Manual of Clinical Problems in Pediatrics
5th Edition

93.
SYSTEMIC LUPUS ERYTHEMATOSUS
Lawrence K. Jung
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
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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
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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.
Reviews
1. Wallace, D., and Hahn, B. (eds.). Dubois’ Lupus Erythematosus (5th ed.). Baltimore: Williams & Wilkins, 1997. Also, Lahita R. (ed.). Systemic Lupus Erythematosus (3rd ed.). New York: Academic Press, 1998. Both books contain information on all aspects of systemic lupus erythematosus (SLE). Although focused mainly on the adult disease, information is pertinent for the childhood disease as well. Included are chapters with specifics for the childhood disease. Good place to begin a detailed study of this disease.
2. Cassidy, J., and Petty, R. (eds.). Textbook of Pediatric Rheumatology. Philadelphia: Saunders, 1995. Contains an excellent, detailed chapter on SLE (62 pages, 562 references).
3. Lehman, T. A practical guide to systemic lupus erythematosus. Pediatr. Clin. North Am. 42:1223–1238, 1995. A sensible clinical approach used by the author in his practice. It should be emphasized that there are other approaches; see Scand. J. Rheum. 26:241–246, 1997.
4. ACR ad hoc committee on SLE guidelines. Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis Rheum. 42:1785–1796, 1999. The American College of Rheumatology (ACR) ad hoc committee attempts to suggest a management guideline for SLE. Included is useful information, including the ACR classification criteria, differential diagnosis, and treatment plans. See Arthritis Rheum. 25:1271–1277, 1982, for the original criteria for the classification of SLE.
5. Carreno, L., et al. Immunological and clinical differences between juvenile and adult onset systemic lupus erythematosus. Lupus 8:287–292, 1999. This study confirms the clinical impression that children with SLE often have more severe disease than adults, with renal and central nervous system (CNS) manifestations as major manifestations in children.
Lupus Immunology
6. Liossis, S., et al. Immune cell biochemical abnormalities in systemic lupus erythematosus. Clin. Exp. Rheumatol. 15:677–684, 1997. A number of immune abnormalities are found in SLE, but the relationships of these findings to the pathogenesis of lupus are still not clear. Autoantibodies, especially anti-DNA antibodies, and aberrant T cell clones might play significant roles in the pathogenesis of lupus. This article summarizes some of the more recent insights into the immune dysregulation in lupus. See also Semin. Nephrol. 19:67–76, 1999.
7. Alarcon Segovia, D., and Cabral, A. Autoantibodies in systemic lupus erythematosus. Curr. Opin. Rheumatol. 8:403–407, 1996. A discussion of the various autoantibodies that might have pathogenetic roles in lupus: anti-DNA in nephritis, anti-ribosomal P in CNS lupus, anti-Ro and anti-La in neonatal lupus, and anti-β2 glycoprotein I in antiphospholipid syndrome. For an in-depth look at the various autoantibodies, read the May 1992 issue of Rheum. Dis. Clin. North Am.
8. Ting, C., and Hsieh, K. A long-term immunologic study of childhood onset lupus erythematosus. Ann. Rheum. Dis. 51:45–51, 1992. Looks at immune parameters associated with exacerbation of disease: fall in C4 and rise in anti-DNA antibodies, while T cell phenotype and function remained relatively constant.
9. Barron, K., et al. Clinical, serologic and immunogenetic studies in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 36:348–354, 1993. Renal involvement was more frequent than adults, while CNS and hematologic involvement less so. Age and race differences were also noted with respect to the HLA antigen type and autoantibody production.
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Systemic Manifestations: Nephritis
10. Gloor, J. Lupus nephritis in children. Lupus 7:639–643, 1998. A review of the treatment and prognosis in children with nephritis. The use of steroid and immunosuppressive drugs has improved the overall outcome but does entail drug-related morbidity, which demands meticulous care by the medical personnel
11. Foster, M., and Kelley, V. Lupus nephritis: Update on pathogenesis and disease mechanisms. Semin. Nephrol. 19:173–181, 1999. Multiple and independent mechanisms contribute to the pathogenesis of the disease, which may explain the phenotypic and histopathologic heterogeneity seen in this condition.
12. Baqi, N., et al. Lupus nephritis in children: A longitudinal study of prognostic factors and therapy. J. Am. Soc. Nephrol. 7:924–929, 1996. Changes in therapeutic approaches in early inclusion of immunosuppressive drugs in class III/IV nephritis have significantly improved the outlook of patients with SLE (see Rheum. Dis. Clin. North Am. 20:213–242, 1994). This retrospective analysis helps to identify certain risk factors for progressive renal disease (hypertension, high creatinine, low C3); their presence would indicate aggressive therapy.
Systemic Manifestations: Central Nervous System
13. West, S. Neuropsychiatric lupus. Rheum. Dis. Clin. North Am. 20:129–155, 1994. A comprehensive treatment of this complex subject, classifying the syndrome into diffuse and focal involvements of the CNS and peripheral nervous system, and a thorough discussion of the diagnostic approaches. Well worth the time to read this article.
14. Reiff, A., et al. Childhood central nervous system lupus; longitudinal assessment using single photon emission computed tomography. J. Rheumatol. 24:2461–2465, 1997. Central nervous system lupus in children includes subtle deficits in cognitive functions that can be difficult to diagnose. Clinical markers such as anti-ribosomal P Ab (Arthritis Rheum. 39:671–676, 1996) or antineuronal Ab (Neurology 37:464–467, 1987) have been explored as clinical markers. Neuropsychiatric testing is very useful in follow-up of these patients. The use of CNS imaging techniques such as magnetic resonance imaging and positron emission tomography has a useful role as well. Single-photon emission computed tomography has been found to be useful by several groups (see also J. Rheumatol. 25:576–582, 1998).
15. Baca, V., et al. Favorable response to intravenous methyl-prednisolone and cyclophosphamide in children with severe neuropsychiatric lupus. J. Rheumatol. 26:432–439, 1999. A small sample size (7), but data reflect the common practice of aggressive therapy to treat this disorder among pediatric rheumatologists.
Systemic Manifestations: Miscellaneous
16. Male, C., et al. Clinical significance of lupus anticoagulants in children. J. Pediatr. 134:199–205, 1999. A retrospective study of 95 patients with lupus anticoagulant. Most patients were symptomatic, and the finding incidental. However, 10% had bleeding tendencies, while 5% had thrombotic events. Only 1 patient had SLE. See also Manco-Johnson, M. Antiphospholipid antibodies in children. Semin. Thromb. Hemost. 24:591–598, 1998, and Ravelli, A., and Martini, A. Antiphospholipid antibody syndrome in pediatric patients. Rheum. Dis. Clin. North Am. 23:657–676, 1997.
17. Lockshin, M. Which patients with anti-phospholipid antibody should be treated? Rheum. Dis. Clin. North Am. 19:235–247, 1993. An excellent review of the interpretation, the clinical manifestations, and treatment of antiphospholipid antibody syndrome by an expert in this field. See Medicine 77:195–207, 1998, for a description of catastrophic antiphospholipid syndrome, which has a high mortality rate.
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18. Moder, K., Miller, T., and Tazelaar, H. Cardiac involvement in systemic lupus erythematosus. Mayo Clin. Proc. 74:275–284, 1999. The various components of the heart: the coronory arteries, pericardium, myocardium, and valves may be involved in lupus. Antiphospholipid syndrome may lead to significant coronary and valvular diseases. This article is a comprehensive review in this area.
19. Cervera, R., et al Cardiac disease in systemic lupus erythematosus: Prospective study of 70 patients. Ann. Rheum. Dis. 51:156–159, 1992. Echocardiographic evidence of cardiac involvement was present in 60% of patients, with valvular disease the most frequently seen (44%). Pericardial effusion was present in 27%, and 20% had myocardial involvement. However, the majority of these findings were clinically silent and their significance remains to be determined.
20. Murin, S., Wiedemann, H., and Matthay, R. Pulmonary manifestations of systemic lupus erythematosus. Clin. Chest Med. 19:641–665, viii, 1998. Pulmonary involvement in SLE includes pleuritis, interstitial lung disease, pneumonitis, pulmonary hemorrhage, and others. Often difficult diagnostic and management problems, which can be fatal without proper intervention. See also Curr. Opin. Pulm. Med. 1:368–375, 1995, and Rheum. Dis. Clin. North Am. 20:159–193, 1994.
Therapy
21. Silverman, E., and Lang, B. An overview of the treatment of childhood SLE. Scand. J. Rheumatol. 26:241–246, 1997. A concise summary of the treatment options available for childhood SLE. However, the authors advocate the use of azathioprine instead of cyclophosphamide in lupus nephritis (see ref. 3). For a review of the basis for use of intravenous cyclophosphamide, see Rheum. Dis. Clin. North Am. 15:455–477, 1989.
22. Urowitz, M. Is “aggressive” therapy necessary for systemic lupus erythematous? Rheum. Dis. Clin. North Am. 19:263–270, 1993. Argues that majority of patients with SLE have mild disease and that aggressive cytotoxic drugs with their potential toxicities are not necessary. More “benign” cytotoxic drugs such as azathioprine and methotrexate are advocated. The companion paper argues that intravenous cyclophosphamide is an effective form of aggressive therapy for the serious complications of lupus (Rheum. Dis. Clin. North Am. 19: 249–262, 1993).
23. The Canadian hydroxychloroquine study group. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N. Engl. J. Med. 324:150–154, 1991. Hydroxychloroquine can maintain clinical quiescence in mild SLE. It has been useful in treating skin and mucosal lesions, and musculoskeletal complaints.
24. Fox, D., and McCune, W. Immunosuppressive drug therapy of systemic lupus erythematosus. Rheum. Dis. Clin. North Am. 20:265–299, 1994. Summarizes the use of cyclophosphamide, azathioprine, and others in the various manifestations of lupus. The short- and long-term toxicities of these drugs are also discussed.
25. Burt, R., et al. Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation. Blood 92:3505–3514, 1998. The authors are the first North American group to apply this technique to treat autoimmune disorders. The results are especially encouraging in patients with recalcitrant lupus. More data are being collected nationally and internationally to determine the role of this procedure in the treatment of autoimmune disorders. Others have argued that intense immunosuppression is the critical element and that autologous stem cell transplantation is not essential (Ann. Intern. Med. 129: 1031–1035, 1998).
Prognosis
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26. White, P. Morbidity of childhood systemic lupus erythematosus. In: Woo, P., White, P., and Ansell, B. (eds.). Pediatric Rheumatology Update. Oxford, England: University Press, 1990:217. A review of several studies on the morbidity and mortality in pediatric lupus, discussing infections, renal diseases, atherosclerosis, CNS involvement, growth abnormalities, and aseptic necrosis as areas clinicians will have to deal with in the management of these patients.
27. Lehman, T. Long-term outcome of systemic lupus erythematosus in childhood. What is the prognosis? Rheum. Dis. North Am. 17:921–930, 1991. It is interesting to compare the survival rate of studies done for the last 40 years (see Pediatrics 42:37–49, 1968, and Am. J. Dis. Child. 130:929–933, 1976). Undoubtedly, aggressive therapy in patients with severe disease helps to reduce the mortality rate. A treatment protocol with intravenous cyclophosphamide is suggested. See also Pediatrics 89:240–246, 1992.
Lupus-Like Syndromes
28. Rubin, R. Etiology and mechanisms of drug-induced lupus. Curr. Opin. Rheumatol. 11:357–363, 1999. Over 30 medications are associated with drug-induced lupus. Of interest to the pediatrician is diphenylhydantoin-related lupuslike syndrome. Also minocycline and related medications are relevant in pediatric practice (see Semin. Arth. Rheum. 28:392–397, 1999). The possible mechanisms leading to drug-induced lupus are discussed.
29. Silverman, E., and Laxer, R. Neonatal lupus erythematosus. Rheum. Dis. Clin. North Am. 23:599–618, 1997. Reviews the many clinical manifestations of neonatal lupus. Nice discussions on the maternal autoantibodies (SSA/Ro and SSB/La) and the pathogenesis. Also good pictures of the skin findings.
30. Buyon, J., et al. Autoimmune-associated congenital heart block: Demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J. Am. Coll. Cardiol. 31:1658–1666, 1998. The presence of anti-Ro and anti-La antibodies in a pregnant woman poses significant risk to her unborn child, with congenital heart block a permanent and often fatal outcome. For the cutaneous manifestations of neonatal lupus, see J. Am. Acad. Dermatol. 40:675–681, 1999.