Systemic Lupus Erythematosus

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Chapter 152 Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem inflammation and the presence of circulating autoantibodies directed against self-antigens. SLE occurs in children and adults, disproportionately affecting women of reproductive age. Although nearly every organ may be affected, the most commonly involved are the skin, joints, kidneys, blood-forming cells, blood vessels, and central nervous system. Compared with adults, children and adolescents with SLE have more severe disease and more widespread organ involvement.

Etiology

The pathogenesis of SLE remains unknown, but several factors likely influence risk and severity of disease, including genetics, hormonal milieu, and environmental exposures.

A genetic predisposition to SLE is suggested by the association with specific genetic abnormalities, including congenital deficiencies of C1q, C2, and C4 and the finding that individuals with SLE frequently have a family history of SLE or other autoimmune disease. In addition, certain HLA types (including HLA-B8, HLA-DR2, and HLA-DR3) occur with increased frequency in SLE. Although SLE has a clear genetic component, its occurrence is sporadic in families and concordance is incomplete, even among identical twins, suggesting that multiple genes are involved and that nongenetic factors are also important in disease expression.

Because SLE preferentially affects women, especially during their reproductive years, it is suspected that hormonal factors are important in pathogenesis. Ninety percent of individuals with SLE are female, making gender the strongest risk factor for SLE. Estrogens are likely to play a role in SLE, and in vitro and animal model studies suggest that estrogen exposure promotes B-cell autoreactivity. Results of studies on the impact of exogenous estrogen on women with SLE are conflicting. Estrogen-containing oral contraceptives do not appear to induce flares in quiescent SLE, but the risk of flares may be increased in postmenopausal women receiving hormone replacement.

The environmental exposures that may trigger the development of SLE remain unknown; however, certain viral infections (including Epstein-Barr virus) may play a role in susceptible individuals, and ultraviolet light exposure is known to aggravate SLE disease activity. Environmental influences also may induce epigenetic modifications to DNA, which increase the risk of SLE and drug-induced lupus. For example, in mouse models, drugs such as procainamide and hydralazine can promote lymphocyte hypomethylation and a lupus-like syndrome.

Epidemiology

The reported prevalence of SLE in children and adolescents (1-6/100,000) is lower than that in adults (20-70/100,000). Prevalence of SLE is highest among African-Americans, Asians, Hispanics, Native Americans, and Pacific Islanders. SLE predominantly affects females, with reported 5 : 1 ratio prior to puberty, a 9 : 1 ratio during reproductive years, and near prepubertal ratios in the postmenopausal period. Childhood SLE is rare before 5 yr of age and is usually diagnosed in adolescence. Up to 20% of all individuals with SLE are diagnosed prior to age 16 yr.

Pathology

Histologic features most suggestive of SLE include findings in the kidney and skin, especially the discoid rash. Renal manifestations of SLE are classified histologically according to the criteria of the International Society of Nephrology (Chapter 508). The finding of diffuse proliferative glomerulonephritis (class IV) significantly increases risk for renal morbidity. Renal biopsies are very helpful to establish the diagnosis of SLE and to stage disease. Immune complexes are commonly found with “full house” deposition of immunoglobulin and complement. The characteristic discoid rash depicted in Figure 152-1D is characterized on biopsy by hyperkeratosis, follicular plugging, and infiltration of mononuclear cells into the dermal-epidermal junction. The histopathology of photosensitive rashes can be nonspecific, but immunofluorescence examination of both affected and nonaffected skin may reveal deposition of immune complexes within the dermal-epidermal junction. This finding is called the lupus band test, which is specific for SLE.

Figure 152-1 Mucocutaneous manifestations of SLE. A, Malar rash; B, vasculitic rash on toes; C, oral mucosal ulcers; D, discoid rash in malar distribution.

Pathogenesis

Developing a model of SLE pathogenesis is challenging, given the need to account for tremendous heterogeneity in disease expression and fluctuations of disease activity over time. It is clear that autoantibodies, cytokines, and aberrant lymphocyte function have important roles in SLE pathogenesis.

A hallmark of SLE is the generation of autoantibodies directed against self-antigens, particularly nucleic acids. These intracellular antigens are ubiquitously expressed but are usually inaccessible and cloistered within the cell. During cell necrosis or apoptosis, the antigens are released. SLE skin cells are highly susceptible to damage from ultraviolet light, and the resulting cell demise results in release of cell contents, including nucleic antigens. Individuals with SLE may have markedly increased levels of apoptosis or significantly impaired ability to clear cell debris, causing prolonged exposure to these nucleic antigens in the bloodstream and ample opportunity for their recognition by immune cells, leading to production of autoantibodies by B cells. Circulating autoantibodies may form immune complexes and deposit in tissues, leading to local complement activation, initiation of a proinflammatory cascade, and, ultimately, tissue damage. Antibodies to double-stranded DNA can form immune complexes, deposit in glomeruli, and initiate inflammation leading to glomerulonephritis. Many individuals with SLE have circulating antibodies to double-stranded DNA yet do not have nephritis, suggesting that autoantibodies alone are not sufficient to cause disease.

Individuals with SLE frequently demonstrate abnormal cytokine levels. In particular, peripheral blood mononuclear cells from patients with SLE exhibit patterns of gene expression suggestive of stimulation by interferon-α (IFN-α). IFN-α production by dendritic cells can be stimulated in vivo by immune complexes. Excess levels of interferon can promote expression of other proinflammatory cytokines and chemokines, maturation of monocytes into dendritic dells, promotion of autoreactive B and T cells, and loss of self-tolerance. Many, but not all, patients with SLE exhibit this interferon signature. Other cytokines with increased expression in SLE include interleukin-2 (IL)-2, IL-6, IL-10, IL-12, B-lymphocyte stimulator (BlyS), and anti–tumor necrosis factor-α (TNF-α).

Both B and T cells demonstrate functional impairments in SLE. In active SLE, B-cell populations have impaired tolerance and increased autoreactivity, enhancing B cells’ ability to produce autoantibodies following exposure to self-antigen. In addition, cytokines such as BlyS may promote abnormal B-cell number and function. T-cell abnormalities in SLE include increased numbers of memory T cells and decreased number and function of T-regulatory cells. SLE T cells display aberrant signaling and increased autoreactivity. As a result, they are resistant to attrition by normal apoptosis pathways.

Clinical Manifestations

Any organ system can be involved in SLE, so the potential clinical manifestations are protean (Table 152-1). The presentation of SLE in childhood or adolescence differs from that in adults. The most common presenting complaints of children with SLE include fever, fatigue, hematologic abnormalities, arthralgia, and arthritis. Renal disease in SLE is often asymptomatic; thus careful monitoring of blood pressure and urinalyses is critical. SLE is often characterized by periods of flare and disease quiescence or may follow a more smoldering disease course. The neuropsychiatric complications of SLE may occur with or without apparently active SLE and are particularly difficult to detect in adolescents, who are already at high risk for mood disorders. Long-term complications of SLE and its therapy, including accelerated atherosclerosis and osteoporosis, become clinically evident in young to middle adulthood. SLE is a disease that evolves over time in each affected individual, and new manifestations may arise even many years after diagnosis.

Table 152-1 POTENTIAL CLINICAL MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS

TARGET ORGAN	POTENTIAL CLINICAL MANIFESTATIONS
Constitutional	Fatigue, anorexia, weight loss, fever, lymphadenopathy
Musculoskeletal	Arthritis, myositis, tendonitis, arthralgias, myalgias, avascular necrosis, osteoporosis
Skin	Malar rash, discoid rash, photosensitive rash, cutaneous vasculitis, livedo reticularis, periungual capillary abnormalities, Raynaud’s phenomenon, alopecia, oral and nasal ulcers
Renal	Hypertension, proteinuria, hematuria, edema, nephrotic syndrome, renal failure
Cardiovascular	Pericarditis, myocarditis, conduction system abnormalities, Libman-Sacks endocarditis
Neurologic	Seizures, psychosis, cerebritis, stroke, transverse myelitis, depression, cognitive impairment, headaches, pseudotumor, peripheral neuropathy, chorea, optic neuritis, cranial nerve palsies
Pulmonary	Pleuritis, interstitial lung disease, pulmonary hemorrhage, pulmonary hypertension, pulmonary embolism
Hematologic	Immune-mediated cytopenias (hemolytic anemia, thrombocytopenia or leukopenia), anemia of chronic inflammation, hypercoaguability, thrombocytopenic thrombotic microangiopathy
Gastroenterology	Hepatosplenomegaly, pancreatitis, vasculitis affecting bowel, protein-losing enteropathy
Ocular	Retinal vasculitis, scleritis, episcleritis, papilledema

Diagnosis

The diagnosis of SLE requires a comprehensive clinical and laboratory assessment revealing characteristic multisystem disease and excluding other etiologies, including infection and malignancy. Presence of 4 of the 11 American College of Rheumatology 1997 Revised Classification Criteria for SLE (Table 152-2) simultaneously or cumulatively establishes the diagnosis of SLE. Of note, although a positive antinuclear antibody (ANA) test result is not required for the diagnosis of SLE, ANA-negative lupus is extremely rare. Hypocomplementemia, although common in SLE, is not represented among the classification criteria.

Table 152-2 AMERICAN COLLEGE OF RHEUMATOLOGY 1997 REVISED CLASSIFICATION CRITERIA FOR SYSTEMIC LUPUS ERYTHEMATOSUS *

Nonerosive, affecting 2 or more joints

Serositis:

Pleuritis, pericarditis, peritonitis

Renal manifestations:

Persistent proteinuria or cellular casts

Consistent renal biopsy

Seizure or psychosis

Hematologic manifestations:

Hemolytic anemia

Leukopenia (<4,000 leukocytes/mm³)

Lymphopenia (<1,500 leukocytes/mm³)

Thrombocytopenia (<100,000 thrombocytes/mm³)

Immunologic abnormalities:

Positive anti–double-stranded DNA or anti-Smith antibody test result

False-positive rapid plasma regain RPR test result, positive lupus anticoagulant test result, or elevated anticardiolipin immunoglobulin (Ig) G or IgM antibody

Positive antinuclear antibody test result

* The presence of 4/11 criteria establishes the diagnosis of SLE. These criteria were developed for classification in clinical trials and not for clinical diagnosis.

Adapted from Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus, Arthritis Rheum 40:1725, 1997.

Differential Diagnosis

Multiorgan disease is the hallmark of SLE, and given its wide array of potential clinical manifestations, SLE can be considered in the differential diagnosis of many clinical scenarios, including unexplained fevers, joint pain, arthritis, rash, cytopenias, neurologic or cardiopulmonary abnormalities, and nephritis.

Drug-induced lupus refers to the presence of SLE manifestations triggered by exposure to certain medications, including minocycline, many anticonvulsants, sulfonamides, antiarrhythmic agents, and other drugs (Table 152-3). In individuals prone to SLE, these agents may act as a trigger for true SLE. In others, these agents provoke a reversible lupus-like syndrome. Unlike SLE, drug-induced lupus affects males and females equally. An inherited predisposition toward slow acetylation may increase the risk of drug-induced lupus. Circulating antihistone antibodies are often present in drug-induced SLE, and these antibodies are detected in up to 20% of individuals with SLE. Hepatitis, which is rare in SLE, is more common in drug-induced lupus. Individuals with drug-induced lupus are less likely to demonstrate antibodies to double-stranded DNA, hypocomplementemia, and significant renal or neurologic disease. In contrast to SLE, manifestations of drug-induced lupus resolve after withdrawal of the offending medication; complete recovery may take several months to years.

Table 152-3 MEDICATIONS ASSOCIATED WITH DRUG-INDUCED LUPUS

DEFINITE ASSOCIATION

Minocycline, procainamide, hydralazine, isoniazid, penicillamine, diltiazem, interferon-α, methyldopa, chlorpromazine, etanercept, infliximab, adalimumab

PROBABLE ASSOCIATION

Phenytoin, ethosuximide, carbamazepine, sulfasalazine, amiodarone, quinidine, rifampin, nitrofurantoin, beta blockers, lithium, captopril, interferon-gamma, hydrochlorothiazide, glyburide, docetaxel, penicillin, tetracycline, statins, gold, valproate, griseofulvin, gemfibrozil, propylthiouracil

Laboratory Findings

A positive ANA test result is present in 95-99% of individuals with SLE. This test has poor specificity for SLE, as up to 20% of healthy individuals also have a positive ANA test result, making the ANA a poor screening test for SLE. ANA titers are not reflective of disease activity; therefore, repeating ANA titers is not helpful in disease management. Antibodies to double-stranded DNA are more specific for SLE, and in some individuals, anti-dsDNA levels correlate with disease activity, particularly nephritis. Anti-Smith antibody, although found specifically in patients with SLE, does not correlate with disease activity. Serum levels of total hemolytic complement (CH₅₀), C3, and C4 are typically decreased in active disease and often improve with treatment. Table 152-4 lists several autoantibodies found in SLE and their clinical associations. Hypergammaglobulinemia is a common but nonspecific finding. Inflammatory markers, particularly erythrocyte sedimentation rate, are often elevated in active disease. C-reactive protein (CRP) correlates less well with disease activity, and elevated CRP values may reflect infection.

Table 152-4 AUTOANTIBODIES COMMONLY ASSOCIATED WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

ANTIBODY	CLINICAL ASSOCIATION
Anti–double-stranded DNA	Correlates with disease activity, especially nephritis, in some with SLE
Anti-Smith antibody	Specific for the diagnosis of SLE
Anti-ribonucleoprotein antibody	Increased risk for Raynaud phenomenon and pulmonary hypertension High titer may suggest diagnosis of mixed connective tissue disorder

Anti-Ro antibody (anti-SSA antibody)
Anti-La antibody (anti-SSB antibody)

Associated with sicca syndrome

May suggest diagnosis of Sjögren syndrome

Increased risk of neonatal lupus in offspring (congenital heart block)

May be associated with cutaneous and pulmonary manifestations of SLE

May be associated with isolated discoid lupus

Antiphospholipid antibodies (including anticardiolipin antibodies) Increased risk for venous and arterial thrombotic events Antihistone antibodies

Present in a majority of patients with drug-induced lupus

May be present in SLE

Antiphospholipid antibodies, which increase clotting risk, can be found in up to 66% of children and adolescents with SLE. Antiphospholipid antibodies can be detected by several means, and laboratory features that point to the presence of these antibodies include the presence of anticardiolipin antibodies, prolonged phospholipid-dependent coagulation test results (partial thromboplastin time, dilute Russell viper-venom time), and a circulating lupus anticoagulant (which confirms that a prolonged partial thromboplastin time is not corrected with mixing studies). When an arterial or venous clotting event occurs in the presence of an antiphospholipid antibody, antiphospholipid antibody syndrome is diagnosed. Antiphospholipid antibody syndrome can occur in the context of SLE or independent of SLE (Chapter 473).

Treatment

Treatment of SLE is tailored to the individual, being based on specific disease manifestations and tolerability. For all patients, sunscreen and avoidance of prolonged direct sun exposure and other ultraviolet light may help control disease. Hydroxychloroquine (5-7 mg/kg/day) is recommended for all individuals with SLE if tolerated. In addition to treating mild SLE manifestations such as rash and mild arthritis, hydroxychloroquine prevents SLE flares, improves lipid profiles, and may have a beneficial impact on mortality and renal outcomes. Potential toxicities include retinal pigmentation, impairing color vision; therefore, ophthalmology exams every 6-12 mo are recommended. Nonsteroidal anti-inflammatory agents (NSAIDs) can be useful for management of arthralgias and arthritis; it is important to keep in mind their potential hepatic, renal, and cardiovascular toxicities.

Corticosteroids are a mainstay for treatment of significant manifestations of SLE; side effects often limit patient compliance, especially in adolescence, and potential toxicities are worrisome. It is important to limit dose and length of exposure to corticosteroids whenever possible. Potential consequences of corticosteroid therapy include growth disturbance, weight gain, striae, acne, hyperglycemia, hypertension, cataracts, avascular necrosis, and osteoporosis. The optimal dosing of corticosteroids in children and adolescents with SLE remains unknown; severe disease is often treated with high doses of intravenous methylprednisolone (e.g., 30 mg/kg/day for 3 days) or high doses of oral prednisone (1-2 mg/kg/day). As disease manifestations improve, corticosteroid dosages are gradually tapered, along with monitoring for evidence of adrenal insufficiency. It often becomes necessary to introduce steroid-sparing immunosuppressive medications in order to limit cumulative steroid exposure.

Steroid-sparing immunosuppressive agents often used in the treatment of pediatric SLE include methotrexate, leflunomide, azathioprine, mycophenolate mofetil, and cyclophosphamide. Methotrexate, leflunomide, and azathioprine are often used to treat persistent moderate disease, including arthritis, significant cutaneous or hematologic involvement, and pleural disease. In general, intravenous or oral cyclophosphamide is reserved for the most severe, potentially life-threatening SLE manifestations, such as renal, neurologic, and cardiopulmonary disease. Although cyclophosphamide is highly effective in controlling disease, the potential toxicities are significant, including cytopenias, infection, hemorrhagic cystitis, premature gonadal failure, and increased risk of future malignancy. Attention to adequate hydration can attenuate the risk of hemorrhagic cystitis. Fortunately, young girls are at much lower risk of gonadal failure than older women, and the use of gonadotropin-releasing hormone agonists, such as leuprolide acetate, may help prevent gonadal failure. Treatment of significant glomerulonephritis usually involves use of azathioprine, mycophenolate mofetil, or cyclophosphamide. Clinical trials with long-term follow-up are needed to determine optimal approaches to treatment of SLE nephritis. While a randomized, controlled, double-blind trial did not suggest that rituximab is an effective treatment for significant glomerulonephritis, this agent has not been studied in children or in refractory disease. Clinical trials are in progress to assess the safety and efficacy of several biologic agents in SLE, including monoclonal antibodies targeting CD22, BlyS, IL-10, TNF-α, and IFN-α. Individuals with antiphospholipid antibody syndrome are treated with long-term anticoagulation to prevent future thrombotic events.

Given the lifelong nature of SLE, care of children and adolescents with this disease also involves preventive practices. Owing to the enhanced risk of atherosclerosis in SLE, attention to cholesterol levels, smoking status, body mass index, blood pressure, and other cardiovascular risk factors is warranted. Adequate intake of calcium and vitamin D is necessary to prevent future osteoporosis. Infections commonly complicate SLE, so routine immunization is recommended, including annual influenza vaccination and administration of the 23-valent pneumococcal vaccine. Pregnancy can worsen SLE, and obstetric complications are more common in SLE. In addition, many of the medications used to treat SLE are teratogenic. As a consequence, it is important to counsel adolescent girls about these risks and appropriate contraceptive options.

Complications

Within the first several years of diagnosis, the most common causes of death in individuals with SLE include infection and complications of glomerulonephritis and neuropsychiatric disease (Table 152-5). Over the long term, the most common causes of mortality include complications of atherosclerosis and malignancy. The increased risk of premature atherosclerosis in SLE is not explained by traditional risk factors and is due in part to the chronic immune dysregulation and inflammation associated with SLE. Increased malignancy rates may be caused by immune dysregulation and exposure to medications with carcinogenic potential.

Table 152-5 MORBIDITY IN CHILDHOOD LUPUS

Renal	Hypertension, dialysis, transplantation
Central nervous system	Organic brain syndrome, seizures, psychosis, neurocognitive dysfunction
Cardiovascular	Atherosclerosis, myocardial infarction, cardiomyopathy, valvular disease
Immune	Recurrent infection, functional asplenia, malignancy
Musculoskeletal	Osteopenia, compression fractures, osteonecrosis
Ocular	Cataracts, glaucoma
Endocrine	Diabetes, obesity, growth failure, infertility, fetal wastage

From Cassidy JT, Petty RE: Textbook of pediatric rheumatology, ed 5, Philadelphia, 2005, Elsevier/Saunders.

Prognosis

Owing to advances in the diagnosis and treatment of SLE, survival has improved dramatically over the past 50 years. Currently, the 5-year survival rate for pediatric SLE is >90%. However, given their long burden of disease, children and adolescents with SLE face a high risk of future morbidity and mortality from the disease and its complications, especially atherosclerosis and malignancy (see Table 152-5). Given the complex and chronic nature of SLE, it is optimal for children and adolescents with SLE to be treated by pediatric rheumatologists in a multidisciplinary clinic.

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152.1 Neonatal Lupus

Stacy P. Ardoin, Laura E. Schanberg

Neonatal lupus, an entity distinct from SLE, is one of the few rheumatic disorders manifesting in the neonate. Clinical manifestations of neonatal lupus include a characteristic annular or macular rash typically affecting the face (especially the periorbital area), trunk, and scalp (Fig. 152-2). Infants may also have cytopenias and hepatitis, but the most feared complication is congenital heart block. Conduction system abnormalities range from prolongation of the PR interval to complete heart block, rarely resulting in progressive cardiomyopathy. The noncardiac manifestations of neonatal lupus are usually reversible, but congenital heart block is permanent. The rash typically appears within the first 6 wk of life after exposure to ultraviolet light and lasts 3-4 mo; however, it can be present at birth. Conduction system abnormalities can be detected in utero beginning at 16 wk of gestational age.