Lupus is a heterogeneous autoimmune disease with a complex pathogenesis that results in interactions between susceptibility genes and environmental factors (Hahn, 2015). Immune system abnormalities include overactive B lymphocytes that are responsible for autoantibody production. These result in tissue and cellular damage when autoantibodies or immune complexes are directed at one or more cellular nuclear components (Tsokos, 2011). In addition, immunosuppression is impaired, including regulatory T-cell function (Tower, 2013). Some autoantibodies produced in patients with SLE are shown in Table 59-1.
TABLE 59-1Some Autoantibodies Produced in Patients with Systemic Lupus Erythematosus (SLE) ||Download (.pdf) TABLE 59-1 Some Autoantibodies Produced in Patients with Systemic Lupus Erythematosus (SLE)
|Antibody ||Prevalence (%) ||Clinical Associations |
|Antinuclear (ANA) ||84–98 ||Best screening test, multiple antibodies; a second negative test makes SLE unlikely |
|Anti-dsDNA ||62–70 ||High titers SLE-specific; may correlate with disease activity, nephritis, and vasculitis |
|Anti-Sm (Smith) ||25–38 ||Specific for SLE |
|Anti-RNP ||33–40 ||Not SLE-specific, high titers associated with rheumatic syndromes |
|Anti-Ro (SS-A) ||30–49 ||Not SLE-specific; associated with sicca syndrome, predisposes to cutaneous lupus, neonatal lupus with heart block, reduced risk of nephritis |
|Anti-La (SS-B) ||10–35 ||Associated with anti-Ro |
|Antihistone ||70 ||Common in drug-induced lupus |
|Antiphospholipid ||21–50 ||Lupus anticoagulant and anticardiolipin antibodies associated with thrombosis, fetal loss, thrombocytopenia, valvular heart disease; false-positive test for syphilis |
|Antierythrocyte ||60 ||Direct Coombs test, may develop hemolysis |
|Antiplatelet ||30 ||Thrombocytopenia in 15%; poor clinical test |
Almost 90 percent of SLE cases are in women, and its prevalence in those of childbearing age approximates 1 in 500 (Lockshin, 2000). Accordingly, the disease is encountered relatively frequently during pregnancy. The 10-year survival rate is 70 to 90 percent (Tsokos, 2011). Infection, lupus flares, end-organ failure, hypertension, stroke, and cardiovascular disease account for most deaths.
Genetic influences are implicated by a higher concordance with monozygotic compared with dizygotic twins—25 versus 2 percent, respectively. Moreover, frequency in patients with one affected family member is 10 percent. The relative risk of disease rises if there is inheritance of the “autoimmunity gene” on chromosome 16 that predisposes to SLE, rheumatoid arthritis, Crohn disease, and psoriasis. Susceptibility genes such as HLA-A1, -B8, -DR3, -DRB1, and -TET3 explain only a portion of the genetic heritability (Tsokos, 2011; Yang, 2013). Interestingly, even maternal exposure to fetal genes elevates susceptibility to SLE development. A case-control study found that a child’s HLA-DRB1 genotype increases the risk of SLE in the mother (Cruz, 2016). Furthermore, neonatal lupus erythematosus has been reported in an infant conceived via oocyte donor to a mother with autoimmune disease with circulating anti-Ro and anti-La antibodies (Chiou, 2016).
Clinical Manifestations and Diagnosis
Lupus is notoriously variable in its presentation, course, and outcome (Table 59-2). Findings may be confined initially to one organ system, and others become involved later. Or, the disease may first be multisystem. Frequent findings are malaise, fever, arthritis, rash, pleuropericarditis, photosensitivity, anemia, and cognitive dysfunction. At least half of patients have renal involvement. SLE is also associated with declines in attention, memory, and reasoning (Hahn, 2015; Kozora, 2008).
TABLE 59-2Some Clinical Manifestations of Systemic Lupus Erythematosus ||Download (.pdf) TABLE 59-2 Some Clinical Manifestations of Systemic Lupus Erythematosus
|Organ System ||Clinical Manifestations ||Percent |
|Systemic ||Fatigue, malaise, fever, weight loss ||95 |
|Musculoskeletal ||Arthralgias, myalgias, polyarthritis, myopathy ||95 |
|Hematological ||Anemia, hemolysis, leukopenia, thrombocytopenia, lupus anticoagulant, splenomegaly ||85 |
|Cutaneous ||Malar (butterfly) rash, discoid rash, photosensitivity, oral ulcers, alopecia, skin rashes ||80 |
|Neurological ||Cognitive dysfunction, mood disorder, headache, seizures, stroke ||60 |
|Cardiopulmonary ||Pleuritis, pericarditis, myocarditis, endocarditis, pneumonitis, pulmonary hypertension ||60 |
|Renal ||Proteinuria, nephrotic syndrome, renal failure ||30–50 |
|Gastrointestinal ||Nausea, pain, diarrhea, abnormal liver enzyme levels ||40 |
|Vascular ||Thrombosis: venous (10%), arterial (5%) ||15 |
|Ocular ||Conjunctivitis, sicca syndrome ||15 |
Identification of antinuclear antibodies (ANA) is the best screening test, however, a positive result is not specific for SLE. For example, low titers are found in normal individuals, other autoimmune diseases, acute viral infections, and chronic inflammatory processes. Several drugs can also cause a positive reaction. Antibodies to double-stranded DNA (dsDNA) and to Smith (Sm) antigens are relatively specific for SLE, whereas other antibodies are not (see Table 59-1). Although hundreds of autoantibodies have been described in SLE, only a few have been shown to participate in tissue injury (Sherer, 2004; Tsokos, 2011). Currently, microarray profiles are being developed for more accurate SLE diagnosis (Putterman, 2016).
Anemia develops frequently, and there may be leukopenia and thrombocytopenia. Proteinuria and casts are found in the half of patients with glomerular lesions. Lupus nephritis can also cause renal insufficiency, which is more common if there are antiphospholipid antibodies (Moroni, 2004). Other laboratory findings include false-positive syphilis serology, prolonged partial thromboplastin time, and higher RF levels. Elevated serum d-dimer concentrations often follow a flare or infection, but unexplained persistent elevations are associated with a high risk for thrombosis (Wu, 2008).
The diagnostic criteria for SLE are listed in Table 59-3. If any four or more of these 11 criteria are present, serially or simultaneously, the diagnosis of lupus is made. Importantly, numerous drugs can induce a lupus-like syndrome. These include proton-pump inhibitors, thiazide diuretics, antifungals, chemotherapeutics, statins, and antiepileptics. Drug-induced lupus is rarely associated with glomerulonephritis and usually regresses when the medication is discontinued (Laurinaviciene, 2017).
TABLE 59-3Clinical Criteria for Classification of Systemic Lupus Erythematosus ||Download (.pdf) TABLE 59-3 Clinical Criteria for Classification of Systemic Lupus Erythematosus
|Clinical Manifestations |
|Oral ulcers |
|Renal: proteinuria, casts, biopsy |
|Neurological: seizures, psychosis, myelitis, neuropathies, confusional state |
|Hemolytic anemia |
|Leukopenia or lymphopenia |
|Immunological Manifestations |
|Direct Coombs |
Of nearly 16.7 million pregnancies from 2000 to 2003 in the United States, 13,555 were complicated by lupus—an incidence of approximately 1 in 1250 pregnancies (Clowse, 2008). During pregnancy, lupus improves in a third of women, remains unchanged in a third, and worsens in the remaining third. Thus, in any given pregnancy, the clinical condition can worsen or flare without warning (Hahn, 2015; Khamashta, 1997).
Petri (1998) reported a 7-percent risk of major morbidity during pregnancy. In a cohort of 13,555 women with SLE during pregnancy, the maternal mortality and severe morbidity rate was 325 per 100,000 (Clowse, 2008). In a review of 13 studies with 17 maternal deaths attributable to SLE and lupus nephritis, all occurred in those with active disease (Ritchie, 2012). Results of a prospective cohort study of 385 women are shown in Figure 59-1.
Frequency of adverse pregnancy outcomes. All women with systemic lupus erythematosus (SLE) in the PROMISSE study are compared with a subset of low-risk SLE patients and with control patients without SLE. (Data from Buyon, 2015.)
During the past several decades, pregnancy outcomes in women with SLE have improved remarkably. For most women with inactive or mild/moderate SLE, pregnancy outcomes are relatively favorable. Women who have confined cutaneous lupus do not usually have adverse outcomes (Hamed, 2013). However, newly diagnosed SLE during pregnancy tends to be severe (Zhao, 2013). In general, pregnancy outcome is best in women for whom: (1) lupus activity has been quiescent for at least 6 months before conception; (2) there is no lupus nephritis manifest by proteinuria or renal dysfunction; (3) antiphospholipid syndrome or lupus anticoagulant is absent; and (4) superimposed preeclampsia does not develop (Peart, 2014; Stojan, 2012; Wei, 2017; Yang, 2014).
Active nephritis is associated with adverse pregnancy outcomes, although these have improved remarkably and especially if disease remains in remission (Moroni, 2002, 2005; Stojan, 2012). Of complications, women with renal disease have a high incidence of gestational hypertension and preeclampsia. Of 80 gravidas with SLE reported by Lockshin (1989), 63 percent of women with preexisting renal disease developed preeclampsia compared with only 14 percent of those without underlying renal disease. In a review of 309 pregnancies complicated by lupus nephritis, 30 percent suffered a flare, and 40 percent of these had associated renal insufficiency (Moroni, 2005). The maternal mortality rate was 1.3 percent. These findings were corroborated in a subsequent prospective study (Moroni, 2016b). In addition, a third of the 113 pregnancies were delivered preterm (Imbasciati, 2009; Moroni, 2016a). Wagner and coworkers (2009) compared outcomes of 58 women with 90 pregnancies and found that active nephritis was linked with a significantly higher incidence of maternal complications—57 versus 11 percent.
Most recommend continuation during pregnancy of immunosuppressive therapy for nephritis. New-onset nephritis or severe renal flare is treated aggressively with intravenous corticosteroids and consideration of immunosuppressive drugs or intravenous immunoglobulin (Lazzaroni, 2016).
Lupus versus Preeclampsia-Eclampsia
Chronic hypertension complicates up to 30 percent of pregnancies in women with SLE (Egerman, 2005). Also, as mentioned, preeclampsia is common, and superimposed preeclampsia is encountered even more often, and earlier, in those with nephritis or antiphospholipid antibodies (Bertsias, 2008). Preeclampsia and lupus nephritis share features of hypertension, proteinuria, edema, and renal function deterioration. However, the management is distinct, as lupus nephritis is treated with immunosuppression, and severe preeclampsia/eclampsia requires delivery (Lazzaroni, 2016). It may be difficult, if not impossible, to differentiate lupus flare with nephropathy from severe preeclampsia if the kidney is the only involved organ (Petri, 2007). Central nervous system involvement with lupus may culminate in convulsions similar to those of eclampsia. One proposed schema for differentiating the two is shown in Table 59-4. Management for preeclampsia-eclampsia is described in Chapter 40 (Preeclampsia).
TABLE 59-4Some Distinctions between Lupus Flare and Preeclampsia Syndrome ||Download (.pdf) TABLE 59-4 Some Distinctions between Lupus Flare and Preeclampsia Syndrome
|Factor ||Lupus ||Preeclampsia |
|Clinical findings ||Fatigue, headache, extra-renal signs (rash, serositis, arthritis) ||Headaches, confusion, visual changes, convulsions |
|Blood pressure ||Normal or high ||High |
|Anemia ||Hemolytic ||Absent |
|Proteinuria ||Present ||Present |
|Creatinine ||Normal or high ||Normal or high |
|Transaminases ||Normal ||Normal or high |
|Complement ||Decreased ||Normal |
Management During Pregnancy
Lupus management consists primarily of monitoring fetal well-being and maternal clinical and laboratory status (Lateef, 2012). Pregnancy-induced thrombocytopenia and proteinuria resemble SLE disease activity, and the identification of a lupus flare is confounded by the increased facial and palmar erythema of normal pregnancy (Lockshin, 2003).
For SLE activity monitoring, various laboratory techniques have been recommended, but interpretation may be challenging. The sedimentation rate may be misleading because of pregnancy-induced hyperfibrinogenemia. Serum complement levels are also normally increased in pregnancy (Appendix, Serum and Blood Constituents). And, although falling or low levels of complement components C3, C4, and CH50 are more likely to be associated with active disease, higher levels provide no assurance against disease activation. Our experiences and those of others suggest that clinical manifestations of disease and complement levels correlate poorly (Lockshin, 1995; Varner, 1983).
Serial hematological studies may detect changes in disease activity. Hemolysis is characterized by a positive Coombs test, anemia, reticulocytosis, and unconjugated hyperbilirubinemia. Thrombocytopenia, leukopenia, or both may develop. According to Lockshin and Druzin (1995), chronic thrombocytopenia in early pregnancy may be due to antiphospholipid antibodies. Later, thrombocytopenia may indicate preeclampsia.
Urine is tested frequently to detect new-onset or worsening proteinuria. The fetus is closely observed for adverse effects such as growth restriction and oligohydramnios. Many recommend screening for anti-SS-A (anti-Ro) and anti-SS-B (anti-La) antibodies, because of associated fetal complications described subsequently. Antepartum, the fetus is surveilled as outlined by the American College of Obstetricians and Gynecologists (2016a) and described in Chapter 17 (Fetal Movements). Unless hypertension or evidence of fetal compromise or growth restriction develops, pregnancy is allowed to progress to term. Peripartum corticosteroids in “stress doses” are given to women who are taking these drugs or who recently have done so.
There is no cure for SLE, and complete remissions are rare. Approximately a fourth of pregnant women have mild disease, which is not life threatening, but may be disabling because of pain and fatigue. Arthralgia and serositis can be managed by nonsteroidal antiinflammatory drugs (NSAIDs). However, chronic or large intermittent dosing is avoided due to related oligohydramnios or ductus arteriosus closure (Chap. 12, Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blocking Drugs). Low-dose aspirin can be used throughout gestation. Severe disease is managed with corticosteroids such as prednisone, 1 to 2 mg/kg/d orally. After the disease is controlled, this dose is tapered to a daily morning dose of 10 to 15 mg. Corticosteroid therapy can lead to gestational diabetes.
Immunosuppressive agents such as azathioprine are beneficial for active disease. These are usually reserved for lupus nephritis or disease that is corticosteroid resistant. Azathioprine has a good safety record during pregnancy (Fischer-Betz, 2013; Petri, 2007). Its recommended daily oral dose is 2 to 3 mg/kg. Teratogenic medications to be avoided include mycophenolate mofetil, methotrexate, and cyclophosphamide (Götestam Skorpen, 2016). However, cyclophosphamide can be considered in the second or third trimester for severe disease (Lazzaroni, 2016). In some situations, mycophenolate is the only treatment that achieves disease stability. In these cases, counseling is essential regarding fetal risks described in Chapter 12 (Immunosuppressant Medications) (Bramham, 2012).
Antimalarials reduced dermatitis, arthritis, and fatigue (Hahn, 2015). Although these agents cross the placenta, hydroxychloroquine is not associated with congenital malformations. Because of the long half-life of antimalarials and because discontinuing therapy can precipitate a lupus flare, most recommend their continuation during pregnancy (Borden, 2001).
When severe disease supervenes—usually a lupus flare—high-dose glucocorticoid therapy is given. Petri (2007) recommends pulse therapy consisting of methylprednisolone, 1000 mg given intravenously over 90 minutes daily for 3 days, then a return to maintenance doses if possible.
In nonpregnant subjects, antihypertensive therapy often includes an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker. For pregnancy, these should be changed to safer fetal options such as calcium-channel blockers, alpha methyldopa, or labetalol (Cabiddu, 2016).
Perinatal Mortality and Morbidity
Adverse perinatal outcome rates are significantly elevated in pregnancies complicated by SLE. Among these are preterm delivery, fetal-growth restriction, stillbirth, and neonatal lupus syndrome (Madazli, 2014; Phansenee, 2017). Perinatal outcome rates worsen in mothers with a lupus flare, significant proteinuria, or renal impairment and in those with chronic hypertension, preeclampsia, or both (Lazzaroni, 2016). Adverse outcomes are also more common in women with neuropsychiatric lupus (de Jesus, 2017). Reasons at least partially responsible for adverse fetal consequences include decidual vasculopathy with placental infarction and decreased perfusion (Hanly, 1988).
This is characterized by newborn skin lesions—lupus dermatitis; a variable number of hematological and systemic derangements; and occasionally congenital heart block (Hahn, 2015). Cutaneous manifestations can be present in 30 to 40 percent of infants and appears at 4 to 6 weeks of age (Silverman, 2010). These are usually associated with anti-SS-A and SS-B antibodies, and approximately 40 percent of women with SLE are positive for these (Buyon, 2015). Thrombocytopenia and hepatic involvement are seen in 5 to 10 percent of affected infants.
In a review of outcomes in 91 infants born to women with lupus, eight of these were possibly affected—four had definite neonatal lupus and four had possible disease (Lockshin, 1988). Cutaneous lupus, thrombocytopenia, and autoimmune hemolysis are transient and clear within a few months (Zuppa, 2017). This is not always so for congenital heart block, discussed next. In subsequent offspring, the recurrence risk for neonatal lupus may near 25 percent (Julkunen, 1993).
Fetal and neonatal heart block results from diffuse myocarditis and fibrosis in the region between the atrioventricular (AV) node and bundle of His. Congenital heart block develops almost exclusively in fetuses of women with antibodies to the SS-A or SS-B antigens (Buyon, 1993). Even in the presence of such antibodies, however, the incidence of fetal myocarditis is only 2 to 3 percent but rises to 20 percent with a prior affected child (Bramham, 2012; Lockshin, 1988). Fetal cardiac monitoring is performed between 18 and 26 weeks’ gestation in pregnancies with either of these antibodies. The cardiac lesion is permanent, and a pacemaker is generally necessary. Long-term prognosis is poor. Of 325 infants with cardiac neonatal lupus, nearly 20 percent died, and of these, one third was stillborn (Izmirly, 2011).
Maternal administration of corticosteroids, plasma exchange, or intravenous immunoglobulin does not reduce the risk of congenital heart block. Maternal corticosteroid administration for treatment congenital heart block is controversial, is currently not recommended, and is discussed further in Chapter 16 (Tachyarrhythmias). Although this therapy to treat fetal heart block has not been studied in randomized trials, some evidence suggests that early fetal exposure to the mother’s corticosteroid treatment for SLE may mitigate fetal myocarditis. Namely, Shinohara and coworkers (1999) reported no heart block in 26 neonates whose mothers received corticosteroids before 16 weeks’ gestation as part of SLE maintenance therapy. By contrast, 15 of 61 neonates with heart block were born to women in whom corticosteroid therapy was begun after 16 weeks for an SLE exacerbation.
There are reports that maternal treatment with hydroxychloroquine (Plaquenil) is associated with a lower incidence of fetal heart block (Izmirly, 2012). Research in this area is ongoing.
Long-Term Prognosis and Contraception
The survival rate for women with SLE is 95 percent at 5 years, 90 percent at 10 years, and 78 percent at 20 years (Hahn, 2015). In general, women with lupus and chronic vascular or renal disease may limit family size because of morbidity associated with the disease and greater risks for adverse perinatal outcomes. For contraception, combination oral contraceptives did not increase the incidence of lupus flares in two large multicenter trials (Petri, 2005; Sánchez-Guerrero, 2005). Progestin-only implants and injections provide effective contraception with no known effects on lupus flares (Sammaritano, 2014). Concerns that intrauterine device (IUD) use and immunosuppressive therapy lead to greater infection rates in these patients are not evidenced-based. Notably, comorbid antiphospholipid antibodies are a contraindication to hormonal methods. Tubal sterilization may be advantageous and is performed with greatest safety postpartum or whenever SLE is quiescent.