31. | Manual of Rheumatology and Outpatient Orthopedic Disorders (LB Spiral Manuals)

Chapter 24 Antiphospholipid Antibody Syndrome and Lupus Pregnancy

Manual of Rheumatology and Outpatient Orthopedic Disorders

Chapter 24 Antiphospholipid Antibody Syndrome and Lupus Pregnancy

Lisa R. Sammaritano

Antiphospholipid Syndrome
	Immunology
	Clinical aspects
Lupus Pregnancy
	Risk for lupus flare
	Antiphospholipid antibody
	Neonatal outcome
	Evaluation and management of the lupus pregnancy

Antiphospholipid Syndrome

Antiphospholipid antibodies (aPL) are antibodies directed at phospholipids. The aPL family includes anti-cardiolipin antibodies (aCL), lupus anticoagulant (LAC) antibodies, and antibodies causing both true-and false-positive tests for syphilis. Autoimmune aPL are associated with arterial and venous thrombosis, midpregnancy fetal loss, thrombocytopenia, stroke, cardiac valvular disease, and other, less common complications. The aPL syndrome may be seen in patients with systemic lupus erythematosus (SLE) or in otherwise healthy persons (as primary antiphospholipid syndrome, or PAPS). The presence of aPL is necessary but not sufficient for the diagnosis of the aPL syndrome (APS); the syndrome requires the presence of aPL in the setting of typical complications (precise definitions vary).

Wasserman first described a type of aPL in 1906, the reagin associated with syphilis. It later became clear that there were biologic false-positive serologic tests for syphilis (BFP-STS) of two types: acute, usually associated with viral or other infections (e.g., tuberculosis, leprosy, endocarditis, malaria), and chronic, often associated with the presence of collagen vascular disease.

The LAC was described by Conley and Hartman in two patients with hemorrhagic complications; later work showed a paradoxical association with thrombosis. The LAC prolongs phospholipid-dependent coagulation steps in vitro by competing with coagulation factors for binding to phospholipid. Because of the numerous assays used for diagnosis with varying sensitivities, difficulty with definition of the LAC arose. This lack of standardization, and increasing interest in aPL and the clinical associations, prompted Harris and colleagues in 1983 to develop a solid-phase radioimmunoassay using cardiolipin (CL) as antigen.

I. Immunology

Concordance/discordance of lupus anticoagulant and anti-cardiolipin antibody. Autoimmune aPL represent a spectrum of autoantibodies including BFP-STS, LAC, and aCL. Although LAC and aCL are often present in the same patients, concordance is only about 80%. This depends partly on the assay used for LAC, which varies widely. The most sensitive assays seem to be the kaolin clotting time (KCT) and the dilute Russell viper venom time (dRVVT). Controversy exists as to which test, LAC or aCL, provides greater predictive value for thrombosis. The presence of both does not seem to confer a greater risk. Antibodies that test positively in both aCL enzyme -linked immunosorbent assay (ELISA) and LAC assay have been purified from patient plasma, but at least two groups have separated such plasma chromatographically into fractions with specific reactivity in one or the other assay. The newly recognized anti- b ₂ -glycoprotein I (anti b ₂ -GPI) antibodies, found in some but not all patients with traditional aPL, may be the most specific marker in predicting risk for complications. BFP-STS alone does not have significant predictive value in non-SLE patients.
Characteristics of antiphospholipid antibodies. aPL of the immunoglobulin M (IgM), IgG, and IgA isotypes are detected in autoimmune, infectious, and drug-induced conditions; however, only the autoimmune aPL appear to be closely associated with clinical complications. Infection- and drug-induced aPL differ from autoimmune aPL in important antibody characteristics: autoimmune aPL are generally IgG2 subclass and lambda light chain-predominant, have high avidity, and require the presence of a phospholipid-binding protein such as b ₂ -GPI for binding in routine ELISA. Common infections that may induce aPL include syphilis and a number of transient and chronic viral infections, including those caused by adenovirus, human immunodeficiency virus (HIV), and hepatitis C virus. These infection-induced antibodies show IgG1 and IgG3 subclass and kappa light chain predominance, low avidity, and lack of requirement for a phospholipid-binding protein cofactor. All aPL appear to bind (directly or indirectly) to anionic (negatively charged) phospholipids. b ₂ -GPI is a requirement for binding of autoimmune but not infection-induced aCL to CL in ELISA. Although the precise function of this protein is not clear, b ₂ -GPI may function as a natural anticoagulant. The presence of anti b ₂ -GPI antibodies has been demonstrated in sera that possess aCL activity, and these antibodies may bind to a cryptic epitope exposed when the protein is bound to negatively charged surfaces. Anti b ₂ -GPI antibodies have been suggested to be more specific than aCL in predicting thrombosis. The presence of the IgG2 subclass of both autoimmune aCL and anti b ₂ -GPI antibodies has been associated with an increased risk for clinical complications. Infection- and drug-induced aPL, usually not pathogenic, is likely to bind directly to anionic phospholipid without requirement for a serum cofactor.
Animal models of aPL do exist. In MRL/lpr mice (one of several autoimmune strains), high levels of aPL are seen. Other murine models of APS may be induced through passive immunization with purified human aPL IgG, or through active immunization with a monoclonal human aCL; the latter is presumably an anti-idiotype response.
Mechanisms of pathogenicity. Any or all of the major components of the clotting system may be involved in aPL pathogenesis, and it is likely that more than one mechanism may be at work, even within the same individual. These components include the coagulation cascade, which contains many phospholipid-dependent steps, and activation of the endothelial cell or platelet . It is clear that b ₂ -GPI is not the only phospholipid-binding protein involved in aPL binding because convincing evidence exists for prothrombin as a cofactor in some sera with LAC activity. Other potential phospholipid-binding cofactor proteins include thrombomodulin, antithrombin III, protein C, protein S, or other natural anticoagulant proteins , including annexin V. The presence of multiple mechanisms may explain the relative heterogeneity of APS presentations, including the variable involvement of the vascular bed (venous vs. arterial) and the location and timing of thrombosis.

II. Clinical aspects (Table 24-1)

Table 24-1. Clinical manifestations of antiphospholipid antibody syndrome

Epidemiology of anti-phospholipid antibodies
1. Prevalence. aPL are present in 25% to 54% of SLE patients. In the general population, the accepted range is 2% to 4%. Infections such as syphilis, HIV, Lyme disease, and common viral infections may cause transient aPL that are not associated with thrombosis. Drug-induced aPL are not usually associated with complications, although thrombosis has been rarely reported . Common drugs associated with aPL induction include chlorpromazine, procainamide, quinidine, and phenytoin. aPL present in other rheumatic diseases are generally infrequent, of low titer, and not clinically significant.
  Familial occurrence of aPL has been reported. Suggested associations include HLA-DR7 and C4 null allele; however, none of these data are as yet compelling for a strong genetic predisposition. Genetic backgrounds of patients with primary versus secondary (i.e., secondary to SLE) APS may fall into different patterns.
2. Primary anti-phospholipid antibody syndrome. As suggested above, not all patients with aPL and associated complications have SLE. PAPS patients may have high-titer aPL with complications similar to those seen with SLE-associated (secondary) aPL. Antinuclear antibody (ANA) is usually negative or low positive (11% to 47%) in PAPS patients, without other serologic abnormalities. The male-to- female ratio in these patients, unlike that in SLE, is close to 1:1.
Clinical complications
1. Recurrent thrombotic events include arterial thrombosis, as in cerebrovascular disease (stroke and transient ischemic attack), peripheral arterial disease, and ocular occlusive disease. Venous thrombosis, often recurrent, is frequently accompanied by pulmonary embolism. Pulmonary hypertension has been associated with aPL; this may represent either recurrent pulmonary embolism or small-vessel thrombosis.
  Cerebrovascular accident and transient ischemic attack may be recurrent, and may lead to multi-infarct dementia in relatively young patients. The wide spectrum of thrombosis in APS may result in unusual presentations, including gangrene, mesenteric ischemia, adrenal insufficiency, Budd-Chiari syndrome, and occlusive ocular vascular disease. Thrombosis may be acute in onset, affect multiple systems, and be fatal. A marked decrease in aPL titer has been reported in several known aPL-positive patients during fulminant occlusive episodes .
2. Cutaneous manifestations. Most common is livedo reticularis, a lattice-like pattern of superficial veins that is strongly associated with aPL in SLE. Other cutaneous manifestations include pyoderma-like leg ulcers, distal digital cyanosis, widespread cutaneous necrosis, and Degos' disease.
3. Fetal loss in women with aPL is common; the rate of pregnancy loss in patients with high-titer antibody and a history of prior fetal loss may approach 80% (untreated). Two factors, high-titer IgG aPL and previous fetal loss, are the most sensitive predictors of fetal distress or death. Women with habitual abortion should be screened for aPL even in the absence of other symptoms or serologies; cross-sectional studies suggest that 13% to 42% will be aPL-positive. Although aPL- related fetal loss is a more significant etiology in the middle and late trimesters, as many as 51% of aPL-associated losses may occur in the first trimester. Placental microthrombosis is the presumed etiology.
  Screening for aPL in asymptomatic pregnant women is not indicated. aPL has been suggested as an etiology for a small proportion of infertility cases; recent data from a murine aPL model suggest normal fertilization but impaired implantation and blastocyst development.
4. Hematologic manifestations are generally thrombocytopenia and hemolytic anemia which is Coombs'-positive (Evans' syndrome when these occur together). IgG aPL has been detected in up to 72% of SLE patients with thrombocytopenia and in 30% of patients with primary autoimmune thrombocytopenia. An association of aPL with microangiopathy has been reported in a number of settings, from severe preeclampsia associated with HELLP syndrome ( h emolysis, e levated l iver enzymes, and l ow p latelets) to a thrombotic microangiopathic hemolytic anemia.
5. Cardiac disease is well recognized in APS. An association with valvular heart disease ( aortic and mitral insufficiency) is well established and may be severe enough to require valve replacement. Libman-Sacks endocarditis is commonly seen in both aPL-positive SLE and PAPS patients. Coronary artery thrombosis may also represent a significant complication: 21% of young survivors of myocardial infarction have been reported to be aPL-positive.
6. Neurologic manifestations other than stroke. Although less common than stroke, transient ischemic attack, multi-infarct dementia, and other neurologic complications may be significant. These include chorea, transverse myelitis, multiple sclerosis-like syndrome, epilepsy, and migraine.
7. Renal insufficiency caused by aPL (and not the glomerulonephritis of SLE) has been increasingly recognized. Thrombosis may develop at any location within the renal vasculature, including the renal artery, intrarenal arteries or arterioles, glomerular capillaries, and renal veins. The aPL-associated glomerular disease is strikingly similar in pathologic features to the thrombotic microangiopathy seen in thrombotic thrombocytopenic purpura and usually presents with a decrease in creatinine clearance, proteinuria, and hypertension.
8. Catastrophic antiphospholipid antibody syndrome is characterized by multisystem vascular occlusion and often manifested by renal dysfunction with hypertension, central nervous system involvement, respiratory insufficiency with possible adult respiratory distress syndrome (ARDS), and ischemic cutaneous lesions with gangrene.
Treatment options. aCL, LAC, and BFP-STS are not identical. If the clinical history is supportive of an APS (whether or not the ANA test result is positive), tests for all three should be performed.
1. Thrombotic events. Treatment of aPL-associated complications has not been well defined in clinical prospective studies. Retrospective studies suggest that lifelong anticoagulation with warfarin at an international normalized ratio (INR) of 3.0 or greater after a clearly documented thrombotic complication is most likely to prevent recurrent thromboembolic events. Reports suggest an especially high risk for recurrent thrombosis in the 6 months following discontinuation of warfarin. Fulminant multisystem thrombotic episodes have been treated with prednisone, cytotoxic therapy , intravenous immunoglobulin, and plasmapheresis, in addition to anticoagulation, in an effort to suppress or remove antibody. No clear evidence exists as yet to support these therapies.
2. Recurrent fetal loss. Treatments for recurrent fetal loss have included prednisone, low-dose (81 mg) aspirin, and heparin, alone or in combination. Although success has been reported with each of these therapies, it is now clear that high-dose prednisone alone worsens fetal outcome and, even in a more efficacious combination with low-dose aspirin, increases maternal morbidity. The currently recommended treatment for aPL-positive women who have a history of prior fetal loss is 5,000 units of unfractionated heparin administered subcutaneously twice daily with daily low-dose aspirin. This regimen is as effective as low-dose aspirin with higher doses of heparin and more effective than low-dose aspirin alone. If patients fail this regimen, a common next step is the addition of intravenous immunoglobulin, shown to be efficacious with combination therapy in case reports.
3. Prophylactic treatment. There is no clear evidence to support the prophylactic treatment of asymptomatic patients with known aPL, although some of these patients, especially those with high titers, will be treated empirically with low-dose aspirin. A change in aPL titer has not been clearly shown to predict a clinical event or remission.

Lupus Pregnancy

SLE is most often diagnosed in women in their childbearing years . Fertility is generally unimpaired unless the patient has been treated with cyclophosphamide or chlorambucil. SLE patients have a high risk for miscarriage or fetal loss, largely because of the presence of aPL. If disease is quiescent for at least 6 months before conception , pregnancy outcome is improved.

I. Risk for lupus flare. Early (uncontrolled) studies suggested an increased risk for disease flare during pregnancy and the immediate postpartum period. Recent case-control studies, however, support little or no increased risk for flare during these periods. The definition of lupus flare at any time is not uniform; however, this issue is more complicated in pregnancy because physiologic changes in normal or complicated pregnancy can mimic symptoms of SLE flare. Some standard measures of lupus activity are invalid in the pregnant patient.

Normal pregnancy may be associated with palmar and facial erythema, chloasma gravidarum, anemia, mild thrombocytopenia, edema, and an increased erythrocyte sedimentation rate. Pregnancy-induced toxemia may present with hypertension, renal insufficiency, proteinuria, generalized edema, marked thrombocytopenia, disseminated intravascular coagulation, and seizures. Eclampsia may also be associated with decreased complement levels. Changes felt to represent SLE activity and not pregnancy include an increase in antidouble-stranded DNA antibody level, lymphadenopathy, true lupus rash, inflammatory arthritis, fever , and renal sediment abnormalities of microscopic hematuria with erythrocyte casts.

II. Antiphospholipid antibody (Table 24-2). As described in detail in the first section of this chapter, Antiphospholipid Syndrome, high-titer IgG aPL and history of pregnancy loss are strong predictors of fetal distress or loss in a current pregnancy. Complications of aPL occur independently of clinical SLE activity and do not generally respond to high-dose corticosteroid therapy. Although aCL and LAC antibodies are strongly associated with fetal loss, women with an isolated BFP-STS in the absence of aCL, LAC, or a diagnosis of SLE are not at increased risk for fetal death.

Table 24-2. Estimated prevalence of aPL and LAC in various patient populations

III. Neonatal outcome depends on several factors: presence of aPL, presence of anti-Ro/SS-A and anti-La/SS-B auto-antibodies, and current maternal medications. The risk for development of SLE in a child of an SLE mother is small; the risk for positive auto-antibodies in the child is about 10%, and the risk for development of clinical SLE is about 1%.

Antiphospholipid antibodies. The primary complication of aPL is fetal loss or premature delivery with fetal distress. aPL appear to act on the placenta rather than on the fetus itself, although antibody does cross the placental barrier and several case reports describe thrombotic complications in newborns of aPL-positive mothers. The major risks to the newborn are those of prematurity, which entails pulmonary insufficiency and neurodevelopmental delay. Thrombocytopenia, whether associated with aPL or another etiology, may be found in the fetus if present in the mother. If sampling of fetal scalp blood indicates that the fetus has a low platelet count, delivery is by cesarean section.
Anti-Ro/SS-A and anti-La/SS-B antibodies. Offspring of mothers positive for anti-Ro/SS-A and anti-La/SS-B (and very rarely anti-U1RNP) are at risk for neonatal lupus erythematosus syndrome, consisting of rash, thrombocytopenia, abnormal results on liver function tests, and congenital heart block. The risk for any manifestation of neonatal lupus erythematosus syndrome in the offspring of a mother positive for anti-Ro/SS-A is about 25%; however, the risk for cardiac involvement with irreversible congenital heart block and myocarditis is significantly smaller, estimated at less than 3%. A specific pattern of reactivity on Western blot may be associated with an increased risk for congenital heart block. Because of the low overall risk for congenital heart block in the offspring of mothers positive for anti-Ro/SS-A, however, prophylactic treatment is not generally indicated. Careful monitoring for fetal bradycardia and echocardiographic abnormalities, especially in the critical gestational period between 20 and 24 weeks, is routine. Treatment of an abnormality with high-dose dexamethasone (which easily crosses the placenta) or even plasmapheresis has been suggested and may be helpful, although no large experience supports this.
Maternal medications. Commonly used medications in SLE include aspirin, prednisone, hydroxychloroquine, and immunosuppressive agents such as azathioprine, cyclophosphamide, methotrexate, and, rarely, chlorambucil.
1. Aspirin. Commonly prescribed for APS, aspirin has been reported to have adverse hemostatic effects on mother and fetus, including prolonged bleeding at labor and prolonged duration of labor. Premature closure of the ductus arteriosus in the neonate is a theoretical concern, but this complications has not been reported with the low-dose aspirin used in APS therapy.
2. Heparin. Limited almost exclusively to aPL pregnancies or to pregnancies of women with prior thrombosis irrespective of aPL status, heparin is generally used for the full 8 to 9 months of gestation. Maternal complications may include excessive bleeding and risk for osteoporosis, although these seem to be less frequent with the newer , low-molecular-weight heparins. Both fractionated and unfractionated heparins are too large to pass through the placenta and so do not reach the fetal circulation.
3. Prednisone. Used for SLE activity (and not for aPL prophylaxis), the major risk to the fetus is adrenal insufficiency at birth. Prednisone and prednisolone, unlike some other corticosteroid preparations , are largely metabolized by the placenta with few, if any, fetal effects.
4. Antimalarial agents. Data are incomplete, and many rheumatologists will discontinue these medications during pregnancy because of theoretical risks for ear and eye toxicity. Some small series of lupus patients maintained on hydroxychloroquine throughout pregnancy have shown no adverse effects. There may be a risk for flare associated with discontinuation before pregnancy.
5. Cytotoxic agents. Chlorambucil, cyclophosphamide, and methotrexate are known teratogens; the safety of azathioprine during pregnancy is uncertain , although it is continued in many patients, especially in the renal transplant population, with few reported complications.

IV. Evaluation and management of the lupus pregnancy (Table 24-3). Both the rheumatologist and an experienced , high-risk obstetrician should participate in the evaluation and management of these patients.

Table 24-3. Valid and invalid measures of lupus activation in the pregnant patient

Initial evaluation. Assessment of disease activity, review of current medications, and discussion with the patient and her partner of specific risks as outlined above.
Laboratory evaluation. Complete blood count with platelet count, biochemical profile with blood urea nitrogen and creatinine, urinalysis , 24- hour urine for creatinine clearance and total protein, aPL (including both aCL and LAC assays), and anti-Ro/SS-A and anti-La/SS-B antibodies. Regular (monthly) follow-up of each of these is helpful, with the exception of the aPL and the anti-Ro/SS-A and anti-La/SS-B antibodies. Complement levels are sometimes but not always helpful; erythrocyte sedimentation rate is generally not useful in monitoring disease activity.
Fetal monitoring. Antepartum testing of the fetal heart rate (non-stress test) is usually initiated at about 26 weeks because abnormal findings on this test may precede a decrease in fetal movement by several weeks. If fetal distress is noted and the fetus is considered viable , early delivery may prevent fetal death. Doppler studies may be similarly useful. Fetal echocardiography, generally at weeks 20 through 24, should be performed in mothers positive for anti-Ro/SS-A and anti-La/SS-B antibodies.

Bibliography

Asherson RA, et al., eds. The antiphospholipid syndrome. Boca Raton, FL: CRC Press, 1996.

Harris EN, et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983;3:1211.

Lockshin MD, et al. Pregnancy in systemic lupus erythematosus. Clin Exp Rheumatol 1989;S3:S195.

Lockshin MD, Sammaritano LR, Schwartzman S. Pregnancy and SLE. In: Lahita R, ed. Systemic lupus erythematosus, 3rd ed. Briarcliff Manor, NY: Hermitage Publishing, 1998.

Sammaritano LR, et al. Antiphospholipid antibody syndrome: immunologic and clinical aspects. Semin Arthritis Rheum 1990;20:81.

Sammaritano LR. Update: antiphospholipid antibodies. JCR J Clin Rheumatol 1997; 3:270.

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Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders

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