Systemic lupus erythematosus (SLE) is a disorder resulting from the formation of antigen-antibody complexes, and the deposition of these complexes in vessel walls and in tissues such as skin (lupus rash), the renal glomerulus (lupus nephritis), and the choroid plexus in the central nervous system (CNS lupus). The cause of the disease is unknown, but it is probably due to a combination of genetic predisposition with a presumed environmental “trigger,” such as viral infection, drugs, pregnancy, sunlight, or emotional stress.
Childhood SLE, about one tenth as common as juvenile rheumatoid arthritis, usually presents in the second decade; the mean age at diagnosis is 12 years, and the onset is often temporally associated with menarche. Less than 5% of children with SLE will present before the age of 5. The disease has a striking female predominance, although the characteristic adult female-male ratio of 9 : 1 decreases to 4 : 1 in children less than 12 years old.
More than 70% of children with SLE present with fever, rash, and arthritis or arthralgia. Another large percentage exhibit weight loss, fatigue, and malaise with or without an arthritis syndrome. Less commonly, the disease at onset is manifested by involvement—primarily or solely—of a single system, occasionally resulting in diagnostic error; examples of such presentations include thrombocytopenic purpura, hemolytic anemia, acute nephritis, nephrotic syndrome, seizures, carditis, pneumonitis, hepatosplenomegaly, recurrent abdominal pain, and sore throat with lymphadenopathy.
Because of the many varied modes of presentation of this disease, the American Rheumatism Association has proposed classification criteria to standardize the diagnosis for research and reporting purposes. The criteria, as revised in 1982, are (1) malar rash; (2) discoid lesions; (3) photosensitivity; (4) oral or nasopharyngeal ulceration; (5) nonerosive arthritis; (6) the presence of LE cells, anti-DNA and anti-Sm antibodies, or chronic false-positive result of the serologic test for syphilis; (7) persistent protein or cellular casts in the urine; (8) pleuritis or pericarditis; (9) psychosis or convulsions; (10) hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia; and (11) the presence of antinuclear antibody (ANA). The presence, simultaneously or serially, of four or more of these features is highly suggestive of SLE (estimated 96% specificity); however, many patients considered to have SLE have less than four of these manifestations and the proposed standard should not be considered necessary for diagnosis.
Tissue injury and manifestations of disease in SLE are caused by the deposition of immune complexes, the cytotoxic effects of activated components of the complement system, and the action of lysosomal enzymes released by polymorphonuclear leukocytes. The antigens involved in the damaging immune complexes are of nuclear origin and, thus, the major screening laboratory test is an assay for the presence of ANA by indirect fluorescence. The absence of ANA virtually rules out the diagnosis of SLE, but its presence is only suggestive of the disease, as it may be found in several other disease states and occasionally in normal persons. The finding of antibody to native (double-stranded) DNA (anti-dsDNA), on the other hand, is highly specific for SLE; it is probable that most, if not all, of the immune complexes formed in the patient with SLE are dsDNA-anti-dsDNA complexes. The anti-dsDNA titer is useful not only for diagnosing, but also for monitoring the disease, since the quantity of antibody appears to correlate well with disease activity. The participation of activated complement in the process of tissue destruction is reflected in the depressed levels of C3, C4, and CH50 generally found during episodes of active disease, especially nephritis; however, the correlation of disease status with complement level may not be as consistent as with the anti-dsDNA titer
The goals of therapy are to (1) suppress inflammation, (2) prevent formation of immune complexes by blocking production of antibodies to DNA, (3) promote normal growth and development, and (4) avoid unacceptable side effects of the medications used. Patients with mild disease, primarily manifested as arthritis and fever, often respond
well to nonsteroidal anti-inflammatory drugs (NSAIDs) alone. Hydroxychloroquine, an antimalarial agent, is helpful for treatment of skin lesions and mild disease unresponsive to NSAIDs. It is also used to modulate the course of lupus. A possible but rare side effect of this drug is ocular toxicity. Methotrexate is used in mild SLE and as a steroid-sparing drug.
The drug of choice for more severe disease is prednisone; indications for its use include severe “toxicity” (e.g., marked weight loss), active nephritis, carditis, or CNS disease. “Flares” of fever or joint symptoms that occur while prednisone is being tapered often respond to NSAIDs, hydroxychloroquine, or methotrexate and may not require an increase in steroid dosage. Rapidly progressive renal disease may respond to intravenous “pulses” of methylprednisolone. The toxic effects of prednisone account for many of the complications seen in children with SLE (such as growth retardation, infection, and aseptic necrosis of bone). The balance between control of the disease and prevention of steroid toxicity is often difficult to attain.
In severe lupus nephritis, the addition of immunosuppressive agents (cyclophosphamide, azathioprine, and chlorambucil) has been found to be superior to the use of prednisone alone. Intravenous pulse cyclophosphamide delays or halts the progression of chronic renal scarring seen when prednisone is used alone; other studies have suggested that it may also be beneficial in CNS disease. Thus, the combination of steroid and intravenous pulse cyclophosphamide has been used to treat patients with the most severe type of lupus nephritis (diffuse proliferative glomerulonephritis) and has resulted in a significantly improved survival rate. In recalcitrant SLE, super-high doses of cyclophosphamide and/or autologous stem cell transplantation offer therapeutic alternatives worthy of consideration. Mycophenolate mofetil has also been used in some cases.
In addition to anti-inflammatory drugs, treatment of the child with SLE must include careful attention to diet, rest, exercise, and psychological support. Patients must be taught to avoid exposure to the sun and to use sun-screening lotions, as direct sunlight may precipitate a flare of skin or systemic disease activities. Hypertension, due to both nephritis and steroid therapy, is a common finding and must be meticulously controlled to prevent additional organ damage.
Although SLE in children was initially described to be a rapidly fatal disorder, it is now apparent that at least 80% survive more than 10 years after diagnosis. The improved outcome is due to wiser use of drugs and improved supportive care, as well as increased success of dialysis and renal transplantation. When death occurs, it is due to either the disease itself or to complication of therapy. Active and intractable disease leads to vasculitis of CNS disease; bowel perforation; and end-organ failure of the kidneys, lungs, and heart. Diffuse proliferative glomerulonephritis is the one of the several types of renal lesions associated most often with azotemia and death. The neuropsychiatric manifestation of lupus may be difficult to distinguish from steroid-induced neurologic or psychological abnormalities, but is usually self-limited. However, stroke and death can result from active disease and CNS vasculitis. Increased susceptibility to infection may be a result of the disease itself, but the major cause is probably the immunosuppressive therapy used; viruses and Pneumocystis carinii are the organisms commonly associated with fatalities.
Some patients with SLE are found to have lupus anticoagulants or antiphospholipid antibodies. Despite the artifactual prolongation of the partial thromboplastin time, these patients are at risk for developing thrombotic disorders including strokes, deep vein thrombosis, and fetal wastage. Patients with episodes of thrombosis need to be on anticoagulation therapy on a long-term basis.
Children treated successfully for SLE are at increased risk in adulthood of premature atherosclerotic heart disease (and myocardial infarction) and of malignancies. The former is likely a consequence of lupus vasculitis and prolonged steroid therapy, while the latter is probably a result of immunosuppression.
Two lupus-like syndromes deserve note: “drug-induced lupus” and neonatal lupus. Occasionally, a drug (e.g., hydralazine, or, of more relevance in pediatrics, phenytoin) triggers the clinical expression of true SLE. More often, these drugs and others such as procainamide and isoniazid elicit the development of ANA and mild symptoms of lupus, both of which generally disappear when the drug is discontinued; nephritis and anti-dsDNA are rarely part of this syndrome
Neonates of mothers with SLE may have serologic abnormalities, occasionally accompanied by discoid lupus, hematologic abnormalities, or both. These findings, which are due to the transplacental passage of pathogenic anti-Ro antibodies, are transient. A more serious concern is an increased incidence of permanent congenital heart block and endomyocardial fibroelastosis in infants of mothers with SLE.