13/11/2017 Pediatric Systemic Lupus Erythematosus: Background, Etiology, Epidemiology

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Pediatric Systemic Lupus Erythematosus

Updated: Nov 02, 2015
Author: Marisa S Klein-Gitelman, MD, MPH; Chief Editor: Lawrence K Jung, MD more...

OVERVIEW

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. The disease can affect, for example, the kidneys, skin, blood cells, and nervous
system. The natural history of SLE is unpredictable; patients may present with many years of
symptoms or with acute, life-threatening disease. (See Etiology, History, and Physical Examination.)

Because of its protean manifestations, lupus must be considered in the differential diagnoses of many
conditions, including fevers of unknown origin, arthralgia, anemia, new-onset kidney disease,
psychosis, and fatigue. Early diagnosis and careful treatment tailored to individual patient symptoms
have improved the prognosis in what was once perceived as an often-fatal disease. (See the image
below.) (See Differentials, Treatment, and Medications.)

The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note
that the fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial
folds.
View Media Gallery

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

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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]

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.

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.

Etiology
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.)

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In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental triggers, antigen-
antibody responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and
perpetuate autoimmunity.
View Media Gallery

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
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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, 21, 22]

Epidemiology
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.

Prognosis

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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.

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.

Patient Education
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.

Clinical Presentation

References

1. Osler W. On the visceral manifestations of the erythema group of skin diseases. Am J Med Sci.
1904. 27:1.

2. Suzuki M, Ross GF, Wiers K, Nelson S, Bennett M, Passo MH, et al. Identification of a urinary
proteomic signature for lupus nephritis in children. Pediatr Nephrol. 2007 Dec. 22(12):2047-57.
[Medline].

3. Yurasov S, Wardemann H, Hammersen J, et al. Defective B cell tolerance checkpoints in

systemic lupus erythematosus. Journal of Experimental Medicine. 2005. 201:703-711. [Medline].

4. Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell differentiation
by IFN-alpha in systemic lupus erythematosus. Science. 2001 Nov 16. 294(5546):1540-3.
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[Medline].

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Media Gallery

The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and
nasal bridge. Note that the fixed erythema, sometimes with mild induration as seen here,
characteristically spares the nasolabial folds.
In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental
triggers, antigen-antibody responses, B-cell and T-cell interactions, and immune clearance
processes interact to generate and perpetuate autoimmunity.

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Contributor Information and Disclosures

Author

Marisa S Klein-Gitelman, MD, MPH Professor of Pediatrics, Northwestern University, The Feinberg
School of Medicine; Head, Division of Rheumatology, Ann and Robert H Lurie Children's Hospital of
Chicago

Marisa S Klein-Gitelman, MD, MPH is a member of the following medical societies: American
Academy of Pediatrics, American College of Rheumatology

Disclosure: Nothing to disclose.

Specialty Editor Board

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13/11/2017 Pediatric Systemic Lupus Erythematosus: Background, Etiology, Epidemiology

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College
of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of

New York Downstate Medical Center; 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,
Phi Beta Kappa

Disclosure: Nothing to disclose.

Chief Editor

Lawrence K Jung, MD Chief, Division of Pediatric Rheumatology, Children's National Medical Center

Lawrence K Jung, MD is a member of the following medical societies: American Association for the
Advancement of Science, American Association of Immunologists, American College of
Rheumatology, Clinical Immunology Society, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Barry L Myones, MD Co-Chair, Task Force on Pediatric Antiphospholipid Syndrome

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, Texas Medical
Association

Disclosure: Nothing to disclose.

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