The first written description of lupus is dated to the 13th century. Rogerius named the disease using the Latin word for wolf because the cutaneous manifestations he described appeared similar to a wolf bite. Osler was the first physician who recognized that systemic features of the disease could occur without skin involvement. Diagnosis was made easier by the discovery of 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 by corticosteroids improved treatment. The substantial side effects of corticosteroids have lead to a strategy of using immunosuppressive drugs to minimize the need for corticosteroids leading to an improved 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.

Pathophysiology: Within the healthy population, a subset of individuals exists who have small amounts of low titer antinuclear antibody (ANA) or other autoantibody. In lupus, much greater production of autoantibodies leads to immune complex formation and tissue damage due to direct binding and/or immune complex deposition in tissues. It is unclear 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. Patients with SLE make antibodies against DNA, other nuclear antigens, ribosomes, platelets, erythrocytes, leukocytes, and other tissue specific antigens. Thus, 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. Immune complex disease in the kidney may manifest as 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 uncertain.

Pulmonary disease is manifested by pulmonary hemorrhage, fibrosis, or infarct. A variety of rashes, GI manifestations, serositis, arthritis, endocrinopathies, and cardiac abnormalities, including endocarditis, exist. No organ is immune from the effects of this multisystem disease. Yet the clinical presentation in any given patient may be highly varied. How the clinical manifestations depend on the underlying specific immunologic disarray in a particular patient remains to be determined.

Frequency:

• In the US: Incidence of this disease varies by location and ethnicity. Incidence rates among children under 15 years of age have been reported to be between 0.5 and 0.6 per 100,000 persons. Prevalence rates of 4-250 per 100,000 persons have been measured with greater prevalence in Native American, Asian, Latin American, and African American patients. In one study of adults the incidence in African American females was estimated at 1 in 500.

Mortality/Morbidity: The 5-year survival rate for children with SLE is more than 90%. Most deaths of children with SLE are the result of infection, nephritis, renal failure, CNS disease, or pulmonary hemorrhage. Myocardial infarction may occur in the young adult years as a complication of chronic corticosteroid use.

Race: Prevalence rates are higher in Native American, Asian, Latin American, and African American patients.

Sex: Prevalence rates are higher in females than in males. A female-to-male ratio of approximately 2:1 occurs before puberty, and a ratio of 4:1 occurs after puberty.

History: The most frequent presenting symptoms of SLE are prolonged fever and malaise with evidence of multisystem involvement. The children often present with a history of fatigue, joint pain, rash, and fever. However, children may present with a variety of acute complaints, including memory loss, psychosis, transverse myelitis, hemoptysis, edema of the lower extremities, headache, and painful mouth sores. There are 11 criteria 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, ANA is almost always present. Diagnosis is not difficult in the child who presents with many manifestations, such as malar rash, pleuritic chest pain, nephritis, and a positive ANA. Some patients present over longer periods and require careful consideration. Occasionally, a definite diagnosis never develops or the patient may have an overlap syndrome with manifestations of several rheumatic diseases.

Diagnostic criteria for SLE include the following:

• Mucocutaneous

• Malar rash

• Naso-oral ulcers

• Photosensitivity 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

• Positive anti–double-stranded DNA, anti-Smith or antiphospholipid antibody

Physical: A detailed physical examination is a critical tool in the diagnosis of SLE. Most of the American College of Rheumatology diagnostic criteria are associated with physical findings. The following is a description of more common clinical manifestations:

• Mucocutaneous findings

• Rash occurs in 70-80% of patients. The characteristic rash is a malar or butterfly rash, including both cheeks and the nasal bridge. The rash varies from an erythematous blush to thickened epidermis to a scaly rash.

• Other diagnostic skin findings include discoid rash, which is rare in childhood, a photosensitive rash, and mucus membrane changes 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 often is associated with antiphospholipid antibodies; alopecia, which usually is 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 Jaccoud-like 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 SLE over time. It occurs both in children with SLE alone and in children receiving corticosteroids for conditions other than SLE, but is much more common in children with SLE who are receiving corticosteroids.

• Abdominal findings

• 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 corticosteroids and SLE.

• Hepatitis on 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 due to myocarditis or infarction. Pulmonary auscultatory findings may be abnormal secondary to pleuritis, infiltrates, or hemorrhage.

• Neurologic manifestations can include both the central and peripheral nervous system.

• 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.

• Up to 40% of children may have CNS disease and perhaps even more when considering psychiatric manifestations, which can be associated with antiribosomal P antibodies and cognitive abnormalities. Quantification 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 observed more frequently in children than in adults.

• Lupus patients may present with the clinical findings of endocrine disease, such as hyperthyroidism and Addisonian crisis.

Causes: The specific causes of SLE 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 exists who have small amounts of autoantibody as manifested by a low titer ANA or other autoantibody. In lupus, much greater production of autoantibodies leads to immune complex formation and tissue damage due to direct binding and/or immune complex deposition in tissues. There is evidence of 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 by-product of polyclonal B-cell activation in which many more B lymphocytes are activated perhaps not in response to specific antigenic stimuli.

• 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 where PCR failed to isolate specific viruses, such as Epstein-Barr 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.

• 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 the persistence of cells with the potential for self-reactivity 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 also have 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 itself as lupus.

• Other immunologic mechanisms also may 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 also may 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. Athreya et al found that lupus patients did not have different serum levels of estrogen and prolactin when compared to controls; however, free androgen was lower, while follicle stimulating hormone (FSH) and luteinizing hormone (LH) were higher in postpubertal boys and girls with SLE.

• Drugs, such as anticonvulsants and antiarrhythmic agents, also can 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.

Lab Studies:

• Initial laboratory evaluation should include a CBC with platelets and reticulocyte count; a complete chemistry panel to evaluate electrolytes, liver, and kidney function; a urine analysis; and a measure of acute phase reactants (eg, erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]).

• Diagnostic laboratory studies include ANA, anti–double-stranded DNA, anti-Smith antibody, and antiphospholipid antibodies.

• 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.

• Besides anti–double-stranded DNA, complement levels, including total hemolytic complement, C3 and C4, are a marker of disease activity and found to be low in many types of active disease.

• Quantitative immunoglobulins are useful as patients with lupus often have hypergammaglobulinemia and have a higher incidence on immunodeficiency.

• Other autoantibodies obtained should be guided by clinical and laboratory manifestations, such as petechiae, anemia, coagulopathy, cerebritis, and thyroid abnormalities.

Imaging Studies:
 

• Obtain a chest radiograph and echocardiography.

• Other imaging studies should be guided by clinical manifestations and may include the following:

• MRI of the brain

• Renal ultrasound

• Nuclear medicine evaluation for renal function,

• High resolution CT to evaluate for pulmonary fibrosis

• Dual-energy x-ray absorptiometry (DXA) to evaluate bone density

Other Tests:
 

• Obtain pulmonary function tests, including diffusing capacity of the lung for carbon monoxide (DLCO) to evaluate baseline pulmonary disease.

Procedures:
 

• The most common procedure in the diagnostic evaluation of SLE is a tissue biopsy to confirm diagnosis and to evaluate disease severity. This is particularly useful in evaluating the severity of renal involvement.

• Although skin biopsy is frequently used for diagnostic purposes when the diagnosis is not clear, lesional and sun-exposed skin may show positive immunofluorescence. Skin biopsy is rarely necessary to make the diagnosis of SLE.

• 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 (sub-epithelial, sub-endothelial, or 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. 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, while class IIB is associated with a 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 the majority of glomeruli demonstrating cellular proliferation of epithelial, endothelial and mesangial cells with cellular or fibrous crescent formation and is associated with an increased risk of end-stage renal disease. Class V disease is defined as a membranous process with significant proteinuria, which often is 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 determine treatment options. Kidney disease is classified as described in Histologic Findings. Staging not only for WHO histologic class but also acuity and chronicity of renal histologic manifestations is important in determining

Medical Care: The most important tool in the medical care of the patient with 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. Lupus is a lifelong illness and patients must be monitored indefinitely. Specific medical interventions are listed below.

Surgical Care: The need for surgical care is dependent on the severity of organ involvement and the need for tissue diagnosis. Under normal conditions SLE is not a surgical condition. If for any reason surgery is necessary, monitor the patient closely 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 nephrology 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 as they may alter metabolism of more traditional medications, such as coumadin, 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.

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 exists. 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 in similar conditions.

The most important management tool in the treatment of SLE is meticulous and frequent reevaluation of patients. Reevaluation includes clinical and laboratory evaluation, allowing prompt recognition and treatment of disease flare that is essential to patient outcome.
 

Drug Category: Antimalarials -- Rash and other minor symptoms can be treated with hydroxychloroquine 3-7 mg/kg/d, usually no more than 400 mg/d PO. Evidence indicates that long-term use of antimalarials is steroid sparing. Chronic 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.

Drug Category: Corticosteroids -- 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 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 IV 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 then switched to alternate-day prednisone.

Alternatively, the patient may be treated with IV pulse methylprednisolone therapy (3 d of high-dose IV corticosteroids) and then switched to intermittent high-dose IV corticosteroids with lower daily prednisone 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.

Drug Category: 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. 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, 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.

Drug Category: Antihypertensive agents -- Treat hypertension aggressively. If hypertension is a consequence of steroid therapy, consider immunomodulating medications as steroid-sparing agents to help control hypertension.

Drug Category: Calcium and vitamin D therapy -- 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.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs) -- The 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 a variety of adverse effects, which should be monitored, including gastritis, bone marrow suppression, hepatitis, interstitial nephritis, and CNS changes. Occasionally, the patient with SLE has a hypersensitivity reaction to NSAIDS, most often characterized as a hepatotoxicity, but the reaction can include other symptoms and must be kept in mind.

Further Inpatient Care:

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

Further Outpatient Care:

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