Systemic lupus erythematosus in childhood

Rheum Dis Clin N Am 28 (2002) 561 – 577

Systemic lupus erythematosus in childhood Marisa Klein-Gitelman, MD a,*, Andreas Reiff b, Earl D. Silverman, MD, FRCPC c a

Division of Immunology/Rheumatology, Department of Pediatrics, Children’s Memorial Hospital, Northwestern University, Chicago, IL USA b Division of Rheumatology, Department of Pediatrics, Children’s Hospital of Los Angeles, University of Southern California, Los Angeles, CA USA c Division of Rheumatology and the Research Institute, Departments of Pediatrics and Immunology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

Systemic lupus erythematosus is a disease of immune dysregulation that strikes approximately 1 in 2000 individuals. The usual patient is a young woman of child-bearing age; however, this illness affects patients of all ages, ethnic backgrounds, and both sexes. In fact, 20% of all cases of lupus are diagnosed during the first 2 decades of life. Although many diagnostic and treatment issues are similar for all patients with lupus, there are special issues for children and adolescents. These special issues include disease severity, disease presentation, laboratory studies, treatment, immunization, and psychosocial and school issues. Perhaps the most essential point in treating a child with lupus is to be aware and concerned about how to deliver treatment to a patient in the midst of their physical, intellectual, and emotional development. The patient must negotiate issues of chronic disease, medications that alter appearance, and information about possible outcomes. In pediatrics, this is done in the setting of a family and with patients whose age and level of physical and emotional maturity raise serious issues about growth, appearance, decision-making, and compliance.

Clinical presentation The frequencies of presenting signs and symptoms in pediatric onset systemic lupus erythematosus differ from that seen in adults. Lupus that begins in childhood tends to be more severe at onset and has a more aggressive clinical course [1– 3]. The most striking finding is an increased need for moderate to high dose corticosteroid therapy to control disease activity. One study showed that 77% of pediatric patients required moderate to high dose corticosteroid compared * Corresponding author. 0889-857X/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 8 8 9 - 8 5 7 X ( 0 2 ) 0 0 0 1 5 - 7

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with 16% of adult patients [4]. Lifetable analysis did not shown a difference in overall survival although the mode of death differed between the two groups. Pediatric patients tended to die earlier during acute SLE whereas adult patients tended to die of complications, such as renal failure, infection, myocardial infarction, and cancer. A final, significant observation was that cardiopulmonary and renal disease accrued over time. Although the prognosis for pediatric onset lupus is related to disease severity at presentation [5], the greatest risks for morbidity and mortality remain a delay in diagnosis and treatment [6,7]. Rates of organ involvement are higher in the child compared with the adult lupus patient. This observation may have been expected because pediatric patients tend to have a more severe disease at onset. Renal disease occurs more frequently in pediatric patients; it is present in 67% to 82% of children compared with 33% to 53% of adults with SLE [8 –11]. Overt neurologic disease generally has an increased incidence in children compared with adults [10,12,13]. Early epidemiological data suggested increased rates of cardiac and pulmonary disease. A recent study found that the only statistically significant difference was an increased rate of hematologic disease in pediatric patients both at 1 year and 5 years after diagnosis although other studies have failed to confirm this [4]. In contrast, secondary Sjogren’s syndrome is more common in adults than in patients with pediatric SLE [12]. Sex/hormonal inf luences The causes of SLE have not yet been elucidated although current research supports the idea that it is multifactorial and includes genetic predisposition, environmental signals, and hormonal influences. Hormonal changes in the female patient are correlated with disease onset which peaks during the child bearing years (15 –40). Female to male disease distribution changes from approximately 4:1 in the first decade of life to 9:1 beginning in the third decade of life to 2:1 after the menopausal years. The possible influence of female hormones in lupus is further supported by the increased incidence of SLE in men with Klinefleter’s syndrome. Few pediatric studies have explored the influence of hormones on age of disease onset. One study revealed higher FSH, LH, and lower free androgens in postpubertal boys and girls with SLE [14]. Another study compared the survival of lupus patients with onset in the child-bearing years (high female hormone levels) with patients with onset prior to puberty and after menopause (low female hormone levels) [15]. These investigators found that there was a relative decreased mortality risk for patients with ‘low hormone levels’ compared with patients with ‘high hormone levels’ (relative risk of 4.2). Because male hormones seem to offer some protection against the development of SLE, the use of male hormones, in particular dehydroepiandrosterone (DHEA), has been advocated to treat adults with lupus. A preliminary trial demonstrated that DHEA improved disease activity as measured by the SLE Disease Activity Index score, patient global assessment, physician global assessment, and reduction in corticosteroid therapy [16,17]. The use of male hormone therapy before and during

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puberty raises significant concerns; to date there have been no pediatric trials using DHEA. Dermatologic Isolated discoid lupus (DLE) and lupus whose sole manifestation is isolated skin disease rarely occur in the pediatric population. It is estimated that 2% to 3% of the reported cases of discoid lupus have disease onset before the age of 15 years [18]. The discoid cutaneous lesions in pediatric patients consist of the same areas of well-defined erythematosus patches with adherent scales and follicular plugging, mostly in sun exposed areas, as seen in adult patients. Discoid lesions often cause atrophic scarring and are exacerbated by ultraviolet light exposure. It is estimated that 7% of DLE patients will progress to SLE over a period of 5 years [19]. Although there are no epidemiologic estimates of disease progression from DLE to SLE in the pediatric population, the unusual presentation of DLE in childhood mandates careful evaluation. It is important to be confident that patients and their parents are aware of the risk of disease progression. Children with DLE should be evaluated on an annual basis for the development of overt SLE. Laboratory abnormalities in DLE patients usually include a positive antinuclear antibody (ANA), high IgG levels, and mild leucopenia. Laboratory and clinical evidence of a more systemic disease is an important predictor of progression from DLE to SLE. Renal Approximately two-thirds of children and adolescents with SLE develop renal involvement during the course of their SLE; in approximately 90% of patients the renal involvement will present within the first year of diagnosis. The most common form of nephritis seen in pediatric patients is World Health Organization Class IV or diffuse proliferative glomerulonephritis (DPGN) which occurs in 40% to 50% of patients. Class II (mesangial nephritis) occurs in 15% to 20% of patients, Class III (focal proliferative) occurs in 10% to15% of patients, and Class V (membranous) occurs in up to 20% of patients. Recently, it has been recognized that there is an increase in the incidence of Class V nephritis in pediatric patients [12,20,21]. Diffuse proliferative glomerulonephritis, the most common form of SLE nephritis seen in pediatric patients, is the most severe type and is most commonly associated with the development of end stage renal disease or death [22 – 24]. Standard treatment of DPGN in children includes the use of corticosteroids in combination with cytotoxic agents, and in particular, azathioprine or intravenous cyclophosphamide. Controlled studies from the National Institutes of Health (NIH) concluded that intravenous cyclophosphamide was superior to prednisone alone for treating DPGN [25 – 27]. Following these articles, intravenous pulse cyclophosphamide was accepted as the standard of care for the treatment of DPGN and other forms of SLE nephritis by most pediatric rheumatology

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centers [28]. The studies of the use of intravenous cyclophosphamide in pediatric patients have been done on a small number of patients. Subsequent to the NIH research, several studies done on large numbers of adults concluded that treatment with cyclophosphamide was not as successful as initially reported. Studies of children and adults have reported that treatment with azathioprine is associated with good long-term outcome in patients with DPGN [29 – 33]. When comparing the usefulness of cyclophosphamide with azathioprine therapy the efficacy and toxicities of the two drugs must be considered in patients who will have a longer disease duration than seen in adults. Children with membranous glomerulonephritis may develop nephrotic syndrome with persistent proteinuria and its increased risk of cardiovascular events [24]. Therapy of patients with membranous glomerulonephritis is more controversial than the treatment of patients with DPGN. Various treatment regimens, such as monotherapy with corticosteroids or in combination with cyclosporin A, cyclophosphamide, azathioprine, or chlorambucil have been proposed [34]. Many case series have suggested that cyclosporin A is beneficial in decreasing proteinuria, but the efficacy of this therapy has not been evaluated in controlled clinical trials and remains anecdotal. It has been suggested that long-term prognosis in patients with membranous lupus nephritis is determined by the amount of associated glomerular inflammation [35]. Mesangial (Class II) has an excellent prognosis and minimal therapy is required to treat the nephritis per se. The clinician must be aware of the possibility that rising proteinuria may herald a transformation of this mild lesion to a more severe form including DPGN. Although focal proliferative nephritis (FPGN) or Class III nephritis, is the least frequently seen form of pediatric SLE nephritis, it deserves special attention. Traditionally, FPGN has been considered to be significantly more benign than DPGN; recent evidence suggests that this lesion may require therapy that is as aggressive as that used to treat DPGN, especially if focal necrotizing lesions are present [36]. The increased risks of infection, infertility, and malignancy associated with the long-term use of cyclophosphamide, or other immunosuppressive agents, for the treatment of patients with pediatric SLE are causes of concern. [37]. Additionally, a substantial proportion of children have an inadequate response or relapse on traditional therapy which underscores the need for therapeutic alternatives [38,39]. Mycophenolate mofetil (MMF) is a new xenobiotic immunosuppressive agent which is a reversible inhibitor of inosine monophosphate dehydrogenase (rate-limiting enzyme in the ‘‘de novo’’ pathway of purine biosynthesis). Recent data from adult patients with treatment-resistant lupus nephritis suggests that MMF may be safe, well-tolerated, and effective in patients with DPGN [40,41], A recent 12-month study demonstrated that MMF and prednisone were as effective as pulse cyclophosphamide and prednisone in the treatment of adult patients with DPGN. [42] A recent pediatric study demonstrated that MMF was well tolerated, resulted in a marked reduction of disease activity, and allowed for a tapering of the steroid dose in the majority of patients; however, it was associated with a significant incidence of infection. A complete response was

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achieved only in the three children with membranous glomerulonephritis [43]. It has been suggested that MMF may be used as long-term therapy following an initial 6 months of therapy with pulse cyclophosphamide. Mycophenolate mofetil should also be considered as the agent of choice in patients who are intolerant of azathioprine. Further investigations should be undertaken to determine the role of MMF in the treatment of pediatric SLE nephritis. Another new therapy is LJP 394, a specific B lymphocyte immunomodulator that was designed to treat lupus renal disease by specifically arresting the production of antibodies to dsDNA antibodies. The initial study suggested that LJP 394 decreased the number of renal flares in patients with high-affinity, antiLJP 394 antibodies. Future therapies may consist of anti-cytokine therapy including anti-interleukin-10 therapy and therapies directed against molecules involved in immune activation such as CD40 ligand and CTLA-4. Preliminary phase I trials have been performed with some of these agents [44,45]. Central nervous system disease Overt central nervous system (CNS) involvement occurs in 20% to 30% of children and adolescents with SLE, and may consist of neurologic or psychiatric symptoms. Unlike other disease manifestations, CNS involvement occurs within the first year of disease in approximately 75% to 80% of patients who will develop CNS disease. In the last 30 years, there have been approximately 200 children and adolescents with psychiatric symptoms or CNS involvement described in the literature. Symptoms of CNS involvement can range from global cerebral dysfunction with paralysis and seizures, to mild or focal symptoms such as headache or memory loss. Neuropsychiatric symptoms were present in from 33% to 60% of adult patients with SLE who had CNS involvement. Women had an eight times higher risk than men; the highest risk was found in black women. In 1997, the criteria for diagnosing SLE were revised to include ‘‘neurologic disorder’’; it was defined as the presence of either seizures or psychosis [46]. In 1999, a multidisciplinary committee recommended the use of DSM-IV criteria in the diagnosis of psychosis, mania, depression, and delirium [47]. Psychiatric symptoms are typically included with neurologic symptoms, but there are no descriptions of the psychiatric features of SLE that utilize specific psychiatric diagnosis and nomenclature in children and adolescents [48]. The diagnosis of CNS-SLE requires a clinical evaluation to exclude reactive psychological disturbances, infection, and metabolic disturbances; a psychiatric consultation is recommended. Many clinical features are similar in children and adults with CNS involvement; these include psychosis, depression, organic brain syndrome, and lesser degrees of cognitive dysfunction. Movement disorders are more common in pediatric patients, and specifically, chorea, which is associated with anti-phospholipid antibodies, is more common in children than adults. Headache is a common symptom in SLE and may have a multitude of causes. Headaches are most commonly secondary to tension or fatigue but this type of headache must be differentiated from headache secondary to intracranial pathology [49]. The so-

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called ‘lupus headache’, a severe unremitting headache, may be secondary to cerebral vein thrombosis and intracranial hypertension. These are more commonly seen in children than in adults; these diagnoses should be considered in all children with severe headache [50,51]. Cerebral vein thrombosis is usually seen in association with the presence of antiphospholipid antibodies. An MRV (vein) or CT scan should be performed on patients in whom this diagnosis is suspected. In contrast to overt neurologic disease that is well recognized in children with lupus, little is known about subclinical neurocognitive dysfunction. Two studies have demonstrated neurocognitive deficits in children with SLE [52,53]. Lupus patients had specific deficits in problem-solving, intellectual function, visual memory, and sequential processing. Behavioral ratings indicated trends towards increased depressive symptoms and somatic complaints. Cognitive function abnormalities were found in children with and without overt neurologic disease. A more recent case control, prospective study using demographic, as well as age and gender matching, demonstrated few differences between a group of lupus patients and healthy controls [54]. This study suggests that demographic factors may be important in assessing patient and control group data. Lupus patients with longer disease duration had more depressive symptoms whereas patients with more severe disease activity at onset, as measured by SLEDAI, had subtle attention problems. Longitudinal evaluation of cognitive function of children with lupus is warranted. The diagnosis of CNS-SLE is often complicated by the lack of correlation between conventional serology, neuroimaging, and the clinical presentation of the patient. Additionally, it is often difficult to differentiate between primary disease and secondary complications caused by other organ involvement or therapy. Unfortunately, there are no serologic studies that are specific for the diagnosis or monitoring of CNS-SLE. Immune complexes and brain specific autoantibodies to neuronal tissue may play an important role in CNS lupus. They can be documented in sera and cerebrospinal fluid in the majority of patients with CNS involvement but are not specific for CNS disease [55 – 61]. Warm reactive IgG antineuronal antibodies have been described in the sera of patients with SLE who experience seizures or diffuse CNS disease but not in patients with focal neurologic deficits [56]. Neurocytotoxic antibodies occur in the sera of 75% of patients with SLE without correlation with CNS disease [57], although CSF antineuronal antibodies may be useful in patients with diffuse neurologic involvement including psychosis, encephalopathy, and generalized seizures [58]. Autoantibodies reactive with neuronal cell membranes or neurofilament antigens have been demonstrated in the sera and CSF of patients with SLE [59] but brain specific autoantibodies have not been identified [55,59]. Antineuronal antibodies (ANAB) and anti-Sm antibodies in the CSF and serum, respectively, have been associated with CNS-SLE but are often positive in an equal percentage of children with or without CNS involvement. Antiribosomal-P antibodies have been found in adults and children with SLE, associated with or without psychosis [61]. The presence of antiphospholipid antibodies is often linked to thrombosis and CNS infarction [62].

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Neuroimaging may be a more clinically useful tool than serologic analyses. Conventional imaging techniques such as CT scan and MRI are useful in diagnosing structural abnormalities including infarction but are often normal in the presence of cognitive dysfunction, organic brain syndromes, depression and psychosis. SPECT scan studies of adult and pediatric patients with SLE with neuropsychiatric symptoms have shown abnormalities, especially when psychosis was present [63,64]. Characteristic of conditions associated with cerebral vasoconstriction or vasculitis, SPECT findings in patients with SLE typically demonstrate a diffuse pattern of perfusion abnormalities with multiple small focal perfusion defects mainly in the parietal and frontal lobes, or generalized patchy hypoperfusion. SPECT scan abnormalities are not specific for the presence of demonstrable CNS disease because identical perfusion abnormalities may be seen in patients without any clinical evidence or history of CNS involvement and may continue to be abnormal after there is full clinical recovery [65]. A recent study described 10 children who presented with depression, psychosis, or delirium [66]. There was associated neurologic symptoms in eight patients. As has been shown in previous studies, lumbar puncture and CSF analysis, EEG, CT scan, and MRI were usually normal. SPECT scans were abnormal in all 10 patients and remained abnormal despite clinical improvement. SPECT scans alone should not be used to diagnose CNS involvement. Arthritis Arthritis which occurs in up to 90% of pediatric patients generally presents as a symmetric polyarthritis involving both large and small joints. The arthritis is usually easy to treat and generally responds to therapy directed to other organ involvement. Unlike the arthritis of JRA, the arthritis associated with SLE is commonly painful and the pain may be out of proportion to the clinical findings. Radiographs of the involved joints usually show osteopenia without any bony changes. There have been reports of patients who initially fulfilled the ACR criteria for JRA and subsequently fulfilled clinical and serological criteria for the classification of SLE [67,68]. The initial case reports were of patients with polyarticular JRA who later developed SLE, but we and others have seen patients with systemic-onset JRA who developed SLE many years after their diagnosis of JRA [69].

Morbidity and mortality Over the last decades there has been a remarkable improvement in the survival rates of patients with juvenile-onset SLE. Studies from the 1950s and 1960s yielded 5-year survival rates of 17.5% to 69% [3,70 –72], whereas published series from the 1980s and 1990s documented 83% to 93% 5-year survival rates [1,12,73,74]; some authors have reported that 76% to 85% of patients were alive at 10 years [1,74,75]. Explanations for improved survival rates may include

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earlier recognition of mild disease, and earlier and more aggressive therapeutic management with more effective therapeutic agents. As a result of the increasing life expectancy, children and adolescents with SLE are now faced with considerable morbidity because of the sequelae of disease activity, side-effects of medications, and co-morbid conditions, such as recurrent infections, delayed bone growth, avascular necrosis, accelerated atherosclerosis, hypertension, and delays in academic achievements. Lacks and White [76] found that at least some degree of long-term and often permanent organ dysfunction from either SLE or its treatment was seen in 88% of patients. Complications included hypertension (41 %), growth retardation (38%), chronic pulmonary impairment (31%), ocular abnormalities (31%), permanent renal damage (25%), neuropsychiatric symptoms (22%), musculoskeletal damage (9%), and gonadal impairment (3%). Morbidity issues may affect long-term quality of life, and raise problems related to the physical and psychological adaptation to a chronic, severe illness. The management of patients with juvenile-onset SLE is aimed at preventing death, and also at attenuation of the development of permanent organ damage resulting from the disease, its therapy, or complications. Standardized methods to assess this morbidity, such as the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (the SLICC/ACR Damage Index or SDI) [77], have been used and validated for adults but only recently for children and adolescents with SLE [78]. In this latter, single-center study it was found that cumulative disease activity, duration of treatment of high-dose corticosteroids, the presence of antiphospholipid antibodies, and acute thrombocytopenia were associated with disease damage as measured by the SLICC/ACR damage index. The use of immunosuppressive agents was associated with less damage. The use of the SLICC/ACR adult damage index however, failed to adequately capture such variables as a differing cut-off for nephrotic range proteinuria in different age groups and cognitive impairment. A larger, multi-center, international study found that central nervous system involvement at disease onset and a higher cumulative corticosteroid dose were the strongest determinants of cumulative organ damage (unpublished data). The association between the cumulative corticosteroid dose and presence of permanent organ damage observed in these studies underscores the need of new corticosteroid-sparing therapies to treat lupus activity and minimize cumulative and high-dose corticosteroid exposure. A pediatric version of the SDI is required and should capture growth, pubertal delay, redefine premature gonadal failure, redefine nephrotic range proteinuria,and reassess the value of weighting of some parameters [78]. Musculoskeletal complications Pediatric lupus patients with musculoskeletal disease or those who receive high dose corticosteroids are at risk for osteopenia. One small pediatric study demonstrated that decreased bone mineral density was correlated with cumulative steroid dose and the duration of steroid dose, but not with disease activity or

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duration [79]. Studies in the adult population have revealed significant morbidity from long-term corticosteroid therapy. The osteopenia and osteoporosis were associated with cumulative steroid dose and amount of damage [80 –82]. The treatment of glucocorticoid-induced osteoporosis has not been well studied in pediatric lupus. In one pediatric study, the use of low-dose daily corticosteroids in association with intermittent high-dose intravenous corticosteroids, vitamin D supplementation, and calcium maintained bone mineral density [83]. Significant bone loss was associated with the decreased ability to maintain activities of daily living, a poor exercise program, and increased weight gain. It is important to note that children should be accruing bone during adolescence; failure to accrue maximal bone density during this period may have profound effects in later life. The best way to study bone mineral density is by dual-energy X-ray absorptiometry (DEXA) as well as by evaluating bone mineral metabolism using a bone mineral panel which approximates osteoclastic and osteoblastic activity. Laboratory analyses of bone mineral activity did not appear to be predictive of bone mineral loss. All DEXA studies in pediatric patients must be corrected for bone age rather than chronological age. Preventive therapies for osteoporosis in pediatric patients with SLE should include a high dietary calcium intake, supplemented with extra calcium as necessary, and vitamin D if the dietary intake is below the recommended standard for age. Additionally, minimizing steroid dose and weight gain and maintaining a good exercise program will help to decrease the negative effects of steroids on bone mineral metabolism. The use of vitamin D and calcium to prevent fractures has not been as successful as treatment with bisphosphonates [84,85]. Preventive treatment with bisphosphanates, the mainstay of therapy in adults, is controversial in pediatric patients; bisphosphanates are contra-indicated in women of child-bearing years who make up the majority of patients with pediatric SLE. Calcitonin or bisphosphanates should be considered in patients with pathologic fractures secondary to osteoporosis. Steroid-induced pathologic fractures are less common in pediatric patients than in adult patients with SLE. The decreased fracture rate is likely the result of a better calcium intake, a better exercise program, and few years of smoking. Of course, post-menopausal osteoporosis is not seen in pediatrics; however, children are still at risk for steroid-induced osteoporosis. Unique to pediatrics is the associated growth failure seen in patients prior to the closure of growth plates. Although there have not been any prospective studies it seems that there is significant growth failure associated with longstanding, early onset SLE. It is unclear how much of the growth failure can be directly attributed to steroid usage and how much is secondary to chronic disease. It has been suggested that the use of alternate day steroids can decrease the degree of growth failure. Despite the association of growth failure and active disease and steroid use, the clinician should be aware of the increased incidence of endocrine causes of growth failure in pediatric patients with SLE. The endocrine causes which include thyroiditis [86] and growth hormone deficiency should be excluded in any patient with significant growth failure.

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It is well recognized that prolonged corticosteroid therapy can lead to avascular necrosis (AVN), osteoporosis, and pathologic fractures. Avascular necrosis occurs in approximately 10% to15% of patients with pediatric SLE and seems to be more common than in adults. The development of AVN is associated with dose and duration of steroid therapy, but unlike what is seen in adults, it may not be associated with the presence of Raynaud’s syndrome or vasculitis. Infection and vaccination Children with SLE more frequently develop infections with streptococcus pneumonia compared with the general healthy pediatric population. Increased susceptibility to pneumococcal infection is likely the result of hypocomplementaemia, surgical or functional asplenia, or abnormal macrophage and neutrophil function. Children with SLE seem to be more susceptible to pneumococcal sepsis than adults with SLE. It is not known why pneumococcal infection, but not infection with other encapsulated organisms, is more common in patients with SLE. It is suggested that patients with SLE should receive immunization with a pneumococcal vaccine. Patients with SLE produce low, relatively nonprotective concentrations of antipneumococcal antibodies following vaccination vide infra. For many years it has been hypothesized that the Epstein Barr Virus (EBV) is responsible for the development of SLE. A recent study demonstrated that more than 99% of pediatric patients with SLE had evidence of EBV infection compared with only 70% of age-matched controls. There were no differences in the rates of infection of other herpes viruses between patients and controls [87]. Additionally, viral infections may be mistaken for SLE. The clinical picture of EBV can overlap with SLE; patients with EBV have recently been described with nephritis [88]. Cases of Kikuchi disease (necrotizing lymphadenitis) with documented EBV infection, and serology consistent with SLE, have been reported [89]. Human parvovirus B19 (HPV-B19), a very common infection in the pediatric age group, can mimic the clinical picture of SLE. This illness can present with a bright red rash over the cheeks in a ‘malar distribution’, lymphadenopathy, cytopenias, and arthritis. There have been cases of patients with HPV-B19 presenting with clinical features of SLE and also with serology suggestive of SLE [90,91]. One group has suggested that HPV-B19 infection may trigger true SLE [91]. Unlike adults, children with SLE frequently require ‘routine’ immunization against childhood diseases. This is particularly true in children younger than ten. It is important, therefore, to be sure of the safety and efficacy of immunization to a variety of bacterial and viral antigens. There have not been any studies in children to address this question; the data must be extrapolated from studies in adults. The majority of adult patients with SLE responded well to immunization with tetanus toxoid and Haemophilus influenzae type B vaccines; patients with active disease who were on immunosuppressive therapy had lower antibody responses [92,93]. Patients with SLE who were immunized with a pneumococcal vaccination generally had a poorer antibody response than healthy controls

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[92,94,95]. There have been case reports of invasive pneumococcal disease occurring subsequent to vaccination [94] but pneumococcal vaccination does not appear to cause disease flare [92,96]. New pneumococcal vaccines are entering clinical practice and they may be more effective in preventing invasive pneumococcal disease in patients with SLE. Immunization with killed influenza virus appears to be safe and relatively effective in patients with SLE [97 – 99] and we suggest that all patients with SLE should receive annual influenza vaccination. It is generally accepted that patients on high-dose steroids or with significant immunosuppression should not be immunized with live viral vaccines [97,100,101]. There have been case reports of SLE following immunization with hepatitis B vaccine and flares of SLE [98]. Children with SLE should receive a hepatitis B vaccine if recommended in their country.

Laboratory studies The laboratory manifestations of SLE include the hallmark antibodies to double-stranded DNA although the presence of anti-Sm (Smith) antibodies is a more specific, but less sensitive, marker for the diagnosis of SLE. Almost all patients have a high titer ANA when tested using human substrates and a variety of antinuclear, anticytoplasmic, and organ-specific autoantibodies. One study demonstrated comparable frequency rates of autoantibodies to single-stranded DNA, Sm, and the 70 kDa protein component of RNP in pediatric and adult patients. A larger study demonstrated that anti-Sm and anti-RNP antibodies are more common in children compared with adults [10,102]. In contrast to the routinely tested IgG autoantibodies, there was an increased presence of IgM isotype antibodies in the pediatric population. Some of the pediatric patients had ‘‘maturation’’ of the IgM response to IgG over time [102] Tucker et al [12] showed a statistically significantly increased prevalence of anti-DNA antibodies in pediatric as compared with adult patients with SLE (85% versus 54%). No study has commented on differences in the pattern of ANA (speckled, homogenous, nucleolar, or centromere) in the pediatric versus adult lupus population. No significant differences in the frequency of anti-Ro or anti-La autoantibodies in pediatric as compared with adult patients have been shown despite the differences in the clinical manifestations of Sjogren’s syndrome between the two age groups. Anticardiolipin antibodies (aCL) are present in up to 65% of pediatric patients; this is not significantly different from the percentage of adult patients with this autoantibody [103]. The level of aCL may vary with disease activity, and, in particular, high titers of these autoantibodies may be associated with neurologic events. It is important to retest autoantibody status in lupus patients over time, particularly if disease manifestations change. Laboratory testing may support clinical observations of change in health status. A risk factor for the development of systemic lupus erythematosus, and in particular pediatric onset, is the presence of a congenital immunodeficiency. The presence of C4 null alleles has been shown in up to 60% of lupus patients

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[104 –107]. One study revealed that 42% of pediatric lupus patients had one or more complement deficiencies [108]. The most commonly noted defects were C2 [109,110] and C4 deficiencies [111,112]. Pediatric patients have more persistently low levels of C3 at onset compared with adult patients (82% versus 30%) [12]. Lupus has also been associated with chronic granulomatous disease [111] and with IgA deficiency where there is a relative increased incidence of 5% in the SLE population compared with the normal population of 0.25% to 0.03% [112]. Finally, one of the most recent findings is the strong association between the low binding phenotype of the FcgRIIIA (CD16) receptor and lupus, especially in patients with nephritis. This low binding phenotype reduces the activation of NK cells and monocytes in comparison to the high binding phenotypes of the FcgRIIIA receptor[113].

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