Pediatric Systemic Lupus Erythematosus

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 ̶ deoxyribonucleic acid (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 SLE’s mechanisms and the importance of immunosuppressive therapy.

The use of adrenocorticotropic hormone (ACTH) in the 1950s resulted in amelioration of disease manifestations. The replacement of ACTH using corticosteroids improved treatment, with improvement in 5-year survival from 5% to 70%. 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, mycophenolate, and cyclophosphamide, has greatly improved kidney organ survival and outcome. (See Treatment and Medications.)

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. Strategies using genomics and proteomics give hope for identification of biomarkers that can be used for early disease detection and treatment.[2]

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. (See the diagram below.)

Within the healthy population, a subset of individuals has small amounts of low-titer antinuclear antibody (ANA) or other autoantibody such as anti-Ro(SSA), anti-La(SSB), or antithyroid antibodies. In lupus, increased production of specific autoantibodies (anti-dsDNA, anti-RNP, and anti-Smith antibodies) leads to immune complex formation and tissue damage from direct binding in tissues, immune complex deposition in tissues, or both.

Evidence suggests that people with systemic lupus erythematosus (SLE) have antigen-specific antibody responses to DNA, other nuclear antigens, ribosomes, platelets, erythrocytes, leukocytes, and tissue-specific antigens. The resulting immune complexes cause widespread tissue damage. Cell-mediated autoimmune responses also play a pathophysiologic role.

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 demonstrated a high percentage of mature naive B cells (25-50% vs 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 virallike particles in lymphocytes in patients with lupus led to the theory that viral infection causes polyclonal activation in lupus. However, these particles may simply be breakdown products of intracellular materials. This assumption was supported by evidence in which specific viruses, such as Epstein-Barr virus and cytomegalovirus, in lupus white blood cells (WBCs), were not isolated in polymerase chain reaction (PCR) assay. Thus, positive titers to infectious agents in patients with lupus may be another manifestation of nonspecific polyclonal activation of B cells, an important point during initial evaluation and diagnosis. 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, subsequent 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.

Over the past 15 years, studies of lupus have implicated the importance of innate immunity. Plasmacytoid dendritic cells are decreased in the blood of lupus patients but are found in high concentration at sites of inflammation such as the kidney and skin, secreting alpha-interferons.[4] The presence of high concentrations of interferon in the sera of lupus patients was originally described by Lars Ronnblom and was a seminal observation of lupus pathophysiologic mechanisms.[5]

Plasmacytoid dendritic cells endocytose immune complexes and nucleic debris through the Fc gamma-receptor IIa, activating toll-like receptors 7 and 9 and triggering production of interferon-alpha and other proinflammatory cytokines. The excess necrotic and apoptotic materials are due to ultraviolet damage, viral infection, and genetic differences, some of which are listed below and which include impaired clearance of these materials. Necrotic materials are also due to neutrophil responses to infection. Neutrophils can extrude their nuclear materials to form neutrophil extracellular traps or NETosis, immobilizing bacteria and fungi. NETosis triggers an interferon signal and plasmacytoid dendritic cell activation that can induce lupus.[6]

Other immunologic mechanisms may also be important, including defects in macrophage phagocytic activity or handling of immune complexes. In addition, deficiencies of complement components, including C4, C2, and C1q, have been associated with lupus, likely due to 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, in association with dyslipoproteinemia, lead to significant vascular complications.

The predominance of lupus in females suggests sex hormones may play a role in autoimmune diseases. Research found that patients with lupus did not have different serum levels of estrogen and prolactin than did controls; however, free androgen was lower, whereas follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were higher in postpubertal boys and girls with SLE.

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.

Genetic susceptibility

The use of microarray technology to detect candidate susceptibility genes has led to the identification of several potential gene-risk candidates, including the P-selectin gene (SELP), the interleukin-1 receptor-associated kinase 1 gene (IRAK1), PTPN22, and the interleukin-16, protein tyrosine phosphatase receptor type T, toll-like receptor (TLR) 8, and CASP 10 genes.[7, 8, 9]

Enhanced Toll-like receptor 7 (TLR7) signaling has been suggested as a mechanism of systemic autoimmune disease. Brown et al identified a previously undescribed single-point missense gain-of-function TLR7 mutation, TLR7Y264H, in a child with severe SLE and subsequently found it in other patients with severe SLE. When introduced into mice, the TLR7Y264H variant caused lupus.[10]

In the United States, the incidence of systemic lupus erythematosus (SLE) varies by location and ethnicity. Incidence rates among children younger than age 15 years have been reported to be 0.5-0.6 case per 100,000 persons. Prevalence rates of 4-250 cases per 100,000 persons have been reported, with greater prevalence in Native Americans, Asian Americans, Latin Americans, and African Americans. In one study of adults, the incidence of lupus in African American females was estimated at 1 in 500. African American children may represent up to 60% of patients younger than 20 years with lupus. In the pediatric population, just under 60% of cases are seen in patients of African American ethnicity. However, lupus does occur in persons of every ethnic and racial background.

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

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, SLE remains uncommon in children younger than age 8 years.

Systemic lupus erythematosus (SLE) 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.

In addition, the treatment of SLE is fraught with potential complications from the adverse effects of steroids, infection from immunosuppression and poorly controlled disease, and cardiovascular disease leading to early myocardial infarction.

Pregnancy can also complicate SLE, increasing 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.

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, central nervous system (CNS) disease, pulmonary hemorrhage, and myocardial infarction. One indicator of morbidity and mortality risk is frequency of emergency department visits.

A study by Rees et al that estimated SLE mortality from 1999-2012 reported that young people with SLE had the greatest relative risk of death. The mortality rate ratio was 3.81 (95% CI 1.43, 10.14) in those under 40 years of age compared to the control group.[11]

The 5-year survival rate for children with SLE is more than 90%. Most deaths in children with SLE 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.

Complications

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.

A study by Giani et in the United Kingdom found that 25% of patients with juvenile-onset SLE had neuropsychiatric involvement within 5 years of diagnosis. The most common neurologic manifestations were headaches, mood disorders, cognitive impairment, anxiety, seizures, movement disorders, and cerebrovascular disease.[12]

Pulmonary disease manifests as pulmonary hemorrhage, fibrosis, or infarct. Various rashes, gastrointestinal (GI) manifestations, serositis, arthritis, endocrinopathies, and cardiac abnormalities (eg, valvulitis and carditis) 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 and is the focus of intense study.

The patient and his or her family must have a thorough understanding of systemic lupus erythematosus (SLE), its potential severity, and the complications of the disease and its 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.

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

For patient education information, see Lupus (Systemic Lupus Erythematosus), Chronic Fatigue Syndrome (CFS), and Chronic Pain.

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 also present with various acute symptoms, including memory loss, psychosis, transverse myelitis, hemoptysis, edema of the lower extremities, headache, and painful mouth sores.

Eleven criteria from the American College of Rheumatology (ACR) are used for the classification of lupus in adults.[13] The same criteria can serve as a guideline in children. Any 4 criteria are sufficient for classificantion and should be sought in the history. (Of note, ANA is almost always present but is not diagnostic.)

The ACR’s diagnostic criteria for SLE include the following:

• Malar rash

• Naso-oral ulcers

• Photosensitive rash

• Discoid rash

• Arthritis

• Pleuritis or pericarditis

• Proteinuria (>500 mg/d) or evidence of nephritis in urinalysis

• Hemolytic anemia, thrombocytopenia, leukopenia, or lymphopenia

• Seizure or psychosis

• Positive ANA finding

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

The Systemic Lupus International Collaborative Clinics recently published a modification of the ACR criteria.[14] Lupus patients meet 4 criteria with at least one clinical and one immunologic criterion or with biopsy-proven nephritis in association with positive ANA and anti-dsDNA. These criteria were thought to improve clinical relevance and specificity of criteria, as well as incorporate current understanding of lupus immunology.

Clinical criteria

1. Acute cutaneous lupus including the following:

• Lupus malar rash (do not count if malar discoid)

• Bullous lupus

• Toxic epidermal necrolysis variant of SLE

• Maculopapular lupus rash

• Photosensitive lupus rash (in the absence of dermatomyositis)

OR subacute cutaneous lupus (nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory dyspigmentation or telangiectasias

2. Chronic cutaneous lupus including the following:

• Classic discoid rash

• Localized (above the neck)

• Generalized (above and below the neck)

• Hypertrophic (verrucous) lupus

• Lupus panniculitis (profundus)

• Mucosal lupus

• Lupus erythematosus tumidus

• Chilblains lupus

• Discoid lupus/lichen planus overlap

3. Oral ulcers in the absence of other causes such as vasculitis, Behçet disease, herpesviruses, inflammatory bowel disease, reactive arthritis, or acidic foods

• Palate

• Buccal

• Tongue

• Nasal

4. Nonscarring alopecia (diffuse thinning or hair fragility with visible broken hairs) in the absence of other causes such as alopecia areata, drugs, iron deficiency, or androgenic alopecia

5. Synovitis involving 2 or more joints, characterized by swelling or effusion OR tenderness in 2 or more joints and at least 30 minutes of morning stiffness

6. Serositis in the absence of other causes such as infection, uremia, and Dressler pericarditis

• Typical pleurisy for more than 1 day

• OR pleural effusions

• OR pleural rub

• Typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day

• OR pericardial effusions

• OR pericardial rub

• OR pericarditis by electrocardiography

7. Renal, as follows:

• Urine-to-creatinine ratio (or 24-hour urine protein) representing 500 mg protein/24 hours

• OR red blood cell casts

8. Neurologic, as follows:

• Seizures

• Psychosis

• Mononeuritis multiplex in the absence of other known causes such as primary vasculitis

• Myelitis

• Peripheral or cranial neuropathy in the absence of other known causes such as primary vasculitis, infection, and diabetes mellitus

• Acute confusional state in the absence of other causes, including toxic/metabolic/uremia/drugs

9. Hemolytic anemia

10. Leukopenia (< 4,000/µL at least once) in the absence of other known causes such as Felty syndrome, drugs, or portal hypertension

OR lymphopenia (< 1,000/µL at least once) in the absence of other known causes such as corticosteroids, drugs, or infection

11. Thrombocytopenia (< 100,000/µL) at least once in the absence of other known causes such as drugs, portal hypertension, or thrombotic thrombocytopenic purpura

Immunologic criteria

1. ANA level above laboratory reference range

2. Anti-dsDNA antibody level above laboratory reference range (or >2-fold the reference range if tested by enzyme-linked immunosorbent assay [ELISA])

3. Anti-Sm: Presence of antibody to Sm nuclear antigen

4. Antiphospholipid antibody positivity as determined by any of the following

• Positive test result for lupus anticoagulant

• False-positive test result for rapid plasma reagin

• Medium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM)

• Positive test result for anti-B2-glycoprotein I (IgA, IgG, or IgM)

5. Low complement, as follows:

• Low C3

• Low C4

• Low CH50

6. Direct Coombs test in the absence of hemolytic anemia

Patients should be evaluated for traditional risk factors of atherosclerosis, including smoking history, family history of atherosclerosis, and physical activity. Risks should be stratified and treated.

The diagnosis of SLE is not difficult in a 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 classification 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.

A detailed physical examination is a critical tool in the diagnosis of systemic lupus erythematosus (SLE). Most of the ACR classification criteria are associated with physical findings.[13] The following is a description of more common clinical manifestations.

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 a thickened epidermis to a scaly rash. (See the image below.)

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, a rare but potentially life-threatening condition as bullae can cover large surfaces and oral mucosa, with loss or skin integrity and compromise of the airway. 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.

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 SLE over time. It is most common in children with SLE who are receiving daily corticosteroids, although it can also occur in children with SLE who are not being treated with corticosteroids and in children receiving corticosteroids for conditions other than SLE.

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 be a result of treatment with corticosteroids or from the SLE itself. Other abdominal findings can include pain secondary to peritoneal serositis or small-vessel vasculitis. The latter can be associated with severe bleeding and necrosis of tissue and is clearly life threatening.

Cardiac involvement includes pericarditis, murmurs associated with valvulitis, carditis, and cardiac failure from myocarditis or infarction. Pulmonary auscultatory findings may be abnormal secondary to pleuritis, infiltrates, or hemorrhage.

Neurologic manifestations can involve the central and the peripheral nervous systems. Clinical findings associated with classification criteria 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 psychiatric manifestations and cognitive abnormalities are considered. 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.

The initial laboratory evaluation should include a complete blood count (CBC) with platelets and reticulocyte count; a 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 ANA, anti–double-stranded DNA, anti-Smith antibody, lupus anticoagulant, and antiphospholipid antibody panel.[15] 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. Initial assessment of quantitative immunoglobulins is useful, because patients with lupus often have hypergammaglobulinemia and have a higher incidence of immunodeficiency, including immunoglobulin A deficiency and other antibody defects. 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 for atherosclerosis, with the patient’s fasting lipid profile, homocysteine level, fasting glucose level, and body mass index obtained. Risks should be stratified and treated. Hepatitis demonstrated by laboratory evaluation is not uncommon.

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.

Cognitive function testing should be considered in patients with systemic lupus erythematosus (SLE), particularly if changes in behavior or school function are observed. Testing should include academics, executive function, attention, and memory. Recently, a set of tests has been established by consensus criteria as a screening evaluation.[16]

The Pediatric Automated Neuropsychological Assessment Metrics, a computer-based neuropsychological evaluation tool, has been initially validated in children diagnosed with SLE.[17] However, further testing is needed to determine its sensitivity and specificity to change in clinical status.

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. Currently there is ongoing work to define disease flare and remission criteria both for systemic disease and lupus nephritis in children.[18]

Obtain chest radiographs and electrocardiograms. Other imaging studies should be guided by clinical manifestations and may include the following:

• Magnetic resonance imaging (MRI) of the brain - However, many patients with central nervous system (CNS) lupus do not have MRI abnormalities or have nonspecific bright areas that do not correlate with clinical observations of CNS deficits

• Renal ultrasonography

• Nuclear medicine evaluation for renal function

• High-resolution computer tomography (CT) scanning to diagnose and evaluate for pulmonary fibrosis

• Dual-energy radiographic absorptiometry to evaluate bone density

• Angiography (usually MR or CT) to assess for thrombi for lupus-related antiphospholipid syndrome (APS)

The most common procedure used in the diagnostic evaluation of systemic lupus erythematosus (SLE) is a tissue biopsy to confirm the diagnosis and to evaluate disease severity. This is particularly useful in evaluating the severity of renal involvement.[19]

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. However, 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.

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. The location of immune complexes (ie, subepithelial, subendothelial, intramembranous) is also important in prognosis.

Renal biopsy findings are classified according to the World Health Organization (WHO) classification and correlate with clinical morbidity and mortality.[20] Staging for WHO histologic class and for acuity and chronicity of renal histologic manifestations is important in determining optimal therapy.

Patients may have combinations of the following classifications on biopsy findings, and all types should be reported:

• Class I - Defined by normal findings on light microscopy, immunofluorescence, and electron microscopy

• Class IIA disease - Has minimal mesangial deposits and a good prognosis

• Class IIB disease - Associated with lymphocytic infiltration and a variable prognosis

• Class III disease - Characterized by focal, segmental, proliferative mesangial changes and is associated with chronic renal disease; it is subtyped into (1) active necrotizing lesions, (2) active sclerosing lesions, and (3) sclerosing lesions

• Class IV disease - 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; this stage is subtyped into (1) without segmental lesions, (2) with active necrotizing lesions, (3) with active sclerosing lesions, and (4) sclerosing lesions

• Class V disease - Defined as a membranous process with significant proteinuria, which is often poorly responsive to treatment; this is subdivided into (1) pure membranous lesions, (2) associated with lesions of Class II, (3) associated with lesions of Class III, and (4) associated with lesions of Class IV

• Class VI disease - Advanced sclerosing glomerulonephritis (≥90% global sclerosis without activity)

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 patient’s 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.

Consideration should be given to the prevention of atherosclerosis and osteoporosis, because these are long-term consequences of SLE and its treatment. Moreover, studies have brought attention to the need for the preservation of gonadal function when gonadotoxic therapies are used to treat severe disease.

Recently, consensus treatment plans have been published for pediatric lupus proliferative nephritis class III and IV. These consensus treatment plans are currently being studied in a comparative effectiveness trial.[21, 22]

Newer biologic therapies are looming as potential treatments for lupus, including belimumab, a B-cell directed therapy,[23]  which was approved for use in adult lupus in 2011.[24]  Belimumab was approved for children with SLE in April 2019. 

Belimumab is the first drug approved for pediatric SLE. Belimumab is a B-lymphocyte stimulator (BLyS)-specific inhibitor. BLyS is a naturally occurring protein required for survival and development of B-lymphocyte cells into mature plasma B cells that produce antibodies. In autoimmune diseases, elevated BLyS levels are thought to contribute to production of autoantibodies.

The FDA approval for belimumab for pediatric SLE was based on the PLUTO phase 2 study (n=93). Patient received standard therapy plus belimumab IV or placebo every 4 weeks. The primary endpoint was the SLE Responder Index 4 (SRI4). At 52 weeks, more patients treated with belimumab had responded compared with placebo. Severe flares were 62% less frequent with belimumab. Median time to first severe flare was 159.5 day with belimumab compared with 82 days for placebo.[25]

Others include T-cell–directed therapies, anticomplement therapies, anticytokine therapies, and peptide manipulation to promote tolerance. Stem cell transplantation and high-dose immunoablative therapies are also being studied, but it is unclear whether these therapies confer an advantage. The most recent therapies under trial are monoclonal antibodies directed again interferon-alpha, which are in phase I and II clinical trials, while plasmacytoid dendritic cell inhibitors are in development and in phase I trials.

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

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.

Deterrence/prevention

Disease flares lead to poor outcome because of reinjury 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. (Fluorescent lights may also cause increased rash in patients with SLE.)

Consultations

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

Patient transfer

Consider transfer to a tertiary care facility for all children with SLE.

Dietary restrictions are driven by the patient’s medical therapy. Most patients require a course of corticosteroids and should be on a no-added-salt, low-fat, 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.

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 (IV) 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 him or her accordingly.

The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative made the following recommendations for each class of childhood-onset lupus nephritis based on the International Society of Nephrology/Renal Pathology Society 2003 classification system.[26]

• Class I: Treatment should be guided by other symptoms.

• Class II: Should be treated initially with low-dose prednisone, a disease-modifying antirheumatic drug should only be added after three months of persistent proteinuria or prednisone dependency.

• Class III/IV: Treatment with mycophenolate mofetil (MMF) or intravenous cyclophosphamide combined with corticosteroids; maintenance treatment MMF and/or azathioprine for at least three years.

• Class V: MMF with low-dose prednisone can be used as induction, MMF as maintenance treatment.

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, while 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.

Belimumab, a B-lymphocyte stimulator (BLyS)-specific inhibitor, is the first drug explicitly developed for pediatric SLE and approved by the FDA. It is indicated for children aged 5 years or older and is administered as an IV infusion.

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 reevaluation of patients. Reevaluation 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 Pediatric Hypertension.)

Class Summary

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 the long-term use of antimalarial drugs is steroid sparing. Hydroxychloroquine may also decrease the risk of thrombotic events. Understanding that antimalarials hinder TLR 7/9 induction of interferon-alpha and tumor necrosis factor underscore the importance of this class of drugs in the treatment of lupus. The 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 the synthesis of DNA, ribonucleic acid (RNA), and proteins by interacting with nucleic acids. Antimalarial drugs have various immunosuppressive effects, can act as antioxidants, and interfere with prostaglandins. Two hundred milligrams of the sulfate salt equals 155 mg of the base.

Class Summary

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 disease with corticosteroids. The dose varies with the intensity of SLE on 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 IV methylprednisolone (30 mg/kg/dose, not to exceed 1 g) on a weekly basis.

Intermittent high-dose IV methylprednisolone is now known to extinguish the interferon signature of systemic lupus for up to 7 days, which oral therapy cannot accomplish, and should be considered for patients with significant disease activity. Patients must be monitored for high blood pressure or arrhythmia, especially if there is heart disease or electrolyte abnormalities.

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 IV pulse methylprednisolone therapy (3 d of high-dose IV corticosteroids) and then switched to intermittent high-dose IV corticosteroids with lower daily prednisone doses, depending on disease severity. Obtain skin testing for tuberculosis (purified protein derivative [PPD]) and candidal infection 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

Prednisone decreases inflammation by suppression of the immune system, which it does by (1) decreasing lymphocyte volume and activity, (2) decreasing polymorphonuclear (PMN) leukocyte migration, and (3) decreasing or reversing capillary permeability. High doses, especially over periods of more than 2-3 weeks, suppress adrenal function.

Methylprednisolone (Solu-Medrol, A-Methapred, Depo-Medrol)

Methylprednisolone decreases inflammation by suppression of the immune system in much the same manner as prednisone, but it has less mineralocorticoid effects. Intravenous high-dose steroids can be given in a hospital setting but also by home health teams.

Class Summary

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 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

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

Mycophenolate (CellCept, Myfortic)

Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, inhibiting their proliferation. It 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.

Azathioprine (Imuran, Azasan)

Azathioprine is an imidazolyl derivative of 6-mercaptopurine. Many of its biological effects are similar to those of its parent compound. Both compounds are eliminated rapidly from blood and are oxidized or methylated in the erythrocytes and liver. No azathioprine or mercaptopurine is detectable in urine 8 hours after it has been taken.

Azathioprine antagonizes purine metabolism and may inhibit the synthesis of proteins, RNA, and DNA. It may interfere with mitosis and cellular metabolism. The mechanism through which azathioprine affects autoimmune diseases unknown. The drug works primarily on T cells. It suppresses hypersensitivities of cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests are suppressed to a greater degree than are antibody responses.

Azathioprine works very slowly; it may require 6-12 months of trial prior to having an effect. Up to 10% of patients may have an idiosyncratic reaction, which results in disallowance of its use. Do not allow the WBC count to drop below 3000/mL or the lymphocyte count to drop below 1000/mL. Azathioprine is available in tablet form for oral administration or in 100-mg vials for IV injection.

Methotrexate (Rheumatrex, Trexall)

Methotrexate is an antimetabolite that binds to dihydrofolate reductase, blocking the reduction of dihydrofolate to tetrahydrofolic acid; depletion of tetrahydrofolic acid leads to depletion of DNA precursors and inhibition of DNA and purine synthesis. This reduces the metabolism of activated T and B cells, reducing the inflammatory response. Adjust the dose gradually to attain a satisfactory response. Consider SC route for patients who do not respond to PO methotrexate or who have GI intolerance to PO dosing.

Cyclosporine (Neoral, Gengraf)

Cyclosporine is an 11-amino acid cyclic peptide and a natural product of fungi. It acts on T-cell replication and activity.

It is a specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in G0 or G1 phase of the cell cycle is suggested.

Cyclosporine binds to cyclophilin, an intracellular protein, which in turn prevents formation of interleukin 2 and the subsequent recruitment of activated T cells.

It has about 30% bioavailability, but there is marked interindividual and brand variability. Patients should stay with one manufacturer of the drug. Some manufacturers have varying bioavailability within their own processing of the medication. It specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that the drug be present during first 24 hours of antigenic exposure.

This agent suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for a variety of organs.

Class Summary

B-lymphocyte stimulator (BLyS) is a naturally occurring protein required for survival and development of B-lymphocyte cells into mature plasma B cells that produce antibodies. In autoimmune diseases, elevated BLyS levels are thought to contribute to production of autoantibodies. 

Belimumab (Benlysta)

Belimumab is an IgG1-lambda monoclonal antibody that prevents the survival of B lymphocytes by blocking the binding of soluble human B lymphocyte stimulator protein (BLyS) to receptors on B lymphocytes. This reduces the activity of B-cell mediated immunity and the autoimmune response. It is indicated for children aged 5 y or older with SLE as an addition to standard therapy. It administered as an IV infusion. The SC injection is only approved for adults and not for children or adolescents younger than 18 y.

Class Summary

All patients with systemic lupus erythematosus (SLE) 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. Of note, natural production of vitamin D involves skin exposure to sun, which is discouraged in the SLE population, increasing the risk of vitamin D deficiency.

Calcium carbonate (Oystercal, Caltrate, Alcalak, Florical)

This is used as an antacid and for the prevention of calcium depletion. Calcium carbonate 1 g equals 400 mg of elemental calcium.

Vitamin D

Many different vitamin D3 (ie, cholecalciferol) supplements are available. Patients may use 400-2000 IU daily, depending on the size of the patient. Vitamin D levels, as well as calcium metabolism, should be monitored when supplements are being given.

Class Summary

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 (SLE) has a hypersensitivity reaction to NSAIDs; this is most often characterized by hepatotoxicity, but the reaction can include other symptoms and must be kept in mind.

There are many NSAIDs; the 3 listed are in common use but are certainly not exclusive in the treatment of lupus.

Naproxen (Aleve, Naprelan, Naprosyn, Anaprox)

Naproxen is used for analgesic and anti-inflammatory properties to treat arthralgia and arthritis. It is available with slightly different safety and efficacy profiles. The drug inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis. It is available in SR formulation (Naprelan) for once daily dosing.

Tolmetin

Tolmetin is used for its analgesic and anti-inflammatory properties in the treatment of arthralgia and arthritis. It is available with slightly different safety and efficacy profiles. Tolmetin inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.

Diclofenac (Voltaren, Cataflam, Cambia, Zipsor)

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

Class Summary

This agent is used investigationally for systemic lupus erythematosus (SLE).

Rituximab (Rituxan)

Rituximab is 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. Rituximab's use in SLE is investigational.

Class Summary

Chronic warfarin therapy is required for lupus-associated APS.

Warfarin (Coumadin)

Warfarin interferes with the hepatic synthesis of vitamin K–dependent coagulation factors. Long-term warfarin is the drug of choice for APS in patients with recurrent thrombotic events. A titrated dose is suggested to maintain an international normalized ratio (INR) of approximately 2.5-3.5.

Therapeutic agents are based on anticoagulant properties, and benefits are weighed carefully against their significant morbidities. Life-long treatment with moderately high-intensity warfarin (INR 2.5–3.5) is standard for recurrent thrombotic events.

Enoxaparin (Lovenox)

This is an alternative therapy for APS in the setting of lupus. It is necessary should a female patient with APS become pregnant during the treatment period.

Enoxaparin is produced by partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). It binds to antithrombin III, enhancing its therapeutic effect. The heparin-antithrombin III complex binds to and inactivates activated factor X (Xa) and factor II (thrombin).

Enoxaparin does not actively lyse but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis.

Advantages include intermittent dosing and decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing.

Low molecular weight heparin differs from UFH by having a higher ratio of antifactor Xa to antifactor IIa compared with UFH.

Enoxaparin prevents deep vein thrombosis (DVT), which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. It is used for prevention in hip replacement surgery (during and following hospitalization), knee replacement surgery, or abdominal surgery in those at risk of thromboembolic complications or in nonsurgical patients at risk of thromboembolic complications secondary to severely restricted mobility during acute illness.

Enoxaparin is used to treat DVT or pulmonary embolism (PE) in conjunction with warfarin for inpatient treatment of acute DVT with or without PE or for outpatient treatment of acute DVT without PE.

Checking the activated partial thromboplastin time (aPTT) is not useful because the drug has a wide therapeutic window and aPTT does not correlate with anticoagulant effect.

The average duration of treatment is 7-14 days.