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Low levels of total cholesterol high-density lipoprotein and apolipoprotein a1 in association with anticardiolipin antibodies in patients with systemic lupus erythematosus.

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ARTHRITIS & RHEUMATISM Volume 36
Number 11, November 1993, pp 1566-1574
0 1993, American College of Rheumatology
1566
LOW LEVELS OF TOTAL CHOLESTEROL,
HIGH-DENSITY LIPOPROTEIN, AND
APOLIPOPROTEIN A1 IN ASSOCIATION WITH
ANTICARDIOLIPIN ANTIBODIES IN PATIENTS WITH
SYSTEMIC LUPUS ERYTHEMATOSUS
R. G. LAHITA, E. RIVKIN, I. CAVANAGH, and P. ROMANO
Objective. To determine if there is an association
between low levels of high-density lipoprotein cholesterol (HDL), apolipoprotein A1 (Apo Al), total cholesterol, and anticardiolipin antibody (aCL) in patients
with systemic lupus erythematosus (SLE) who are not
taking corticosteroids.
Methods. We studied 75 outpatients with documented SLE who were attending our hospital clinics: 57
were aCL positive and 18 were aCL negative. Both IgG
and IgM aCL levels were determined by enzyme-linked
immunosorbent assay. Lipid fractions (total cholesterol,
HDL, low-density lipoprotein, very-low-density lipoprotein, and trigtycerides) were determined by standard
enzymatic techniques. Apo A1 and Apo B levels were
determined by nephelometry.
Results. Patients with SLE who were IgG aCL+
had low levels of serum cholesterol (mean f SD 173.6 f
34.6 mg/dl) and HDL (43.9 2 16.3 mgldl) compared
with aCL- SLE patients, normal donors, and patients
with other diseases. Apo A1 levels were also low in the
aCL+ group (95.5 -+ 50.9 mg/dl) compared with the
aCL- group (152.7 f 32.6 mg/dl). There was no
Presented in part at the 55th Annual Meeting of the American College of Rheumatology, Boston, MA, November 1991.
From the Saint Luke’s Roosevelt Medical Center, Columbia University, New York, New York, and Clinical Diagnostic
Laboratories, Englewood, New Jersey.
R. G. Lahita, MD, PhD: Saint Luke’s Roosevelt Medical
Center, Columbia University; E. Rivkin, PhD: Saint Luke’s
Roosevelt Medical Center, Columbia University; I. Cavanagh, MS:
Saint Luke’s Roosevelt Medical Center, Columbia University; P.
Romano, MD: Clinical Diagnostic Laboratories.
Address reprint requests to Robert G. Lahita, MD, PhD,
Chief, Division of Rheumatology and Connective Tissue Diseases,
Saint Luke’s Roosevelt Hospital Center, 432 West 58th Street, New
York, NY 10019.
Submitted for publication November 21, 1991; accepted in
revised form April 14, 1993.
association of total cholesterol level or aCL titer with
clinical activity.
Conclusion. These data indicate that in SLE
patients, there is an association between antibody
against the phospholipid cardiolipin and low levels of
cholesterol, HDL, and Apo Al.
Many mechanisms have been proposed for the
actions of anticardiolipin antibodies (aCL) in systemic
lupus erythematosus (SLE) (1,2). These include aCL
binding to endothelial cells or platelets via membrane
phospholipids, with consequent disruption of such
functions as prostacyclin release, fibrinolysis, protein
C pathways, or platelet aggregation. However, recent
evidence indicates that membrane binding of antibody
to phospholipid alone is unlikely, because a lipidprotein epitope has been found which may be the
principal target of these antibodies in patients with
lupus and related diseases.
Anticardiolipin antibodies can be found in 3040% of patients with SLE (3) or related illnesses (4),
those exposed to certain drugs (5) or infections (6), and
patients with a malignancy (7), as well as in approximately 6% of normal individuals (8,9), increasing with
age. The incidence of cardiovascular events, such as
myocardial infarction and cerebral thrombosis, is reported to be increased in men and women with SLE
(lo), and atherosclerosis is known to be accelerated in
this patient group (11,12). There is certainly an association of thrombotic events with aCL, but the relationship of this antibody to atherosclerosis is unclear.
Apart from the suggested appearance of atherosclerosis in SLE patients as a result of long-term steroid
therapy, no explanation for the accelerated atherosclerosis has been proposed.
LOW LEVELS OF HDL AND APO A1 IN SLE
The data we present here suggest that there is
an association between anticardiolipin antibody and
low levels of total cholesterol, high-density lipoprotein
(HDL), and apolipoprotein A1 (Apo Al) in patients
with SLE.
PATIENTS AND METHODS
Patient selection. Patients were selected from the
Rheumatology Service of Saint Luke’s Roosevelt Hospital
Center of Columbia University. Such patients formed several groups. There were 97 patients with SLE who fulfilled
the American College of Rheumatology (formerly, the American Rheumatism Association) criteria (13), only 75 of whom
were not taking steroids at the time of the study. A series of
54 patients with other rheumatic diseases also were studied.
These included 9 patients with rheumatoid arthritis, 10
patients with osteoarthritis, 4 patients with inflammatory
muscle disease, and 31 patients with other inflammatory
diseases. The patients with the other inflammatory diseases
included 5 patients with tendinitis, 1 with fibromyalgia, 5
with mixed connective tissue disease, 4 with Sjogren’s
syndrome, 1 with CREST syndrome (calcinosis, Raynaud’s
phenomenon, esophageal dysmotility, sclerodactyly, and
telangiectasias), 1 with subacute cutaneous lupus, 1 with
vasculitis, 1 with urticaria, 6 with scleroderma, 1 with
dermatomyositis, 1 with Still’s disease, 1 with Reiter’s
syndrome, 2 with discoid lupus, and 1 with Lyme disease. A
total of 72 normal volunteer blood donors also served as a
control group.
Blood samples were drawn in the early morning in all
cases. Although the patients were not necessarily fasting,
fasting samples would have favored the results of normal-tolow plasma cholesterol levels. Antibody, lipid, and apolipoprotein analyses were done on the same samples in all cases.
Since cholesterol levels are raised by the presence of renal
disease and by the ingestion of steroids, such patients were
eliminated from analysis. Those with other confounding
variables, such as diabetes, liver disease, and ingestion of
certain lipid-raising drugs, which might affect apolipoprotein
levels were also eliminated from the final study population.
Anticardiolipin antibodies. Serum aCL levels were
determined by a solid-phase enzyme-linked immunosorbent
assay, as described by Loizou et a1 (14) and modified by
Gharavi et a1 (15). Sera were diluted 1:lOO and samples
were placed in a 96-well flat-bottomed polystyrene 350 IU
immunoplate (Beckman, Palo Alto, CA). Reagents used
were cardiolipin (Sigma, St. Louis, MO), at a concentration
of 50 pg/ml and coated on the plate by evaporation at 4°C for
12 hours, alkaline phosphatase-conjugated monospecific
goat anti-human y chain or anti-p chain antibodies (Cappel,
Baltimore, MD), p-nitrophenyl phosphate substrate (Sigma
#104), phosphate buffered saline (PBS), pH 7.4, 10% fetal
calf serum (FCS) in PBS, and glycine buffer. The enzymatic
reaction was read at 405 nm on a Titertek multiscan MC 340
(Flow, McLean, VA).
Wells used as blanks contained 10% FCS in PBS
instead of the target sera. Known positive and negative sera
were provided to us by Dr. Nigel Harris (University of
1567
Louisville Medical College, Louisville, KY). Standard normal values used in our laboratory are 0-15 units IgG aCL and
0 4 units IgM aCL.
Analysis of lipids. Total cholesterol and HDL levels
were measured with a Hitachi 736-30 analyzer (Boehringer
Mannheim, Indianapolis, IN). The Hitachi utilizes an enzymatic methodology, which is based on a colorimetric reaction. Samples are read photometrically. The method utilizes
the enzymatic reaction of cholesterol with peroxidasei
phenol-4-aminophenazone. Microbial esterase produces
complete hydrolysis of all cholesterol esters that occur in
human sera, thus allowing standardization by primary and
secondary standards and direct comparison to the Centers
for Disease Control and Prevention (Atlanta, GA) reference
procedures (16,17). Serum levels of all lipids were determined within 24 hours after drawing samples of blood.
HDL levels were determined by precipitation of
very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) with phosphotungstic acid and magnesium
ions. Subsequent centrifugation left only the HDL fraction
in the supernatant, which was then measured photometrically (18).
Triglyceride levels were determined by the glycerol
phosphate oxidase technique following enzymatic cleavage
of fatty acids (Boehringer Mannheim). It was not possible to
measure all lipid fractions in all patients. However, cholesterol and HDL were measured in all patients in whom
anticardiolipin antibodies were determined.
Measurement of apolipoproteins A1 and B. Levels of
human Apo A1 and B were determined by nephelometry
(Behring Diagnostic Company, Marburg, Germany) of serum samples that had been stored at -40°C. Standard
antisera and antigens for apolipoprotein were a gift from
Behring Diagnostics. Standard curves revealed that the
standard range for Apo A1 was 105-215 mg/dl and that for
Apo B was 59-155 mg/dl. Single-point analysis of patient
sera indicated that they fell within the confidence limits of
15% of the control sera.
Clinical activity. Clinical activity was measured according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), as previously described (19).
Statistical analysis. Statistical analysis was performed
with the BMDP statistical programs (BMDP, Los Angeles,
CA) on a personal computer. These programs were simple
data description, comparison of 2 groups with t-tests, and
description of groups (strata) with histograms and analysis of
variance.
*
RESULTS
T h e sex and age distribution and mean aCL
titers of the 75 SLE patients studied are given in Table
1 . The 72 SLE patients who were not taking prednisone had lower cholesterol levels (mean SD 180.9
39.3 mg/dl, range 10CL275) than did the group of 72
normal blood donors (236.5 2 46.2 mg/dl, range 14&
330). This difference was significant, at a level of
P = 0.001.
*
*
LAHITA ET AL
1568
In 22 patients with SLE who were taking 5-30
mg/day of prednisone, the overall cholesterol level
(186.5 t 55.0 mg/dl, range 115405) was not significantly increased compared with that in the group of
SLE patients who were not taking steroids. Cholesterol values were lower in the non-steroid-treated
patients regardless of aCL status. Because the cholesterol levels of patients using corticosteroids were
elevated, their data were eliminated from analysis and
not a part of this study.
Cholesterol and HDL values in IgG aCL+ SLE
patients were compared with those in IgG aCL- SLE
patients, revealing lower cholesterol levels ( P = 0.02)
and lower HDL levels ( P = 0.03) in the aCL+ SLE
patients (Figure 1). Chi-square analysis of the aCL+
versus the aCL- SLE patients, regardless of sex
(Figure 2), showed that more patients with cholesterol
values <180 mg/dl were aCL+ (76% and 25%, respectively; P = 0.0005).
Comparison of the lipid values in male and
female aCL+ patients with those in the group of 72
normal donors showed significantly lower cholesterol
and HDL levels in the aCL+ patients (Table 2). We
also compared these plasma lipid profiles with those in
patients with immunologic diseases other than SLE
(Table 2). There was a significantly lower level of total
cholesterol compared with this group as well ( P <
0.001). Although differences in the VLDL levels also
reached significance ( P = 0.03), the low numbers of
subjects in the normal control group and in the group
of patients with other immunologic diseases invalidate
this comparison; likewise, differences in HDL levels
were also invalid.
Table 1. Anticardiolipin antibody (aCL) titers and mean ages of
the 75 patients with systemic lupus erythematosus (SLE), categorized by sex
aCL+ SLE patients
No. of patients
Age
Mean t SD
Range
IgG aCL titer
(mean t SD)
aCL- SLE patients
No. of patients
Age
Mean t SD
Range
IgG aCL titer
(mean 2 SD)
Males
(n = 16)
Females
(n = 59)
14
43
31.4 5 17.4
10-63
31.5 +- 18.4
39.7 f 14.3
17-72
30.9 f 15.6
2
16
50.1 2 17.7
7*4
38.5 t 14.3
23-56
10.1 f 3.7
250
*
**
T
T
200
rz
** P=
3
0.02
e
5 loo
50
0
aCLUPlD FRACTIONS
aCL+
Figure 1. Comparison of lipid fractions in systemic lupus erythematosus patients with and without anticardiolipin antibodies (aCL).
Both the cholesterol (CHOL) and high-density lipoprotein (HDL)
fractions were significantly decreased in the aCL+ group; triglycerides (TRIG) were increased. Values are the mean and SD. LDL =
low-density lipoprotein: VLDL = very-low-density lipoprotein.
P = 0.0005
cn
c
Y
.o 15 Y
O
n
10 -
5 -
0
L
<
L
140
140-180
180-225
>225
Cholesterol
Figure 2. Cholesterol levels in aCL+ and aCL- systemic lupus
erythematosus (SLE) patients, showing that a highly significant
number of aCL+ SLE patients had cholesterol levels <180 mg/dl (P
= 0.0005 by chi-square analysis). See Figure 1 for abbreviations.
LOW LEVELS OF HDL AND APO A1 IN SLE
1569
Table 2. Comparison of plasma lipid profiles of aCL+ SLE patients with those in patients with other
immunologic diseases and in normal control subjects*
Chol
aCL+ SLE patients
Mean f SD mg/dl
No. of patients
Other immunologic
disease patients
Mean f SD mg/dl
No. of patients
Normal controls
Mean f SD mg/dl
No. of subiects
HDL
LDL
43.9 f 16.3$: 116.7 f 32.7
33
24
173.6 t 34.6t
56
Trig
VLDL
121.7 f 83.9
23
23.9 f 7.0
7
17
133.0 f 29.4
11
145.9 ? 127.2
27
37.5
44
236.5 t 46.2
72
58.8 t 23.7
62
161.5 f 40.0
6
185.3 f 153.0
75
50.0
209.9
f 44.9
54.3
f
13.7
f 0.7
2
f
11.3
2
* Patients with other immunologic diseases were as follows: 5 with tendinitis, 1 with fibromyalgia, 5
with mixed connective tissue disease, 4 with Sjogren’s syndrome, 1 with CREST syndrome
(calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias), 1
with subacute cutaneous lupus, 1 with vasculitis, 1 with urticaria, 6 with scleroderma, 1 with
dermatomyositis, 1 with Still’s disease, 1 with Reiter’s syndrome, 2 with discoid lupus, and 1 with
Lyme disease. aCL+ = anticardiolipin antibody positive; SLE = systemic lupus erythematosus; Chol
= cholesterol; HDL = high-density lipoprotein; LDL = low-density lipoprotein; Trig = triglycerides;
VLDL = very-low-density lipoprotein.
t P < 0.001 versus patients with other rheumatic diseases, and P = 0.003 versus normal controls.
$: P < 0.001 versus patients with other rheumatic diseases, and P < 0.05 versus normal controls.
72
350
‘In=
56
43
8
7
27
!
1
I
1
vl
8
!l
-I
Y
B
0
500-
200 250
150
U
loot
50 I
I
1
I
Normal aCLt aCL- OA
RA
Other
Figure 3. Boxplot analysis of cholesterol levels in aCL+ and aCLsystemic lupus erythematosus (SLE) patients compared with normal
blood donors and with patients with other rheumatic diseases. The
horizontal line within each box is the 50th percentile; the bar at the
bottom is the 25th percentile; open circles at the bottom and top of
some plots are the 5th and 95th percentiles, respectively. The 50th
percentile €or the aCL+ SLE patients is significantly lower ( P <
0.05) than that in all other groups, except the aCL- SLE patients.
Approximately 25% of patients with cholesterol values (150 are in
the aCL+ group. OA = osteoarthritis; RA = rheumatoid arthritis;
Other = other inflammatory diseases. See Figure 1 for other
abbreviations.
Boxplot comparisons of cholesterol levels in
aCL+ and aCL- SLE patients with those in normal
volunteers and patients with other rheumatic diseases
showed the lowest median value in aCL+ SLE patients (Figure 3). Approximately 25% of SLE patients
with cholesterol levels <150 mg/dl were found in this
aCL+ group.
Plots of the various lipid fractions in the SLE
patients according to IgG aCL positivity showed significantly lower levels of the HDL fraction in the
aCL+ patients: 44.3 ? 16 mg/dl in 33 aCL+ patients
versus 57.3 ? 18.0 mg/dl in 10 aCL- patients; P <
0.03. However, there was no correlation of IgG aCL
titer and HDL level in this group of SLE patients.
There were several patients with extremely high aCL
titers who did not have either a low total cholesterol or
a low HDL level. Triglyceride levels were also significantly elevated in the aCL+ group (139 ? 82 mg/dl,
n = 25, versus 77.7 ? 32 mg/dl, n = 10, in the
aCL- group).
No significant differen between the lipid fractions in any group and IgM antibodies to cardiolipin
was found (data not shown).
Because the HDL levels in the IgG aCL+
patients were lower, we examined the levels of both
Apo A1 and Apo B. Apo A1 is the major apolipoprotein of HDL; Apo B is the major apolipoprotein of
LDL. Where possible, we compared these values in
LAHITA ET AL
1570
lupus patients who had significantly elevated aCL
levels (>I5 units) at the time of study (Table 3). The
patients whose aCL titers were > 15 units at the time of
study had significantly lower levels of both HDL and
Apo A1 and elevated levels of Apo B compared with
those whose titers were <I5 units. Serum samples
from patients with a history of aCL but without
significant titers (>I5 units) at the time of study had
lower Apo A1 levels than did those whose aCL titers
had never been over 15 units; however, there was no
statistically significant decrease in HDL. Apo B levels
were not appreciably different between groups.
Chi-square comparison of Apo A1 levels in IgG
aCL- and aCL+ patients showed a higher percentage
of aCL+ patients (15 of 33, 45%) than aCL- patients
(1 of 11,9%) with Apo A1 levels < 105 mg/dl (P = 0.03,
Figure 4). There was no significant depression or
elevation of Apo B levels in any aCL+ patients.
The Apo A1:B ratio is of considerable importance in relation to the risk of coronary heart disease
(CHD), and some investigators have reported it to be
the best single predictor (20). Figure 5 shows the Apo
A1:B ratio plotted against the IgG aCL titers of
patients with SLE. Ratios of 1.4 for males and 1.6 for
20
=
HDL
Apo A1
Apo B
aCL+ at time of study
>15 units
Mean r SD
40.1 2 15.17 95.5 f 50.9$ 99.9 t 42.0
Range
25-70
48-207
25-1 88
No. of patients
11
I1
11
<15 units
66.0 2 10.9 152.7 t 32.6 77.9 t 18.3
Mean t SD
Range
54-78
108-178
51-90
No. of patients
4
4
4
aCL- at time of study
>I5 units
Mean t SD
46.6 t 18.8 106.4 k 49.88 90.4 t 31.7
Range
20- 198
45-207
No. of patients
9
33
33
<I5 units
Mean t SD
62.3 t 15.4 146.6 f 45.9 105.4 2 23.1
Range
55-198
51-139
No. of patients
4
11
I1
* HDL
= high-density lipoprotein; Apo A1 = apolipoprotein A l ;
SLE = systemic lupus erythematosus; aCL = anticardiolipin antibody.
t P = 0.011 versus those aCL+ at <15 units at the time of study.
t P = 0.03 versus those aCL+ at <15 units at the time of study.
0 P = 0.02 versus those aCL- at the time of study and aCL+ at <15
units at some time during the disease course.
I
15
3
C
.$
10
2
5
I
0
1
<lo5 -mg/dl
>lo5 mg/dl
I
Apo A1 levels
Figure 4. Apolipoprotein A1 (Apo A l ) levels in aCL+ and aCLsystemic lupus erythematosus patients. A significantly greater number of aCL+ patients had Apo A1 levels <I50 mg/dl (lower limit of
normal) than is expected by chance (P = 0.03). See Figure 1 for
other definitions.
Table 3. Levels of HDL, Apo Al, and Apo B in SLE patients
positive for aCL at the time of study and in those without significant
aCL titers (aCL-) at the time of study but positive at some time
during their disease course*
IgG aCL titer
aCL-
0= aCL+
100
-
80
-
: . :
60
8
c
0
0
...
-20“ 1
-0.5
.
1
I
0.0
0.5
: \
1.0
1.5
2.0
I
I
J
2.5
3.0
3.5
R a t i o ADO A1:B
Figure 5. Apolipoprotein AI:B (Apo A1:B) ratios plotted against
the titer of IgG aCL in systemic lupus erythematosus patients.
Ratios of 1.4 (males) and I .6 (females) represent an average risk of
developing coronary heart disease (CHD). Ratios 51.0 convey 3
times the average for CHD. The regression line is shown, flanked by
the 95% confidence limits. Correlation coefficients are r = -0.23 for
the entire group, r = 0.42 for those with aCL values below Apo
AI:B ratios of 1.0, and r = -0.20 for those with values above 1.0.
See Figure 1 for other definitions.
LOW LEVELS OF HDL AND APO A1 IN SLE
Clinical activity was measured using the
SLEDAI instrument (19). Figures 7A and B show the
apparent lack of association between the clinical activity indices and aCL titers, as well as between
disease activity and cholesterol values.
11
{
10
DISCUSSION
U
' 3 9
0
n
O
8
7
a
6
r
ii
s
2
1571
5
4
3
2
1
0
Relative Risk
Figure 6. Numbers of aCL+ and aCL- systemic lupus erythematows patients and their risks for coronary heart disease (CHD),
based on apolipoprotein A1:B ratios of 51.0. Note the significant
number of aCL+ patients with 3 times the average risk (3x Avg) of
developing CHD. See Figure 1 for other definitions.
females represent an average risk of developing CHD.
Over 50% (n = 15) of these SLE patients had A1:B
ratios 5 1.O, and therefore have a 3 times higher risk of
developing CHD (Figure 6).
There was no significant decrease in Apo A1 or
Apo B values in patients who had elevated levels of
IgM aCL (data not shown).
To determine whether changes in levels of total
cholesterol affect the aCL titer, 5 aCL+ SLE patients
were evaluated for the effects of corticosteroid therapy
(doses up to 60 mg/day). There was an overall increase
in plasma cholesterol levels after the corticosteroid
therapy. However, there was an appropriate decline in
the IgG aCL titers (Table 4).
Table 4. Effect of prednisone (60-day course) on cholesterol and
anticardiolipin antibody (aCL) levels
Before therapy
Patient,
prednisone
dose
Cholesterol
(mg/dl)
PC, 13 mglday
JG, 20 mg/day
AW, 60 mg/day
LH, 30 mg/day
SG, 5 mgiday
115
126
157
125
126
IgG
aCL
(units)
23
>60
39
40
25
After therapy
Cholesterol
(mg/dl)
IgG
aCL
(units)
164
236
213
171
138
12
7
20
19
11
In this study, we found that SLE patients who
were not taking corticosteroids had lower cholesterol
levels than expected. Moreover, aCL+ SLE patients
had lower total cholesterol, HDL, and Apo A1 levels
than did aCL- SLE patients. Patients with a variety of
unrelated illnesses and normal volunteer donors had
higher values. The HDL values and Apo A1:B ratios
were inversely associated with the level of IgG aCL in
most SLE patients, and these values did not always
correlate with the aCL titers. There was no association
of low cholesterol or high IgG aCL values with clinical
activity. The evidence supports the notion that SLE
patients with IgG aCL have low total cholesterol,
HDL, Apo Al , and Apo A1:B ratios.
We considered all of the possible reasons for
altered lipid metabolism in the design of this study. We
excluded hospitalized patients who were critically ill,
those who had disturbed liver metabolism and might
therefore rapidly clear cholesterol, those who had fat
malabsorption, and any patient who appeared to be
suffering from starvation. We also eliminated patients
who were taking hydroxychloroquine (21). While elimination of these patients would control for lower lipid
values, the most common concerns were for hyperlipidemia. Renal disease is a cause of hyperlipidemia and
consequent hypertension, and patients with severe
renal disease were not included in the study group.
Medication histories were of particular importance
since an increase in cholesterol levels can be seen with
corticosteroid therapy at any dosage (22,23). Concern
about drawing the blood samples while the patients
were fasting would have been of importance if the
features of interest were associated with an increase in
plasma cholesterol levels. Risk factors such as smoking and hypertension are also associated with elevated
cholesterol levels, which were not of concern in these
studies. There are usually no studies of lowered lipid
levels in patients with SLE because of attempts to
associate elevated levels with atherosclerosis.
Antiphospholipid antibodies are present in patients who do not have SLE, as well as in normal
subjects. Our principal concern about IgG aCL is the
associated thrombotic syndrome. The vasculopathy of
the anticardiolipin syndrome in SLE includes both
LAHITA ET AL
1572
401-
A
0
-
arB
35
-a
0
0
t-.
0
0
3
0
0
0
3025-
0
20U
0
34
15-
3
105-
8.
0
-10
-
0
10
20
30
40
50
60
01
100
0 .
I
150
I
200
I
250
I
300
CARDlOLlPlN TITER
CHOLESTEROL
Figure 7. A, IgG anticardiolipin antibody levels and B, cholesterol levels plotted against SLE clinical activity, as assessed using the Systemic
Lupus Erythematosus Disease Activity Index (SLEDAI). The regression line is shown, flanked by the 95% confidence limits.
venous and arterial thromboses (24). Ischemic heart
disease, transient ischemic attacks, and “stroke” occur frequently in patients with the antiphospholipid
syndrome and are said to be the result of “thromboses”; however, very few of these patients have undergone angiography (cerebrakoronary) (25) to prove this
as a cause of the acute events. Anticardiolipin antibodies
in SLE have also been associated with deep vein thrombosis, cerebrovascular accidents, early myocardial infarction, recurrent abortions, thrombocytopenia, pulmonary hypertension, and more recently, valvular
heart disease (2632). Less commonly, Addison’s disease, peripheral arterial occlusions, bowel infarcts,
avascular necrosis of bone, and a variety of neurologic
conditions have been reported in association with
these antibodies (33,34).
Recent studies of the antigen for the aCL assay
indicate that phospholipid is associated with a cofactor
which is an apolipoprotein. Apolipoprotein H (&glycoprotein I) is part of the major antigen for these
antibodies (35,36). Apolipoprotein H is involved in the
coagulation process as a natural antagonist of plasminogen inhibitor (37) and as a direct inhibitor of platelet
prothrombinase activity (38). Apolipoproteins such as
Apo A1 are also closely associated with phospholipids, but have not been shown to be cofactors with
phospholipids in the in vitro antiphospholipid assay.
Apo A1 is a protein that has been found to have
immunogenicity in at least one patient with SLE (39),
as shown by data from our laboratory in which a gene
homologous to Apo A1 was cloned using serum from
an SLE patient with cerebrovascularatherosclerosis (39).
Evidence in support of a greater role of apolipoproteins as antigens comes from the present study and
from previous studies of SLE patients not ingesting
steroids (40). Levels of HDL and Apo A1 were found
to be decreased; however, aCL levels were not measured (40). Antibody binding to epitopes on phospholipid, apolipoprotein, or both might account for a
variety of pathologic effects found in certain diseases
like SLE, and the type of apolipoprotein bound might
determine the pathologic effect. The data presented
herein indicate that the SLE patients were at risk of
developing atherosclerosis and CHD even if their aCL
status was unknown.
Any relationship between the apolipoproteins
and antiphospholipid antibody and atherosclerosis in
SLE would be of considerable interest. The incidence
of atherosclerosis is noticeably higher in patients with
SLE than in the normal population as well as in
patients with other rheumatic diseases. Many cases of
myocardial infarction have been described in patients
with SLE (11,41-44), and accelerated atherosclerosis
has always been a curious aspect of SLE. One study
LOW LEVELS OF HDL AND APO A1 IN SLE
(12) showed that 5% of female SLE patients were
affected, and in another study of 507 lupus patients, 45
had angina or early myocardial infarctions (45). The
incidence of atherosclerosis seems to be astonishingly
high by some reports, coronary atherosclerosis being
found in 40% of lupus patients versus 2% of agematched controls (46,47), and the mortality rate for
myocardial infarction in SLE patients is 10 times
higher than in age-matched controls. This accelerated
atherosclerosis seems to occur predominantly in
young premenopausal women, an age group in which
the prevalence should be low (48,49). Many reasons
for this accelerated atherosclerosis have been proposed, such as steroid therapy for the SLE (22,50,51)
and dyslipoproteinemia (21,40,47,52). As mentioned
above, several studies report abnormalities of HDL
and Apo A1 in patients not ingesting prednisone
(40,52). Although thrombosis is frequently mentioned
and associated with aCL, particularly in patients with
myocardial infarction (24,25,53-55), atherosclerosis is
rarely mentioned, despite the clinical observation that
myocardial infarctions are frequent in patients with
SLE (25,53,5&58).
The fate of immune complexes that form and
involve Apo A1 would be of considerable interest to
those studying the origins of atherosclerosis. These
antibodies might occur in diseases unrelated to lupus,
and a role in atherosclerosis in other conditions might
be possible. There are data, for example, which present an immune etiology for atherosclerosis (59-61),
and antigen-driven processes associated with infections have also been linked to atherosclerosis (62-64).
Patients with infections as well as other conditions
have had aCL, and we believe aCL titers should be
measured in patients with accelerated atherosclerosis.
ACKNOWLEDGMENTS
T h e authors thank Drs. R. A. Asherson, S. Hashim,
and S. Majewski for their helpful comments.
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