Systemic lupus erythematosus in children

Systemic lupus erythematosus in children
Jul 25, 2000

Thomas JA Lehman, MD

Systemic lupus erythematosus (SLE) in children is fundamentally the same disease as in adults with similar etiology, pathogenesis, clinical manifestations, and laboratory findings. (See "General symptomatology and diagnosis of systemic lupus erythematosus"). However, the care of children and adolescents with SLE is very different from that of adults because of the impact of the disease and its therapy on physical and psychological growth and development.

Failure of therapy of childhood SLE frequently results from efforts to care for a child or adolescent with a complex and chronic disease without considering the special needs of the growing individual and their family. As a result, the adult rheumatologist who is unprepared to deal with these needs should refer these patients to a pediatric rheumatology center.

EPIDEMIOLOGY – The current best estimate is that SLE affects between five and ten thousand children in the United States [1]. Childhood SLE affects girls more often than boys. Although it can occur at any age, SLE becomes more frequent after five years of age and is increasingly prevalent after the first decade of life [2].

Since the incidence of childhood SLE varies by race, a comparison of data from institutions serving racially diverse populations is meaningless [2]. Asians, Hispanics, and Blacks are all more frequently affected than Caucasians. Preliminary estimates of disease incidence between the ages of 10 and 18 in the United States among females of different ethnic groups are:

• 31 cases per 100,000 female Asians
• 20 cases per 100,000 Blacks
• 13 cases per 100,000 Hispanics
• 4 cases per 100,000 Caucasians

In addition, despite statements by others that SLE is uncommon among Blacks in Africa, my personal observation is that SLE is not infrequent among black children at the Baragwanath Hospital in Soweteo, South Africa.

CLINICAL PRESENTATION – The presenting manifestations of SLE in children are diverse as they are in adults [1]. Although some children are acutely ill with "full-blown" SLE, the most commom (or frequent) initial symptoms are fever, malaise, and failure to thrive over several months. Children may also have small joint arthritis and renal disease, both of which are commonly overlooked before the diagnosis of SLE is established. The classic malar rash is absent in two-thirds of individuals.

Neurologic involvement – SLE may be associated with a variety of neurologic manifestations [3-5]. Adolescents commonly present with progressive deterioration in academic performance, withdrawal, and social isolation. Often these findings are initially thought to represent teenage adjustment problems. SLE is only suspected when a full physical assessment and appropriate laboratory testing are performed. More dramatic neurologic presentations of SLE include seizures, chorea, stroke, and coma.

Renal disease – Renal involvement in SLE may vary from the detection of hematuria and proteinuria on routine examination to the presence of nephrotic syndrome or acute renal failure. Some degree of renal involvement is present in two-thirds of children with SLE evaluated at major medical centers.

Diffuse proliferative glomerulonephritis occurs in about 20 percent of all children presenting with SLE who are subjected to renal biopsy, independent of the presence or absence of active disease [6]. This histologic finding is far more frequent among those biopsied because of clinically evident ongoing renal involvement. (See "Types of renal disease in systemic lupus erythematosus").

Pulmonary disease – The respiratory system is involved in up to 77 percent of patients. The most common manifestations are pleural disease and a restrictive disease pattern with pulmonary function testing [7].

Hematologic abnormalities – Hematologic manifestations of SLE at presentation in children and adolescents include thrombocytopenia, hemolytic anemia, menorrhagia, and persistent leukopenia. The presence of any of these findings should prompt a test for antinuclear antibodies (ANA). If an elevated ANA titer is found, the patients should be carefully evaluated for other manifestations of SLE. (See "Measurement and clinical significance of antinuclear antibodies").

Patients with childhood SLE may also have antiphospholipid antibodies (APL), an abnormality associated with menorrhagia, prolonged clotting times, unexplained thrombosis, and stroke. Children with a positive ANA who lack additional criteria for the diagnosis of SLE may be APL positive in high titer. Children and adolescents with SLE and APL should be presumed to have the same increased risk of developing a clotting disorder as adults with APL [8]. (See "Clinical manifestations and diagnosis of the antiphospholipid antibody syndrome").

Anti-neutrophil cytoplasmic antibodies (ANCA) have also been observed; however, their presence does not appear to be associated with disease activity or specific organ involvement [9]. Antiribosomal P antibodies, an abnormality associated with active disease, are found more frequently in children than adults [7].

Other organ system involvement – As observed in adults, every organ system (musculoskeletal, gastrointestinal, skin) may be involved by childhood SLE [1,10]. (See appropriate cards).

DIAGNOSIS – The diagnosis of systemic lupus erythematosus (SLE) in childhood is based upon the same American College of Rheumatology (ACR) criteria used for adults (show table 1) [11]. (See "General symptomatology and diagnosis of systemic lupus erythematosus", section on Clinical criteria for diagnosis).

Systemic lupus erythematosus in children Xjav6fajue

Systemic lupus erythematosus in children Xjav6fajue

The diagnosis of SLE is made if four or more of the criteria in Table 1 are present, either serially or simultaneously, during any interval of observations [11]. Using the analogy of the ARA criteria for the diagnosis of RA, we have suggested that, in the presence of a significant titer of antinuclear antibodies, children with appropriate symptomatology be classified as follows:

• Classical SLE – many criteria
• Definite SLE – 4 or more criteria
• Probable SLE – 3 criteria
• Possible SLE – 2 criteria

A low index of suspicion for SLE in childhood is the primary impediment to a proper diagnosis. Delayed diagnosis is in part due to the frequent absence of the typical malar rash at disease onset and to the high frequency of nonspecific complaints such as weight loss with a chronic low-grade fever and malaise [1].

A single manifestation of SLE, such as thrombocytopenia, may predominate early in the course of the disease. Such children should be carefully evaluated for the presence of additional manifestations of SLE, including an elevated ANA titer. Repeated evaluation is necessary as children who initially fulfill less than four of the ACR criteria may progress over time to definitive SLE. Such progression may occur over a period of three to five years or longer.

Less frequently, some children with SLE present acutely with a fever, rash, leukopenia and thrombocytopenia, findings which are suggestive of overwhelming infection. Even among those with preexisting SLE, the differentiation of a disease flare from intercurrent sepsis may be difficult, and may require simultaneous treatment for both conditions.

THERAPY – The treatment for most manifestations of SLE does not differ among adults, children, and adolescents. (See "Overview of the therapy and prognosis of systemic lupus erythematosus"). However, children and adolescents with SLE have unique problems related to growth and development that affect both the need for and the impact of aggressive therapy [12].

General considerations – Physicians caring for children with SLE must remember that normal laboratory values for children differ from those for adults. As an example, a "normal" serum creatinine concentration in a child under ten years of age is 0.5 mg/dL (44 µmol/L); as a result, a level of 1.1 mg/dL (97 µmol/L), while "normal" in an adult, represents substantial renal failure in a young child. In addition, levels of compromised renal function that may have no clear adverse effect among adults may be inadequate to sustain normal growth and development in a child or adolescent.

The psychologic impact of SLE and its treatment also makes the care of children and adolescents distinct. Adolescence is a period of substantial psychologic stress associated with evolving self-identity. It is very difficult for these children to internalize the concept of chronic illness. The resultant sense of being different is markedly intensified by changes in their appearance, whether directly due to the illness or its therapy (eg, with corticosteroids). Failure to appropriately deal with these issues often leads to noncompliance and poor outcome.

In particular, high-dose corticosteroids have a profound impact on growth and appearance in children and adolescents. This impact often associated with both physical impairment (short stature, possible osteonecrosis) and psychological devastation. (See "Major side effects of corticosteroids"). For many adolescents with SLE, their current cushingoid appearance is of greater significance than any potential future event. Thus, both overt and covert suicide (eg, surreptitious refusal to take necessary medications) are well recognized in centers caring for large numbers of adolescents. The treating physician must do everything possible to minimize corticosteroid toxicity (including the use of other immunosuppressive agents as described below). (See "Major side effects of corticosteroids").

Mild SLE – Restrained care is indicated for the child with mild SLE who does not have renal or other life-threatening organ system involvement. The use of nonsteroidal antiinflammatory drugs (to control musculoskeletal manifestations) and hydroxychloroquine (7 mg/kg per day up to a usual maximum of 200 mg per day) may be sufficient in this setting. In addition, dapsone may be helpful for the occasional child with primarily dermatologic manifestations. However, low-dose corticosteroids (less than 0.35 mg/kg per day of prednisone) are often necessary to attain adequate disease control.

Although infrequent, apparently mild cases may progress in severity over time. Children with mild disease are increasingly common in large centers as more pediatricians screen for SLE and a greater number of children with mild SLE are appropriately identified.

Moderate SLE – Children and adolescents with moderate SLE often require the continued use of high-dose corticosteroids to control disease activity. Because of the concerns noted above about steroid toxicity, some centers utilize azathioprine and/or methotrexate as steroid-sparing agents in these children. There is extensive experience with azathioprine, while reports of methotrexate's usefulness in SLE are less conclusive. One study evaluated 10 children in whom further therapy with prednisone with or without cyclophosphamide was precluded [13]. Eight showed marked improvement with low-dose (5 to 10 mg per week) methotrexate; these patients were able to taper prednisone and to discontinue cyclophosphamide. However, most centers find a lower incidence of success with methotrexate in SLE. At the Hospital for Special Surgery, children whose disease does not quickly come under control with these regimens are often advanced to intravenous cyclophosphamide.

Severe SLE – Children and adolescents with severe SLE (eg, substantial renal or neurologic disease) require more aggressive therapy. As in adults, children with the diffuse proliferative type of lupus nephritis have the worst prognosis [14]. (See "Types of renal disease in systemic lupus erythematosus").

Although there are proponents of alternative regimens, the use of intravenous cyclophosphamide appears to have the best documented long-term success rate in children and adults [15-17]. The regimen we prefer consists of monthly intravenous pulses of cyclophosphamide (500 mg/m2 increasing to 1 gram/m2 as tolerated) for six months, followed by every three month cyclophosphamide for an additional thirty months. (See "Treatment of lupus nephritis-I").

The intravenous cyclophosphamide regimen has been very successful in the treatment of children with diffuse proliferative glomerulonephritis. In one study, for example, intravenous cyclophosphamide was given to eight children with steroid-unresponsive lupus nephritis and eight with either steroid-dependent nephrosis or active lupus nephritis and unacceptable steroid -induced side effects [15]. Cyclophosphamide therapy significantly reduced proteinuria (1.0 versus 3.2 gm per day, p<0.05) and increased the creatinine clearance among those with decreased function prior to therapy (121 versus 57.5 mL/min per 1.73 m2, p<0.05). We have also documented that this program of cyclophosphamide administration prevents progression of renal scarring in a study of sixteen children with renal biopsies performed before and following three years of cyclophosphamide therapy [17].

The use of intravenous cyclophosphamide was initially restricted to children with life-threatening diffuse proliferative glomerulonephritis. With extensive use, however, we have found that this regimen permits a reduction in daily corticosteroid use to a minimal level and is associated with acceptable long-term safety [16]. We have therefore broadened its use to all children with SLE who cannot be maintained on an acceptable level of corticosteroids; specifically, we use intravenous cyclophosphamide in children who cannot otherwise be maintained on a prednisone dose of less than 0.5 mg/kg per day.

The need for extended cyclophosphamide therapy varies based upon organ involvement. In children with nephritis, for example, there is an unacceptable level of disease flare when cyclophosphamide is discontinued after the initial seven doses. In comparison, in children with extrarenal disease (eg, central nervous system involvement), we are often able to withdraw therapy after the initial year of 7 monthly cyclophosphamide doses followed by two doses at three month intervals without difficulty.

The long-term safety of intravenous pulse cyclophosphamide in children is not well defined. With respect to gonadal toxicity, data from oral therapy suggest that the risk is greatest in sexually mature males and lowest in prepubertal children; girls rarely become infertile. With the use of MESNA the risk of bladder toxicity is markedly reduced, but the effect on other toxicities is not yet known. (See "Mechanism of action and general toxicity of alkylating agents").

A small percentage of children have had recurrent disease following withdrawal of intravenous cyclophosphamide therapy. We are currently treating these children with a multi-drug regimen consisting of intravenous cyclophosphamide and intravenous methotrexate monthly for one year with good success. Some have advocated autologuous stem cell transplant for children with severe SLE. In our hands, "conventional" therapy has proven adequate to date.

Efficacy of different therapeutic regimens – It is difficult to compare the long-term results of differing regimens used at various centers. Much of the problem results from racial and socioeconomic disparities in the populations served. These differences are compounded by the frequent failure to adequately describe the condition of children being entered in different protocols. Within pediatric rheumatology, the routine use of staging criteria is therefore gaining increasing acceptance [18]. These criteria should substantially improve our ability to compare series of children receiving different regimens.
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PROGNOSIS – The prognosis of children and adolescents with SLE who receive appropriate care is generally very good. The primary causes of an unsatisfactory outcome are due to:

• Poor compliance secondary to poor patient and family education

• Renal disease, particularly diffuse proliferative glomerulonephritis [14]

• Neurologic complications

• Intercurrent infections

Our obligation in caring for a child or adolescent with SLE extends beyond the narrow view of providing adequate five- or ten-year survival rates. For a fifteen year old, for example, surviving for this period of time means to live to an age of only 20 or 25 years. We must therefore seek optimal fifty-year survivals if our adolescent patients are to achieve a normal life span.

Many regimens provide good results for five and ten years, but fifteen-year survival for adolescents with SLE was only 27 percent in the era before the routine use of cyclophosphamide [19]. At present, it is too early to assess the fifteen-year survival rate for adolescents treated with systematic intravenous cyclophosphamide pulses. However, the experience of the last ten years has taught us that this regimen is associated with a profound improvement in the quality of life with a dramatic reduction in total corticosteroid dose and related complications, decreased school absence, decreased infections, and decreased emergency hospitalizations.

References

1. Lehman, TJ. Systemic lupus erythematosus in children and adolescents. In: Dubois' systemic lupus erythematosus. 5th ed, Wallace, DA, Hahn, B (Eds), WB Saunders, Philadelphia, 1996.

11. Tan, EM, Cohen, AS, Fries, JF, et al. The 1982 revised criteria for the diagnosis of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271.[/color

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