Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis

INTRODUCTION — Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease of unknown cause that can affect any organ system, most frequently the skin, joints, kidneys, and the nervous, hematologic, and cardiovascular systems. It is characterized by the production of multiple autoantibodies. Although SLE in children is fundamentally the same disease as in adults, with similar etiology, pathogenesis, and laboratory findings, there are some differences in frequency and severity of certain clinical manifestations. It is generally accepted that children with SLE have greater disease severity and earlier accrual of disease damage than adults with SLE [1-5]. The care of children and adolescents with SLE is different from that of adults because of the impact of the disease and its therapy on physical, psychosocial, and emotional growth and development. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

The epidemiology, clinical features, diagnosis, and classification of childhood-onset SLE (cSLE) are reviewed here. The treatment, complications, and prognosis of cSLE are discussed separately. (See "Systemic lupus erythematosus (SLE) in children: Treatment, complications, and prognosis".)

EPIDEMIOLOGY — The best estimate is that cSLE affects between 5000 and 10,000 children in the United States [6] and affects females more often than males (8 to 9:1), even in the prepubescent age group (4 to 5:1) [7-9]. SLE can occur at any age, although it is rare before five years of age and is increasingly prevalent after the first decade of life [7,10-12]. Between 10 to 20 percent of all persons who develop SLE do so in childhood. (See "Epidemiology and pathogenesis of systemic lupus erythematosus", section on 'Epidemiology'.)

Worldwide, estimates of cSLE incidence are between 0.3 to 2.2 per 100,000 children-years, while prevalence rates range widely from 3.3 to 9.7 per 100,000 children and adolescents, depending upon the population studied and its ethnic distribution [13-24]. Persons of Asian, African, Indigenous North American, and Hispanic/Latino ancestry are more frequently and more severely affected than those of European ancestry [13,25-28].

PATHOGENESIS — The etiology of SLE remains unknown, but genetic, hormonal, immunologic, and environmental factors are suspected to play a role. However, unique to cSLE is the identification of monogenic forms of SLE, mainly due to defects in the complement system; type I interferon pathway; aberrant nucleic acid repair, degradation, and sensing; or abnormal B cell development [29,30]. Many of the clinical manifestations are mediated directly or indirectly by antibody formation and the creation of immune complexes. The etiology and pathogenesis of SLE are discussed in greater detail separately. (See "Epidemiology and pathogenesis of systemic lupus erythematosus".)

CLINICAL MANIFESTATIONS — The presenting manifestations of cSLE are diverse, and any organ system may be involved (table 1) [31]. Many children and adolescents have an insidious onset of persistent fever, weight loss, fatigue, and arthralgia with general deterioration over weeks to months. Major organ involvement typically occurs within the first two to three years of disease onset. However, some new patients have acute or even life-threatening symptoms at presentation due to concomitant macrophage activation syndrome (MAS), severe renal disease, severe neuropsychiatric manifestations, or acute thromboembolic disease. Children with earlier-onset cSLE (<10 years of age) tend to have more severe disease activity and poorer prognosis [32,33].

Children may have small joint arthritis and renal disease, both of which are commonly overlooked before the diagnosis of SLE is established. The classic malar rash (picture 1 and picture 2) may be absent or overlooked when there are only subtle changes. The rash may also appear as less conspicuous erythema or hypopigmentation in persons with darker skin pigmentation. Thus, the malar rash must not be relied upon to suggest the diagnosis.

In reviews from multiple different countries, the most common presenting manifestations were as follows [1,7,11,13,34-36]:

●Hematologic (55 to 77 percent) – Anemia, lymphopenia, leukopenia, and/or thrombocytopenia

●Mucocutaneous (70 percent) – Malar rash, photosensitivity, oral or nasal ulcers, and/or discoid rash

●Musculoskeletal (61 to 64 percent) – Arthritis, arthralgia, and/or serositis

●Renal abnormalities (27 to 59 percent) – Proteinuria, hematuria, and/or casts suggestive of nephritis; nephrotic syndrome; and/or biopsy-proven lupus nephritis

●Fever (26 to 58 percent)

Pulmonary, thromboembolic, cardiac, neuropsychiatric, and gastrointestinal manifestations are also reported [7,11,13,36].

Hematologic abnormalities, lupus nephritis, fever, ocular symptoms, seizures, and lymphadenopathy are more common in cSLE than adult-onset SLE (aSLE), whereas Raynaud phenomenon, pleuritis, and sicca symptoms (dry eyes, dry mouth) are more common manifestations in aSLE [37,38]. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

Mucocutaneous — Skin and mucous membrane findings include the butterfly (malar) rash (picture 1 and picture 2), oral and/or nasal ulcers, and nonscarring alopecia. However, the classic skin findings may be absent in children at presentation. Although the classic malar rash crosses the nasal bridge and spares the nasolabial folds, the rash also frequently affects the chin and the ears or may present as a hypopigmented rash, especially in children with darker pigmentation. Other skin manifestations in cSLE include a frequently diffuse maculopapular rash, discoid lupus erythematosus (DLE), and cutaneous vasculitis [39].

Following the dermatology classification [40], cutaneous lesions can be classified into:

●Acute cutaneous (eg, malar rash, generalized maculopapular rash)

●Subacute cutaneous (eg, annular subacute cutaneous lupus erythematosus [SCLE])

●Chronic cutaneous (eg, DLE, lupus profundus, chilblain lupus erythematosus [LE]) lesions

DLE (or chronic cutaneous lupus) occurs as an isolated syndrome in 90 to 95 percent of adults with localized lesions and 70 to 85 percent of adults with generalized lesions. In children, "isolated" DLE progresses to SLE in up to 25 percent of patients [41]. Acute cutaneous lesions are most common in cSLE, and mucocutaneous involvement in SLE is reviewed in greater detail separately. (See "Overview of cutaneous lupus erythematosus", section on 'Lupus erythematosus-specific skin disease' and "Overview of cutaneous lupus erythematosus", section on 'Lupus nonspecific skin disease' and "Overview of cutaneous lupus erythematosus", section on 'Mucosal manifestations'.)

Thinning of the hair, especially in the frontotemporal areas, is common in cSLE, while diffuse alopecia is less frequent. "Lupus hair" (thin, unruly hair that easily fractures) can occur in addition to one or multiple localized patches of alopecia areata [42]. Telogen effluvium is also seen, occurring up to three months following a flare of cSLE disease. (See "Overview of cutaneous lupus erythematosus", section on 'Nonscarring alopecia'.)

Systemic — Low-grade fever, fatigue, anorexia, and lymphadenopathy are common manifestations of SLE at onset but do not differentiate the diagnosis of SLE from other systemic illnesses. Persistent high fevers above 38.6°C (101.5°F) may occur; however, coexisting infection and MAS should always be excluded in these cases.

Musculoskeletal — The most common musculoskeletal findings in children with SLE are arthritis and arthralgias. The arthritis of cSLE affects both large and small joints. Contrary to usual teaching, the arthritis of cSLE is not always painful and, in many cases, may be asymptomatic and only noted on careful physical examination [43]. These manifestations are reviewed in greater detail separately. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Joint involvement'.)

Additional bony abnormalities include osteopenia, osteoporosis, and osteonecrosis (avascular necrosis) [44,45]. Low bone mineral density (BMD) is frequently observed at cSLE diagnosis and does not improve throughout the disease course, even when glucocorticoids are tapered and stopped [46,47]. In one case series of 64 consecutive children with SLE, dual x-ray absorptiometry (DXA) scanning demonstrated lumbar spine osteopenia in 24 patients (38 percent), osteoporosis in 13 (20 percent), and decreased hip BMD in 12 patients (19 percent) [44]. Osteoporosis in SLE is discussed in greater detail separately, and vitamin D deficiency is discussed below. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Osteoporosis' and 'Laboratory findings' below.)

Renal — Renal involvement in SLE may vary from the detection of hematuria and proteinuria on routine examination to the presence of nephrotic syndrome or acute kidney injury. Some degree of renal involvement is present in up to two-thirds of patients with cSLE evaluated at major medical centers [48]. However, in a study of US children with SLE enrolled in Medicaid from 2000 to 2004, only 37 percent had lupus nephritis [16]. A higher rate of lupus nephritis was seen in adolescent-onset SLE compared with aSLE in one series [49]. Similar to aSLE patients with lupus nephritis, Black patients have worse prognosis regardless of socioeconomic status. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis" and "Lupus nephritis: Diagnosis and classification".)

Lupus nephritis is classified by histopathology and ranges from class I (normal or near normal) to class VI (end-stage kidney disease), with proliferative nephritis (class III or class IV) representing almost half of all renal lesions [50]. Proliferative lesions are the most severe and require intensive immunosuppression as they are the most likely to progress to end-stage kidney disease. If urinalysis demonstrates any proteinuria or if the sample is dilute and mild proteinuria is not elucidated on dipstick, quantification of the urine protein is required. Spot urine protein-to-creatinine ratio is an accurate alternative to a 24-hour collection. Orthostatic proteinuria should be excluded in isolated proteinuria by examination of a first morning urine sample.

A renal biopsy is required for accurate diagnosis of lupus nephritis. Indications include cSLE with proteinuria or renal insufficiency as suggested by increased creatinine or decreased estimated glomerular filtration rate (eGFR). Isolated hematuria is unusual in cSLE and therefore warrants a biopsy to rule out other causes, if present. Absolute contraindications to biopsy include a requirement for anticoagulation, uncorrected thrombocytopenia, or uncontrolled hypertension; a relative contraindication is a solitary kidney [51]. (See "Lupus nephritis: Diagnosis and classification".)

Hematologic — Hematologic abnormalities, including anemia, leukopenia, lymphopenia, and thrombocytopenia, are common among children with SLE [52-58]. Isolated thrombocytopenia (immune thrombocytopenia [ITP]) or Evans syndrome (immune thrombocytopenia and concomitant autoimmune hemolytic anemia) may be diagnosed months to years prior to the diagnosis of cSLE [59]. (See "Hematologic manifestations of systemic lupus erythematosus" and 'Laboratory findings' below and "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Evans syndrome'.)

●Anemia – Anemia, defined as a hemoglobin concentration more than two standard deviations below the mean for age and sex (defined as hemoglobulin ≤12 g/dL in several studies), is present in 50 to 75 percent of affected children [55,56,60]. The most common types of anemia, which may occur separately or in combination, are iron deficiency anemia, Coombs-positive autoimmune hemolytic anemia (AIHA), and anemia of chronic disease [55,56,61]. Concomitant hemoglobinopathies, such as alpha or beta thalassemia trait or sickle cell trait, may also contribute to anemia. (See "Approach to the child with anemia" and "Anemia of chronic disease/anemia of inflammation" and "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis" and "Overview of hemolytic anemias in children".)

●Leukopenia – Leukopenia, defined as a total white blood cell (WBC) count <4000/microL [62,63], occurs in nearly two-thirds of children at some point during the course of illness [53,54,60,64]. The decrease in WBC count is primarily due to a fall in absolute lymphocyte count [7,11,64]. Neutropenia is less common in SLE. Lymphopenia and neutropenia may be due to the underlying disease process or to treatment or infection. In the case of high-dose glucocorticoid therapy, the total WBC count usually increases due to demargination while the lymphocyte count decreases.

●Thrombocytopenia – The reported prevalence of thrombocytopenia varies from 10 to 50 percent [65-68]. Frequently, the degree of thrombocytopenia is mild (platelet counts between 100,000 and 150,000/microL), and hemorrhage is rare [65], although platelet counts under 10,000/microL with associated petechiae, purpura, and bleeding do occur. ITP, although isolated thrombocytopenia by definition, may be the first manifestation of cSLE, antedating this diagnosis by many years [69-73]. Thrombotic thrombocytopenic purpura (TTP) is an uncommon, acute and life-threatening complication that may also be the initial presenting feature of cSLE [74-76]. Antiphospholipid antibodies (aPLs) and other autoantibodies are discussed below [65,77,78]. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis" and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Approach to the child with unexplained thrombocytopenia".)

Neuropsychiatric — cSLE is associated with many neuropsychiatric syndromes and additional unclassified neuropsychiatric manifestations (NPSLE) [79]. One or more neuropsychiatric manifestations are reported in up to two-thirds of cSLE patients [80-88]. The most common manifestation is headache, followed by cognitive impairment, psychosis, seizures, mood disorders, anxiety disorders, and cerebrovascular disease. Less common manifestations include acute confusional state, peripheral neuropathy, chorea (movement disorders), cranial nerve palsy, and transverse myelitis. Neuropsychiatric symptoms can present with a gradual onset of symptoms over weeks to months but, if untreated and severe, can result in significant impairment in thought, cognition, and even consciousness. Cognitive impairment in cSLE occurs during a time of important brain development, and significant challenges remain in diagnosis and management [89-91]. Neurologic manifestations of SLE are discussed in greater detail separately. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus" and "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system".)

Appropriate attribution of neuropsychiatric manifestations to underlying SLE is important because it influences the approach to treatment. Differentiating active SLE from underlying infection, primary neuropsychiatric illness, a medication side effect, or other autoimmune disease requires careful history taking, physical examination, and appropriate laboratory and imaging studies that may include bloodwork, magnetic resonance imaging (MRI), electroencephalogram (EEG), and lumbar puncture (LP) [92,93]. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus", section on 'Attribution of a clinical syndrome to SLE'.)

Pulmonary — Most reviews of cSLE report respiratory findings in 30 to 50 percent of patients, with pleuritis being the most common (30 to 35 percent of children with SLE) [7,64,94-96]. Chest pain is the most common presenting symptom, whereas predominant complaints of shortness of breath are rare [94,97,98]. Children with pleuritis typically complain of chest pain that is sharp ("stabbing"), often severe, exacerbated by deep inspiration, and usually well localized. The diagnosis of pleuritis in a child with SLE is usually made with plain radiographs of the chest that demonstrate pleural fluid on one or both sides. Significantly elevated C-reactive protein (CRP) levels are frequently observed in patients with serositis (pleuritis and/or pericarditis) in contrast to the normal or minimally elevated levels observed in patients with other manifestations of active cSLE [99,100]. (See "Pulmonary manifestations of systemic lupus erythematosus in adults".)

Subclinical lung disease (eg, restrictive lung disease or reduced diffusion capacity identified through pulmonary function testing [PFT] with diffusing capacity for carbon monoxide [DLCO]) is present in as many as 60 to 70 percent of patients who are tested [95,97,101-103]. As such, PFTs with DLCO should be performed whenever there are new or increasing complaints of shortness of breath. (See "Overview of pulmonary function testing in children".)

Acute pulmonary hemorrhage [94,98,104-107] and pulmonary hypertension [98,108] are the most severe forms of lupus-associated pulmonary involvement, although they occur infrequently in children with SLE (<5 and <2 percent, respectively). Pulmonary hemorrhage is an acute emergency. The clinical manifestations of acute pulmonary hemorrhage include fever, cough, fatigue, pallor, tachypnea, and epistaxis or hemoptysis, although frank hemoptysis is frequently absent. Any child with SLE who experiences acute shortness of breath with a sudden drop in hemoglobin should be evaluated promptly for pulmonary hemorrhage. Other considerations for a patient with cSLE and hemoptysis are infection and pulmonary embolism. (See "Hemoptysis in children".)

Pulmonary hypertension in cSLE is rare, and, although initially attributed to multiple thromboses, the etiology is now thought to be multifactorial [108,109]. Symptoms include dyspnea on exertion, fatigue, lethargy, chest pain, exertional syncope, cough, hemoptysis, and hoarseness (caused by compression of the left recurrent laryngeal nerve by a dilated main pulmonary artery). It should be suspected in any child with increasing tricuspid insufficiency on echocardiogram and is confirmed by demonstrating increased pulmonary arterial systolic pressure. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis".)

Other rare pulmonary manifestations of SLE in children include shrinking lung syndrome [110-112] and pneumonitis [94,98]. (See "Pulmonary manifestations of systemic lupus erythematosus in adults".)

Thromboembolic — Thromboembolic disease can complicate SLE, particularly in the context of aPLs. Although one-quarter to two-thirds of patients with cSLE are positive for aPLs, fewer than half of these patients will have a thrombotic event (see 'Laboratory findings' below). In cSLE, the lupus anticoagulant is the greatest risk factor for the subsequent development of thrombosis [78], and the contribution of anticardiolipin antibodies and other aPLs (eg, anti-beta-2-glycoprotein 1) antibodies is not as well delineated. Antiphospholipid syndrome (APS) is diagnosed when a cSLE patient with aPLs has a thrombotic event [113,114]. In cSLE-associated APS, venous thromboembolic events are far more common than arterial events. Deep vein thrombosis (DVT) is most frequent, followed by cerebral sinus venous thrombosis (CSVT), pulmonary embolus, and lastly arterial stroke [115]. (See "Clinical manifestations of antiphospholipid syndrome" and 'Laboratory findings' below and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

Although lupus anticoagulant predisposes to thrombosis, bleeding in a patient with cSLE, prolonged prothrombin time (PT), partial thromboplastin time (PTT), and a positive lupus anticoagulant is probably due to antibodies to prothrombin (factor II) and is known as lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) [116].

Cardiac — Pericarditis is the most common cardiac abnormality in children with SLE, particularly within the first six months of diagnosis, and is clinically significant in nearly one-quarter [7,98,117]. Other cardiovascular disease, such as myocarditis, valvular disease (eg, endocarditis) [102,118,119], and coronary artery disease (CAD), are rare. (See "Coronary artery disease in systemic lupus erythematosus" and "Clinical manifestations and diagnosis of myocarditis in children" and "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults".)

The prevalence of clinical heart disease among children with SLE ranges in various studies from 12 to 54 percent [98,117,119,120], and myopericardial manifestations occur at a rate 4.4-fold higher in cSLE compared with aSLE [121]. Subclinical disease, detected by echocardiography or found in autopsy studies, also occurs in many children [102,118,122,123]. In a retrospective review of 40 children with SLE who had at least one echocardiogram, 68 percent of subjects (27 of 40) had abnormalities [102]. These abnormalities were persistent in 5 of 14 subjects who had a second echocardiogram, of whom three were found to have moderately severe cardiac defects.

The classic presentation of pericarditis is an acute, sharp, anterior chest pain, often accompanied by dyspnea. Inspiration exacerbates the pain, which may be alleviated by an upright forward leaning position. On physical examination, low-grade fever, tachycardia, and tachypnea are commonly present. A pericardial rub also may be heard. Bloodwork frequently demonstrates a significantly elevated CRP level [99,100]. Large pericardial effusions may accumulate without symptoms until they cause cardiac tamponade [124-127]. These children present with symptoms suggestive of heart failure and accompanied by findings of distant heart sounds, pulsus paradoxus, hepatomegaly, and jugular venous distention. The diagnosis is suggested by enlargement of the cardiac silhouette on chest radiographs (ie, water bottle-shaped heart) and confirmed by echocardiography. (See "Acute pericarditis: Clinical presentation and diagnosis".)

Children with SLE have an increased risk for early atherosclerosis and CAD that may not become clinically apparent until they are young adults [128-131]. CAD directly impacts the long-term prognosis of children with SLE, particularly since the first recognized manifestation of CAD in children with SLE is often myocardial infarction [119,132,133]. (See "Coronary artery disease in systemic lupus erythematosus".)

Heart failure in children with SLE is usually the result of renal or pulmonary compromise (eg, hypertension, glomerulonephritis and/or nephrosis, and pulmonary disease) rather than intrinsic cardiac disease. (See 'Renal' above and 'Pulmonary' above.)

Gastrointestinal — Gastrointestinal involvement occurs in approximately 20 percent of children with SLE. In one case series, 39 of 201 children with SLE had gastrointestinal involvement [134]. Symptoms included pain due to ascites (n = 14), pancreatitis (n = 12), or complications of treatment (n = 1) or infection (n = 1). Pancreatitis in particular has increased morbidity. Asymptomatic mild hepatitis (liver enzyme elevations two to three times the upper range of normal) is a frequent finding at disease onset, although it is important to rule out infectious causes of hepatitis [135,136].

Autoimmune hepatitis (AIH) may be diagnosed prior to cSLE diagnosis, with positive antismooth muscle antibodies but without antiliver kidney microsomal antibodies [137]. Hepatomegaly may differentiate primary AIH from cSLE-associated hepatitis, although the histopathology are similar and are probably within a spectrum of disease. (See "Gastrointestinal manifestations of systemic lupus erythematosus".)

LABORATORY FINDINGS — Common laboratory findings in children with SLE, in addition to the hematologic abnormalities discussed above, include presence of autoantibodies such as antinuclear antibodies (ANAs), double-stranded DNA (dsDNA) antibodies, antibodies to the extractable nuclear antigens (ENAs), and antiphospholipid antibodies (aPLs) (table 1). Vitamin D deficiency is frequent at presentation in children and adolescents with SLE and may contribute to decreased bone density and osteopenia [138]. These findings are in addition to elevated erythrocyte sedimentation rate (ESR), a common marker of inflammation. C-reactive protein (CRP), however, may be normal or only mildly elevated in active SLE and is often elevated only when a patient with cSLE has concomitant infection, serositis, or macrophage activation syndrome (MAS). Findings more specific to SLE include hypocomplementemia and urinary sediment abnormalities. (See 'Hematologic' above and 'Renal' above and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Laboratory testing'.)

In most series, 100 percent of children with SLE are ANA positive. Occasional cases of "ANA-negative" SLE are described, although the concept is controversial, and an ANA-negative child should be vigorously evaluated for alternative diagnoses. Rarely, false-negative ANAs are observed when antibodies in high concentration fail to agglutinate unless multiple serum dilutions are done (a prozone effect). Additional autoantibodies such as anti-dsDNA and anti-Smith (anti-Sm) help to confirm the diagnosis of SLE but are not uniformly present. Antibodies to Ro, La, and ribonucleoprotein (RNP) are found with varying frequency and are more frequent in cSLE than in adult-onset SLE (aSLE). Although anti-Ro and anti-La antibodies occur in up to 30 percent of patients with cSLE, one study found that only 2.5 percent of patients with cSLE and these antibodies have Sjögren's syndrome manifested by sicca symptoms including dry mouth, dry eyes, and/or parotitis [139]. Antiribosomal P antibodies are found more frequently in children than adults and are associated with active disease and neuropsychiatric, renal, or hepatic involvement [140,141]. However, they are not specific for particular manifestations and do not provide prognostic value.

Antineutrophil cytoplasmic antibodies (ANCAs) are observed in SLE, but their presence is not associated with disease activity or specific organ involvement [142].

All of these antibodies may also be found in children who do not fulfill classification criteria for SLE. Some of these children will go on to develop SLE, others will develop other rheumatic diseases, and some will remain asymptomatic. The diagnostic utility of these tests varies with the population under study.

The prevalence of aPLs in children and adolescents with SLE has been evaluated in cross-sectional cohort studies and ranges from 24 to 62 percent for lupus anticoagulant (LA) to 27 to 66 percent for anticardiolipin antibodies [77,78,115,143,144]. aPLs are associated with thrombocytopenia, prolonged clotting times (eg, activated partial thromboplastin time [PTT]), menorrhagia, unexplained thrombosis, and stroke [65]. However, aPLs are also found in many children with SLE without these complications. Children and adolescents with SLE who have aPLs should be presumed to have the same increased risk of developing a clotting disorder as adults with aPLs [65,77,143], and they should be treated accordingly. (See 'Thromboembolic' above and "Clinical manifestations of antiphospholipid syndrome".)

DIAGNOSIS — In addition to children with obvious manifestations of cSLE such as malar rash, polyarthritis, serositis, and nephritis, the diagnosis should be suspected in any child with a gradual onset of fever, anorexia, weight loss, and/or fatigue with persistent or worsening symptoms over several weeks to months. Although fatigue is frequent, isolated chronic fatigue without other physical findings at presentation of cSLE is rare. Additional suggestive clinical features include arthralgia, discoid rash, alopecia, lymphadenopathy, peripheral edema, headache, cognitive impairment, psychosis, seizures, mood disorders, anxiety disorders, and cerebrovascular disease (stroke). Suggestive laboratory findings include persistent thrombocytopenia, hemolytic anemia, lymphopenia, and leukopenia. A low index of suspicion for SLE in childhood is the primary impediment to a proper diagnosis. Delayed diagnosis may be due to the frequent absence of the typical findings of SLE at disease onset (eg, malar rash) or may be due to the high frequency of nonspecific constitutional symptoms. The diagnosis is generally based upon clinical judgment after excluding alternative diagnoses. In the absence of SLE diagnostic criteria, SLE classification criteria are often used by clinicians to help identify some of the salient clinical features when making the diagnosis. Serologic findings are important to suggesting the possibility of SLE. (See 'Clinical manifestations' above and 'Classification criteria' below and 'Hematologic' above and 'Laboratory findings' above.)

Children who fulfill the American College of Rheumatology (ACR) criteria, Systemic Lupus International Collaborating Clinics (SLICC) criteria, or 2019 European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism)/ACR criteria (see 'Classification criteria' below) are considered to have definite SLE. However, not all of the manifestations required for a definite diagnosis may be present when the child is first seen, and there are no official criteria for probable or possible SLE. 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 antinuclear antibody (ANA) titer [145]. If an elevated ANA titer is found, the patient should be carefully evaluated for other manifestations of SLE [65,77,143]. Children with two or three classification criteria may go on to develop a fourth over time, but others may ultimately develop SLE without fulfilling the classification criteria. The key to proper care is to appropriately treat the manifestations present when the child is first seen and to carefully follow for several years those who present with fewer than four criteria for the development of additional findings over time. (See 'Hematologic' above and 'Laboratory findings' above.)

Some children with SLE present acutely with a fever, rash, leukopenia, and thrombocytopenia; findings that are suggestive of overwhelming infection [146,147] or macrophage activation syndrome (MAS) [148]. The differentiation of SLE from intercurrent sepsis may be difficult and may require simultaneous treatment for both conditions. (See 'Differential diagnosis' below and "Sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis" and "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)" and "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications", section on 'Macrophage activation syndrome'.)

DIAGNOSTIC APPROACH — SLE is the "disease of a thousand faces." As such, a clinician should consider the diagnosis when both specific and nonspecific signs and symptoms occur. Often there is a gestalt "sense" that cSLE may be the underlying culprit, especially when a child or adolescent presents with a typical constellation of mucocutaneous findings. However, even the most experienced clinicians have been surprised when an unusual presentation eventually is diagnosed as cSLE. Because of the myriad of presenting signs and symptoms, it is important to think of cSLE in order to proceed with the appropriate testing in a timely way.

As a start, suspect cSLE when a child or adolescent presents with any of the typical clinical symptoms or laboratory findings shown in the table (table 1). In particular, certain clinical scenarios should prompt a further workup for cSLE. These include:

●The adolescent female with chronic thrombocytopenia

●The patient hospitalized with new-onset psychosis, acute confusional state, or atypical anorexia nervosa

Although cSLE has a higher incidence in non-White females and usually has its onset after age 10 years, monogenic forms of cSLE are more likely in young patients (<5 years old) who have severe disease and whose parents are consanguineous.

If cSLE is suspected, remember to look at the vital signs for evidence of hypertension, abnormal heart rate, increased respiratory rate, or fever. A careful history should be followed by a physical exam looking for alopecia (diffuse or circumscribed), malar rash, oral and nasal ulcers, papilledema, lymphadenopathy (diffuse or localized), abnormal breath sounds, increased respiratory effort, abnormal heart sounds and rhythm, hepatosplenomegaly, and peripheral edema. A complete skin exam should be performed, looking for any rash on the scalp, face, trunk, or extremities, and abnormalities of the nailfold capillaries such as hemorrhage or dropout consistent with Raynaud syndrome. A musculoskeletal exam is important to examine for arthritis and/or tenosynovitis, and a focused neurologic exam is imperative, especially in the face of symptoms consistent with myositis, increased intracranial pressure, focal deficits, or cranial or peripheral nerve abnormalities on history.

A basic laboratory workup should include a complete blood count (CBC) with differential, creatinine, alanine aminotransferase (ALT), albumin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complement components 3 and 4 (C3, C4), total immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM), and antinuclear antibodies (ANAs), in addition to a urinalysis and a spot urine for protein and creatinine.

If ANA testing is positive and there are other signs or symptoms of cSLE, it is reasonable to check for double-stranded DNA (dsDNA) antibodies and extractable nuclear antigens (ENAs). The latter testing usually includes a panel of anti-Ro, anti-La, anti-Smith (anti-Sm), and anti-ribonuclear protein (RNP) antibodies. Additionally, check for the presence of a lupus anticoagulant, anticardiolipin (aCL) antibodies, direct antibody test (Coombs), and look for an elevated reticulocyte count if the hemoglobin is reduced with signs of hemolysis. In the face of a febrile or ill patient, ferritin and other markers of macrophage activation syndrome (MAS) should be ascertained. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications", section on 'Macrophage activation syndrome'.)

When clinically indicated by history and/or physical exam, supplemental laboratory testing can include measuring thyroid-stimulating hormone (TSH) levels for hypothyroidism, anti-tissue transglutaminase acid (TTG) antibodies for concomitant celiac disease, and serum electrolytes if there are concerns around fluid status or renal function. In the presence of fever, cytopenias, or signs of MAS, look for viruses including Epstein-Barr virus (EBV) and cytomegalovirus (CMV) in particular as these can precipitate and/or occur concomitantly with the onset of cSLE. Testing for tuberculosis with a tuberculin skin test and/or interferon (IFN) gamma release assay (IGRA) should be done in patients with appropriate risk factors. A patient with pleural or pericardial symptoms warrants an electrocardiogram (ECG), echocardiogram, and chest radiograph, while patients with lymphadenopathy and/or hepatosplenomegaly may benefit from abdominal and/or neck ultrasound. Magnetic resonance imaging (MRI) of affected organs (in particular the brain and/or spinal cord) should be obtained when there are significant central nervous system (CNS) or peripheral nervous system (PNS) symptoms. If there is any suspicion of thrombosis, then the appropriate investigation(s) (usually ultrasound depending upon location of the suspected thrombosis) should be obtained urgently. Many of these investigations should be ordered only after consulting with the appropriate subspecialty services. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis".)

REFERRAL — Pediatric rheumatology should be consulted when cSLE is suspected, especially in a hospitalized patient. In some centers, pediatric nephrology is involved in the care of all patients with cSLE, and other subspecialists including pediatric neurology, hematology, psychiatry, dermatology, ophthalmology, cardiology, and pulmonology are frequently involved in the diagnosis and management.

CLASSIFICATION CRITERIA — Three classification criteria exist: one from the American College of Rheumatology (ACR), last revised in 1997, a set of criteria titled the Systemic Lupus International Collaborating Clinics (SLICC) group classification criteria (based upon ACR criteria and published in 2012), and the 2019 European Alliance of Associations for Rheumatology (EULAR)/ACR classification criteria [149]. Any of these criteria may be used to aid in the diagnosis of SLE in both children and adults (table 2 and table 3) [62,63,150-152], although the SLICC criteria are more sensitive, especially early on in cSLE [153].

For the older ACR criteria, a patient is classified as having SLE if four or more of the criteria are present, either serially or simultaneously during any interval of observation in the absence of another explanation for the findings. Similarly, for the SLICC criteria, four or more of the criteria are required for classification, but the criteria present must include at least one clinical and one immunologic criterion. An alternative to the requirement of four criteria is positive antinuclear antibodies (ANAs) or anti-double-stranded DNA antibodies (anti-dsDNA) in conjunction with biopsy-proven lupus nephritis. Other factors, such as family history, age, duration of symptoms, and evolution of findings, must be considered before classifying a child as having SLE since none of the individual clinical or immunologic criteria for the classification of SLE are disease specific. Some patients may have severe organ manifestations of SLE without fulfilling classification criteria and must be treated urgently or emergently without waiting for other criteria to develop. As an example, a child with a positive ANA, positive anti-Ro antibody, hypocomplementemia, and acute confusional state probably has SLE but would only fulfill one ACR and three SLICC classification criteria. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Classification criteria' and 'Diagnosis' above.)

The 2019 joint EULAR/ACR classification criteria are notably different in that a positive ANA is required for further consideration of SLE [149,154,155]. As seen in the table (table 3), the criteria are weighted within domains, providing a clinician a sense of the relative likelihood of SLE (versus another disease) depending upon the clinical or laboratory feature present within a domain. A total score of 10 or greater classifies a patient as having SLE. As an example, a patient with mucocutaneous features might have nonscarring alopecia (score 2), oral ulcers (score 2), subacute cutaneous lupus or discoid lupus (either scores 4), or acute cutaneous lupus (ie, malar rash; score 6). Only the highest score is counted within each domain, so a child with a malar rash and an oral ulcer would score 6.

Only one study (using the proposed rather than final published criteria) has examined the validity of these criteria in cSLE, suggesting that sensitivity is similar to prior classification criteria, although specificity might be improved by using a higher cutoff score of 13 rather than 10 [156]. Although classification criteria are designed to classify similar patients for research studies and not for clinical diagnosis, clinicians recognize the utility of these criteria to aid in diagnosis. Further study will determine if these criteria are suitable for use to distinguish a patient with cSLE from a patient with another systemic autoimmune disease such as dermatomyositis or systemic sclerosis.

DIFFERENTIAL DIAGNOSIS — Ten percent or more of "healthy" children have a positive antinuclear antibody (ANA) [157-159]. Thus, most children with a positive ANA and arthralgias in the absence of other supporting manifestations do not have cSLE. (See "Measurement and clinical significance of antinuclear antibodies".)

The major considerations in the differential diagnosis and evaluation of a child with a positive ANA and multisystem illness are infection and other autoimmune and systemic inflammatory diseases. However, children with malignancies such as acute lymphoblastic leukemia may also have a positive ANA, and it may be challenging to differentiate these two entities as both can present with fever, bicytopenia or pancytopenia, lymphadenopathy, hepatosplenomegaly, weight loss, and fatigue. A bone marrow aspirate and biopsy may be required when other features that are exclusively in cSLE (such as a malar rash, nephritis, psychosis, or multiple autoantibodies) are absent. Night awakening due to pain and leukopenia with significant neutropenia are symptoms suggestive of underlying malignancy rather than cSLE. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

While the differential diagnosis remains wide, other, rarer nonmalignant diseases to consider include Kikuchi-Fujimoto disease and Castleman disease:

●Kikuchi-Fujimoto disease most frequently presents with unilateral cervical lymphadenopathy and systemic features of fever, cytopenias, and elevated inflammatory markers. The constellation of symptoms can resemble SLE, and patients can also develop concomitant macrophage activation syndrome (MAS) with hyperferritinemia. The histology of the lymph node biopsy (required for the diagnosis) reveals necrotizing histiocytic lymphadenitis. Children with Kikuchi-Fujimoto disease may have a self-limited episode, although up to 25 percent will go on to develop SLE within weeks to years [160,161]. In our practice, we follow children with Kikuchi-Fujimoto disease (especially in the presence of any positive autoantibodies) longitudinally. (See "Kikuchi disease".)

●Castleman disease is a nonclonal lymphoproliferative disorder that presents with localized (unicentric) or diffuse (multicentric) lymphadenopathy, with concomitant systemic features including fever, cytopenias, and elevated inflammatory markers. Differentiation from SLE may rely on lymph node biopsy and the detection of autoantibodies, which should be absent in Castleman disease [162,163]. (See "HHV-8-negative/idiopathic multicentric Castleman disease" and "Unicentric Castleman disease".)

Viral infections in particular are associated with the transient appearance of ANA. Parvovirus and the herpesviruses, in particular Epstein-Barr virus (EBV) and cytomegalovirus (CMV), can present with symptoms suggestive of cSLE (fever; cytopenias; organ involvement including liver, lung, and joints; and additional constitutional symptoms). Infection with these viruses may also occur concomitant with the initial presentation and diagnosis of cSLE, suggesting a possible role in the pathogenesis of cSLE. Viral testing including serologic or polymerase chain reaction (PCR) testing in addition to evaluation of the clinical course can usually differentiate infection from cSLE. Other infections (eg, bacterial, mycobacterial) are less likely to be confused for cSLE, but appropriate cultures and other testing should differentiate the underlying etiology.

Other systemic autoimmune rheumatic diseases such as mixed connective tissue disease (MCTD), primary Sjögren's syndrome, juvenile dermatomyositis, scleroderma, and some systemic vasculitides (granulomatosis with polyangiitis and polyarteritis nodosa), may present with a positive ANA and multisystem findings. The majority of these can be excluded by a careful history, physical examination, selected laboratory tests, and, when required, histopathologic evaluation of the appropriate tissues (eg, muscle, skin, kidney, salivary gland). MCTD is rare in children and adolescents, and differentiation from cSLE may initially be challenging. However, the diagnosis can usually be made if the clinical symptoms of Raynaud, puffy fingers, and myositis are predominant, in the presence of high-titer anti-ribonucleoprotein (RNP) antibodies and in the absence of renal disease. (See "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis" and "Vasculitis in children: Incidence and classification", section on 'Polyarteritis nodosa' and "Mixed connective tissue disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic lupus erythematosus".)

SUMMARY AND RECOMMENDATIONS

●Overview – Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease of unknown cause that can affect any organ, most commonly the skin and mucous membranes, joints, kidneys, and central nervous system (CNS). Hematologic manifestations (cytopenias) and serositis are also frequent. Childhood-onset SLE (cSLE) is fundamentally the same disease as in adults, with similar etiology, pathogenesis, clinical manifestations, and laboratory findings. However, the frequency of specific manifestations varies between cSLE and adult-onset SLE (aSLE), and the disease may be more severe in children, especially if diagnosis is delayed. (See 'Introduction' above and 'Pathogenesis' above and 'Clinical manifestations' above and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

●Clinical manifestations – The most common initial symptoms are the gradual onset of fever, weight loss, and fatigue, often with progression of symptoms for several weeks to months prior to diagnosis (table 1). Nonpainful arthritis of the small joints and renal disease are commonly overlooked before the diagnosis of SLE is established. The classic malar rash is present in only approximately one-third of individuals at the onset of disease and therefore must not be relied upon to suggest the diagnosis. Hematologic, neuropsychiatric, and pulmonary manifestations are also common at presentation. (See 'Clinical manifestations' above.)

●Laboratory findings – Common laboratory findings in children with SLE, in addition to the hematologic abnormalities, include hypocomplementemia and the presence of autoantibodies, such as antinuclear antibodies (ANAs) double-stranded DNA (dsDNA) antibodies, antibodies to the extractable nuclear antigens (ENAs), and antiphospholipid antibodies (aPLs) (table 1). Vitamin D deficiency is frequent at presentation but is not pathognomonic for cSLE. (See 'Laboratory findings' above.)

●Diagnosis – Three sets of classification criteria are available (table 2 and table 3): one from the American College of Rheumatology (ACR), last revised in 1997; a set of criteria published in 2012 titled the Systemic Lupus International Collaborating Clinics (SLICC) group classification criteria (based upon ACR criteria); and the 2019 European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism)/ACR classification criteria for SLE. Any of these criteria may be used to aid in the diagnosis of SLE in both children and adults. A patient is classified as having SLE if four or more of the ACR criteria are present or if four or more of the SLICC criteria, including at least one clinical and one immunologic criterion, are present either serially or simultaneously during any interval of observations in the absence of another explanation for the findings. For the 2019 criteria, presence of a positive ANA is a required entry criterion, following which a score is calculated based upon domains of clinical and laboratory features. A total score of 10 or greater is required for classification. (See 'Diagnosis' above and 'Classification criteria' above and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Our diagnostic criteria'.)

●Differential diagnosis – The differential diagnosis of children with a positive ANA and multisystem disease includes infection, malignancy, and other rheumatic diseases. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Thomas JA Lehman, MD, who contributed to earlier versions of this topic review.