Childhood-onset or juvenile-onset systemic lupus erythematosus (SLE) is an autoimmune disorder with multisystem involvement, causing inflammatory damage to skin, joints, and internal organs with symptom onset before the age of 16 to 18 years.
The etiology of juvenile SLE is not fully understood. Genetic factors are centrally involved as multiple variants and mutations resulting in SLE or SLE-like disease have been identified. However, single gene mutations result in SLE in only 1-4% of patients, thereby indicating that environmental factors (e.g., infections, medication, ultraviolet light exposure) play a significant role in most of these patients.
Epidemiology including risk factors and primary prevention
Incidence of jSLE ranges between 0.36 to 2.5 per 100,000 children, with a prevalence of 1.89 to 34.1 per 100,000 children. Peak age of onset in jSLE is between 12 and 14 years, and while the female predominance is less marked when compared to adults, it is more common in girls and young women (4.7-5.6:1). Gender distribution varies, however, and is approximately equal between boys and girls under 5 years of age. Similar to adult-onset SLE, jSLE more frequently affects individuals of non-Caucasian heritage, with poorer prognosis in individuals of African or Asian descent.
The pathogenesis of SLE remains an important area of research. Juvenile-onset SLE is associated with a greater number of previously identified SLE-susceptibility risk alleles, which may partially explain why children with SLE generally have more aggressive disease and less favorable outcomes when compared with adults. Type 1 interferons are associated with early onset SLE, as many genetic variants associated with SLE can be linked to type 1 interferon production or signaling.
Overall dysregulated immune responses lead to stimulation of innate and adaptive immune mechanisms thereby resulting in the release of inflammatory cytokines, aberrant activation of effector T cells, production of autoantibodies, and deposition of immune complexes, which subsequently contribute to tissue inflammation and organ damage.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time):
Juvenile-onset SLE is characterized by extremely variable presentation and clinical courses, even as compared to adult-onset SLE. Clinical features can cover a spectrum within each affected organ system from relatively mild disease to severe, life-threatening presentations that often occur during disease flares.
- Constitutional symptoms include fever, fatigue, anorexia, weight loss, alopecia, and arthralgias.
- Mucocutaneous symptoms most often involve skin on the face and scalp as well as oral and nasal mucosa. Most commonly, the facial malar rash, also known as the butterfly rash, is seen in 60-85% of children and is associated with photosensitivity in over one-third of patients.
- Musculoskeletal manifestations that occur as a consequence of active SLE include arthritis that is generally non-erosive and non-deforming as well as arthralgias that can be secondary to a pain amplification syndrome that occurs during or following a disease flare.
- Renal involvement (lupus nephritis) occurs in 50-75% of all childhood-onset SLE patients, usually occurring within the first 2 years of diagnosis. The spectrum of features of renal disease includes minimal proteinuria or microscopic hematuria to nephrotic-range proteinuria or acute renal failure.
- Neuropsychiatric symptoms involve the central nervous system more often than the peripheral nervous system, and can include headache, mood disorders, cognitive dysfunction, psychosis, and seizures, among others. Up to 65% of childhood-onset SLE patients develop neuropsychiatric lupus, usually occurring within the first 2 years of diagnosis.
- Hematologic features of SLE primarily involve cytopenias, which occur in over half of patients.
- Cardiopulmonary involvement with serositis, namely pericarditis and pleuritis, occur in up to 30% of childhood-onset SLE patients.
- Vascular manifestations can involve inflammation and/or thrombosis of any vessel, similar to an active vasculitis.
Specific secondary or associated conditions and complications
Conditions associated with juvenile-onset SLE include hemoglobinopathies (such as sickle cell anemia or thalassemia trait), hypercoagulability due to antiphospholipid syndrome, thrombotic thrombocytopenia purpura, celiac disease, sterile peritonitis, pancreatitis, myocarditis, non-infective endocarditis, interstitial pneumonitis, pulmonary hemorrhage, and pulmonary hypertension.
Common complications include those associated with common treatments. For example, patients on chronic steroids may experience avascular necrosis, osteoporosis, bone fragility fractures, gastrointestinal ulcers/bleeding, or hypertension, among others. Neutropenia in juvenile-onset SLE is often associated with cyclophosphamide treatment.
Essentials of Assessment
Clinical presentation of SLE can vary between patients. Patients meet criteria if they have 4 or more of 11 symptoms classically associated with disease (as described by the American College of Rheumatology) which have 95% sensitivity and specificity. Symptoms and signs include
- malar rash
- discoid rash
- oral ulcers
- renal disorder
- neurologic disorder
- hematologic disorder
- immunologic disorder
- antinuclear antibodies
Traditional presentation of SLE is an adolescent female with photosensitive malar rash, oral ulcers, polyarthritis, Raynaud’s phenomenon and/or pleural effusion. However, most patients present with vague symptoms including fever, fatigue, weight loss, rash, leukopenia or arthralgias.
Neuropsychiatric lupus can occur in 65% of patients at any time of their disease and includes mood disorder, cognitive dysfunction, psychosis, or seizures. Antiphospholipid antibodies are present in 40% of patients and associated with hypercoagulability. Serositis (pericarditis) occurs in up to 30% SLE patients and presents with tachycardia and retrosternal chest pain.
Clinical functional assessment: mobility, self-care cognition/behavior/affective state
Childhood-onset SLE is associated with decreased health-related quality of life. The clinical functional assessment should focus on frequently affected factors impacting quality of life, including but not limited to, fatigue, mood, pain, cognitive dysfunction, and functional impairment. Cognitive dysfunction is often diagnosed with neuropsychological testing and has been observed in more than a third of asymptomatic childhood-onset SLE patients.
Some measures of health-related quality of life in this population include the Childhood Health Assessment Questionnaire (C-HAQ), Child Health Questionnaire (CHQ), Pediatric Quality of Life Inventory Generic Core Module (PedsQL-GC), Pediatric Quality of Life Inventory Rheumatology Module (PedsQL-RM), and Simple Measure of Impact of Lupus Erythematosus in Youngers (SMILEY).
Antinuclear antibody (ANA) is found in 95% of pediatric SLE patients. If ANA is positive, it is important to assess for double stranded DNA which has a higher specificity. Anti-Smith antibodies are highly specific (but have low sensitivity) for SLE. Urinalysis assessing for proteinuria, hematuria, and casts monitors for lupus nephritis.
There are no universal imaging criteria for the diagnosis of SLE. Risk of pulmonary infection is three times higher in SLE patients and pneumonia found on CXR is common. Exudative pericarditis can occur in up to 50% of patients and ECHO or CT chest with contrast can assist with identification. Renal disease is common and renal biopsy is gold standard for evaluation, however kidney US can be helpful as patients with chronic renal involvement have small, echogenic kidneys. Over 80% of patients with SLE have nonerosive polyarthritis that is symmetric, affecting the joints of the hands, wrists, and knees.
Supplemental assessment tools
Kidney biopsy to evaluate the histology of renal parenchyma is gold standard for assessment. There are additional serum markers that can be used for earlier diagnosis of potentially fatal organ involvement, including C1q and urinary neutrophil gelatinase-associated lipocalin. Antiribosomal P antibodies and antineuronal antibodies are now associated with neurocognitive dysfunction, depression, and anxiety.
Early prediction of outcomes
Multiple studies show patients with diagnosis at younger age typically have more severe disease. The 10-year survival rate has improved to >85%, however average age of onset is 12. Mortality in early stages of the disease is often related to infection, whereas later in the course cardiovascular disease is the driving force.
African American, Afro-Caribbean and Hispanic patients have associated worse outcomes, as do patients of lower socioeconomic status.
Stress, toxic exposures (e.g., silica), infections, and ultraviolet radiation are only a few among a list of potential environmental triggers of SLE flares.
Social role and social support system
SLE presents with many symptoms, including alopecia and discoid rash, which can not only be painful but emotionally challenging at a time of challenging life stress, made worse by ongoing peer pressure. The added side effects of these medications lead to many patients being reluctant to take them or attend school. Strong social support and involvement of counselors can help manage these issues.
There is a 50-fold increase in risk of MI in female patients with SLE and patients should be counseled appropriately. Also given the risk of clotting in SLE, counseling adolescent female patients about birth control is important. For patients with antiphospholipid antibodies, progesterone only birth control should be used.
Rehabilitation Management and Treatments
Available or current treatment guidelines
Management is based on symptoms. NASIDs are the main treatment for arthritis and musculoskeletal complications of lupus. Low dose steroids can be implemented in patients with dermatitis, arthritis and serositis. Hydroxychloroquine can be used to skin manifestation or in combination with steroids to reduced steroid does. For high severity of disease, immunosuppressive agents and/or disease-modifying antirheumatic drugs (DMARDs) are employed.
At different disease stages
- Treatment for mild disease maintenance:
- Managing rash and arthritis: hydroxychloroquine, anti-malarials, chloroquine
- Managing musculoskeletal symptoms and serositis: NSAIDs
- Treatment for rapid disease control for flares:
- IV and or PO steroids
- Treatment for moderate/severe persistent disease
- Persistent arthritis: methotrexate
- Arthritis, vasculitis rash, cytopenia, serositis: azathioprine
- Symptoms resistant to steroid taper such as cytopenia, serositis: immunosuppressive agents
- Maintenance therapy for other organ manifestation: mycophenolate mofetil
- Renal lupus involvements:
- For glomerulonephritis, NPSLE: immunosuppressive agents provide improved outcomes and choice of immunosuppressant should be based on histological classification and race/ethnicity (e.g. Hispanic/African American patients respond better to Mycophenolate).
- Induction of remission of lupus nephritis: mycophenolate mofetil
- ACE inhibitors can be used to reduce proteinuria
- Severe/life threatening symptoms, severe renal involvement, patients who are non-complaint due to other medications toxicity: cyclophosphamide
- Rehabilitation goals throughout disease course
- The overall goal is to maintain physical activity as much as is possible. Other factors to consider are limiting sun exposure and optimizing nutrition. For patients with high burden of open discoid lesions, individualized wound care plans similar to care of burns.
- There have been multiple studies reviewing exercise programs for patients with SLE. The consensus was 20-50 minutes of aerobic exercise, 3 times a week for 8-12 weeks to reduce fatigue and assist with symptoms of depression. Resistance training for upper and lower extremities, 3 sets of 15 reps, 3 times per week for 12 weeks.
Coordination of care
Managing the lifelong disease in the setting of the usual challenges during adolescence is crucial to maintaining patients’ independence. The approach to SLE is multidisciplinary and at the very least involves Rheumatology, Nephrology, PM&R, Psychology, therapy services and social work. Equally important is planning for transition to adult care to prevent loss to follow up.
Patient & family education
Patient and family education should emphasize understanding of and recognition of symptoms of childhood-onset SLE given the multisystem manifestations that can occur. It can be useful to equip patients and families with symptom trackers. Furthermore, the importance of regular monitoring and follow-up cannot be stressed enough.
At the same time, it is also vital for providers to acknowledge the potential stress associated with childhood-onset SLE. For example, associated depression or anxiety, financial burden, and uncertainty related to safety of treatment options and disease course, among others.
Measurement of Treatment Outcomes including those that are impairment-based, activity participation-based and environmentally-based.
Pediatric Automated Neuropsychology assessment metrics contain 10 subtests that assess cognitive abilities in the setting of neuropsychiatric lupus. The cutaneous lupus erythematosus disease area and severity index is valid in assessing skin manifestations in children. There is not yet an evaluation of the outcomes for kidney disease, though several have been investigated but have little correlation with the severity of renal involvement. The SLE disease activity index is commonly used to measure disease activity; higher scores correlate with higher risk of additional damage from SLE.
Translation into Practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Childhood-onset SLE is a multisystem disorder. As a result, a provider caring for a patient with childhood-onset SLE is part of a care team that can include rheumatologists, dermatologists, nephrologists, hematologists, neurologists, immunologists, gastroenterologists, cardiologists, endocrinologists, infectious disease specialists, psychologists and/or neuropsychologists. Thereby, communication with patients and families as well as between providers is necessary and helpful.
Cutting Edge/ Emerging and Unique Concepts and Practice
Newer therapies include Rituximab which is helpful in treating cytopenia and usually used in combination with other immunosuppressives. Belimumab has recently been shown to be effective for mild/moderate treatment in the adult population and is the first new drug that has been FDA approved to treat SLE in the last 50 years. There are ongoing studies focusing on biologics targeting specific cells/mediators of the immune system that will hopefully lead to new treatment options in the near future.
Gaps in the Evidence-Based Knowledge
While various aspects of childhood SLE resemble adult SLE, important differences remain including genetic predisposition, environmental triggers, pharmacokinetics, and concerns specific to the pediatric population such as neurodevelopment, growth, puberty, educational development, and mental health. However, management principles are largely extrapolated from clinical trials performed on adults with SLE, and future directions of research seek to expand upon these areas.
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Annie Mary Abraham, MD
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Sarah Jane Matthews, MD
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Rajashree Srinivasan, MD, MBBS
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Kelli Chaviano, DO
Children’s Health/University of Texas Southwestern; Service Package Grant; Co-PI for research “Team ME”