein fractionation. J Clin Pathol Suppl. 1973;5:3237.
13. Palinski W, Yla -Herttuala S, Rosenfeld ME, et al. Antisera and monoclonal antibodies specific for epitopes generated during oxidative
modification of low density lipoprotein. Arteriosclerosis. 1990;10:
325335.
14. Wu R, de Faire U, Lemne C, et al. Autoantibodies to OxLDL are
decreased in individuals with borderline hypertension. Hypertension.
1999;33:5359.
15. Shih DM, Xia YR, Wang XP, et al. Combined serum paraoxonase
knockout/apolipoprotein E knockout mice exhibit increased lipoprotein
oxidation and atherosclerosis. J Biol Chem. 2000;275:1752717535.
16. Lemne C, Jogestrand T, de Faire U. Carotid intima-media thickness and
plaque in borderline hypertension. Stroke. 1995;26:34 39.
17. McNeil HP, Simpson RJ, Chesterman CN, et al. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding
inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc
Natl Acad Sci U S A. 1990;87:4120 4124.

Downloaded from http://circ.ahajournals.org/ by guest on May 17, 2016

Svenungsson et al

CVD Risk Factors in Systemic Lupus Erythematosus

18. Rantapaa-Dahlqvist S, Neumann-Andersen G, Backman C, et al. Echocardiographic findings, lipids and lipoprotein(a) in patients with systemic
lupus erythematosus. Clin Rheumatol. 1997;16:140 148.
19. Hamsten A, Norberg R, Bjorkholm M, et al. Antibodies to cardiolipin in
young survivors of myocardial infarction: an association with recurrent
cardiovascular events. Lancet. 1986;1:113116.
20. Vaarala O, Mnttri M, Manninen V, et al. Anti-cardiolipin antibodies
and risk of myocardial infarction in a prospective cohort of middle-aged
men. Circulation. 1995;91:2327.
21. Ho rkko S, Olee T, Mo L, et al. Anticardiolipin antibodies from patients
with the antiphospholipid antibody syndrome recognize epitopes in both
beta(2)-glycoprotein 1 and oxidized low-density lipoprotein. Circulation.
2001;103:941946.
22. Harris EN, Gharavi AE, Boey ML, et al. Anticardiolipin antibodies:
detection by radioimmunoassay and association with thrombosis in SLE.
Lancet. 1983;2:12111214.
23. Eikelboom JW, Lonn E, Genest J Jr, et al. Homocyst(e)ine, and cardiovascular disease: a critical review of the epidemiologic evidence. Ann
Intern Med. 1999;131:363375.

1893

24. Petri M, Roubenoff R, Dallal GE, et al. Plasma homocysteine as a risk

factor for atherothrombotic events in systemic lupus erythematosus.
Lancet. 1996;348:1120 1124.
25. Voutilainen S, Morrow JD, Roberts LJ II, et al. Enhanced in vivo lipid
peroxidation at elevated plasma total homocysteine levels. Arterioscler
Thromb Vasc Biol. 1999;19:12631266.
26. Makheja AN, Bloom S, Muesing R, et al. Anti-inflammatory drugs in experimental atherosclerosis, 7: spontaneous atherosclerosis in WHHL rabbits and
inhibition by cortisone acetate. Atherosclerosis. 1989;76:155161.
27. Hak AE, Pols HA, van Hemert AM, et al. Progression of aortic calcification is associated with metacarpal bone loss during menopause: a
population-based longitudinal study. Arterioscler Thromb Vasc Biol.
2000;20:1926 1931.
28. Vaarala O, Alfthan G, Jauhiainen M, et al. Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic
lupus erythematosus. Lancet. 1993;341:923925.
29. Romero FI, Amengual O, Atsumi T, et al. Arterial disease in lupus and
secondary antiphospholipid syndrome: association with anti-beta2-glycoprotein I antibodies but not with antibodies against oxidized low-density
lipoprotein. Br J Rheumatol. 1998;37:883 888.

Downloaded from http://circ.ahajournals.org/ by guest on May 17, 2016

Risk Factors for Cardiovascular Disease in Systemic Lupus Erythematosus

Elisabet Svenungsson, Kerstin Jensen-Urstad, Mikael Heimbrger, Angela Silveira, Anders
Hamsten, Ulf de Faire, Joseph L. Witztum and Johan Frostegrd
Circulation. 2001;104:1887-1893
doi: 10.1161/hc4101.097518
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2001 American Heart Association, Inc. All rights reserved.
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