Definition and Classification

Pediatric SLE (pSLE) is a chronic multisystem autoimmune disease with remitting, relapsing course and onset of symptoms before age 18 years, accounting for approximately 20% of all SLE.¹ This clinically heterogeneous disease is characterized by a distinct spectrum of autoantibodies including antinuclear antibody (ANA), double-stranded deoxyribonucleic acid (dsDNA), and antibodies against extractable nuclear antigens (ENAs). In genetically susceptible hosts B cell–mediated autoimmune processes lead to a variable combination and severity of clinical symptoms including antibody-mediated vasculitis, direct antibody binding to target cells, and thrombotic organ dysfunction.

The American College of Rheumatology (ACR) classification criteria for adults with SLE are commonly applied to children with pSLE.² The classification of neuropsychiatric SLE (NPSLE) in children and adolescents remains a challenge.^3,4 The 1990 ACR NPSLE nomenclature and case definitions appear to have limited applicability for children in certain domains.^5–7

Epidemiology

Pediatric SLE affects children and adolescents around the world.^8–10 On average, 60% of patients develop pSLE after age 10, 35% between 5 and 10 years, and only 5% before age 5. In studies from Asia, the mean ages at diagnosis were reported to be 8.6 to 13.5 years.^8,9 The incidence and prevalence of pSLE varies between populations. Similar to adults, SLE more commonly affects non-Caucasian populations.^8,9,11 Overall, incidence rates of pSLE have been reported to be 0.28 to 0.48 per 100,000 children with prevalence rates of 6.3 to 24 per 100,000 depending on the ethnic background of the population.⁹ The prevalence of pSLE is consistently higher in girls than boys: Canadian and Taiwan studies estimated a factor of 6.^12,13 Female predominance increases with age. This observation strongly supports the suggested role of female hormones.¹⁴ Although pSLE is less common than adult SLE, childhood onset was recently found to be a strong, independent predictor of overall lupus mortality.¹⁵

Children with pSLE are likely to have relatives with SLE. The pattern of familial aggregation for siblings with SLE suggests a polygenic inheritance.¹⁶ In addition, pSLE patients often have asymptomatic relatives with evidence of autoantibodies.¹⁷

Causes

Clinical Features

The clinical presentation of pSLE was reported in large series from many countries, allowing a better understanding of the clinical diversity, impact of ethnicity, confounding factors including infections, and access to health care^8,11,36–47 (Table 108-1).

Table 108-1 Clinical Characteristics of Children at Diagnosis of Pediatric Systemic Lupus Erythematosus (pSLE): Comparison of Four Recent Cohorts

Systemic features including fever and fatigue are found in more than 90% of children at diagnosis of pSLE. Arthritis is the most frequently reported organ manifestation in pSLE. Typically pSLE arthritis is a nonerosive, painful polyarthritis. Mucocutaneous involvement includes the typical “butterfly” or malar rash, an erythematous rash in the malar distribution sparing the nasolabial folds (Figure 108-1). Diffuse hair loss is commonly seen in children with active disease. In addition, children with lupus can present with a photosensitive rash, exacerbated in sun-exposed areas including upper arms, neckline, and face; Raynaud’s phenomenon of fingers and toes; a vasculitic skin rash, which is often raised and painful affecting the fingers and toes; and oral and/or nasal ulcers. Oral ulcers are typically located on the hard palate and are painless (Figure 108-2). Uncommon skin manifestations include discoid lupus lesions, which heal with scarring.⁴⁸

Figure 108-1 Malar rash of a 14-year-old patient with pediatric systemic lupus erythematosus. The disease’s typical “butterfly” or malar rash is an erythematous rash in the malar distribution, which includes the cheeks and crosses the nasal bridge but spares the nasolabial folds.

Figure 108-2 Oral ulcers in a 16-year-old girl with active pediatric systemic lupus erythematosus. Characteristic oral ulcers and hyperemia in children with lupus can be found on the hard palate. These ulcers are typically painless.

Nephritis is the most common major organ manifestation and occurs in more than 50% of children with pSLE, most commonly at diagnosis. Children with lupus nephritis present with peripheral edema, proteinuria, active urine sediment, and hypertension. Focal or diffuse proliferative glomerulonephritis accounts for more than 50% of all pediatric lupus nephritis in most series. Acute renal failure can occur in a third of children presenting with proliferative lupus nephritis.³³ Mesangial and membranous nephritis are less common and can occur in conjunction with proliferative lupus nephritis. Posterior reversible encephalopathy (PRES) is an increasingly recognized central nervous system (CNS) complication of lupus nephritis and hypertension.⁴⁹

Neuropsychiatric disease affects about a quarter of children with pSLE. Headaches in conjunction with psychosis or cerebrovascular disease presenting as seizures or severe cognitive dysfunction are the most common clinical phenotypes. Isolated lupus headache is uncommon.⁷ Psychosis in pSLE is characterized by optic and acoustic hallucinations and visual distortions. Many patients have overlapping features of cognitive dysfunction, headaches, and mood disorder.⁵ Isolated mood disorders such as depression are uncommon in pSLE. CNS vasculitis in pSLE more commonly affects the small vessels. Angiography-positive disease and strokes are uncommon.⁷ Transverse myelitis is an uncommon, serious manifestation of pSLE.⁵⁰ Peripheral neuropathies are uncommon in children with lupus.

The diagnosis of NPSLE in children is based on clinical assessment including comprehensive neurocognitive testing,⁵¹ inflammatory markers, and neuroimaging. Children with neuropsychiatric disease commonly have antiphospholipid antibodies, in particular anti–β₂-glycoprotein I (anti-β₂GPI).⁵² A positive lupus anticoagulant is often detectable in children with cerebrovascular disease including sinus vein thrombosis (SVT) and chorea. Neuroimaging demonstrates only subtle abnormalities in half of patients⁵ including the majority of children presenting with psychosis.

Hematologic disease is common in pSLE and affects a quarter of children. Treatment-refractory idiopathic thrombocytopenic purpura (ITP) or severe autoimmune hemolytic anemia can be the presenting features of pSLE. A positive ANA and older age were found to be risk factors of pSLE in ITP.⁵³ Serositis including pleuritis, pericarditis, and less commonly peritonitis affects about 20% of children with pSLE. Chest pain is the most common presenting feature. Inflammatory lung lesions including capillaritis and alveolar hemorrhage are uncommon. Although cardiomegaly due to pericarditis and arrhythmia/conduction anomaly occur frequently, myocarditis and coronary arteritis are serious yet uncommon lupus features in children.^54,55 The most common gastrointestinal (GI) manifestation of pSLE is lupus hepatitis. Inflammatory bowel manifestations are rare. Overall atypical presentations can be found in up to a quarter of children ultimately diagnosed with pSLE and, when present, were found to correlate with poor outcome.⁵⁶ Endocrinopathies of pSLE include hypothyroidism or hyperthyroidism and diabetes mellitus.⁵⁷ Menstrual cycle disturbances and transient amenorrhea are common in girls with pSLE and may be associated with pituitary dysfunction or treatment with cyclophosphamide, leading to a decreased progesterone production.⁵⁸

Diagnosis and Diagnostic Tests

The diagnosis of pSLE is based on clinical findings, laboratory test results including inflammatory markers, complement levels, markers of organ involvement, and specific autoantibodies. Tissue biopsies and imaging studies can further support and/or classify pSLE subtypes. The presence of 4 of 11 ACR classification criteria was found to have a sensitivity of 96% and a specificity of 100%.² A careful evaluation of potential organ involvement of pSLE is mandatory. Characteristic abnormal laboratory markers of active pSLE may include a raised erythrocyte sedimentation rate (ESR), anemia, which may be Coombs positive and hemolytic, a low white blood count with predominant lymphopenia, low platelets, and low C3 and/or C4 complement levels. Paradoxically, the C-reactive protein (CRP) is normal in the vast majority of children with active lupus, except for those presenting with serositis or concurrent infections. An abnormal urinalysis including microscopic evidence of casts indicated renal involvement. Renal function impairment is best evaluated by serum creatinine, albumin, and urine protein–to-creatinine ratio. Lupus anticoagulant and specific lupus autoantibody testing including ANA, dsDNA, ENA, and antiphospholipid antibodies is mandatory. ANA is found is almost every child with pSLE, while dsDNA is detected in more than 80%.^41,59 Novel antibodies have been proposed and require prospective validation in pSLE.⁶⁰ Children may have frank hypothyroidism or hyperthyroidism or solely raised titers of thyroid antibodies.⁴¹

Lipid abnormalities are increasingly recognized in children with pSLE.⁶¹ Dyslipidemia may contribute to a risk of premature arteriosclerosis in pSLE patients.^62,63 Cytokines derived from adipocytes including leptin, adiponectin, and ghrelin were recently shown to correlate with disease activity in pSLE.⁶⁴ Markers of bone health and fracture risk have been extensively evaluated in children with pSLE.⁶⁵ A comprehensive assessment may include these markers in conjunction with bone density measurement.

The differential diagnosis of pSLE is wide and includes infections such as cytomegalovirus (CMV), Epstein-Barr virus, and tuberculosis, malignancies such as lymphomas, endocrinopathies, primary inflammatory or idiopathic organ diseases such as membranoproliferative nephritis, or idiopathic psychosis and pediatric autoimmune diseases including JDM, systemic sclerosis, Sjögren’s syndrome, overlap syndromes, and polyarticular and systemic juvenile idiopathic arthritis.^66,67 Children with a recent diagnosis of pSLE can present with concurrent infections such as CMV, which may confound the clinical presentation and response to therapy.⁶⁸ Uncommon infections may be present.⁶⁹ Macrophage activation syndrome (MAS, a secondary hemophagocytic lymphohistiocytosis [HLH] syndrome) is a newly recognized inflammatory emergency and can present in pSLE patients.⁷⁰ MAS has to be considered in a child with pSLE and unexplained fever and cytopenia, when associated with marked hyperferritinemia.

Treatment

The care for children with lupus, similar to other multiorgan rheumatic diseases, mandates a multidisciplinary approach of different subspecialty physicians including pediatric rheumatologists, nephrologists, psychiatrists, and adolescent medicine, allied health care specialists, social workers, and teachers.

Outcome

Lupus in children and adults is a relapsing/remitting disease. The burden of pSLE is complex to determine because many factors such as access to health care, individual patient characteristics, disease activity, confounding diseases such as infections, and responsiveness to treatment all contribute to overall mortality and morbidity.¹

The overall mortality as captured by standard mortality rate (SMR) for all SLE in the United States between 1992 and 2001 was 3.06 deaths per million inhabitants per year,¹⁰³ in Brazil between 1985 and 2004 it was 3.8 (2601 deaths, 90% female),¹⁰⁴ and in Denmark it was 4.6.¹⁰⁵ With improved therapies, mortality rates were shown to decrease in Canada (SMR, 10.1 in 1970-1977; 4.8 in 1978-1985, and 3.3 in 1986-1994).¹⁰⁶ When comparing childhood- with adult-onset SLE, childhood-onset SLE was found to be independently associated with an increased mortality risk (hazard ratio [HR], 3.1), as was low socioeconomic status measured by education (HR, 1.9), and end-stage renal disease (HR, 2.1).¹⁵

Young age at disease onset was repeatedly shown to be a predictor of adverse outcome.^47,107 Children with pSLE in poor countries clearly have a higher mortality: In a small study from Nigeria the mortality was 30%.¹⁰⁸ The Latin American LUMINA cohort had an 81% survival at last follow-up, the recent 5-year patient survival rate in Iran was 82.5%,³² and in Canada it was 100%.^41,109 Infections continue to be the main cause of death in developing countries with limited access to health care.^34,110 Nephritis has been consistently identified as a predictor of poor outcome in pSLE. Histologic subtype of proliferative disease, evidence of disease relapse, certain ethnicities, and poor response to therapy were strong predictors of end-stage renal disease in pSLE.¹¹¹ Gibson demonstrated that treatment resistance portended a high risk of end-stage kidney disease and disproportionately affected African-American children with lupus nephritis.¹¹¹

Children with pSLE accrue disease- and treatment-related damage as captured in the domains of the Systemic Lupus International Collaborative Clinics (SLICC) Damage Index (see Chapter 80), constantly adding to the overall disease burden.^1,57 Osteoporosis, cataracts, and osteonecrosis/avascular necrosis (AVN) are the leading domains of damage accrual. Individual patient characteristics, disease activity, corticosteroid therapy, calcium/vitamin D deficiency, and immobility contribute to impaired bone health in pSLE.^112,113 AVN occurs in 6% to 10% of pSLE patients overall and is associated with corticosteroid therapy.⁴¹ Nakamura¹¹⁴ recently observed the complete absence of AVN in children younger than 14 years of age and suggested that age at the time of the initial corticosteroid therapy affects AVN occurrence. Neurocognitive deficits secondary to disease and treatment are increasingly recognized and significantly affect school performance and overall health-related quality of life.^115,116 Early cardiovascular events including myocardial infarctions and strokes have become a major cause of morbidity and mortality.¹

Drug-Induced Lupus Erythematosus

Several medications can cause systemic and subacute or chronic cutaneous lupus phenotypes in children.¹¹⁷ The cutaneous manifestations of systemic drug-induced lupus (DIL) include malar rash, purpura, erythema nodosum, urticaria, and photosensitivity. Systemic symptoms include arthritis, oral ulcers, pleuritis, hematologic manifestations, and less commonly renal disease. Characteristic laboratory findings of DIL are positive ANA and antihistone antibodies. Drugs implicated are minocycline, anticonvulsive drugs, hydralazine, procainamide, and isoniazid.¹¹⁸

Management of drug-induced lupus is based on the withdrawal of the offending drug. Topical and/or systemic corticosteroids and other immunosuppressive agents may be required in resistant cases.

Neonatal Lupus Erythematosus

Neonatal lupus erythematosus (NLE) is an acquired disease of the newborn caused by placental transfer of maternal anti-SSA/Ro and anti-SSB/La IgG antibodies. These can be present in mothers with SLE, Sjögren’s syndrome, and other autoimmune connective disorders, as well as clinically healthy women. Antibody transfer can lead to inflammation of the cardiac conducting system and subsequent fibrosis resulting in congenital heart block (CHB), which may be detected as early as 20 weeks of gestation. A prolonged PR interval is the first electrocardiographic sign of conduction system abnormality in NLE. The degree of heart block can vary, and rapid clinical progression from normal sinus rhythm to complete CHB over 2 weeks may be observed, causing life-threatening cardiomyopathy and fetal hydrops in the most severe cases. Isolated endocardial fibroelastosis can be found in some infants.¹¹⁹ Interestingly, infants with prenatal exposure to high-titer anti-SSB/La antibody levels are more likely to have noncardiac features of NLE, whereas cardiac disease tends to be associated with moderate or high maternal anti-SSA/Ro levels, independent of anti-SSB/La titers in CHB.¹²⁰ The overall risk of CHB in anti-SSA/Ro–positive women is estimated to be 2% to 5%,¹²⁰ but this risk may be increased by 10-fold in women with a previous child with CHB.¹²¹ A recent study suggests an overall recurrence rate of cardiac NLE of 17%, independent of maternal health, antenatal use of steroids, antibody status, severity of cardiac disease in the first affected child, or sex of the subsequent child.¹²²

In addition to heart block, newborns with NLE can present with a characteristic NLE rash, hepatic dysfunction, and hematologic abnormalities including significant thrombocytopenia. Typically the NLE rash is located around the eyes but may present elsewhere on the body.¹²³ Hepatobiliary disease can have three distinct presentations: (1) transient conjugated hyperbilirubinemia with mildly raised liver function tests (LFTs) in the first weeks of life; (2) mild elevations of LFTs at 2 to 3 months of life; and (3) severe liver failure during gestation or in the neonatal period.¹²⁴ NLE neurologic involvement can include magnetic resonance imaging (MRI) findings of nonspecific white matter changes and calcification of the basal ganglia. NLE “vasculopathy” is reported. Recently, an association of NLE and hydrocephalus has been recognized.¹²⁵ Chondrodysplasia punctata, a stippling of the epiphyses, and pulmonary capillaritis are rare clinical presentations of NLE.^123,126

In a prospective multicenter study of 128 infants whose mothers had been referred for the presence of anti-SSA/Ro antibodies, regardless of their diagnosis, hematologic abnormalities and raised liver enzymes were seen in 27% and 26%, respectively.¹²⁷ Cutaneous NLE manifestations were present in 16%. Only 2 of the 128 infants (1.6%) presented with complete CHB. In a recent Japanese review, 193 infants with NLE were described reporting CHB in 23%.¹²⁸

Treatment of CHB in NLE remains controversial. Prevention of progression to complete CHB may be achieved by treating the mother with fluorinated steroids (dexamethasone or betamethasone), which are not metabolized by the placenta and are available to the fetus in an active form. IV immunoglobulin had been used to prevent the development of CHB in the index patient and in subsequent pregnancies.¹²⁹ The current recommendation is to screen anti-Ro/SSA antibody–positive mothers with serial echocardiograms and obstetric sonograms biweekly starting from week 16 of gestation. Early detection of cardiac manifestations of NLE including premature atrial contractions or moderate pericardial effusion preceding CHB may potentially be targeted with preventive therapy.^129–131 First-degree heart blocks can be reversed by dexamethasone treatment of the mother.¹³² Once third-degree block is unequivocally identified, reversal is unlikely to be achieved. The majority of children with CHB require pacemakers.¹²¹

The treatment approach to extracardiac manifestations of NLE is conservative. Skin disease may require topical corticosteroids and sun protection.¹³³ Transient elevations of LFTs and cytopenias commonly do not require therapy.¹²⁴

The morbidity of cardiac neonatal lupus is estimated to be 20%.¹²¹ Mortality is particularly high in patients with CHB and concurrent cardiomyopathy. Children with NLE can develop SLE later in life. Concerns of potential long-term neurocognitive deficits of NLE patients need further evaluation.¹³⁴