Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of disease manifestations that can involve any organ system, and can lead to significant morbidity and even mortality. This article reviews the epidemiology, common clinical features, and complications of the disease, and briefly discusses the available treatment options. In addition, important medical and psychosocial issues relevant to the pediatrician caring for children and adolescents with SLE are discussed.
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cSLE is a rare but severe autoimmune disease with multisystem involvement and wide heterogeneity of disease manifestations.
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Making the diagnosis of cSLE can be difficult, but early recognition of the disease is important to limit adverse outcomes.
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cSLE follows a more severe disease course than adult-onset SLE, with higher frequency of morbidity and lower survival rates.
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Dealing with the diagnosis of a lifelong, unpredictable, and relapsing-remitting disease in adolescence is challenging for cSLE patients, and recognition of the specific needs of this age group is important for optimal outcome.
Epidemiology
Childhood-onset SLE (cSLE) is a rare disease with an incidence of 0.3 to 0.9 per 100,000 children-years and a prevalence of 3.3 to 8.8 per 100,000 children. A higher frequency of cSLE is reported in Asians, African Americans, Hispanics, and Native Americans. When compared with 2 more common childhood autoimmune diseases, juvenile idiopathic arthritis (JIA) and type 1 diabetes, cSLE is approximately 10 to 15 times less common in White children. However, in Asian children, cSLE is reported to be equally as common as JIA. Most studies report a median age of onset of cSLE between 11 and 12 years; the disease is rare in children younger than 5 years. As in adult-onset SLE, approximately 80% of patients with cSLE are female.
Classification and diagnosis of c SLE
SLE is called the great mimicker, as the disease shares characteristics with many other (autoimmune) diseases. Especially when the classic malar rash is absent, diagnosing SLE can be a challenge. However, the astute pediatrician who considers SLE when presented with an unusual constellation of symptoms can recognize important patterns of disease manifestations crucial for the diagnosis. Most patients who are diagnosed with cSLE fulfill 4 or more of the American College of Rheumatology classification criteria for SLE ( Table 1 ). The criteria were designed for use in research studies, and it must be cautioned that the diagnosis of SLE should not solely be based on fulfilling these criteria. Although not rigorously studied in cSLE, the criteria have a greater than 95% sensitivity and specificity for the diagnosis of cSLE.
| Criterion | Definition |
|---|---|
| 1. Malar rash | Flat or raised erythema over the malar eminences, spares the nasolabial folds |
| 2. Discoid rash | Erythematosus raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur |
| 3. Photosensitivity | Rash following sunlight exposure, by history or physician observation |
| 4. Oral ulcers | Oral or nasopharyngeal ulceration, usually painless |
| 5. Arthritis | Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion |
| 6. Serositis | Pleuritis—convincing history of pleuritic pain or rub on auscultation or evidence of pleural effusion or Pericarditis—documented by electrocardiogram, echocardiogram or rub |
| 7. Renal disorder | Persistent proteinuria >0.5 g/d or Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed |
| 8. Neurologic disorder | Seizures in the absence of offending drugs or metabolic derangements or Psychosis in the absence of offending drugs or metabolic derangements |
| 9. Hematologic disorder | Hemolytic anemia with reticulocytosis or Leukopenia <4000/μL on 2 or more occasions, or Lymphopenia <1500/μL on 2 or more occasions, or Thrombocytopenia <100,000/μL |
| 10. Immunologic disorder | Antibody to native DNA, or Antibody to Sm protein, or Antiphospholipid antibodies—either anticardiolipin antibodies, presence of the lupus anticoagulant, or false-positive serologic test for syphilis |
| 11. Antinuclear antibody | Presence of antinuclear antibody by immunofluorescence or an equivalent assay |
Classification and diagnosis of c SLE
SLE is called the great mimicker, as the disease shares characteristics with many other (autoimmune) diseases. Especially when the classic malar rash is absent, diagnosing SLE can be a challenge. However, the astute pediatrician who considers SLE when presented with an unusual constellation of symptoms can recognize important patterns of disease manifestations crucial for the diagnosis. Most patients who are diagnosed with cSLE fulfill 4 or more of the American College of Rheumatology classification criteria for SLE ( Table 1 ). The criteria were designed for use in research studies, and it must be cautioned that the diagnosis of SLE should not solely be based on fulfilling these criteria. Although not rigorously studied in cSLE, the criteria have a greater than 95% sensitivity and specificity for the diagnosis of cSLE.
| Criterion | Definition |
|---|---|
| 1. Malar rash | Flat or raised erythema over the malar eminences, spares the nasolabial folds |
| 2. Discoid rash | Erythematosus raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur |
| 3. Photosensitivity | Rash following sunlight exposure, by history or physician observation |
| 4. Oral ulcers | Oral or nasopharyngeal ulceration, usually painless |
| 5. Arthritis | Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion |
| 6. Serositis | Pleuritis—convincing history of pleuritic pain or rub on auscultation or evidence of pleural effusion or Pericarditis—documented by electrocardiogram, echocardiogram or rub |
| 7. Renal disorder | Persistent proteinuria >0.5 g/d or Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed |
| 8. Neurologic disorder | Seizures in the absence of offending drugs or metabolic derangements or Psychosis in the absence of offending drugs or metabolic derangements |
| 9. Hematologic disorder | Hemolytic anemia with reticulocytosis or Leukopenia <4000/μL on 2 or more occasions, or Lymphopenia <1500/μL on 2 or more occasions, or Thrombocytopenia <100,000/μL |
| 10. Immunologic disorder | Antibody to native DNA, or Antibody to Sm protein, or Antiphospholipid antibodies—either anticardiolipin antibodies, presence of the lupus anticoagulant, or false-positive serologic test for syphilis |
| 11. Antinuclear antibody | Presence of antinuclear antibody by immunofluorescence or an equivalent assay |
Clinical features
This review does not attempt to describe all possible clinical manifestations but instead focuses on specific features that may be crucial for immediate recognition. Table 2 summarizes the frequencies of the common manifestations of cSLE. SLE can affect any organ system, and leads to glomerulonephritis and central nervous system (CNS) involvement arguably more often in cSLE than in adults with SLE.
| Clinical Feature | Prevalence of Involvement (%) |
|---|---|
| Constitutional and generalized symptoms | |
| Fever | 37–100 |
| Lymphadenopathy | 13–45 |
| Weight loss | 21–32 |
| Mucocutaneous | 60–90 |
| Musculoskeletal | 60–90 |
| Nephritis | 48–78 |
| Neuropsychiatric disease (NPSLE) | 15–95 |
| Gastrointestinal | 24–40 |
| Hematologic | 50–100 |
| Cardiovascular | 25–60 |
| Pulmonary | 18–81 |
Constitutional Symptoms
Patients ultimately diagnosed with cSLE frequently recount nonspecific constitutional symptoms that include fever, fatigue, anorexia, weight loss, alopecia, and arthralgias. These and other signs of diffuse generalized inflammation, including lymphadenopathy and hepatosplenomegaly, may occur both at onset and during disease flares.
Mucocutaneous
The hallmark of SLE is the malar, or butterfly, rash. Seen in 60% to 85% of children with SLE, the rash is generally described as erythematous, raised, nonpruritic, and nonscarring. It often extends over the nasal bridge, affects the chin and ears, but spares the nasolabial folds ( Fig. 1 ). It is photosensitive in more than one-third of patients, and exacerbation of the photosensitive rash frequently heralds the onset of a systemic flare. Therefore, sunscreen with a high sun-protection factor, as well as hats and protective clothing, are recommended year-round for all individuals with SLE.
Discoid rash, unlike in adult-onset SLE, is a rare manifestation of cSLE, occurring in fewer than 10% of patients. This scarring rash most frequently occurs on the forehead and scalp, and its scaly appearance may be mistaken as a tinea lesion. Box 1 summarizes the spectrum of dermatologic involvement, illustrating the diverse range of skin manifestations. Children and adolescents with SLE can develop a rash of (almost) any morphology, location, and distribution, often presenting a diagnostic challenge to the primary care physician. A skin biopsy for histology aids in making the correct diagnosis, although biopsies of facial skin should be avoided. Nonscarring hair loss is common, but not specific for SLE. The alopecia is most often noted as thinning of the temporal areas of the scalp, although rarely it is more global and severe enough to require systemic immunosuppressive therapy. Nevertheless, for the affected child or adolescent even minimal hair loss can be distressing.
Rash
Malar (butterfly) rash
Annular erythema
Discoid lupus erythematosus
Maculopapular and/or linear (nonspecific) rash
Bullous lupus (rare)
Photosensitivity
Alopecia
Raynaud phenomenon
Palmar/plantar/periungual erythema
Livedo reticularis
Vasculitis
Petechiae
Palpable purpura (leukocytoclastic vasculitis)
Chilblains/nodules
Digital ulcers
Involvement of the oral and nasal mucosa ranges from oral and/or nasal hyperemia to painless oral ulcers of the hard palate ( Fig. 2 ) and shallow nasal septal ulcers and, rarely, nasal septal perforation. Because of both the location and painless nature of these lesions, the practitioner may overlook these findings if the degree of suspicion for SLE is low.
Musculoskeletal
The range of musculoskeletal involvement includes features that occur as a consequence of active SLE, and those that are secondary to treatment and/or chronic illness. Manifestations include arthralgias and arthritis, avascular necrosis, bone-fragility fractures, and secondary pain amplification. Arthritis occurs in 80% of patients with cSLE, and although the typical description is that of a painful polyarthritis, in practice a significant proportion of children with SLE experience minimal pain. The arthritis is identical in many ways to JIA, with effusions and decreased range of motion of both small and large joints and significant morning stiffness; however; the arthritis is almost always nonerosive and nondeforming. Arthralgias also commonly occur, and can be secondary to a pain amplification syndrome that occurs during or following a disease flare with resultant poor sleep and daytime fatigue, decreased cardiovascular conditioning, and generalized pain.
Avascular necrosis can occur in patients treated with corticosteroids, and may be idiosyncratic to the dose of medication, although it occurs more frequently in patients with SLE than with other diseases that are similarly treated with corticosteroids. In addition, osteoporosis is frequent, related to corticosteroid use, and associated with an increased risk of fracture.
Renal Disease
Renal involvement occurs in 50% to 75% of all cSLE patients, and more than 90% of those who develop renal disease will do so within the first 2 years after diagnosis. Initial manifestations of renal disease range from minimal proteinuria and microscopic hematuria to nephrotic-range proteinuria, urinary casts, severe hypertension, peripheral edema, and renal insufficiency or acute renal failure. SLE most commonly affects the glomerulus (ie, lupus nephritis), with rare involvement of the renal interstitium. In a patient with acute renal failure, thrombotic thrombocytopenic purpura (TTP), a thrombotic microangiopathy and infrequent complication of SLE, should also be considered. As the severity of the nephritis may not correlate with the severity of the clinical signs and symptoms, a renal biopsy should be performed for any suspicion of glomerulonephritis, including persistent mild proteinuria. Histologic diagnosis using a standardized classification ( Table 3 ) guides treatment and aids in determining overall prognosis.
| Lupus Nephritis Class | Description | Histology |
|---|---|---|
| Class I | Minimal mesangial lupus nephritis | Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence |
| Class II | Mesangial proliferative lupus nephritis | Mesangial hypercellularity or mesangial matrix expansion by light microscopy, with mesangial immune deposits by immunofluorescence |
| Class III | Focal lupus nephritis | Active or chronic focal, segmental, or global glomerulonephritis involving <50% of all glomeruli with diffuse subendothelial immune deposits |
| Class IV | Diffuse lupus nephritis | Active or chronic diffuse, segmental, or global glomerulonephritis involving >50% of all glomeruli with diffuse subendothelial immune deposits |
| Class V | Membranous lupus nephritis | Global or segmental subepithelial immune deposits by immunofluorescence or electron microscopy |
| Class VI | Advanced sclerosing lupus nephritis | ≥90% glomeruli globally sclerosed without residual activity |
The classification of glomerulonephritis in SLE ranges from Class I (minimal mesangial) to Class VI (advanced sclerosing lupus nephritis), and contains descriptions of the mesangial involvement, degree of renal involvement (focal vs diffuse), and degree of involvement of the affected glomeruli (segmental vs global). In general, Class I (minimal mesangial) and Class II (mesangial proliferative) nephritis are mild lesions, and often require little to no immunosuppressive treatment because their natural history is favorable. Class III (focal proliferative) and Class IV (diffuse proliferative) lesions are the most frequent and severe lesions, with more than 80% of cSLE biopsies done at the Hospital for Sick Children, Toronto demonstrating one of these lesions. Patients with these proliferative lesions have the highest risk of end-stage renal disease (ESRD), and thus are treated with aggressive immunosuppression in attempts to avert this outcome. By contrast, Class V (membranous lupus nephritis), when it occurs as the exclusive lesion, rarely leads to ESRD and therefore is generally not treated with the same degree of immunosuppression as Class III or IV disease. However, Class V lesions are frequently observed in conjunction with other lesions (usually Class III or IV), and in this case the presence of the proliferative lesion directs therapy. Any patient with SLE should have regular measurements of blood pressure, serum creatinine, and urinalysis for proteinuria, hematuria, and evidence of urinary casts.
With the use of an aggressive treatment regimen, the incidence of ESRD is lower than in past decades, but still remains between 10% and 20% by 10 years from diagnosis. Patients who develop ESRD require dialysis, and can undergo renal transplant when a donor organ is available providing their disease is stable at the time of transplant. A recent study noted that whereas one-third of cSLE patients with ESRD received a transplant within 5 years, another 22% died in that same time period. Moreover, there is a risk of recurrence of nephritis in the graft kidney. Overall, renal disease remains a significant cause of morbidity and mortality, with the possibility of disease flares even after years of remission.
Neuropsychiatric Involvement
SLE can involve both the central and peripheral nervous systems, with 19 distinct neuropsychiatric SLE (NPSLE) syndromes described ( Table 4 ). Up to 65% of cSLE patients will develop NPSLE at some time during their disease course, and up to 85% of these patients develop NPSLE within the first 2 years from diagnosis. Because many of the syndromes are infrequent, only the commonest are briefly outlined here.
| Central Nervous System | Peripheral Nervous System |
|---|---|
|
|
Headache
Symptoms ranging from mild intermittent tension-type headaches to daily, debilitating severe headaches that require prescription pain medication occur in 50% to 95% of patients. Headache on its own can be a manifestation of active SLE, an indication of increased intracranial pressure, or of an intracranial abnormality such as cerebral vein thrombosis, especially in patients with antiphospholipid antibodies. The occurrence of a new severe headache is a red flag in a patient with SLE, and immediate evaluation is required.
Mood disorder
Depressive affect may be a normal and appropriate reaction for an adolescent dealing with a chronic disease, and thus attribution of depression to SLE is often challenging and requires input from psychiatry colleagues. Major depression is not as frequent, and occurs in fewer than 10% to 20% of patients.
Cognitive dysfunction
Impairment of cognition may be manifested by declining school performance and subtle difficulties with working memory and concentration tasks. Cognitive dysfunction is diagnosed with traditional neuropsychological testing, and has been observed in more than one-third of asymptomatic cSLE patients.
Psychosis
Hallucinations, predominantly visual but also auditory, are experienced by more than 10% of all patients with cSLE. Visual distortions are also common, with children reporting that the clock or light is distorted, or that the words on the page are “popping out.” The psychosis differs from that of primary psychiatric disease in that SLE patients have preserved insight; however, evaluation by a psychiatrist is recommended to assist with the diagnosis. Psychosis is frequently concomitant with cognitive dysfunction and acute confusional state. Although investigations including magnetic resonance imaging (MRI) are often normal, aggressive treatment is recommended and frequently leads to complete resolution of symptoms.
Seizures
Seizures are rarely seen in cSLE as an isolated event, but instead are frequently observed concomitantly with other NPSLE syndromes. When they do occur, seizures are more often generalized than focal. Seizures may also occur in patients with CNS infections or severe hypertension, and in patients who have a recently recognized complication known as posterior reversible encephalopathy syndrome.
In contrast to CNS disease, peripheral nervous system involvement is rarely observed in cSLE. Any cSLE patient presenting with new neurologic symptoms warrants consideration for a full diagnostic workup. This workup may include a lumbar puncture, MRI with MR angiography and venography, electroencephalogram (EEG), and psychiatry, psychology, and neurology evaluations as appropriate. Before attribution to SLE, other possible causes, in particular infection in the immunocompromised host, inappropriate prescription or illicit drug use, and new-onset primary psychiatric disease, must be considered in this predominantly adolescent population. Furthermore, patients rarely present with isolated features of one syndrome, and instead one may think of NPSLE as a series of overlapping symptoms, with coexistent symptoms in most patients. Treatment of NPSLE depends on the clinical presentation, with psychosis and acute confusional state requiring the most aggressive immunosuppressants, whereas other NPSLE syndromes require therapies directed at the observed manifestations.
Hematologic Features
Cytopenias are common in cSLE, with more than 50% of patients presenting a decrease in at least 1 cell line. Mild leukopenia (white blood cell count 3000–4000/mm 3 ) is the most common hematologic manifestation, and is usually due to lymphopenia (<1500 cells/mm 3 ) and, less frequently, neutropenia. Whereas persistent lymphopenia may be a feature of active disease, neutropenia is more frequently a result of treatment (eg, during treatment with cyclophosphamide). Anemia can take any form: the anemia of chronic disease that is normocytic and normochromic, iron-deficiency anemia, or a Coombs positive hemolytic anemia. In addition, coexistent hemoglobinopathies such as sickle cell anemia and thalassemia trait must be considered. The workup includes iron studies, hemoglobin electrophoresis depending on the patient’s indices, and other markers of hemolysis (reticulocyte count, haptoglobin, lactate dehydrogenase). Hemolytic anemia, occurring in 10% to 15% of patients, is rarely severe enough to require transfusion. The thrombocytopenia observed in cSLE patients spans the spectrum from mild (<150,000 platelets/μl) to profound (<10,000 platelets/μl). However, in the absence of excess bleeding and/or bruising, little treatment is required for patients with a stable platelet count of ≥20,000/μl. The risks of bleeding (intracranial, intraperitoneal) in SLE-related thrombocytopenia are similar to those in immune thrombocytopenic purpura (ITP), thus treatment is generally reserved for symptomatic or severe thrombocytopenia, and for patients with a history of severe thrombocytopenia who demonstrate an acute drop (ie, flare) in their platelet count. Children and adolescents with chronic ITP should be assessed for the presence of antinuclear antibodies, as they are at high risk of developing SLE.
Antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies) are present in 40% of patients with cSLE and are generally associated with hypercoagulability. However, fewer than half of these patients manifest a thrombotic or thromboembolic event. The most common events are deep venous thrombosis, cerebral vein thrombosis, and pulmonary embolus. Arterial events, including stroke, are less frequent.
Gastrointestinal Involvement
Abdominal pain and discomfort are frequent, although not well characterized manifestations of SLE. Abdominal vessel vasculitis, with or without bowel perforation, is rare. A sterile peritonitis occurs in fewer than 10% of patients, leading to abdominal pain and ascites, and is akin to pleuritis and pericarditis (ie, serositis). Pancreatitis is another well documented although infrequent manifestation of disease. More often, (epigastric) abdominal pain is an adverse effect of prescribed medications including corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). As there is an association between cSLE and celiac disease, patients with persistent abdominal pain, diarrhea, and/or weight loss should have the appropriate testing. Elevated liver enzyme tests occur in up to 25% of patients, and may be due to a medication side effect, active SLE, fatty infiltration, thrombosis, or infection. Testing for anti-liver kidney microsomal (anti-LKM) and anti–smooth muscle antibodies should be considered, as this may indicate primary autoimmune hepatitis that would require appropriate treatment.
Cardiopulmonary Features
Serositis, namely pericarditis and/or pleuritis, occurs in up to 30% of cSLE patients. Symptoms of pleuritis include shortness of breath and pleuritic chest pain, whereas pericarditis presents with tachycardia, precordial or retrosternal chest pain, and the inability to lie flat. Either pericarditis or pleuritis may present with or without associated fever. An inflammatory process, serositis is one of the few SLE manifestations that is associated with a significantly elevated C-reactive protein (CRP), and this laboratory test may be a useful clue. Although large pericardial and pleural effusions are seen on chest radiograph or echocardiogram, a serositis flare can present with only pain, bloodwork indicative of disease activity, and increased CRP in the face of minimal findings on radiographic investigations.
Other infrequent cardiopulmonary manifestations of SLE include myocarditis, noninfective (Libman-Sacks) endocarditis, interstitial pneumonitis, pulmonary hemorrhage, and pulmonary hypertension. These conditions are frequently severe, and can be life-threatening complications requiring prompt and aggressive treatment.
Vascular Manifestations
Although SLE is not generally thought of as an active vasculitis, inflammation and/or thrombosis of almost any vessel is possible. Cutaneous vasculitis may manifest as small, tender nodules of the digits, or palpable purpura (leukocytoclastic vasculitis) of the lower extremities, while retinal vasculitis (cotton-wool spots) and small-vessel CNS vasculitis are rare, but recognized. Although often clustered under the term vasculitis, neither livedo reticularis nor Raynaud phenomenon are due to inflammation within a vessel wall, but instead are a result of vasospasm that is common in SLE. Finally, TTP is an infrequent but life-threatening manifestation of SLE. TTP is a thrombotic microangiopathy that is diagnosed on observation of the triad of acute renal failure, thrombocytopenia, and CNS involvement, closely resembling atypical hemolytic uremic syndrome. Treatment involves plasmapheresis and significant immunosuppression with corticosteroids and a second-line agent.
Laboratory Findings
In the presence of suggestive clinical signs and symptoms, laboratory testing can support and confirm the diagnosis of SLE. A hallmark of SLE is the production of multiple autoantibodies. The commonest autoantibody is the antinuclear antibody (ANA), present in more than 95% of cSLE patients. In the presence of an ANA, it is appropriate to examine for specific autoantibodies including double-stranded DNA (dsDNA) and the extractable nuclear antigens, recognizing that particular autoantibodies correlate with certain disease features. The test for ANA has high sensitivity (>95%), but its specificity for SLE is as low as 36%. Moreover, up to 10% of healthy children demonstrate a positive ANA. In SLE, anti-dsDNA antibodies have high specificity. Anti-Smith antibodies (anti-Sm, not to be confused with anti–smooth muscle antibodies indicating autoimmune hepatitis) have the greatest specificity but low sensitivity for SLE. Both anti-dsDNA and anti-Sm antibodies are associated with renal involvement, and anti-Sm may be associated with more severe disease. Other autoantibodies observed in cSLE include anti–ribonuclear protein (anti-RNP), anti-Ro (also known as anti-SSA), and anti-La (or anti-SSB) antibodies. Offspring of females with anti-Ro antibodies are at risk for neonatal lupus erythematosus (NLE). NLE can lead to congenital heart block in these neonates, therefore any adolescent female with cSLE and anti-Ro antibodies should be informed of this risk prior to pregnancy, and referred for fetal echocardiogram monitoring by the end of the first trimester.
Other supporting features for SLE include hypocomplementemia (particularly C3 and C4, which are readily testable), cytopenia of one or more cell line as discussed earlier, and elevated erythrocyte sedimentation rate (ESR) in the face of a normal CRP level. CRP is often normal or only minimally elevated during an SLE flare except when the flare is of serositis, or in the presence of concurrent infection or macrophage activation syndrome (MAS) (see later discussion and see also the relevant article by Canna and Behrens elsewhere in this issue). Elevated liver enzymes can indicate fatty liver (secondary to corticosteroids), an adverse drug reaction, or active SLE. Less common causes in cSLE would include an intrahepatic thrombotic process, or elevated transaminases as a reflection of muscle inflammation. Routine hematology and biochemistry testing are used to monitor disease status for flare and remission, side effects of medication, and the effects of chronic disease and inflammation. Urinalysis should be done regularly for proteinuria and hematuria, and to examine for casts, while urine protein to creatinine ratios (spot or 24-hour collection) are required for monitoring response to treatment of lupus nephritis.
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