eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Systemic Lupus Erythematosus

Marisa S Klein-Gitelman, MD, MPH, Associate Professor of Pediatrics, Northwestern University Feinberg School of Medicine; Head, Division of Rheumatology, Children's Memorial Hospital

Updated: Dec 8, 2008

Introduction

Background

Systemic lupus erythematosus (SLE) is a rheumatic disease characterized by autoantibodies directed against self-antigens, immune complex formation, and immune dysregulation, resulting in damage to essentially any organ, including the kidney, skin, blood cells, and the nervous system. The natural history of this illness is unpredictable; patients may present with many years of symptoms or with acute life-threatening disease. Because of its protean manifestations, lupus must be considered in the differential diagnoses of many conditions, including fevers of unknown origin, arthralgia, anemia, nephritis, psychosis, and fatigue. Early diagnosis and careful treatment tailored to individual patient symptoms have improved the prognosis from what was once perceived as an often-fatal disease.

The first written description of lupus dates to the 13th century. Rogerius named the disease using the Latin word for wolf because the cutaneous manifestations he described appeared similar to those of a wolf bite. Osler was the first physician who recognized that systemic features of the disease could occur without skin involvement.¹ Diagnosis was made easier with the discovery of lupus erythematosus (LE) cells in 1948. In 1959, the presence of anti-DNA antibodies was noted. The use of the New Zealand black/white mouse model, which manifested spontaneous Coombs-positive anemia and many other manifestations of lupus, has allowed intensive study of the disease mechanisms and the importance of immunosuppressive therapy.

The use of adrenocorticotropic hormone (ACTH) in the 1950s resulted in amelioration of disease manifestations. Replacement of ACTH using corticosteroids improved treatment. The substantial adverse effects of corticosteroids led to a strategy of using various immunosuppressive drugs to minimize the need for corticosteroids, improving the prognosis for patients. For children with renal disease, recognition of the steroid-sparing effect of immunosuppressive agents such as azathioprine and cyclophosphamide has greatly improved the outcome. New advances in treatment using targeted biological therapies may further improve treatment outcomes. As patients continue to improve and survive, physicians now must assess patients for long-term disease sequelae, such as atherosclerosis, and develop prevention strategies. New strategies using genomics and proteomics give hope for identification of biomarkers that can be used for early disease detection and treatment.

Pathophysiology

Within the healthy population, a subset of individuals has small amounts of low titer antinuclear antibody (ANA) or other autoantibody. In lupus, increased production of autoantibodies leads to immune complex formation and tissue damage from direct binding in tissues, immune complex deposition in tissues, or both. Whether these antibodies are produced in reaction to exposure of normally nonexposed self-antigens or as a consequence of a broad spectrum of immune dysregulation resulting in excessive production of many antibodies without regard to prior stimulation is unclear. Both mechanisms may play a role.

Recently, new details about the role of dendritic cells and the regulation of complement activity and cell death have been explored. Patients with systemic lupus erythematosus make antibodies against DNA, other nuclear antigens, ribosomes, platelets, erythrocytes, leukocytes, and other tissue-specific antigens. The resulting immune complexes result in widespread tissue damage. Cell-mediated autoimmune responses also play a pathophysiologic role.

Children with lupus may have hematologic abnormalities, including hemolytic anemia, thrombocytopenia, leukopenia, or lymphopenia. Patients with immune complex disease in the kidneys may present with nephritis or nephrotic syndrome. Numerous neurologic abnormalities, from psychosis and seizure to cognitive disorders to peripheral neuropathies, may also occur. Their exact relationship to the presence of immune complexes and autoantibodies remains unclear.

Pulmonary disease manifests as pulmonary hemorrhage, fibrosis, or infarct. Various rashes, GI manifestations, serositis, arthritis, endocrinopathies, and cardiac abnormalities (eg, endocarditis) are observed. No organ is spared from the effects of this multisystem disease. However, the clinical presentation widely varies. How the clinical manifestations depend on the underlying specific immunologic disarray in a particular patient remains to be determined.

Frequency

United States

Incidence of this disease varies by location and ethnicity. Incidence rates among children younger than 15 years have been reported to be 0.5-0.6 per 100,000 persons. Prevalence rates of 4-250 per 100,000 persons have been reported, with greater prevalence in Native American, Asian American, Latin American, and blacks. In one study of adults, the incidence in black females was estimated at 1 in 500. African American children may represent up to 60% of patients younger than 20 years.

Mortality/Morbidity

The 5-year survival rate for children with systemic lupus erythematosus is more than 90%. Most deaths of children with systemic lupus erythematosus are the result of infection, nephritis, renal failure, neurologic disease, or pulmonary hemorrhage. Myocardial infarction may occur in the young adult years as a complication of persisting inflammation and, possibly, long-term corticosteroid use.

Race

Prevalence rates are higher in Native American, Asian American, Latin American, and black patients.

Sex

Prevalence rates are higher in females than in males. A female-to-male ratio of approximately 4:1 occurs before puberty, and a ratio of 8:1 occurs after puberty.

Age

Approximately 20% of patients with systemic lupus erythematosus initially present by the second decade of life. Disease onset has been reported as early as the first year of life. However, systemic lupus erythematosus remains uncommon in children younger than 8 years.

Clinical

History

The most frequent presenting symptoms of systemic lupus erythematosus (SLE) are prolonged fever and malaise with evidence of multisystem involvement. Children often present with a history of fatigue, joint pain, rash, and fever. However, children may present with various acute symptoms, including memory loss, psychosis, transverse myelitis, hemoptysis, edema of the lower extremities, headache, and painful mouth sores. Eleven criteria are used for the classification of lupus in adults. The same criteria can serve as a guideline in children. Any 4 criteria are sufficient and should be sought in the history. Of note, antinuclear antibody (ANA) is almost always present but is not diagnostic.

Diagnosis is not difficult in the child who presents with many manifestations, such as malar rash, pleuritic chest pain, nephritis, and a positive ANA finding. Some patients present over longer periods and require careful consideration. Occasionally, patients do not fulfill the classification criteria, a definite diagnosis is never made, or the patient may have an overlap syndrome with manifestations of several rheumatic diseases. Treatment should never be delayed in patients who do not fulfill classification criteria, particularly when patients are seriously ill.

Diagnostic criteria for systemic lupus erythematosus include the following:

• Mucocutaneous
  • Malar rash
  • Naso-oral ulcers
  • Photosensitive rash
  • Discoid rash
• Systemic
  • Arthritis
  • Pleuritis or pericarditis
  • Proteinuria (>500 mg/d) or evidence of nephritis in urinalysis
  • Hemolytic anemia, thrombocytopenia, leukopenia, or lymphopenia
  • Seizure or psychosis
• Laboratory
  • Positive ANA finding
  • Positive anti–double-stranded DNA, anti-Smith, or antiphospholipid antibody/lupus anticoagulant

Physical

A detailed physical examination is a critical tool in the diagnosis of systemic lupus erythematosus. Most of the American College of Rheumatology (ACR) classification criteria are associated with physical findings.² The following is a description of more common clinical manifestations.

• Mucocutaneous findings include the following:
  • Rash occurs in 70-80% of patients. The characteristic rash is a malar or butterfly rash, including both cheeks and the nasal bridge sparing the nasolabial fold. The rash varies from an erythematous blush to thickened epidermis to a scaly rash.
  • Other diagnostic skin findings include discoid rash, which is less common in childhood, a photosensitive rash, and mucous membrane changes that range from vasculitic erythema to large deep ulcers on the palate and nasal mucosa.
  • Other common rashes include vasculitic macular eruptions, particularly on the distal extremities and often in the subungual region with visible microinfarcts from small vessel vasculitis; purpura; livedo reticularis, which is often associated with antiphospholipid antibodies; alopecia, which is usually frontal or hairline; and Raynaud phenomenon, which is characterized by sequential color changes in the fingers and toes.
  • Less common rashes include subacute psoriasiform or annular skin lesions, often associated with anti-Ro antibodies and bullous lesions.
• Musculoskeletal findings include arthritis, arthralgia, tendonitis, and myositis.
  • Deforming arthritis is unusual and, if present, is usually secondary to a Jaccoudlike arthropathy.
  • This arthritis can lead to ligament damage and severely lax joints.
  • Avascular necrosis of bone is a frequent complication occurring in about 25% of children with systemic lupus erythematosus over time. It occurs both in children with systemic lupus erythematosus who are not being treated with corticosteroids and in children receiving corticosteroids for conditions other than systemic lupus erythematosus, but it is most common in children with systemic lupus erythematosus who are receiving daily corticosteroids.
• Abdominal findings include the following:
  • Patients often present with lymphadenopathy and hepatosplenomegaly. Many have chronic abdominal pain secondary to recurrent vascular insults to the intestinal tract and/or chronic pancreatitis, which may result from both treatment with corticosteroids and systemic lupus erythematosus itself.
  • Hepatitis demonstrated by laboratory evaluation is not uncommon.
  • Other abdominal findings can include pain secondary to peritoneal serositis or small-vessel vasculitis.
• Cardiac involvement includes pericarditis, murmurs associated with endocarditis, and cardiac failure from myocarditis or infarction. Pulmonary auscultatory findings may be abnormal secondary to pleuritis, infiltrates, or hemorrhage.
• Neurologic manifestations can include both the central and the peripheral nervous systems.
  • Diagnostic findings include seizure and psychosis; however, patients may present with stroke, pseudotumor cerebri, cerebral venous thrombosis, aseptic meningitis, chorea, global cognitive deficits, mood disorders, transverse myelitis, and peripheral neuropathy as well as many less common neurologic findings.
  • As many as 40% of children may have neurologic disease and perhaps even more when considering psychiatric manifestations and cognitive abnormalities. Quantification of cognitive function with formal neuropsychiatric testing may be advisable.
• Renal disease is manifested by hypertension, edema of the lower extremities, retinal changes, and clinical manifestations associated with electrolyte abnormalities, nephrosis, or acute renal failure. Renal disease is more frequently observed in children than in adults.
• Patients with lupus may present with the clinical findings of endocrine disease, such as hyperthyroidism and Addisonian crisis.

Causes

The specific causes of systemic lupus erythematosus remain undefined. Research suggests that many factors, including genetics, hormones, and the environment (eg, sunlight, drugs), contribute to the immune dysregulation observed in lupus.

• Within the healthy population, little measurable evidence exists of antibody to self. A subset of individuals has small amounts of autoantibody as manifested by a low-titer ANA or other autoantibody. In lupus, increased production of autoantibodies leads to immune complex formation and tissue damage from direct binding in tissues, immune complex deposition in tissues, or both. Evidence suggests antigen-specific antibody responses to DNA, other nuclear antigens, ribosomes, platelets, erythrocytes, leukocytes, and other tissue-specific antigens.
• Additionally, autoantibody production, by relatively few B lymphocytes, may be a byproduct of polyclonal B-cell activation in which many more B lymphocytes are activated, perhaps not in response to specific antigenic stimuli. Data on 3 adolescents with lupus demonstrate a high percentage of mature naive B cells (25-50% versus 5-20% in healthy adolescents), producing self-reactive antibodies even before they participated in an immune response, suggesting defective checkpoints in B-cell development.³
• The discovery of viral-like particles in lymphocytes in patients with lupus led to the theory that viral infection caused polyclonal activation in lupus. However, these particles may simply be breakdown products of intracellular materials. This assumption is supported by recent evidence in which polymerase chain reaction (PCR) did not isolate specific viruses, such as Epstein-Barr virus and cytomegalovirus, in lupus WBCs. Thus, positive titers to infectious agents in patients with lupus may be another manifestation of nonspecific polyclonal activation of B cells. However, viral stimulation of the innate immune system (dendritic cells) coupled with genetic defects in the innate and adaptive immune responses could lead to loss of tolerance and increasingly specific autoantibody formation.
• The presence of measurable autoantibodies implies a loss of tolerance to self-antigens and may include T-lymphocyte abnormalities. Early studies suggested a loss of T-suppressor function; however, recent investigations have centered on defects of programmed cell death, or apoptosis. This process of programmed cell death may be dysregulated in lupus, resulting in cells with the potential for self-reactivity persisting instead of undergoing the normal process of apoptosis. T cells from patients with lupus have been found with increased levels of Bcl-2, a protein that delays apoptosis. Patients have also been found to have lymphocytes that underwent increased apoptosis. One explanation may be that in lupus, lymphocytes that make self-reactive antibodies survive in the host but undergo increased cell turnover after an inciting trigger, such as a viral infection, begins the process that manifests as lupus.
• Other immunologic mechanisms may also be important, including defects in macrophage phagocytic activity or handling of immune complexes.
  • Deficiencies of complement components, including C4, C2, and C1q, have been associated with lupus, perhaps because of defective clearance of immune complexes.
  • Complement receptors may be abnormal in some patients, leading to problems with clearance of immune complexes and subsequent deposition into tissues. This may also be associated with dyslipoproteinemia, leading to significant vascular complications.
  • The predominance of lupus in females suggests sex hormones may play a role in autoimmune diseases. Research has found that patients with lupus did not have different serum levels of estrogen and prolactin when compared with controls; however, free androgen was lower, whereas follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were higher in postpubertal boys and girls with systemic lupus erythematosus.
  • Drugs, such as anticonvulsants and antiarrhythmic agents, can also play a role in the pathogenesis of lupus. These drugs can cause a lupuslike syndrome, which resolves when the drug is discontinued or can be implicated as the trigger in systemic lupus.
• Sun exposure leading to inflammation and apoptosis of skin cells can also trigger systemic lupus.

Differential Diagnoses

Other Problems to Be Considered

ACR classification criteria require 4 of 11 specific findings, which have 96-99% specificity (see History). Differential diagnoses should include the following:

Infection
Malignancy
Toxic exposures
Other multisystem diseases

Workup

Laboratory Studies

The following may be observed in patients with systemic lupus erythematosus (SLE):

• Initial laboratory evaluation should include CBC count with platelets and reticulocyte count; complete chemistry panel to evaluate electrolytes, liver, and kidney function; urine analysis; and a measure of acute phase reactants (eg, erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]).
• Diagnostic laboratory studies include antinuclear antibody (ANA), anti–double-stranded DNA, anti-Smith antibody, lupus anticoagulant, and antiphospholipid antibody panel.
• Obtain other autoantibodies, which may be associated with specific disease manifestations, including anti-Ro, anti-La antibodies associated with Sjögren syndrome, and antiribonucleoprotein (anti-RNP) antibodies.
• In addition to anti–double-stranded DNA, complement levels, including total hemolytic complement, C3, and C4, are markers of disease activity and are found to be low in most patients with active disease.
• Quantitative immunoglobulins are useful, because patients with lupus often have hypergammaglobulinemia and have a higher incidence of immunodeficiency.
• Other autoantibodies obtained should be guided by clinical and laboratory manifestations, such as petechiae, anemia, coagulopathy, cerebritis, and thyroid abnormalities.
• Patients should be evaluated for traditional risk factors of atherosclerosis, including fasting lipid profile, homocysteine level, fasting glucose level, smoking history, body mass index, family history of atherosclerosis, and physical activity. Risks should be stratified and treated.

Imaging Studies

• Obtain chest radiographs and ECG.
• Other imaging studies should be guided by clinical manifestations and may include the following:
  • MRI of the brain
  • Renal ultrasonography
  • Nuclear medicine evaluation for renal function
  • High-resolution CT scan to diagnose and evaluate for pulmonary fibrosis
  • Dual-energy x-ray absorptiometry (DEXA) to evaluate bone density

Other Tests

• Obtain pulmonary function tests, including diffusing capacity of the lung for carbon monoxide (DLCO), to evaluate baseline pulmonary status and to look for subtle disease not seen on chest radiographs.
• Test of cognitive function should be considered in patients with systemic lupus erythematosus, particularly if changes in behavior or school function are observed. Currently, pediatric rheumatologists are determining the appropriate tests that should be used to standardize this evaluation. Testing should include academics, executive function, attention, and memory.

Procedures

• The most common procedure in the diagnostic evaluation of systemic lupus erythematosus is a tissue biopsy to confirm diagnosis and to evaluate disease severity. This is particularly useful in evaluating the severity of renal involvement.
• Skin biopsy is used for diagnostic purposes when the diagnosis is not clear; lesional and sun-exposed skin may show positive immunofluorescence for complement and immune complexes. Skin biopsy is rarely necessary to make the diagnosis of systemic lupus erythematosus.
• Renal or liver biopsy is obtained more often for evaluation of disease severity and to determine the intensity of the medical regimen required for treatment.

Histologic Findings

• Fibrinoid deposits are found in blood vessel walls of affected organs. The parenchyma of these organs may contain hematoxylin bodies representing degenerated cells. Other histologic manifestations are associated with the particular organ. Immunofluorescence often reveals immune complexes and complements. The most important histology related to treatment decision is renal histopathology. Location of immune complexes (ie, subepithelial, subendothelial, intramembranous) is also important in prognosis.
• Biopsy findings are classified according to the World Health Organization (WHO) classification and correlate with clinical morbidity and mortality. This classification system has been recently updated.⁴ Patients may have combinations of the following classifications on biopsy findings, and all types should be reported.
  • Class I is defined by normal findings on light microscopy, immunofluorescence, and electron microscopy.
  • Class IIA disease has minimal mesangial deposits and a good prognosis, whereas class IIB is associated with lymphocytic infiltration and a variable prognosis.
  • Class III disease is characterized by focal segmental proliferative mesangial changes and is associated with chronic renal disease.
  • Class IV disease is defined as diffuse proliferation, with most glomeruli demonstrating cellular proliferation of epithelial, endothelial, and mesangial cells with cellular or fibrous crescent formation. Class IV has been further subdivided into segmental disease (IV-S) and global disease (IV-G). Class IV is associated with an increased risk of end-stage renal disease. Class IV disease involves advanced sclerosing lesions.
  • Class V disease is defined as a membranous process with significant proteinuria, which is often poorly responsive to treatment. 

Staging

• Lupus is not generally staged as a disease. However, staging criteria have been proposed to help assess the degree of illness.
• Determining which set of organs is inflamed is useful to decide treatment options.
• Kidney disease is classified as described in Histologic Findings. Staging for both WHO histologic class and for acuity and chronicity of renal histologic manifestations is important in determining optimal therapy.

Treatment

Medical Care

The most important tool in the medical care of the patient with systemic lupus erythematosus (SLE) is careful and frequent clinical and laboratory evaluation to tailor the medical regimen and to provide prompt recognition and treatment of disease flare, which is the cornerstone of successful intervention. Because lupus is a lifelong illness, patients must be indefinitely monitored. Specific medical interventions are listed below. New studies bring attention to the need for preservation of gonadal function when gonadotoxic therapies are used to treat severe disease. Consideration should be given to prevention of atherosclerosis and osteoporosis because these are long-term consequences of the disease and its treatment.

Surgical Care

The need for surgical care depends on the severity of organ involvement and the need for tissue diagnosis. Usually, systemic lupus erythematosus is not a surgical condition. If surgery is necessary, closely monitor the patient for healing and evidence of infection.

Consultations

A rheumatologist should be an integral part of the medical care team supporting the lupus patient. Other consultants depend on the type of organ involvement. Consider consultation with a nephrologist for severe end-organ disease.

Diet

Diet restrictions are driven by the medical therapy. Most patients require a course of corticosteroids and should be on a no added salt, low-fat, and calcium-sufficient diet. Recognize that patients frequently try nontraditional medical remedies and food supplements. These remedies should be met with an open and supportive response. Monitoring nontraditional remedies and food supplements is important because they may alter metabolism of more traditional medications, such as warfarin sodium, or they may have a negative effect. Of note, L-canavanine in alfalfa sprouts has been implicated in causing lupus, and excess use should be avoided.

Activity

Encourage patients with systemic lupus erythematosus to maintain a normal lifestyle. Exercise is important in maintaining bone density and an appropriate weight. Caution patients that fatigue and stress have been associated with disease flares. Caution patients to avoid sunlight and to liberally apply waterproof sunblock every 2 hours when exposed to the sun. Fluorescent lights may also cause increased rash in patients with systemic lupus erythematosus.

Medication

Therapeutic interventions for pediatric lupus should occur under the direction or with the advice of an experienced physician. Many medications are used to treat lupus and are chosen depending on disease manifestations. The goal of therapy is to control disease manifestations, allowing the child to have a good quality of life without major disease exacerbations, as well as preventing serious organ damage that adversely affects function or life span. At the same time, the physician is challenged to prevent intolerable adverse effects from the therapeutic regimen.

Before treatment, identify organ system involvement and exclude other possible diagnoses. Many of the therapeutic options have serious adverse effects, contraindications, and drug interactions. A high risk for infection, infertility, and future cardiovascular disease is noted. Most medications are considered a high risk during pregnancy. Patients with lupus who are pregnant should seek the expertise of an obstetrician and rheumatologist with experience in treating other patients with similar conditions.

The most important management tool in the treatment of systemic lupus erythematosus (SLE) is meticulous and frequent re-evaluation of patients. Re-evaluation includes clinical and laboratory evaluation, allowing prompt recognition and treatment of disease flare that is essential to patient outcome.

Patients with hypertension should be aggressively treated. If hypertension is a consequence of corticosteroid therapy, consider immunomodulating medications as steroid-sparing agents to help control hypertension. For more information, see eMedicine's topic on pediatric Hypertension.

Antimalarial agents

Rash and other minor symptoms including musculoskeletal symptoms can be treated with hydroxychloroquine 3-7 mg/kg/d, usually no more than 400 mg/d orally. Evidence indicates that long-term use of antimalarial drugs is steroid sparing. Hydroxychloroquine may also decrease risk of thrombotic events. Long-term use of this medication requires monitoring for retinal pigment changes every 6 months. Adverse effects are infrequent and include eye changes, GI symptoms (of which diarrhea is most prominent), and CNS changes.

Hydroxychloroquine (Plaquenil)

Antimalarial drugs inhibit synthesis of DNA, RNA, and proteins by interacting with nucleic acids. Antimalarial drugs have various immunosuppressive effects, can act as antioxidants, and interfere with prostaglandins.
200 mg of the sulfate salt = 155 mg of the base.

Dosing

Adult

200-400 mg (as sulfate salt)/d PO (3-7 mg/kg/d)

Pediatric

3-7 mg (as sulfate salt)/kg/d PO; not to exceed 400 mg/d

Interactions

Few reported; chloroquine may potentiate possible ocular toxicity of other drugs (eg, cisplatin); serum levels increase with cimetidine; magnesium trisilicate may decrease absorption

Contraindications

Documented hypersensitivity; G-6-PD deficiency;
retinal or visual field changes; porphyria; psoriasis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; perform periodic (6 mo) ophthalmologic examinations; test periodically for muscle weakness; adverse effects are infrequent and include eye changes, GI symptoms (of which diarrhea is most prominent), and CNS changes

Corticosteroids

These agents elicit anti-inflammatory and immunosuppressive properties, cause profound and varied metabolic effects, and modify the body's immune response to diverse stimuli.

Treat children who have evidence of severe renal, CNS, or hematologic diseases with corticosteroids. The dose varies with intensity of the organ system involved and in select individuals with serologic disease activity. Consider initiating therapy with daily prednisone (1 mg/kg/d) or higher-dose alternate-day prednisone (5 mg/kg/d, not to exceed 150-250 mg depending on the size of the patient). Alternatively, lower-dose daily prednisone (0.5 mg/kg) may be used in conjunction with intermittent high-dose intravenous methylprednisolone (30 mg/kg/dose, not to exceed 1 g) on a weekly basis.

Children who are systemically ill with renal, neurologic, severe hematologic, cardiac, or pulmonary disease are begun on high-dose daily prednisone 2 mg/kg/d (not to exceed 80 mg/d) in divided doses, which are consolidated after serologic disease activity is controlled and finally switched to alternate-day prednisone.

Alternatively, the patient may be treated with intravenous pulse methylprednisolone therapy (3 d of high-dose intravenous corticosteroids) and then switched to intermittent high-dose intravenous corticosteroids with lower daily prednisone doses depending on disease severity. Obtain PPD and Candida testing before commencement of medical therapy in patients who require steroids. Consider further evaluation for mycobacterial disease in patients who are anergic to both tests.

Prednisone (Deltasone, Orasone, Sterapred)

Decreases inflammation by suppression of the immune system: (1) decreased lymphocyte volume and activity, (2) decreased PMN migration, (3) decreased or reversal of capillary permeability. High doses, especially over periods >2-3 wk, suppress adrenal function.

Dosing

Adult

1-2 mg/kg/d PO

Pediatric

1-2 mg/kg/d PO initially in divided doses up to qid, then consolidated to a daily dose before tapering the total mg/d
Severe disease: 30 mg (as methylprednisolone)/kg IV infused over 1 h initially; not to exceed 1 g; may be administered as a 3-d pulse regimen or as part of a steroid regimen under the guidance of a rheumatologist

Interactions

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; serious infection (eg, systemic fungal infection, varicella), except septic shock or tuberculous meningitis; GI bleeding or ulceration

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Carefully monitor patients receiving corticosteroids for infection and carefully evaluate in the setting of fever with no obvious source; monitor patients for diabetes mellitus, osteoporosis, osteonecrosis, hypertension, glaucoma, cataract, altered mood, and gastritis; evaluate patients for occult infection, including TB and HIV, before starting corticosteroids; avoid discontinuing suddenly in patients receiving long-term steroids, even in active infection; infection can cause disease flare, and sudden discontinuation of steroids may cause an Addisonian crisis (carefully consider steroids in active infection and discuss with experienced physicians); consider alternate immunosuppression in patients who develop diabetes mellitus while on corticosteroids and taper steroids carefully; in the interim, the use of insulin may be required

Immunosuppressive agents

Evaluate children with signs of active nephritis to determine the WHO classification category of their nephritis. Patients with class IV nephritis and some patients with class III nephritis should be treated with corticosteroids and cyclophosphamide. Mycophenolate mofetil has become an alternative therapy for lupus nephritis. Azathioprine is used for more mild nephritis. Consider cyclophosphamide for severe systemic involvement of other vital organs, especially the brain. Other agents (eg, mycophenolate mofetil, cyclosporine, methotrexate) are considered when standard therapies have failed.

Other treatments under study include hormonal therapy and biologic agents that target cytokine production and anti-DNA antibodies. Clinical trials using autologous and stem cell transplantation are in progress for severe persistent disease. Most recently, anti-CD19 monoclonal antibodies (ie, rituximab) initially developed for treatment of B cell malignancies have shown promise in the treatment of lupus, in particular cytopenias and kidney disease resistant to other forms of therapy.

Cyclophosphamide (Cytoxan, Neosar)

Interferes with normal function of DNA by alkylation and cross-linking the strands of DNA and by possible protein modification.
Chemically related to nitrogen mustards. As an alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Dosing

Adult

500-1000 mg/m² IV q3-4wk

Pediatric

500-750 mg/m² IV q3-4wk; not to exceed 1 g/m²
Note: Should be administered IV with continuous hydration and monitoring; monitor WBCs at 8-14 d following each dose (adjust dose to maintain WBCs >2000-3000/μL)
Concomitant use of mesna to reduce toxicity is strongly recommended; antiemetics are often necessary adjuncts

Interactions

Allopurinol, may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function; infection

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examining urine for RBCs is not useful because most patients already have RBCs in their urine secondary to lupus nephritis; patients have WBC nadir 8-11 d after therapy, monitor closely for infection; pregnancy test required for females with child-bearing potential prior to each infusion

Mycophenolate (CellCept, Myfortic)

Immunosuppressant agent used in conjunction with other immunosuppressive therapies (eg, corticosteroids) to treat lupus kidney disease. May be considered as steroid-sparing agent for other organ-specific disease manifestations.
Inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, inhibiting their proliferation. Inhibits antibody production by inhibiting T-cell and B-cell proliferation, cytotoxic T-cell generation, and antibody secretion.
Two formulations are available and are not interchangeable. The original formulation, mycophenolate mofetil (MMF, CellCept), is a prodrug that, once hydrolyzed in vivo, releases active moiety mycophenolic acid. A newer formulation, mycophenolic acid (MPA, Myfortic), is an enteric-coated product that delivers the active moiety.

Dosing

Adult

CellCept: 1-1.5 g PO bid
0.5 g/dose may be considered for nonrenal disease manifestations
Myfortic: 720 mg PO bid

Pediatric

CellCept: 600 mg/m²/dose PO bid; not to exceed 1 g bid
Alternatively, may dose according to BSA:
BSA 1.25-1.5 m²: 750 mg cap PO bid
BSA >1.5 m²: 1 g cap or tab PO bid
Myfortic:
BSA <1.19 m²: Unable to accurately administer Myfortic tab
BSA 1.19-1.58 m²: 400 mg/m² PO bid; not to exceed 1080 mg/d
BSA >1.58 m²: 400 mg/m² PO bid; not to exceed 1440 mg/d

Interactions

Drugs that alter GI flora and antacids decrease MPA absorption; acyclovir and ganciclovir increase plasma concentrations; cholestyramine decreases mycophenolate concentration by 40%; probenecid increases mycophenolate concentration; salicylates increase free fraction of MPA; phenytoin decreases protein binding of phenytoin from 90% to 87%; theophylline decreases protein binding of theophylline from 53% to 45%

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Dosage has to be adjusted in patients with chronic renal impairment, hepatic impairment or neutropenia; immunosuppression with mycophenolate may result in an increased susceptibility to infection and an increased risk of developing lymphomas and other malignancies, particularly of the skin; effective contraception should be initiated prior to use and continued for 6 wk after discontinuation; caution in active peptic ulcer disease; commonly causes constipation, nausea, diarrhea, urinary tract infection, and nasopharyngitis; rare reports include interstitial lung disorders, colitis, pancreatitis, intestinal perforation, GI hemorrhage, gastric ulcers, duodenal ulcers, ileus; do not chew, crush, or cut Myfortic tab

Azathioprine (Imuran)

Antagonizes purine metabolism and may inhibit synthesis of proteins, RNA, and DNA. May interfere with mitosis and cellular metabolism.

Dosing

Adult

1-2.5 mg/kg/d PO qd

Pediatric

1-3 mg/kg/d PO qd

Interactions

Toxicity increases with allopurinol (decrease azathioprine dose by 25-33%); concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor carefully for renal toxicity and hepatotoxicity; use with care in patients with liver or renal disease

Calcium and vitamin D supplements

All patients with systemic lupus erythematosus who are on corticosteroids or who have arthritis are at increased risk for osteopenia and its complications. Diet and appropriate supplementation with vitamin D and calcium are important tools for bone health in these patients.

Calcium carbonate (Oystercal, Caltrate)

Used as an antacid and for the prevention of calcium depletion. Calcium carbonate 1 g = 400 mg elemental calcium.

Dosing

Adult

800-1200 mg (as elemental Ca)/d PO

Pediatric

Doses are expressed as elemental calcium
<6 months: 360 mg/d PO
6-12 months: 540 mg/d PO
1-10 years: 800 mg/d PO
11-18 years: 1200 mg/d PO

Interactions

Use with caution in patients using digitalis; may antagonize effects of calcium channel blockers; decreases bioavailability of tetracyclines, fluoroquinolones, iron salts, salicylates

Contraindications

Hypercalcemia; renal calculi; ventricular fibrillation; risk of digitalis toxicity; renal or cardiac disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use with caution in patients with renal disease, cardiac disease, or sarcoidosis

Calcifediol (Calderol)

25-Hydroxycholecalciferol. Vitamin D regulates calcium homeostasis, promoting absorption of calcium by the gut, resorption of calcium by the kidney, and increasing bone mineral metabolism.

Dosing

Adult

20-100 mcg/d PO; titrate to obtain reference range serum calcium and phosphorus levels

Pediatric

Not established, limited data suggest:
<30 kilograms: 20 mcg PO 3 times/wk
>30 kilograms: 50 mcg PO 3 times/wk

Interactions

Effects enhanced by thiazide diuretics and reduced by cholestyramine and colestipol; may precipitate arrhythmia in conjunction with digitalis

Contraindications

Documented hypersensitivity; hypercalcemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Calcium-phosphorus product (serum calcium X serum phosphorus) must not exceed 70; avoid hypercalcemia

Nonsteroidal anti-inflammatory drugs (NSAIDs)

A child who presents with mild disease with no evidence of nephritis, hypocomplementemia, and elevated anti–double-stranded DNA antibodies is treated symptomatically and is monitored closely for signs of disease progression. Arthritis is treated with NSAIDs. Select a specific agent based on patient response to medication, history of previous drug allergy or reaction, and ease of use.

Administer NSAIDs with caution in any patient with renal or liver disease and avoid administering NSAIDs during pregnancy. NSAIDs have various adverse effects that should be monitored, including gastritis, bone marrow suppression, hepatitis, interstitial nephritis, and CNS changes. Occasionally, a patient with systemic lupus erythematosus has a hypersensitivity reaction to NSAIDs, most often characterized as hepatotoxicity, but the reaction can include other symptoms and must be kept in mind.

Naproxen (Aleve, Naprelan, Naprosyn)

Used for analgesic and anti-inflammatory properties to treat arthralgia and arthritis. Available with slightly different safety and efficacy profiles.
Inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis. Available in SR formulation (Naprelan) for once daily dosing.

Dosing

Adult

500-1000 mg/d PO divided bid

Pediatric

7-20 mg/kg/d PO divided bid/tid; not to exceed adult dose

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; gastritis; hepatic or renal insufficiency; coagulopathy; other conditions in which changes in platelet function could be harmful

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Pregnancy category D in third trimester; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Tolmetin (Tolectin)

Used for their analgesic and anti-inflammatory properties treating arthralgia and arthritis. Available with slightly different safety and efficacy profiles.
Inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.

Dosing

Adult

1200-1800 mg/d PO divided tid

Pediatric

15-30 mg/kg/d PO divided tid/qid; not to exceed adult dose

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; closely monitor PT (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; gastritis; hepatic or renal insufficiency; coagulopathy; other conditions in which changes in platelet function could be harmful

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Pregnancy category D in third trimester; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Diclofenac (Voltaren, Cataflam)

Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclo-oxygenase, which, in turn, decreases formation of prostaglandin precursors. Also available in SR formulation (Voltaren-XR [100 mg]) that allows once or twice daily dosing.

Dosing

Adult

100-200 mg/d PO divided bid

Pediatric

<12 years: Not recommended
>12 years: 2-3 mg/kg/d PO divided bid; not to exceed adult dose

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; gastritis; hepatic or renal insufficiency; coagulopathy; other conditions in which changes in platelet function could be harmful

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Pregnancy category D in third trimester; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; low WBC counts occur rarely and usually return to normal in ongoing therapy; discontinuation of therapy may be necessary if persistent leukopenia, granulocytopenia, or thrombocytopenia occurs

Monoclonal Antibody

This agent is used investigationally for systemic lupus erythematosus.

Rituxamab (Rituxan)

An anti-CD20 monoclonal antibody. Originally used to treat B-cell lymphoma, the monoclonal antibody is now used to treat persisting immune thrombocytopenia in children and rheumatoid arthritis. Use in SLE is investigational.

Dosing

Adult

375 mg/m2 IV qwk for 3-8 wk; infuse at initial rate of 50 mg/h, if tolerated may escalate by 50 mg/h q30min, not to exceed 400 mg/h
Premedication with IV corticosteroids is recommended

Pediatric

Not established, limited data available; off-label use, administer as in adults

Interactions

Coadministration with cisplatin is known to cause severe renal toxicity including acute renal failure; may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 months of vaccine)

Contraindications

Documented hypersensitivity; IgE-mediated reaction to murine proteins; breastfeeding

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution with dormant infections such as hepatitis B, hepatitis C, or CMV due to risk of reactivation; caution with abnormal cardiac, pulmonary, or renal function; hypotension, bronchospasm, and angioedema may occur, premedication with acetaminophen and diphenhydramine may decrease incidence; discontinue treatment if life-threatening cardiac arrhythmias occur; must administer by slow IV infusion, do not administer IV push or bolus

Follow-up

Further Inpatient Care

• Further inpatient care in patients with systemic lupus erythematosus (SLE) is required for severe hematologic, nephrologic, neurologic, or psychiatric disease or for complications from these (eg, severe anemia, renal failure, stroke, seizure), including the use of intravenous high-dose corticosteroids or chemotherapy as required.
• Hospitalization may also be required for severe hypertension.
• Inpatient care is appropriate for the patient with unexplained fever to provide sepsis evaluation and treatment, as well as to evaluate the patient for disease flare and to treat accordingly.

Further Outpatient Care

• Patients with systemic lupus erythematosus have a chronic, often persistent, disease and require constant monitoring of disease activity and modification of medical regimen according to fluctuations in disease status.

Inpatient & Outpatient Medications

• See Medication.

Transfer

• Consider transfer to a tertiary care facility for all children with systemic lupus erythematosus.

Deterrence/Prevention

• Disease flares lead to poor outcome because of re-injury to vital organs. A poor outcome can be prevented with meticulous medical surveillance and attention to the chronic nature of the disease. Patient and family education is extremely important in this regard.
• Some flares are the result of excessive sun exposure. These can be avoided using sun protection.

Complications

• Systemic lupus erythematosus is a high-risk disease with the possibility of end-organ damage to any vital or nonvital organ. This damage can severely affect organ function and can lead to decreased quality of life.
• Treatment of systemic lupus erythematosus is also fraught with potential complications from steroid adverse effects, infection from immunosuppression, and cardiovascular disease leading to early myocardial infarction.
• Pregnancy can also complicate systemic lupus erythematosus. Pregnancy increases the risk of renal disease, thrombophlebitis, and disease flare. The infant is at risk for being small for gestational age (SGA) and for neonatal lupus.

Prognosis

• Current mortality figures suggest that patients have a 95% rate of survival at 5 years. Some clinicians report a 98-100% survival rate at 5 years. These figures depend on disease severity and compliance with therapy.
• Mortality rates rise over time, with the major causes of death being infection, nephritis, CNS disease, pulmonary hemorrhage, and myocardial infarction. One indicator of morbidity and mortality risk is frequency of emergency department visits.

Patient Education

• The patient and family must have a thorough understanding of the disease, potential severity, and complications of the disease and therapy.
• Treatment is difficult, especially for adolescent patients. The physician and parents should expect issues, including depression and noncompliance, to arise. The best method for deterrence is to thoroughly educate the patient and family through discussion, support groups, and literature.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Muscle Disorders Center. Also, see eMedicine's patient education articles, Lupus (Systemic Lupus Erythematosus), Chronic Fatigue Syndrome, and Chronic Pain.

Miscellaneous

Medicolegal Pitfalls

• Review disease and medication risks carefully with the patient and family prior to treatment with any new medication.
• Review the risks of discontinuing therapy and noncompliance with the patient and family.
• Review diagnosis and prognosis of any new organ manifestations with patient and family.

Special Concerns

• Educate all patients with systemic lupus erythematosus (SLE) with regard to the serious complications possible from unplanned pregnancy, poor compliance, recreational drug use, and infection, including sexually transmitted diseases (STDs). Poor compliance, in particular, is a significant prognostic factor.

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Keywords

systemic lupus erythematosus, lupus, SLE, lupus erythematosus, LE, fevers of unknown origin, arthralgia, anemia, nephritis, psychosis, fatigue, rheumatic disease, atherosclerosis, hemolytic anemia, thrombocytopenia, leukopenia, lymphopenia, nephritis, nephrotic syndrome, serositis, arthritis, memory loss, psychosis, transverse myelitis, hemoptysis, edema of the lower extremities, headache, painful mouth sores, pleuritis, pericarditis, livedo reticularis, alopecia, Raynaud phenomenon, tendonitis, myositis, lymphadenopathy, hepatosplenomegaly, stroke, pseudotumor cerebri, cerebral venous thrombosis, aseptic meningitis, chorea, global cognitive deficits, mood disorders, transverse myelitis, hyperthyroidism

Contributor Information and Disclosures

Author

Marisa S Klein-Gitelman, MD, MPH, Associate Professor of Pediatrics, Northwestern University Feinberg School of Medicine; Head, Division of Rheumatology, Children's Memorial Hospital
Marisa S Klein-Gitelman, MD, MPH is a member of the following medical societies: American College of Rheumatology
Disclosure: Nothing to disclose.

Medical Editor

Barry L Myones, MD, Associate Professor, Departments of Pediatrics and Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital
Barry L Myones, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American College of Rheumatology, American Heart Association, American Society for Microbiology, Clinical Immunology Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Thomas JA Lehman, MD, FAAP, FACR, Clinical Professor of Pediatrics, Department of Pediatrics, Division of Pediatric Rheumatology, Weill-Cornell University; Chief, Hospital for Special Surgery
Thomas JA Lehman, MD, FAAP, FACR is a member of the following medical societies: PM American Allergy Society
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting; Pfizer Honoraria Consulting

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; Merck, Amgen, Biogen, Zimmer, Wyeth, Johnson&Johnson, Stryker, Medtronic, Zimmer.Abbott,  Ownership interest Other; West Penn Allegheny Health System Consulting fee Consulting; Alpharma Honoraria Consulting; Proctor&Gamble Grant/research funds Independent contractor

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