Antiphospholipid Syndrome in Systemic Lupus

Erythematosus
Gary S. Hill and Dominique Nochy
Ho pital Europe en Georges Pompidou and INSERM Unite 652, Paris, France
The antiphospholipid syndrome, which
may occur in a primary form,
1
is increas-
ingly recognizedas a complicationof sys-
temic lupus erythematosus.
2,3
Indeed, it
is likely that many examples of what has
been termed in the past lupus vasculopa-
thy or lupus vasculitis
4
were infact exam-
ples of antiphospholipid syndrome, be-
cause most were described in the era
before widespread recognition of the
syndrome as a complication of lupus.
The following case is an apt example of
this entity, both clinically and morpho-
logically.
CASE HISTORY
The patient was a 32-yr-old white
woman with a 2-yr history of lupus, pre-
senting initially with articular manifesta-
tions and mild malar rash, with positive
antinuclear antibodies and elevated dou-
ble-stranded DNA antibodies but with-
out renal abnormalities. History revealed
a normal term pregnancy at age 20, fol-
lowed by three spontaneous abortions
during the subsequent 6 yr. There was
also an ill-defined episode of phlebitis
in one leg 5 yr previously, resolving with-
out specific treatment. She responded
promptly to low-dosage steroid therapy.
However, on routine follow-up at 2 yr,
she was found hypertensive (170/105
mmHg) with moderate leg edema. Eval-
uation revealed a frank nephrotic syn-
drome with proteinuria of 5.2 g/24 h,
marked hematuria (200,000 red blood
cells/ml), serum creatinine (SCr) of 180
mol/L, hemoglobin of 10.4 g/dl, ele-
vated DNA, and low C3 and C4.
Because of the findings on renal bi-
opsy, further testing was performed
and she was found to have both a lupus
anticoagulant (LA) and anticardiolipin
antibodies (aCL) of IgG type in high
titer (40 GPL units, the normal in our
laboratory being 10 GPL units), with
anti2-glycoprotein 1 (B2GP-1) anti-
bodies as well. Despite the evidence for
a thrombotic microangiopathy, stan-
dard coagulation studies were normal
and platelets were minimally reduced
at 130,000 mm
3
.
RENAL BIOPSY
Her renal biopsy revealed active class
IV-Glupus nephritis, withfairly uniform
glomerular endocapillary proliferation,
definite wire loops, and occasional
crescents. There was widespread tubular
atrophy and interstitial fibrosis with a
diffuse interstitial infiltrate. The vascular
lesions, however, were the most impres-
sive part of the biopsy. Numerous arter-
ies showed intimal lesions varying from
clear subendothelial swelling to cellular
fibrous hyperplasia (Figure 1). Associ-
ated with these lesions was variable
thrombus formation, from mural
plaques to near-complete occlusion,
with one artery showing an organized,
partially re-canalized thrombus. In addi-
tion, one artery showed fibrinoid necro-
sis of myocytes in the media (Figure 1A).
Despite the widespread arterial/arterio-
lar lesions, only one small glomerular
thrombus was seen, although several glo-
meruli seemed somewhat ischemic (Fig-
ure 1B). The overall complex of vascular
lesions qualified as a thrombotic mi-
croangiopathy; no venous lesions were
recognized. Because the biopsy did not
extend to the capsule, a frequent feature
of antiphospholipid syndrome nephrop-
athy (APSN), focal cortical atrophy,
Published online ahead of print. Publication date
available at www.jasn.org.
Correspondence: Dr. Gary S. Hill, 26, rue Edouard
Jacques, 75014 Paris, France. Phone: 331-4320-
4686; Fax: 331-4395-9190; E-mail: garyhillparis@
aol.com
Copyright 2007 by the American Society of
Nephrology
ABSTRACT
Renal biopsies occasionally show a combination of thrombotic microangiopathy as
a result of antiphospholipid syndrome and lupus nephritis. The thrombosis in this
case preceded the onset of lupus probably by approximately 8 yr, consisting of
repeated fetal loss and venous thrombosis. More severe disease may have both
arterial and venous thrombotic manifestations, including pulmonary emboli and
cerebrovascular lesions. The antiphospholipid syndrome bears no relationship to
the class of lupus nephritis but is accompanied by more frequent and greater
hypertension and greater azotemia and interstitial fibrosis, and is associated with
worse outcomes than lupus nephritis without antiphospholipid syndrome.
J Am Soc Nephrol 18: 24612464, 2007. doi: 10.1681/ASN.2007030257
PATHOPHYSIOLOGY of the RENAL BIOPSY
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J Am Soc Nephrol 18: 24612464, 2007 ISSN : 1046-6673/1809-2461 2461
which is most pronounced in the sub-
capsular region,
1
could not be identified.
Immunofluorescence studies re-
vealed bright glomerular mesangial and
irregular coarsely granular capillary
staining for IgG, C3, and C1q, with lesser
amounts of IgM and IgA. Arteries and
arterioles showed widespread staining of
the media for IgG, IgM, and C3, with
some C1q. There was widespread intimal
and focal medial staining for fibrinogen,
some in apparent thrombi. Electron mi-
croscopy was not performed.
DISCUSSION
This patient had a history typical of pri-
mary antiphospholipid syndrome, fortu-
nately fairly mild in that she had three
spontaneous abortions plus an episode
of phlebitis likely related to venous
thrombosis. She was ultimately tested
and found to have circulating aCL and
LA antibodies. In its more severe form,
antiphospholipid syndrome may include
arterial thrombi, particularly cerebral,
and venous thrombi, which may be com-
plicated by pulmonary emboli and even
pulmonary hypertension. Cerebral vas-
cular events are frequent and may lead to
neurologic deficits, seizures, or simply
diminished intellectual function. In lu-
pus, even in patients without frank cere-
bral infarcts, antiphospholipid antibod-
ies and neuropsychiatric manifestations
are strongly linked.
5
It is interesting that
there is also an association in lupus be-
tween antiphospholipid antibodies and
mitral valve nodules and mitral regurgi-
tation.
6
The antiphospholipid syndrome, as
its name implies, is caused by antibodies
to normally occurring phospholipids.
2,7
In fact, these antibodies do not recognize
anionic phospholipids directly but
rather plasma proteins bound to anionic
surfaces. Of these, B2GP-I and pro-
thrombin are the best studied.
7
The most
used and best characterized clinically are
aCL,
2,710
but antibodies other phospho-
lipids, notably phosphatidylserine, also
exist. The antibodies, measured by
ELISA, are usually IgG or IgM, the
former more associated with venous
thrombosis and pulmonary emboli, the
latter with cerebrovascular accidents.
11
Recent studies suggest that anti-phos-
phatidylserine/prothrombin antibodies
and anti-B2GP-I antibodies may show
the best correlations with thrombosis in
lupus.
8
Antibodies to prothrombin alone
seem to be as good or better than aCL
9,10
but not as good as anti-phosphatidylser-
ine/prothrombin antibodies in direct
Figure 1. (A) Artery in antiphospholipid syndromelupus. An interlobular artery showing
marked clear subendothelial swelling with a small mural thrombus. The medium shows
fibrinoid necrosis in places clearly involving individual myocytes (arrows). The glomerulus
shows diffuse endocapillary proliferation with evident wire loops. (B) Arteries in an-
tiphospholipid syndromelupus. An artery (center right) shows mild subendothelial swell-
ing in its lower branch, whereas the upper branch reveals near-total occlusion by a
thrombus. An arteriole (arrow) shows marked fibrous intimal hyperplasia, and, in conse-
quence, its glomerulus, although showing mild diffuse proliferation, is clearly ischemic.
Magnification, 350 (Masson trichrome stain).
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2462 Journal of the American Society of Nephrology J Am Soc Nephrol 18: 24612464, 2007
comparison of the two.
8
In our study,
2
aCL were found in 72% of patients with
lupus, but only 22% had symptomatic
antiphospholipid syndrome, figures
roughly comparable to other studies.
The other major category of antiphos-
pholipid antibodies are the LA, which
contrary to their name are not confined
to lupus.
1,7
These heterogeneous anti-
bodies behave as acquired inhibitors of
coagulation, prolonging phospholipid-
dependent coagulation tests,
7
and this is
the manner in which they are measured,
rather than by ELISA. In our studies, LA
were present in all patients with primary
antiphospholipid syndrome
1
and 30%of
patients with lupus.
2
We found that
APSNwas statistically associated with LA
but not with aCL. This is consistent with
an analysis of studies totaling 5102 pa-
tients showing that LA is a better predic-
tor of risk for thrombosis than aCL.
7
The pathogenesis of thrombosis in
antiphospholipid syndrome is not en-
tirely clear and may differ among pa-
tients. It has been proposed that the sta-
ble trimolecular complexes formed on
the binding of antiB2GP-I and anti-
prothrombin antibodies to anionic
phospholipids at the phospholipid sur-
face; these interactions may interfere
with proper assembly of the prothrombi-
nase complex, inhibit the formation of
thrombin in the coagulation cascade
(Figure 2), and/or alternately hamper in-
activation of factor Va (Figure 3).
7
Antiphospholipid syndrome in lupus
is not infrequent. We found that 24
(22.4%) of 107 lupus patients who un-
derwent biopsy had an associated an-
tiphospholipid syndrome,
2
correspond-
ing to the experience of other groups.
10
Similarly, the antiphospholipid syn-
drome frequently precedes the diagnosis
of lupus, often by a decade or more.
2,4
In
fact, a recent report indicated that posi-
tivity for antinucleosome antibodies at
the time of diagnosis of antiphospholipid
syndrome may help predict subsequent
development of lupus.
12
In our patient,
the history of spontaneous abortions
suggests that antiphospholipid syn-
drome may have antedated the lupus by
8 to 10 yr. The reverse question, what
percentage of cases of antiphospholipid
syndrome are associated with lupus, is
not clearly answered. It should be re-
membered that antiphospholipid syn-
drome was, in fact, first defined in the
setting of lupus and only later as a pri-
mary entity. It is clear that lupus is by far
the most frequently associated condi-
tion. Acasual review of four recent series
suggests that lupus-associated antiphos-
pholipid syndrome is actually more
common than primary antiphospholipid
syndrome.
Antiphospholipid syndrome may also
occur with any class of lupus nephritis.
Importantly, there is no association be-
tween the class of lupus nephritis and an-
tiphospholipid syndrome
2,13
or with ac-
tivity or chronicity scores.
13
There also is
no correlation between antiphospho-
lipid antibody titers and anti-DNA anti-
body or serum complement levels.
4
However, patients with lupus-antiphos-
pholipid syndrome are more frequently
hypertensive (60%) than those with lu-
pus nephritis only (28%).
2
In our series,
2
two aspects of antiphospholipid syn-
drome were particularly associated with
the development of APSN: History of ar-
terial thrombi (odds ratio 8.0) and his-
tory of obstetric complications (odds ra-
tio 6.3), as in the patient in this study.
2
The SCr was higher in patients who had
lupus with APSN than in those without
(median 100 versus 77mol/L; P
0.0007) and consistent with this had a
greater amount of interstitial fibrosis.
2
It
stands to reason that patients with a
greater frequency of hypertension (gen-
erally at substantial levels), higher SCr,
and more extensive interstitial fibrosis
should have a worse renal prognosis. Al-
though our study had too short a fol-
low-up (median 22 mo) to demonstrate
this,
2
a long-term Italian study with a
mean followup of 173 100 mo showed
a strong association between antiphos-
pholipid antibodies and development of
chronic renal insufficiency.
3
Present therapy for the thrombotic
aspects of the antiphospholipid syn-
dromelupus complex is anticoagula-
tion with Coumadin or similar agents.
Standard steroid and immunosuppres-
sive therapy seem to have little effect on
antibody levels.
4
However, a new mode
of treatment recently reported showed
marked and durable reduction of not
only aCL but also antidouble-stranded
DNA antibodies by immunoadsorption
therapy in 11 patients.
14
Another novel
approach with promising results has
been treatment of antiphospholipid syn-
drome in lupus by autologous hemato-
poietic stem cell transplantation.
15
Whether patients who have lupus with
antiphospholipid antibodies but no
symptoms relatable to antiphospholipid
syndrome should be treated is not clear.
DISCLOSURES
None.
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Figure 2. Inhibition of phospholipid-de-
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7
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2464 Journal of the American Society of Nephrology J Am Soc Nephrol 18: 24612464, 2007