Antiphospholipid Syndrome in Systemic Lupus Erythematosus
Gary S. Hill and
Dominique Nochy
Hôpital Européen Georges Pompidou and INSERM Unité 652, Paris, France
Correspondence: Dr. Gary S. Hill, 26, rue Edouard Jacques, 75014 Paris, France. Phone: +331-4320-4686; Fax: +331-4395-9190; E-mail: garyhillparis{at}aol.com
Renal biopsies occasionally show a combination of thromboticmicroangiopathy as a result of antiphospholipid syndrome andlupus nephritis. The thrombosis in this case preceded the onsetof lupus probably by approximately 8 yr, consisting of repeatedfetal loss and venous thrombosis. More severe disease may haveboth arterial and venous thrombotic manifestations, includingpulmonary emboli and cerebrovascular lesions. The antiphospholipidsyndrome bears no relationship to the class of lupus nephritisbut is accompanied by more frequent and greater hypertensionand greater azotemia and interstitial fibrosis, and is associatedwith worse outcomes than lupus nephritis without antiphospholipidsyndrome.
The antiphospholipid syndrome, which may occur in a primaryform,1 is increasingly recognized as a complication of systemiclupus erythematosus.2,3 Indeed, it is likely that many examplesof what has been termed in the past lupus vasculopathy or lupusvasculitis4 were in fact examples of antiphospholipid syndrome,because most were described in the era before widespread recognitionof the syndrome as a complication of lupus. The following caseis an apt example of this entity, both clinically and morphologically.
The patient was a 32-yr-old white woman with a 2-yr historyof lupus, presenting initially with articular manifestationsand mild malar rash, with positive antinuclear antibodies andelevated double-stranded DNA antibodies but without renal abnormalities.History revealed a normal term pregnancy at age 20, followedby three spontaneous abortions during the subsequent 6 yr. Therewas also an ill-defined episode of "phlebitis" in one leg 5yr previously, resolving without specific treatment. She respondedpromptly to low-dosage steroid therapy. However, on routinefollow-up at 2 yr, she was found hypertensive (170/105 mmHg)with moderate leg edema. Evaluation revealed a frank nephroticsyndrome with proteinuria of 5.2 g/24 h, marked hematuria (200,000red blood cells/ml), serum creatinine (SCr) of 180 µmol/L,hemoglobin of 10.4 g/dl, elevated DNA, and low C3 and C4.
Because of the findings on renal biopsy, further testing wasperformed and she was found to have both a lupus anticoagulant(LA) and anticardiolipin antibodies (aCL) of IgG type in hightiter (40 GPL units, the normal in our laboratory being 10 GPLunits), with anti–2-glycoprotein 1 (B2GP-1) antibodiesas well. Despite the evidence for a thrombotic microangiopathy,standard coagulation studies were normal and platelets wereminimally reduced at 130,000 mm3.
Her renal biopsy revealed active class IV-G lupus nephritis,with fairly uniform glomerular endocapillary proliferation,definite "wire loops," and occasional crescents. There was widespreadtubular atrophy and interstitial fibrosis with a diffuse interstitialinfiltrate. The vascular lesions, however, were the most impressivepart of the biopsy. Numerous arteries showed intimal lesionsvarying from clear subendothelial swelling to cellular fibroushyperplasia (Figure 1). Associated with these lesions was variablethrombus formation, from mural plaques to near-complete occlusion,with one artery showing an organized, partially re-canalizedthrombus. In addition, one artery showed fibrinoid necrosisof myocytes in the media (Figure 1A). Despite the widespreadarterial/arteriolar lesions, only one small glomerular thrombuswas seen, although several glomeruli seemed somewhat ischemic(Figure 1B). The overall complex of vascular lesions qualifiedas a thrombotic microangiopathy; no venous lesions were recognized.Because the biopsy did not extend to the capsule, a frequentfeature of antiphospholipid syndrome nephropathy (APSN), focalcortical atrophy, which is most pronounced in the subcapsularregion,1 could not be identified.
Figure 1. (A) Artery in antiphospholipid syndrome–lupus. 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 antiphospholipid syndrome–lupus. An artery (center right) shows mild subendothelial swelling 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 consequence, its glomerulus, although showing mild diffuse proliferation, is clearly ischemic. Magnification, x350 (Masson trichrome stain).
Immunofluorescence studies revealed bright glomerular mesangialand irregular coarsely granular capillary staining for IgG,C3, and C1q, with lesser amounts of IgM and IgA. Arteries andarterioles showed widespread staining of the media for IgG,IgM, and C3, with some C1q. There was widespread intimal andfocal medial staining for fibrinogen, some in apparent thrombi.Electron microscopy was not performed.
This patient had a history typical of primary antiphospholipidsyndrome, fortunately fairly mild in that she had three spontaneousabortions plus an episode of "phlebitis" likely related to venousthrombosis. She was ultimately tested and found to have circulatingaCL and LA antibodies. In its more severe form, antiphospholipidsyndrome may include arterial thrombi, particularly cerebral,and venous thrombi, which may be complicated by pulmonary emboliand even pulmonary hypertension. Cerebral vascular events arefrequent and may lead to neurologic deficits, seizures, or simplydiminished intellectual function. In lupus, even in patientswithout frank cerebral infarcts, antiphospholipid antibodiesand neuropsychiatric manifestations are strongly linked.5 Itis interesting that there is also an association in lupus betweenantiphospholipid antibodies and mitral valve nodules and mitralregurgitation.6
The antiphospholipid syndrome, as its name implies, is causedby antibodies to normally occurring phospholipids.2,7 In fact,these antibodies do not recognize anionic phospholipids directlybut rather plasma proteins bound to anionic surfaces. Of these,B2GP-I and prothrombin are the best studied.7 The most usedand best characterized clinically are aCL,2,7–10 but antibodiesother phospholipids, notably phosphatidylserine, also exist.The antibodies, measured by ELISA, are usually IgG or IgM, theformer more associated with venous thrombosis and pulmonaryemboli, the latter with cerebrovascular accidents.11 Recentstudies suggest that anti-phosphatidylserine/prothrombin antibodiesand anti-B2GP-I antibodies may show the best correlations withthrombosis in lupus.8 Antibodies to prothrombin alone seem tobe as good or better than aCL9,10 but not as good as anti-phosphatidylserine/prothrombinantibodies in direct comparison of the two.8 In our study,2aCL were found in 72% of patients with lupus, but only 22% hadsymptomatic antiphospholipid syndrome, figures roughly comparableto other studies.
The other major category of antiphospholipid antibodies arethe LA, which contrary to their name are not confined to lupus.1,7These heterogeneous antibodies behave as acquired inhibitorsof coagulation, prolonging phospholipid-dependent coagulationtests,7 and this is the manner in which they are measured, ratherthan by ELISA. In our studies, LA were present in all patientswith primary antiphospholipid syndrome1 and 30% of patientswith lupus.2 We found that APSN was statistically associatedwith LA but not with aCL. This is consistent with an analysisof studies totaling 5102 patients showing that LA is a betterpredictor of risk for thrombosis than aCL.7
The pathogenesis of thrombosis in antiphospholipid syndromeis not entirely clear and may differ among patients. It hasbeen proposed that the stable trimolecular complexes formedon the binding of anti–B2GP-I and anti-prothrombin antibodiesto anionic phospholipids at the phospholipid surface; theseinteractions may interfere with proper assembly of the prothrombinasecomplex, inhibit the formation of thrombin in the coagulationcascade (Figure 2), and/or alternately hamper inactivation offactor Va (Figure 3).7
Figure 2. Inhibition of phospholipid-dependent coagulation reactions. The sites of action of anti–B2GP-I and antiprothrombin antibodies are indicated by Xs. Adapted from Galli and Barbui.7
Figure 3. Inhibition of inactivation of factor Va by the protein C pathway. The stable trimolecular complexes formed by antiphospholipid antibodies (APL) at the anionic phospholipid surface hamper the inactivation of factor Va.
Antiphospholipid syndrome in lupus is not infrequent. We foundthat 24 (22.4%) of 107 lupus patients who underwent biopsy hadan associated antiphospholipid syndrome,2 corresponding to theexperience of other groups.10 Similarly, the antiphospholipidsyndrome frequently precedes the diagnosis of lupus, often bya decade or more.2,4 In fact, a recent report indicated thatpositivity for antinucleosome antibodies at the time of diagnosisof antiphospholipid syndrome may help predict subsequent developmentof lupus.12 In our patient, the history of spontaneous abortionssuggests that antiphospholipid syndrome may have antedated thelupus by 8 to 10 yr. The reverse question, what percentage ofcases of antiphospholipid syndrome are associated with lupus,is not clearly answered. It should be remembered that antiphospholipidsyndrome was, in fact, first defined in the setting of lupusand only later as a primary entity. It is clear that lupus isby far the most frequently associated condition. A casual reviewof four recent series suggests that lupus-associated antiphospholipidsyndrome is actually more common than primary antiphospholipidsyndrome.
Antiphospholipid syndrome may also occur with any class of lupusnephritis. Importantly, there is no association between theclass of lupus nephritis and antiphospholipid syndrome2,13 orwith activity or chronicity scores.13 There also is no correlationbetween antiphospholipid antibody titers and anti-DNA antibodyor serum complement levels.4 However, patients with lupus-antiphospholipidsyndrome are more frequently hypertensive (60%) than those withlupus nephritis only (28%).2 In our series,2 two aspects ofantiphospholipid syndrome were particularly associated withthe development of APSN: History of arterial thrombi (odds ratio8.0) and history of obstetric complications (odds ratio 6.3),as in the patient in this study.2 The SCr was higher in patientswho had lupus with APSN than in those without (median 100 versus77µmol/L; P = 0.0007) and consistent with this had a greateramount of interstitial fibrosis.2 It stands to reason that patientswith a greater frequency of hypertension (generally at substantiallevels), higher SCr, and more extensive interstitial fibrosisshould have a worse renal prognosis. Although our study hadtoo short a follow-up (median 22 mo) to demonstrate this,2 along-term Italian study with a mean follow up of 173 ±100 mo showed a strong association between antiphospholipidantibodies and development of chronic renal insufficiency.3
Present therapy for the thrombotic aspects of the antiphospholipidsyndrome–lupus complex is anticoagulation with Coumadinor similar agents. Standard steroid and immunosuppressive therapyseem to have little effect on antibody levels.4 However, a newmode of treatment recently reported showed marked and durablereduction of not only aCL but also anti–double-strandedDNA antibodies by immunoadsorption therapy in 11 patients.14Another novel approach with promising results has been treatmentof antiphospholipid syndrome in lupus by autologous hematopoieticstem cell transplantation.15 Whether patients who have lupuswith antiphospholipid antibodies but no symptoms relatable toantiphospholipid syndrome should be treated is not clear.
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Abstract
Introduction
10 GPL units), with anti–
2-glycoprotein 1 (B2GP-1) antibodies as well. Despite the evidence for a thrombotic microangiopathy, standard coagulation studies were normal and platelets were minimally reduced at 130,000 mm3. 
