Chapter 41
Autoimmune Disorders
Phil Popham BSc, MBBS, FRCA, MD, Robert W. Reid MD
Chapter Outline
In the late 19th century Ehrlich proposed the dictum of horror autotoxicus, the belief that immunity is directed against foreign material and never against one’s own body. The demonstration of autoantibodies in the 1950s disproved the theory and demonstrated the failure of self-tolerance.1 Autoimmunity has been described in more than 40 disorders, and it may result in chronic illness and severe disability.
The cause of autoimmunity involves genetic and environmental factors, and consequently the classification of autoimmune diseases has been controversial. The traditional clinical classification recognizes immune responses that are directed against a particular antigen and are limited to a particular organ or cell type (organ-specific disease), and those that are directed against a range of antigens that produce multisystem involvement (systemic disease). Some examples are shown in Box 41-1. Classification now incorporates a “spectrum of autoimmunity” from low-level (possibly beneficial to self) to high-level (clearly detrimental to self) autoimmunity.2
The pathogenesis of autoimmunity is complex. A genetic predisposition underlies abnormal reactivity of B cells and immunoglobulins, T-cell receptors, and genes within the major histocompatibility complex (MHC).3 Specific allotypes within the MHC are associated with certain diseases; for example, HLA-DR2 is strongly positively associated with systemic lupus erythematosus (SLE) but negatively associated with diabetes mellitus type 1, HLA-DR4 is associated with rheumatoid arthritis and diabetes mellitus type 1, and HLA-B27 is associated with ankylosing spondylitis. Recent work using genome-wide association studies has identified genetic associations between single nucleotide polymorphisms (SNPs) and autoimmune conditions4 and may lead to a new classification of autoimmune disease.5 Meta-analyses of HLA subclasses show similar associations with autoimmunity.6
Environmental factors may predispose to autoimmunity. Parasitic infection may reduce the incidence of autoimmunity, whereas bacterial infection with Klebsiella may predispose to ankylosing spondylitis. Drug-induced SLE is well described.
Sex hormones, notably the androgen-estrogen balance and its effect on cytokine production, have been implicated in the development of autoimmunity.7 Autoimmune disorders are more common in women than men, with the highest incidence of several conditions occurring during the childbearing years; occasionally, the initial diagnosis is made during pregnancy. During normal pregnancy, altered immune function allows maternal tolerance of the fetal allograft. Both mother and fetus produce immunologic factors that inhibit maternal cell-mediated immunity,8,9 prevent rejection of the fetus, and limit the expression of autoimmunity. Conversely, the high estrogen environment of pregnancy may enhance immune function.10 Although this may protect the mother and fetus from peripartum infection, it increases the likelihood of autoimmune conditions.
Systemic lupus erythematosus, lupus anticoagulant, scleroderma, and polymyositis/dermatomyositis are discussed in this chapter. Other autoimmune disorders are discussed elsewhere in this text, including diabetes mellitus type 1 (see Chapter 43) autoimmune thrombocytopenic purpura and autoimmune hemolytic anemia (see Chapter 44), rheumatoid arthritis and ankylosing spondylitis (see Chapter 48), and myasthenia gravis (see Chapter 49).
Systemic Lupus Erythematosus
Definition and Epidemiology
Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease of unknown etiology that is characterized by the production of autoantibodies against nuclear, cytoplasmic, and cell membrane antigens. Although SLE may occur at any age, it is recognized most commonly in women during their childbearing years, with a female-to-male ratio of 9 : 1. African-Americans, Asians, and Native Americans are affected more often than whites.11 An estimated 1 in 1200 deliveries occur in women with SLE.12
Pathophysiology
The etiology of SLE remains unclear. The principal mechanism is thought to be an immune complex disease involving IgG antibodies to double-stranded DNA and other nuclear proteins. Intracellular autoantigens are released by necrotic and apoptotic cells, leading to aberrant sensitization against these antigens. Impaired clearance of apoptotic cells and prolonged exposure to nuclear autoantigens may be involved.13 Affected individuals have both hyperactivity of the antibody-producing B cells and defects of the helper and suppressor T cells.14 Genetic defects of immune regulation and possibly environmental triggers including viruses and bacteria lead to a proliferation of B cells capable of producing autoantibodies. More than 30 classes of antigens have been identified as targets of these antibodies. A variety of antigen-antibody immune complexes are formed, followed by secondary inflammatory responses. Deposition of immune complexes and continued inflammation within the glomerulus may lead to irreversible renal injury. Deposits also occur within the skin, choroid plexus, and other endothelial surfaces, with or without an inflammatory response. However, SLE is not simply an immune complex disorder because some autoantibodies actively bind to erythrocytes, granulocytes, lymphocytes, and macrophages, leading to their removal from the circulation.11
Diagnosis
Clinical manifestations of SLE are diverse, owing to the widespread antigenic targets. Box 41-2 outlines objective criteria for the diagnosis of SLE.15,16 Although epidemiologic studies require the presence of four or more of these criteria, the clinical diagnosis may be suspected if fewer features are present without another explanation. Typically, the diagnosis of SLE is made before conception, but in 20% of cases the initial diagnosis is made during pregnancy.17
Effect of Pregnancy
Although pregnancy does not worsen the long-term course of SLE,18,19 disease activity may increase during pregnancy.20,21 A preconception history of nephritis predicts adverse maternal outcome.22 The risk for significant disease activity during pregnancy is increased sevenfold if active disease is present in the 6 months before conception.23 Assessments using the SLE Disease Activity Index found that 50% to 65% of women with active disease had deterioration during pregnancy in both retrospective24 and prospective25 studies. Such flares occur most commonly in the second and third trimesters and the puerperium and are not more severe than those in nonpregnant patients; most respond to conservative management.
Effect on the Mother
Most women with SLE do not have renal impairment at conception, possibly because renal insufficiency impairs fertility. If lupus nephritis does preexist, deterioration in renal function may occur during pregnancy. This is generally mild and reversible, but 12% of pregnant women with SLE suffer irreversible progression of renal dysfunction.26,27 Long-term glomerular filtration rate may be preserved.28
The presence of hypertension, edema, and proteinuria in both lupus nephritis and preeclampsia makes distinguishing between the two difficult. It is not clear whether preeclampsia is more common in patients with SLE, but a large meta-analysis suggests an association between lupus nephritis and preeclampsia.29 The distinction is critical because treatments are different (immunosuppressive therapy for lupus nephritis versus delivery for preeclampsia). Increased serum uric acid concentration, proteinuria without active urinary sediment, and liver enzyme abnormalities suggest preeclampsia rather than SLE.
SLE may cause thrombocytopenia. When thrombocytopenia occurs in a pregnant woman, preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, and disseminated intravascular coagulation must also be considered. Anemia, a common manifestation of SLE, must be differentiated from nutritional anemia and the physiologic anemia of late pregnancy.
Ligamentous relaxation often occurs during late pregnancy and may worsen the pain of lupus arthritis. Patients with SLE occasionally require joint replacement, most commonly of the femoral head. These prostheses may become painful, dislocated, or infected during pregnancy.30 Neurologic complications of SLE are rare during pregnancy but include seizures, chorea gravidarum, and stroke.
Effect on the Fetus
Maternal SLE impairs fetal survival and increases the risk for preterm delivery. A systematic review of papers published between 1980 and 2009 showed that preterm delivery occurred in 39.4% of 2751 pregnancies in 1842 patients.29 In the Hopkins Lupus Pregnancy Cohort, preterm birth occurred in 38 of 57 (67%) pregnancies in women with moderate to severe active SLE, compared with 68 of 210 (32%) pregnancies in women with inactive or mild active SLE.31 Improved perinatal management and control of disease activity has reduced the rate of fetal loss from 43% (between 1960 and 1965) to 17% (between 2000 and 2003).32 Data from California showed a preterm delivery rate in SLE that was six times higher than that found in the general population.33
Neonatal lupus erythematosus (NLE) is a syndrome that results from maternal autoantibodies against Ro (SS-A) or La (SS-B) crossing the placenta and binding to fetal tissue. These autoantibodies are found in up to 87% of patients with SLE,34 but NLE occurs in only a small proportion of patients. The condition is generally benign and self-limiting, and reversible manifestations such as cutaneous lupus, elevation in aminotransferase levels, and thrombocytopenia resolve as maternal antibodies disappear from the neonatal circulation within 8 months of birth. Anti-Ro/anti-La antibodies may bind to fetal cardiac conduction cells in utero, leading to cell death and irreversible fetal heart block. Neonatal congenital heart block occurs in 2% of neonates when anti-Ro antibody is detected in the mother.35 Fetal echocardiography reveals atrioventricular dissociation, cardiac dilation, and pericardial effusion. Treatment includes prompt delivery, newborn cardiac pacing, antepartum administration of dexamethasone, and consideration of apheresis to remove maternal antibodies.36
Medical Management
Optimally, women with SLE should delay pregnancy until their disease has been quiescent for at least 6 months, and they should be taking “acceptably safe” medications at the time of conception.21,23,27,37 Medications with acceptable safety are used to minimize disease activity during gestation.
Disease-modifying antirheumatic drugs (DMARDs) and immunosuppressive agents form the mainstay of treatment. Antimalarial drugs are frequently used to reduce SLE activity.38 Discontinuation of hydroxychloroquinine just before conception or in early pregnancy leads to a significant increase in disease activity.39 A systematic review of English literature (1982-2007) found that antimalarial drugs, particularly hydroxychloroquinine, prevent lupus flares; increase long-term survival; contribute to protection against irreversible organ damage, thrombosis, and bone loss; and have low toxicity.40 Hydroxychloroquinine should be continued in all women who were taking it before conception and may be used to treat flares during gestation. In contrast, mycophenolate mofetil should be discontinued before conception owing to the risk for teratogenicity. Azathioprine is an acceptable substitute and should be continued if used before conception.21,23 The fetal liver does not express the enzyme necessary to convert azathioprine to its active form,41 but maternal use of azathioprine has been associated with reversible neonatal lymphopenia, depressed serum immunoglobulin levels, and decreased thymic size in the newborn.41,42
Corticosteroids may be used to treat flares of SLE disease activity. Antenatal exposure to low-dose prednisone (< 20 mg daily) appears to be safe, and most children develop normally. However, there is concern that prolonged fetal exposure to other corticosteroids such as dexamethasone or betamethasone may lead to fetal growth restriction and abnormal neuronal development.43 Corticosteroid therapy may precipitate gestational diabetes, and patients should be monitored for evidence of glucose intolerance. Striae, gastrointestinal ulceration, and bone demineralization may complicate long-term corticosteroid therapy. Affected patients should receive postprandial and bedtime antacids.44 The pediatrician should be alerted to the possibility of neonatal adrenal suppression.
Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and stronger analgesics may be used to manage lupus arthritis. Although there is no evidence of teratogenicity with these agents,41 concern exists that NSAIDs may cause premature closure of the fetal ductus arteriosus,45 impairment of maternal and neonatal hemostasis,46 and adverse effects on maternal renal function.
Obstetric Management
Patients with SLE are at increased risk for intrauterine fetal death and preterm delivery. Estimation of the gestational age is obtained with ultrasonography at the first prenatal visit and again at 20 weeks’ gestation. Continued surveillance consists of nonstress testing, biophysical profile measurement, and/or umbilical artery Doppler velocimetry beginning at 26 to 28 weeks’ gestation and performed weekly until delivery.27
The coexistence of antiphospholipid antibodies predicts a much higher maternal and fetal risk. Maternal serologic markers are checked regularly, together with platelet count, creatinine clearance, 24-hour urine protein level, and presence or absence of anti-Ro/anti-La antibodies.47 Platelet count measurement is repeated monthly. If anti-Ro/anti-La antibodies are detected or the fetal heart rate is 60 beats per minute without variability in the second trimester, fetal echocardiography and fetal heart rate testing are performed to check for signs of congenital heart block or failure.48 Thromboprophylaxis is important in patients with antiphospholipid syndrome (see later discussion). In normal pregnancy, serial complement levels gradually increase. However, declining levels of C3 and C4 suggest active disease and lupus nephritis.21 Aspirin resistance may predict adverse maternal and neonatal outcome.49 Regular assessment of blood pressure, weight gain, and proteinuria is performed to detect the development of preeclampsia.
The timing and route of delivery are individualized. Although vaginal delivery is preferred, the cesarean delivery rate in parturients with SLE is 40%.12
Anesthetic Management
The obstetrician, rheumatologist, and anesthesiologist should formulate a joint plan for delivery. Maternal organ system involvement, current disease severity, and particularly the presence of flares must be assessed.50
Pericarditis is common in patients with SLE and is typically asymptomatic. A history of dyspnea on exertion or unexplained tachycardia may suggest pericarditis or myocarditis. Cardiac tamponade has been reported.51 Prolongation of the PR interval or nonspecific T-wave changes may be seen on the electrocardiogram. Coronary artery vasculitis, accelerated atherosclerosis leading to myocardial ischemia, and even myocardial infarction in young women have been reported.52,53
An echocardiographic study in 69 patients with SLE showed a high incidence of valvular abnormalities, including valvular thickening in 51%, vegetations in 43%, regurgitation in 25%, and stenosis in 4%.54 Current American Heart Association guidelines recommend antibiotic prophylaxis only for patients at highest risk for infective endocarditis in whom there is both significant risk and consequence of infection.55 Prophylactic antibiotics are not recommended for women with common valvular lesions undergoing genitourinary procedures, including vaginal delivery, but are specifically indicated for those with previous infective endocarditis, unrepaired cyanotic congenital heart disease, implanted prosthetic material or devices, or a history of cardiac transplantation with cardiac valvulopathy.
The prevalence and progression of pulmonary hypertension in 28 patients with SLE has been studied.56 The prevalence increased from 14% at initial evaluation to 43% 5 years later. Epidural anesthesia for cesarean delivery in parturients with pulmonary hypertension has been reported (see Chapter 42). The abrupt onset of sympathetic blockade and decreased venous return may cause precipitous systemic hypotension and hypoxemia. One report described the administration of general anesthesia in a parturient with SLE and pulmonary hypertension, with coexisting SLE-related restrictive lung disease, pulmonary edema, and orthopnea.57 In one report of three parturients with pulmonary hypertension secondary to SLE and antiphospholipid syndrome, two died of right-sided heart failure within 48 hours of delivery.58
Subclinical pleuritis is common, but significant pleural effusions occur rarely. Patients may suffer from infectious pneumonia or lupus pneumonitis. The latter condition is characterized by fleeting hemorrhagic infiltrates that may become consolidated. Pulmonary embolism and diaphragmatic dysfunction have been reported.52
Central and peripheral sensorimotor and autonomic neuropathies are observed in as many as 25% of patients with SLE.59 Vocal cord palsy has been reported in SLE.50,60 These deficits should be documented before the administration of either neuraxial or general anesthesia. Migraine headache and cerebral vasculitis resulting from SLE must be considered in the differential diagnosis of a postpartum headache. Psychological disorders and frank psychosis can occur during disease flares.11,61 Seizures can occur, especially if chronic anticonvulsant medications are discontinued inadvertently.
Hematologic abnormalities, including anemia, thrombocytopenia, and coagulopathy, should be documented. An abnormality of the activated partial thromboplastin time (aPTT), which is not corrected with a 1 : 1 control plasma mix, suggests the presence of either lupus anticoagulant (a coexistent but separate disease entity) or, more rarely, true autoantibodies against specific coagulation factors (e.g., VIII, IX, XII). Lupus anticoagulant is a laboratory artifact that does not cause clinical coagulopathy. True coagulation factor autoantibodies (or inhibitors) may result in a significant bleeding diathesis, which contraindicates the administration of neuraxial anesthesia.
Long-term use of NSAIDs leads to qualitative platelet abnormalities but has rarely been associated with epidural or subdural hematoma, and the role of NSAIDs in causing spinal epidural hematoma remains conjectural.62,63 In a prospective study of 924 patients undergoing orthopedic procedures with spinal or epidural anesthesia, preoperative antiplatelet medications were taken by 39% of these patients; no cases of spinal epidural hematoma were observed.64 The same investigators similarly studied 1035 patients undergoing epidural steroid injection.65 NSAID use was reported by 32% of patients undergoing chronic pain management; there were no cases of spinal hematoma. In the CLASP study, a large, multicenter randomized trial, 9364 pregnant women received either low-dose aspirin (60 mg daily) or placebo for prevention and treatment of preeclampsia.66 Of 5000 enrollees, at least 1069 patients received epidural analgesia, and no cases of epidural hematoma were observed.67 Determination of the bleeding time before neuraxial injection in patients taking aspirin or NSAIDs is no longer indicated. Measurement of thromboelastography has been suggested as an alternative but is not widely available.68
Atypical blood antibodies may complicate crossmatching of blood for patients with SLE. Additional time should be allowed for this possibility.
Prosthetic orthopedic joints should be positioned carefully during vaginal or cesarean delivery. Lupus arthritis rarely involves the cervical spine. Women who have undergone long-term corticosteroid therapy should receive a peripartum stress dose of a corticosteroid.
Antiphospholipid Syndrome
Definition and Epidemiology
The antiphospholipid syndrome (APS, also known as Hughes’ syndrome) was first recognized in the early 1980s69–71 and classified by international consensus in 2005.72 It is a prothrombotic disorder characterized by the presence of two autoantibodies, lupus anticoagulant and anticardiolipin antibody. Affected patients are at risk for both arterial and venous thrombosis. Patients with SLE may show lupus anticoagulant (34%) and anticardiolipin antibody (44%).73 However, APS is a distinct and separate entity from SLE. A long-term cohort study found that among patients with APS, only 11 of 128 (8%) had SLE.74
The population prevalence of APS is unclear. In 1990, commenting on the volume of publications on APS, Harris75 remarked that the syndrome “probably occurs less frequently than the number of papers published on the subject.” But in 2007, with greater clinical recognition, Hughes predicted that the prevalence of APS will exceed that of SLE.70
Pathophysiology
APS is characterized by two important misnomers. First, the antiphospholipid antibodies do not bind directly to phospholipids but to phospholipid-binding plasma proteins such as β2-glycoprotein I, prothrombin, and annexin V. Second, the lupus anticoagulant has no true anticoagulant activity in vivo
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