Systemic Lupus Erythematosus in Children

Disease/Disorder

Definition

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 18 years.^1-6 

Etiology

The etiology of juvenile-onset SLE is not fully understood.¹ Genetic factors are centrally involved as multiple variants and mutations resulting in SLE or SLE-like diseases have been identified.³ However, single gene mutations result in SLE in only 1-4% of patients, thereby indicating that environmental factors play a significant role in most of these patients. Environmental factors include ultraviolet light exposure (especially ultraviolet B), infections (i.e. EBV), toxins, drugs, smoking, metals, diet, and hormones.^3,4 It is felt that these triggers alter the degree of DNA methylation and the phosphorylation of histones, leading to a change in gene transcription rates without modifying the gross genetic structure of the DNA itself.³ SLE has been associated with reduced DNA methylation in gene regions that can promote loss of B- and T-cell tolerance.³ Very early disease onset, atypical disease presentation, and severe manifestations may be the result of disease-causing mutations in single genes or the combination of multiple genomic variants that individually increase an individual’s risk for the development of SLE.⁷ 

Epidemiology including risk factors and primary prevention

Incidence of juvenile-onset SLE ranges between 0.3 to 0.9 per 100,000 children, with a prevalence of 1.89 to 25.7 per 100,000 children.⁸ Peak age of onset in juvenile-onset SLE 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).^3,4,6 Gender distribution varies, however, and is approximately equal between boys and girls under 5 years of age.^4,6 Diagnosis under the age of 5 is rare.^4,9 Similar to adult-onset SLE, juvenile-onset SLE more frequently affects individuals of non-Caucasian heritage, including African Americans, Asians, Hispanics, and Native Americans; with poorer prognosis in individuals of African or Asian descent.^3,4,6,9 Patients of lower socioeconomic status also have worse outcomes.⁴ Approximately 20% of individuals with SLE develop the disease in childhood.^2,6 

Patho-anatomy/physiology

The pathogenesis of SLE is not fully understood and remains an important area of research.⁴ 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.⁴ 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.¹⁰

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.⁶ 

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

SLE has been called the great mimicker, as the disease shares characteristics with many other autoimmune diseases.⁹ Juvenile-onset SLE is characterized by extremely variable presentation and clinical courses, even as compared to adult-onset SLE.⁴ 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.¹ Studies have shown that individuals with juvenile-onset SLE have more pervasive and life-threatening organ involvement than adults.^2-4 It is associated with more severe organ involvement (including renal and central nervous system disease), increased disease activity, presence of greater damage at time of diagnosis, and higher steroid burden.⁷ Diagnosis under 5 years of age is associated with atypical presentations and a more severe disease course.⁷ Early recognition and treatment of these manifestations of juvenile-onset SLE is essential for prevention of potential morbidity and mortality.⁸ Childhood-onset of antiphospholipid syndrome is also associated with juvenile-onset SLE although the prevalence is very low.⁸ 

• Constitutional symptoms include fever, fatigue, anorexia, weight loss, lymphadenopathy, and arthralgias.³ 
• Mucocutaneous symptoms most often involve skin on the face and scalp as well as oral and nasal mucosa.⁹ 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.⁶ Unlike in adults, isolated discoid lupus rash is rare in children.^3,9 Alopecia is also commonly seen, typically in the frontal area.^3,9  
• Musculoskeletal manifestations that occur because 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. Joint stiffness in the morning or after prolonged inactivity is typical.³ Myositis or muscle pain can also occur.³ Osteoporosis is commonly seen as a side effect of chronic steroid use.¹¹ 
• Renal involvement (lupus nephritis) occurs in in up to 80% of all juvenile-onset SLE patients, usually occurring within the first 2 years of diagnosis, resulting in higher mortality rates when compared to adult-onset SLE.^2,6,8 The spectrum of features of renal disease includes minimal proteinuria or microscopic hematuria to nephrotic-range proteinuria or acute renal failure.^3,9  
• Neurological symptoms involve the central nervous system more often than the peripheral nervous system, and can include headache, mood disorders, cognitive dysfunction, psychosis, new-onset seizures, cerebrovascular disease, and chorea.^3,6,9 Up to 65% of juvenile-onset SLE patients develop neuropsychiatric lupus, usually occurring within the first 2 years of diagnosis.⁹ This diagnosis is exclusionary.³ 
• Hematologic features of SLE primarily involve cytopenias, such as leukopenia and thrombocytopenia, which occur in over half of patients.^3,6,9 Coombs-positive hemolytic anemia is the most common hematologic manifestation in juvenile-onset SLE. Other hematologic abnormalities include myelodysplasia, secondary hemophagocytosis, macrophage activation syndrome, and coagulation disorders, such as antiphospholipid antibody syndrome, that increase the risk of thrombotic events.³ Antiphospholipid antibody syndrome prevalence is low but can occur with SLE.⁸
• Cardiopulmonary involvement with serositis, namely pericarditis and pleuritis, occur in up to 30% of juvenile-onset SLE patients.3,9 Atherosclerosis is commonly seen in juvenile-onset SLE. However, the APPLE study demonstrated no significant benefit from Atorvastatin in reducing progression of atherosclerosis during three years of treatment in patients with SLE aged 10-21 years.8 Dyspnea and hemoptysis may be seen.
• Vascular manifestations can involve inflammation and/or thrombosis of any vessel, similar to active vasculitis.⁹ 
• Gastrointestinal abnormalities include abdominal pain and anorexia.^3,9 Vomiting, and nausea can occur from treatment (i.e. steroids, nonsteroidal anti-inflammatory medications).³ 

The course of SLE is often fluctuating, with episodes of disease exacerbation followed by periods of improvement.⁵ Disease activity can be defined as reversible manifestations of the underlying inflammatory disease process. A disease flare, or increase in disease activity, is defined as a “measurable worsening of SLE disease activity” in at least 1 organ system, causing new or worsening clinical signs that may be associated with new or worsening SLE symptoms.³ Whereas, disease damage refers to irreversible degenerative tissue and organ changes from disease activity or SLE treatment.³ Tracking disease flares are important to monitor the course of juvenile-onset SLE overtime and to assess the effectiveness of drug therapies in clinical trials.⁵ 

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.^3,8,9

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.^3,11 Neutropenia in juvenile-onset SLE is often associated with cyclophosphamide treatment.

Essentials of Assessment

History

Clinical presentation of SLE can vary between patients.⁶ Children meet criteria if they have 4 or more of 11 symptoms classically associated with disease (as described by the American College of Rheumatology), also known as ACR criteria, which have 95% sensitivity and specificity.³ The 11 symptoms for criteria for SLE include:^3,4,6,9 

1. Malar rash 
2. Discoid rash 
3. Photosensitivity 
4. Oral ulcers 
5. Arthritis 
6. Serositis 
7. Renal disorder 
8. Neurologic disorder 
9. Hematologic disorder 
10. Immunologic disorder 
11. Antinuclear antibodies 

Physical examination 

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.³ 

Neuropsychiatric lupus can occur in 65% of patients at any time of their disease and includes mood disorder, cognitive dysfunction, psychosis, or seizures.^3,9 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.⁹ 

Clinical functional assessment: mobility, self-care cognition/behavior/affective state

Juvenile-onset SLE is associated with decreased health-related quality of life.¹² 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.¹² Cognitive dysfunction is often diagnosed with neuropsychological testing and has been observed in more than a third of asymptomatic juvenile-onset SLE patients.^5,12 

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).¹² The Health Education for Lupus Feasibility Trial suggested that female adolescents with SLE who received cognitive behavioral therapy had increased coping skills.⁸ 

Laboratory studies 

Antinuclear antibody (ANA) is found in 95% of pediatric SLE patients, though ANA is not specific for to SLE.^3,9 If ANA is positive, it is important to assess for double stranded DNA which has a higher specificity.^3,9 In juvenile-onset SLE, ANA titers do not correlate with disease activity, but high-titer ANA are a hallmark of juvenile-onset SLE at the time of diagnosis.³ Other antibodies seen in juvenile-onset SLE include anti-Smith, anti-ribonucleoprotein, anti-Ro (also called SS-A), and anti-La (also called SS-B).^3,9 Anti-Smith antibodies are highly specific (but have low sensitivity) for SLE. Urinalysis assessing for proteinuria, hematuria, and casts, as well as the presence of urinary neutrophil gelatinase-associated lipocalin (NGAL), monitors for lupus nephritis.¹³ 

Massias et al., found that when compared to younger children, adolescents with SLE have an increased number of ACR criteria (the 11 symptoms listed above), show typical autoantibody patterns with ANA and dsDNA positivity, hematological involvement (leukopenia, thrombocytopenia) and immunological characteristics (hypocomplementemia) reflecting “classical” SLE. They also present with higher disease activity at diagnosis when compared to younger children.⁷ Children diagnosed at the age of 7 or younger had lower rates of ANA positivity. They found that most patients who were initially autoantibody negative in the prepubertal and peripubertal age grouped eventually developed ANA positivity; and patients with ANA positivity had an increased likelihood of having renal, musculoskeletal, and hematological manifestations.⁷  

Imaging

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 chest x-ray 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 although renal biopsy is the gold standard for evaluation, a kidney ultrasound can be helpful as patients with chronic renal involvement have small, echogenic kidneys.³ Over 80% of patients with SLE have nonerosive polyarthritis that is symmetric, affecting the joints of the hands, wrists, and knees; which can be captured on x-rays. Neurocognitive testing and magnetic resonance imaging of the brain are widely used for evaluation of central nervous system abnormalities.³  

Supplemental assessment tools

Kidney biopsy to evaluate the histology of renal parenchyma is gold standard for assessment.³ 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.¹³ Antiribosomal P antibodies, antineuronal antibodies, and plasma levels of anti-NR2A/B antibodies, are associated with neurocognitive dysfunction, depression, and anxiety.³

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 the early stages of the disease is often related to infection, whereas later in the course cardiovascular disease is the driving force. Renal disease, infections, myocardial infarction, and coronary artery disease remain important causes of morbidity and mortality in adulthood for patients with juvenile-onset SLE.³ Malignancies are more frequent in juvenile-onset SLE than in the age-matched population.³  

Environmental

Environmental factors include ultraviolet light exposure (especially ultraviolet B), infections (i.e. EBV), toxins, drugs, smoking, metals, diet, and hormones.^3,4

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.¹⁴ Strong social support and involvement of counselors can help manage these issues.

Professional 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

Historically, there have been no medications approved by the FDA specifically for children with juvenile-onset SLE, so treatments generally come from clinical trials performed on adults with SLE.² Management is based on symptoms. NSAIDs are the main treatment for arthritis and musculoskeletal complications of lupus. Systemic glucocorticoids remain the mainstay of treatment for juvenile-onset SLE.^3,4,6 Low dose steroids can be implemented in patients with dermatitis, arthritis and serositis. Hydroxychloroquine is an antimalarial agent given as a first-line therapy to reduce mortality and morbidity.^3,6 It also can alleviate skin and musculoskeletal disease, along with decreasing disease activity and flares.³ It may also promote cardiovascular health and improve bone density and glucose metabolism in children with SLE.³ Per the SHARE initiative in Europe, Hydroxychloroquine should be given regularly to all children with SLE.⁸ However, this recommendation is based off adult studies. They also advise yearly eye screening in children who take Hydroxychloroquine to monitor for retinopathy.⁸ Cyclophosphamide is an alkylating agent that is used primarily for the management of severe organ involvement.^3,4,6,8 Mycophenolate mofetil, Azathioprine, and Methotrexate have also been used to treat juvenile-onset SLE.^3,4,6 For high severity of disease, immunosuppressive agents and/or disease-modifying antirheumatic drugs (DMARDs) are employed. The SHARE initiative recommended that when it is not possible to taper the prednisone taper, a DMARD should be added to the therapy.⁸ Belimumab is a human immunoglobin (Ig)G1 monoclonal antibody that has been used off-label in children with SLE. ^3,4,6,8,10 It has been shown to improve disease control and reduce glucocorticoid use.³ More recently, the PLUTO study, a RTC comparing intravenous Belimumab plus standard juvenile-onset SLE to placebo in 93 patients with active juvenile-onset SLE, found that a numerically higher proportion of patients on Belimumab met the primary endpoint of SLE Responder Index 4, which was used as the primary outcome measure for comparability with the original adult-onset SLE Belimumab trial.⁸ Both the European Medicines Agency and the Food and Drug Administration have approved the use of Belimumab in juvenile-onset SLE.¹⁰ Rituximab is an anti-CD20 monoclonal antibody that has been shown to be effective in treating juvenile-onset SLE-associated cytopenias, lupus nephritis, refractory manifestations, neuropsychiatric manifestations, and cutaneous disease.^3,4,6 A case series of three juvenile-onset SLE patients suggested Rituximab may be a useful steroid-sparing treatment for lupus anticoagulant hypoprothrombinemia syndrome, a rare manifestation of SLE that increases the risk of serious bleeding and thrombosis.⁸ 

Although pharmacological treatments have improved overall survival, SLE continues to have an overwhelming impact on quality of life, regarding fatigue, pain, and psychological symptoms.¹ It has been shown that the aerobic capacity is reduced in many patients with SLE, and the musculoskeletal involvement may lead to muscle weakness.¹ For this reason, exercise is important, but also for increased risk of cardiovascular disease and metabolic syndrome.¹ Individuals with mild or inactive SLE and no or little organ damage are recommended aerobic exercise to improve aerobic fitness, and decrease symptoms of fatigue and depression.¹ 

At different disease stages

• Treatment for mild disease maintenance: 
  • Managing rash and arthritis: hydroxychloroquine, antimalarials, 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 lupus nephritis: 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 and Cyclophosphamide have been studied in both adult-onset and juvenile-onset SLE and the results were comparable. Studies have shown the with the addition of Rituximab, steroid dosing is reduced.⁸ 
  • Maintenance treatment for lupus nephritis: Mycophenolate mofetil or Azathioprine for at least 3 years for class III or IV lupus nephritis   
  • ACE inhibitors can be used to reduce proteinuria⁸ 
• Neuropsychiatric manifestations:⁸ 
  • Corticosteroids and immunosuppressants  
  • Rituximab, Cyclophosphamide, Mycophenolate mofetil, and Deflazacort have all been studied and have shown benefit 
  • Antiepileptic medications should be considered in recurrent seizures, but not necessary for one seizure in the absence of MRI lesions and definite epileptic abnormalities on EEG 
• Musculoskeletal manifestations: 
  • A randomized double-blind placebo-controlled study done in 2019 found that Risedronate significantly increased bone mass in patients with low bone mass in patients with SLE. They concluded that Risedronate should be considered for children receiving steroid treatment to reduce fracture risk.⁸ 
• Severe/life threatening symptoms, severe renal involvement, patients who are non-complaint due to other medications toxicity: cyclophosphamide 
• Treatment for lupus anti-phospholipid syndrome⁸ 
  • Treatment is challenging due to lack of large-scale prospective studies, most treatment recommendations are from adult studies 
  • Hydroxychloroquine is thought to have anti-thrombotic properties 
  • If they have already suffered a thrombosis then the goal is to prevent further thrombosis with long term anti-coagulation therapy such as Warafin⁸ 
• 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. There is moderately strong evidence that aerobic exercise at a moderate to vigorous intensity, 30-75 minutes, 2-3 times per week, for 8-16 weeks can improve aerobic capacity.¹ Disease activity is unchanged by resistance training for upper and lower extremities, 3 sets of 15 reps, 3 times per week for 12 weeks.¹

Coordination of care

Managing the lifelong disease in the setting of the usual challenges during adolescence is crucial to maintaining patients’ independence. Treatment goals include shared decision-making with patients and families, control of disease activity aiming towards full remission, avoidance of flares, tissue damage prevention, and minimizing the iatrogenic effects of medications while maximizing quality of life.^3,15 Addressing health-related quality of life includes proactively addressing fatigue, pain, mental health, educational challenges, and medication side effects.¹⁵ The approach to SLE is multidisciplinary and at the very least involves Rheumatology, Nephrology, PM&R, Psychology, therapy services and social work.³ 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 juvenile-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.

Children with SLE are at higher risk for infection, which can be greatly reduced through the reinforcement of vaccinations and universal precautions such as hand washing.^3,9 Bone loss and vitamin D deficiency are seen in patients who are on chronic glucocorticoid threapy.^3,11 Patients with juvenile-onset SLE have several risk factors of osteoporosis, including biochemical abnormalities, active inflammation, low physical activity due to musculoskeletal involvement, and corticosteroid use.¹¹ Sun avoidance and sunscreen use are also recommended for children with SLE since sun exposure can trigger a SLE flare.^3,9 Prophylactic treatment with bisphosphonates has been suggested to be effective in improving bone health for patients receiving corticosteroids.¹¹ Patients should receive regular counseling about modifiable risk factors such as sedentary lifestyle, dyslipidemia, hypertension, obesity, and smoking are recommended as they have an increased risk of premature atherosclerosis.^3,6 At the same time, it is also vital for providers to acknowledge the potential stress associated with juvenile-onset SLE. For example, associated depression or anxiety, financial burden, and uncertainty related to safety of treatment options and disease course. A referral to mental health services may be warranted. 

Young patients with SLE can have growth restriction, delayed puberty, concern for future fertility issues, chronic pain, cosmetic problems (secondary to both disease and treatment), as well as social, emotional, and financial difficulties.¹⁴ There is a high rate of non-adherence to medications among adolescents and young adults with juvenile-onset SLE which leads to increased number of lupus flares, higher hospital admission rates, and increased risk of end-stage renal disease and mortality.¹⁴ Adherence to medications should be routinely assessed and barriers should be addressed. 

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.¹⁶ 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.¹⁶

Translation into Practice:  practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Juvenile-onset SLE is a multisystem disorder. As a result, a provider caring for a patient with juvenile-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. Therefore, communication with patients, families, and 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 juvenile-onset SLE in the last 50 years.¹⁰ 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 future. Blocking IL-6 signaling (Tocilizumab), TNF inhibition, and Janus kinases inhibition are being looked at for the treatment of juvenile-onset SLE.⁴ 

Gaps in the Evidence-Based Knowledge

While various aspects of childhood juvenile-onset SLE resemble adult-onset 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.² 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. Although some of these trials included children, drawing statistically significant results is difficult if there are not enough enrolled children compared to adults, and most of these active trials exclude younger children.² To address these knowledge gaps, the Lupus Foundation of America and Childhood Arthritis and Rheumatology Research Alliance partnered to help guide future research decisions and funding mechanisms.² Per Ardoin et al, nephritis, clinical trials, biomarkers, neuropsychiatric disease, and refractory skin disease merged as the highest priority for juvenile-onset SLE research domains.²

References

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2. Ardoin SP, Daly RP, Merzoug L, Tse K, Ardalan K, Arkin L, Knight A, Rubinstein T, Ruth N, Wenderfer SE, Hersh AO. Childhood Arthritis and Rheumatology Research Alliance and Lupus Foundation of America. Research priorities in childhood-onset lupus: results of a multidisciplinary prioritization exercise. Pediatr Rheumatol Online J. 2019 Jul 1;17(1):32. doi: 10.1186/s12969-019-0327-4. PMID: 31262324. 
3. Harry O, Yasin S, Brunner H. Childhood-Onset Systemic Lupus Erythematosus: A Review and Update. J Pediatr. 2018 May;196:22-30.e2. doi: 10.1016/j.jpeds.2018.01.045. 
4. Hedrich CM, Smith EMD, Beresford MW. Juvenile-onset systemic lupus erythematosus (jSLE) – Pathophysiological concepts and treatment options. Best Pract Res Clin Rheumatol. 2017 Aug;31(4):488-504. doi: 10.1016/j.berh.2018.02.001. 
5. Rosina S, Tibaldi J, Mazzoni M, Bava C, Natoli V, Ravelli A. Update on Outcome Measures for Pediatric Systemic Lupus Erythematosus. Arthritis Care Res (Hoboken). 2020 Oct;72 Suppl 10:163-170. doi: 10.1002/acr.24212. 
6. Smith EMD, Lythgoe H, Midgley A, Beresford MW, Hedrich CM. Juvenile-onset systemic lupus erythematosus: Update on clinical presentation, pathophysiology and treatment options. Clin Immunol. 2019 Dec;209:108274. doi: 10.1016/j.clim.2019.108274. 
7. Massias JS, Smith EMD, Al-Abadi E, Armon K, Bailey K, Ciurtin C, Davidson J, Gardner-Medwin J, Haslam K, Hawley DP, Leahy A, Leone V, McErlane F, Mewar D, Modgil G, Moots R, Pilkington C, Ramanan AV, Rangaraj S, Riley P, Sridhar A, Wilkinson N, Beresford MW, Hedrich CM. Clinical and laboratory characteristics in juvenile-onset systemic lupus erythematosus across age groups. Lupus. 2020 Apr;29(5):474-481. doi: 10.1177/0961203320909156. Epub 2020 Mar 31. PMID: 32233733; PMCID: PMC7528537. 
8. Gallagher KL, Patel P, Beresford MW, Smith EMD. What Have We Learnt About the Treatment of Juvenile-Onset Systemic Lupus Erythematous Since Development of the SHARE Recommendations 2012? Front Pediatr. 2022 Apr 14;10:884634. doi: 10.3389/fped.2022.884634. PMID: 35498799; PMCID: PMC9047745. 
9. Levy DM, Kamphuis S. Systemic lupus erythematosus in children and adolescents. Pediatr Clin North Am. 2012 Apr;59(2):345-64. doi: 10.1016/j.pcl.2012.03.007. 
10. Mina R, Brunner HI. Update on differences between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Res Ther. 2013 Aug 21;15(4):218. doi: 10.1186/ar4256. 
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12. Hersh A. Measures of health-related quality of life in pediatric systemic lupus erythematosus: 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 Youngsters (SMILEY). Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11:S446-53. doi: 10.1002/acr.20559. PMID: 22588765. 
13. Gao Y, Wang B, Cao J, Feng S, Liu B. Elevated Urinary Neutrophil Gelatinase-Associated Lipocalin Is a Biomarker for Lupus Nephritis: A Systematic Review and Meta-Analysis. Biomed Res Int. 2020 Jun 30;2020:2768326. doi: 10.1155/2020/2768326. PMID: 32685458; PMCID: PMC7346103. 
14. Semo-Oz R, Wagner-Weiner L, Edens C, Zic C, One K, Saad N, Tesher M. Adherence to medication by adolescents and young adults with childhood-onset systemic lupus erythematosus. Lupus. 2022 Oct;31(12):1508-1515. doi: 10.1177/09612033221115974. Epub 2022 Aug 7. PMID: 35938626. 
15. Smith EMD, Aggarwal A, Ainsworth J, Al-Abadi E, Avcin T, Bortey L, Burnham J, Ciurtin C, Hedrich CM, Kamphuis S, Levy DM, Lewandowski LB, Maxwell N, Morand EF, Ozen S, Pain CE, Ravelli A, Saad Magalhaes C, Pilkington CA, Schonenberg-Meinema D, Scott C, Tullus K, Beresford MW; cSLE T2T International Task Force. Towards development of treat to target (T2T) in childhood-onset systemic lupus erythematosus: PReS-endorsed overarching principles and points-to-consider from an international task force. Ann Rheum Dis. 2023 Jun;82(6):788-798. doi: 10.1136/ard-2022-223328. Epub 2023 Jan 10. PMID: 36627168; PMCID: PMC10314055. 
16. de Amorim JC, Sepresse SR, Vivaldo JF, Julio PR, Kishimoto ST, Marini R, Fernandes PT, Costallat LTL, Appenzeller S. Cognitive Performance in Patients with Systemic Lupus Erythematosus Using the Ped-ANAM. Cells. 2022 Dec 15;11(24):4054. doi: 10.3390/cells11244054. PMID: 36552818; PMCID: PMC9777136.

Original Version of the Topic

Annie Mary Abraham, MD, Sarah Jane Matthews, MD, Rajashree Srinivasan, MD, MBBS, Kelli Chaviano, DO. Systemic Lupus Erythematosus in Children. 12/22/2021

Author Disclosure

Clarice Sinn, DO, MHA
Nothing to Disclose

Gabrielle McDermott Schneider, DO
Nothing to Disclose