Pediatric-onset Systemic Lupus Erythematosus Research Articles

Dnase1L3 Regulates Inflammasome-Dependent Cytokine Secretion.

Pediatric-onset systemic lupus erythematosus arises in humans and mice lacking the endonuclease Dnase1L3. When Dnase1L3 is absent, DNA from circulating apoptotic bodies is not cleared, leading to anti-DNA antibody production. Compared to early anti-DNA and anti-chromatin responses, other autoantibody responses and general immune activation in Dnase1L3−/− mice are greatly delayed. We investigated the possibility that immune activation, specifically inflammasome activation, is regulated by Dnase1L3. Here, we report that Dnase1L3 inhibition blocked both NLR family, pyrin domain containing 3 (NLRP3) and NLRC4 inflammasome-mediated release of high-mobility group box 1 protein and IL-1β. In contrast to IL-1β release, Dnase1L3 inhibition only mildly impaired NLRP3-dependent pyroptosis, as measured by propidium iodide uptake or LDH release. Mechanistically, we found that Dnase1L3 was needed to promote apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) nuclear export and speck formation. Our results demonstrate that Dnase1L3 inhibition separates cytokine secretion from pyroptosis by targeting ASC. These findings suggest that Dnase1L3 is necessary for cytokine secretion following inflammasome activation.

Serum IL-18 as biomarker in predicting long-term renal outcome among pediatric-onset systemic lupus erythematosus patients.

An urge of biomarker identification is needed to better monitor lupus nephritis (LN) disease activity, guide clinical treatment, and predict patient's long-term outcome. With the proinflammatory effect and its association with inflammasomes, the significance of interleukin-18 (IL-18) among pediatric-onset systemic lupus erythematous (pSLE) patient, especially, its importance in predicting long-term renal outcome was investigated.In a pSLE cohort of 96 patients with an average follow-up period of 10.39 ± 3.31 years, clinical data and laboratory workups including serum IL-18 were collected at time of disease onset and 6 months after treatment despite their initial renal status. Through Cox regression analysis, the parameters at baseline and at 6 months posttreatment were carefully analyzed.Average age of all cases was 12.74 ± 3.01 years old and 65 of them underwent renal biopsy at the time of diagnosis. Nine subjects (9.38%) progressed to end-stage renal disease (ESRD) and 2 cases (2.08%) died during follow-up. Through multivariate analysis, serum IL-18 level 6 months posttreatment was found to be the most unfavorable factor associating poor clinical outcome despite patient's initial renal status. In addition, the presentation of serum IL-18 in its correlation with SLE global disease activity as well as the presence and severity of LN were all significant (P < 0.001, P = 0.03, and P = 0.02, respectively). The histological classification of LN, however, was not associated with the level of IL-18 among the pSLE patients (P = 0.64).The role of serum IL-18 as biomarker representing global disease activity and status of renal flares among pSLE population was shown for the first time. Additionally, we have identified IL-18 at 6 months posttreatment a novel marker for long-term renal outcome prediction.

Dnase1L3 trafficking is redirected from secretion to the nucleus in lupus-prone mice

Abstract Pediatric-onset Systemic Lupus Erythematosus (SLE) is linked to a deficiency of the endonuclease Dnase1L3. Dnase1L3 can function extracellularly as a barrier to transfection or localize to the nucleus of macrophages to cleave DNA during apoptosis, though the mechanism by which Dnase1L3 protects from pediatric-onset SLE is unknown. Two polygenic lupus murine models, MRL-lpr and NZB/W F1, bear the activity-reducing T89I mutation in Dnase1L3. Dnase1L3 T89I has an eight-fold decrease in barrier-to-transfection activity, while the endonuclease activity is only decreased two-fold compared to the wildtype, providing a tool with which to dissect Dnase1L3 trafficking in SLE. We hypothesized that Dnase1L3 T89I localizes to the nucleus, which decreases barrier-to-transfection activity and enhances SLE onset. We transfected HEK cells with wild type or T89I Dnase1L3, and determined the subcellular localization of Dnase1L3. We found that the majority of wild type Dnase1L3 is secreted from the cell, while Dnase1L3 T89I showed increased nuclear localization. Since Dnase1L3 alters inflammasome function, we tested whether inflammatory stimuli alter Dnase1L3 trafficking. LPS treatment of cells transfected with Dnase1L3 T89I reduced its nuclear localization. Altered Dnase1L3 trafficking may impair inflammasome function, since macrophages from NZB/W F1 mice secreted less IL-1β than wild type mice. Overall, the increase in nuclear localization of Dnase1L3 T89I suggests that barrier to transfection or extracellular nuclease activity may promote IL-1β release and protect against pediatric-onset SLE.

Correlation between disease activity of pediatric-onset systemic lupus erythematosus and level of vitamin D in Taiwan: A case-cohort study.

Vitamin D deficiency has been associated with systemic lupus erythematosus (SLE), but there is no consensus on the role of serum vitamin D in evaluating or predicting disease activity. This study aimed to demonstrate the direct correlation between vitamin D level and pediatric-onset SLE disease activity by a retrospective cohort study design. Thirty-five patients with pediatric-onset SLE and paired sera at the active and inactive disease states were enrolled. Disease activity was defined by Systemic Lupus Erythematosus Disease Activity Index 2000, and active lupus nephritis (LN) was defined as active urine sediment, and proteinuria >2+on stick or >500mg/day. All data were reviewed and calculated from previous medical records. The levels of both vitamin D2 and vitamin D3 were checked by electrochemiluminescence immunoassay. Serum 25-hydroxyvitamin D (25-OH D) levels in the active status were significantly lower compared to that in inactive disease status (12.0±7.2ng/mL vs. 15.4±7.4ng/mL, p=0.005). A subgroup analysis revealed that at active disease status, patients with LN had lower 25-OH D levels than patients without LN (16.3±8.2ng/mL vs. 9.8±5.6ng/mL, p=0.023). Moreover, there is a significant inverse correlation between serum 25-OH D levels and Systemic Lupus Erythematosus Disease Activity Index 2000 at both inactive (r=-0.335, p=0.003) and active (r=-0.373, p=0.016) disease status. Serum vitamin D levels are inversely correlated with SLE disease activity at both active and inactive disease status, and also with the presence of LN at active disease stage.

Transition of Care and Health‐Related Outcomes in Pediatric‐Onset Systemic Lupus Erythematosus

Transition from pediatric to adult care is a complex process and can negatively impact patients with chronic disease. We describe the transition experience of patients with pediatric-onset systemic lupus erythematosus (SLE) and its associated outcomes in adulthood. A telephone survey of 41 pediatric-onset SLE patients was conducted following their transition to adult care. Data on medical and social outcomes during and after the transition were collected. Health status was compared to retrospectively collected baseline data at pediatric discharge. The mean ± SD followup interval was 5 ± 3.7 years; the mean ± SD age at followup was 24 ± 4.2 years. More than half of patients (22 of 41) experienced transition difficulties, primarily due to loss of insurance and emotional readjustment, which were associated with poor symptom control (P = 0.03) and multiple organ system involvement (P = 0.05) at followup. After the transition, most patients (35 of 41) were followed by an adult-care rheumatologist, and the majority (37 of 41) reported recent symptoms of active disease; 41% (13 of 29) had developed symptoms suggestive of new renal manifestations following transition. One-third (15 of 41) reported new or ongoing neuropsychiatric symptoms. Both renal and neuropsychiatric manifestations were associated with unemployment (P < 0.05). Direct referral by a pediatric rheumatologist was associated with fewer hospitalizations following transition (P = 0.04). The majority of patients transitioned successfully to adult rheumatologic care. Major challenges were loss of insurance and attachment to pediatric providers, highlighting the importance of a structured transition process that focuses on providing emotional and financial guidance. Disease activity in pediatric-onset SLE remains high throughout adulthood, with morbidity primarily related to renal and neuropsychiatric manifestations.

Mosaic tetrasomy 9p: a mendelian interferonopathy associated with pediatric-onset overlap myositis

Background and objectives Pediatric-onset inflammatory myositis (IM) and systemic lupus erythematosus (SLE) are rare inflammatory diseases. They result from the complex interaction between genetic and environmental factors. An increasing number of Mendelian conditions predisposing to the development of SLE have been recently identified. They mostly include monogenic conditions, especially type I interferonopathies, associated with an up-regulation of type I interferon (IFN), a key cytokine in SLE and some IM pathogenesis.

Multicentric Prevalence Study of Anti-P Ribosomal Autoantibodies in Juvenile Onset Systemic Lupus Erythematosus Compared With Adult Onset Systemic Lupus Erythematosus

ObjectiveTo investigate the prevalence and associations with clinical manifestations of anti-P ribosomal antibodies in patients with juvenile-onset and adult-onset systemic lupus erythematosus (SLE). MethodsClinical and serological data of 30 patients with juvenile-onset SLE (age at onset younger than 16 years) were compared with data of 92 patients with adult-onset SLE. Symptoms occurring during the entire disease course were considered. Anti-P ribosomal antibodies were tested by ELISA. ResultsAnti-P ribosomal antibodies were found significantly more often in pediatric-onset SLE patients (26.7% vs 6.5%; OR=5.21 [95% CI=1.6–16.5], P=.003). Alopecia (OR=10.11, 95% CI=1.25–97) and skin rash (non-discoid) (OR=4.1, 95% CI=1.25–13.89) were significantly associated with anti-P ribosomal antibodies. ConclusionAnti-ribosomal P antibodies are more often found in patients with juvenile SLE. Alopecia and skin rash were the only clinical manifestations associated to anti-ribosomal P antibodies.

AB0902 Pubescent Status-Related Differential Presentation in Pediatric-Onset Systemic Lupus Erythematosus: an Experience in the Single Center

BackgroundPediatric-onset SLE (pSLE) represents 10-20% of all SLE patients, and several studies suggest that SLE tends to be more severe in pSLE than in adult-onset SLE. However, the impact of...

Estudio multicéntrico de prevalencia de anticuerpos antirribosomal P en lupus eritematoso sistémico de comienzo juvenil comparado con lupus eritematoso sistémico del adulto

ObjectiveTo investigate the prevalence and associations with clinical manifestations of anti- P ribosomal antibodies in patients with juvenile-onset and adult-onset systemic lupus erythematosus (SLE). MethodsClinical and serological data of 30 patients with juvenile-onset SLE (age at onset younger than 16 years old) were compared with data of 92 patients with adult-onset SLE. Symptoms occurring during the entire disease course were considered. Anti- P ribosomal antibodies were tested by ELISA. ResultsAnti- P ribosomal antibodies were found significantly more often in pediatric-onset SLE patients (26.7% vs. 6.5%; OR=5.21 [CI95%=1.6-16.5], p=0.003). Alopecia (OR=10.11, CI 95%=1.25-97) and skin rash (non discoid) (OR=4.1, CI 95%=1.25-13.89) were significantly associated with anti- P ribosomal antibodies. ConclusionAnti-ribosomal P antibodies are more often found in patients with juvenile SLE. Alopecia and skin rash were the only clinical manifestations associated to anti-ribosomal P antibodies.

PReS-FINAL-2355: Comparison of pediatric and adult SLE genetic load

Systemic Lupus Erythematosus (SLE) is a chronic, multisystem autoimmune disease that is the result of the interaction between genetic and environmental factors. Specific genes have been found to be related to the development of SLE and also single nucleotide polymorphisms (SNPs) have been associated to this condition. Although patients with pediatric-onset SLE (pSLE) and adult-onset SLE (aSLE) differ in disease presentation, activity, and outcomes, all studies to date have not found any specific or unique set of genes in pSLE compared to aSLE. Moreover, it has been shown that the frequency of genes in these two SLE populations is the same. However, is possible that an increased genetic load may explain the earlier onset and more severe disease seen in pSLE as compared to aSLE patients.

The outcome of patients with renal involvement in pediatric-onset systemic lupus erythematosus – a 20-year experience in Asia

Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age, but 15-20% of cases are diagnosed during childhood. It is important for physicians to understand the epidemiology and clinical presentation for early detection and diagnosis of this disease in difference races. The aim of this retrospective review was to provide a 20-year experience for initial clinical and laboratory manifestations and outcomes in pediatric-onset SLE (pSLE) in a medical center in Asia. We reviewed medical records between April 1990 and June 2012 of patients with a diagnosis of International Classification of Diseases, Ninth Revision (ICD-9) code 710.0 (SLE), who admitted or received follow-up in the Department of Pediatrics at Chang Chung Memorial Hospital. Patients with a diagnosis of SLE prior to their 18th birthday and followed up at our hospital were eligible for inclusion in this study. Medical records regarding age, gender, date of birth and diagnosis, clinical manifestations at diagnosis, laboratory results, image studies and the classification criteria were reviewed. Patients received regular outpatient department follow-up and laboratory survey every 1-6 months. The study cohort consisted of 189 patients; 164 females (86.87%) and 25 males (13.23%). The overall mean age at pSLE diagnosis was 12.62 ± 2.77 years. The most common clinical symptom was malar rash, followed by arthritis and oral ulcers. There was no significant difference in clinical and laboratory manifestations between females and males. More than half of the patients presented with renal involvement initially. The most common histological finding was Class IV lupus nephritis (LN), especially in males (p = 0.034) and young age. Even with severe LN, the rate of end-stage renal disease (ESRD) was low if adequate treatment was initiated. The 5, 10 and 15-year ESRD-free survival rates were 95.4%, 94.0% and 89.9% in patients with biopsy-proven LN. However, infection was the leading cause of mortality. Therefore, aggressive treatment for major organ involvement is important, but physicians must also be aware of fatal infection. The overall survival rates were 5 years: 93.4% and 10-20 years: 89.6%.

Paediatric-onset systemic lupus erythematosus

Paediatric-onset systemic lupus erythematosus (SLE) is usually more severe than its adult counterpart. In particular, there is a higher incidence of renal and central nervous system involvement. Specific measures to assess disease activity and damage have been implemented. The disease is very rare before the fifth birthday and therefore the onset of an SLE picture in the first years of life should lead to the suspicion of the presence of one of the rare monogenic diseases that causes SLE or of one of those congenital diseases that has been showed to be closely associated with the SLE.

Cardiovascular risk in pediatric-onset rheumatological diseases

Cardiovascular morbidity and mortality are becoming major health concerns for adults with inflammatory rheumatic diseases. The enhanced atherogenesis in this patient population is promoted by the exposure to traditional risk factors as well as nontraditional cardiovascular insults, such as corticosteroid therapy, chronic inflammation and autoantibodies. Despite definite differences between many adult-onset and pediatric-onset rheumatologic diseases, it is extremely likely that atherosclerosis will become the leading cause of morbidity and mortality in this pediatric patient population. Because cardiovascular events are rare at this young age, surrogate measures of atherosclerosis must be used. The three major noninvasive vascular measures of early atherosclerosis - namely, flow-mediated dilatation, carotid intima-media thickness and pulse wave velocity - can be performed easily on children. Few studies have explored the prevalence of cardiovascular risk factors and even fewer have used the surrogate vascular measures to document signs of early atherosclerosis in children with pediatric-onset rheumatic diseases. The objective of this review is to provide an overview on cardiovascular risk and early atherosclerosis in pediatric-onset systemic lupus erythematosus, juvenile idiopathic arthritis and juvenile dermatomyositis patients, and to review cardiovascular preventive strategies that should be considered in this population.

Clinical and immunological profile of systemic lupus erythematosus

Pediatric onset systemic lupus erythematosus (SLE) is not uncommon and female to male ratio varies. Pediatric SLE patients have more severe disease at onset, higher rates of organ involvement and more aggressive clinical course than adults. We compared the clinical and immunological parameters among pediatric SLE and adult SLE from Western India. Twenty five children and 60 adult patients fulfilling American College of Rheumatology SLE criteria were included. Antinuclear antibodies, anti-dsDNA and complement (C3, C4) levels were tested. Of 25 pediatric SLE patients studied, 24% showed CNS involvement vs. 8.3% in adults SLE (P=0.0499). Lupus nephritis was seen in 75% adult patients vs. 52% among children. Hepatosplenomegaly was noted more among adult SLE 26.8% vs 12% among children. Alopecia was an exclusive features among adult SLE.

What is the Background Incidence of Malignancy in Children with Rheumatic Disease?

Until recently, relatively little was known about the background risk of malignancy in pediatric rheumatic diseases. Worrying reports about the development of malignancies in children treated with new biologic agents have prompted rigorous studies of the incidence of malignancy associated with juvenile idiopathic arthritis (JIA). These studies reveal that JIA is likely to be associated with an increased risk of incident malignancy, irrespective of treatment with new biologic agents. A preliminary study indicates that the background risk of malignancy is also elevated in pediatric-onset systemic lupus erythematosus. On the basis of simple observation, the background risk of malignancy among children with Sjögren syndrome and dermatomyositis seems much lower than the markedly elevated risk found in adults with the same diagnoses. Clearly, the background risk of malignancy must be considered in any evaluation of the safety of new therapeutic agents.

Impaired phagocytosis and susceptibility to infection in pediatric-onset systemic lupus erythematosus

Impaired function of polymorphonuclear cells (PMNs) in systemic lupus erythematosus (SLE) leads to severe gram-positive and gram-negative bacterial infection, and to major morbidity and mortality. Few studies have focused on the association of impaired function of PMNs and SLE patients' susceptibility to infection. This study aimed to analyze function of PMNs in peroxidase production, chemotaxis, and phagocytosis in pediatric-onset SLE with severe infection. This study compared function of PMNs among pediatric-onset SLE patients with and without histories of severe infection and in normal control subjects. Human peripheral blood PMNs were isolated from patients and controls. Function of PMNs was measured by analyzing peroxidase, chemotaxis, and phagocytic activities. Different disease activity and severity, and drug use in newly diagnosed SLE patients were also compared. In total, 34 SLE patients (12 patients with severe infection, 22 patients without infection) and 25 healthy controls were analyzed. There were no differences in function of PMNs between SLE patients with or without severe infection. Regardless of infection status, medication, and disease activity, SLE patients had impaired phagocytic ability against Salmonella-specific lipopolysaccharides (LPS) compared with normal controls (p < 0.01). The use of immunosuppressants did not influence phagocytic ability against Salmonella-derived LPS. Immunosuppressant agents do not influence phagocytic ability against Salmonella in SLE subjects. Impaired phagocytosis against Salmonella is prominent in pediatric-onset SLE subjects, which may result in the high prevalence of Salmonella infection. There is no deficiency of peroxidase production and chemotaxis activity among SLE subjects.

Cancer risk in childhood-onset systemic lupus

IntroductionThe aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE).MethodsWe ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population.ResultsThere were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian; mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this interval, only three invasive cancers were expected. However, 14 invasive cancers occurred with an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers were found (two non-Hodgkin’s lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1 to 15.2). The SIRs stratified by age group and sex, were similar across these strata. There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis.ConclusionsThese results suggest an increased cancer risk in pediatric onset SLE versus the general population. In absolute terms, this represents relatively few events. Of note, risk may be highest only after patients have transferred to adult care.

Patterns and influence of familial autoimmunity in pediatric systemic lupus erythematosus

BackgroundA high prevalence of autoimmune disease (AD) has been documented in relatives of adult patients with systemic lupus erythematosus (SLE). However, data on familial inheritance patterns in pediatric SLE patients is scarce.FindingsThe charts of 69 patients with pediatric-onset SLE were reviewed retrospectively. The primary aim was to describe the prevalence and types of AD in relatives of children with SLE. The secondary aims were: 1) to compare severity of SLE in children with and without relatives affected by AD, and 2) to evaluate the impact of baseline demographics on severity of SLE in subjects. At diagnosis, 42% of subjects had one or more first, second, or third degree relative(s) with AD; and 32% of subjects had one or more first degree relative(s) with AD. The most common diseases in relatives of children with SLE were SLE (21%) and thyroid disease (15%). Subjects with no family history of AD were more likely to have severe SLE. SLE severity in subjects did not differ by gender. Children presenting with SLE at an earlier age were found to have more severe disease.ConclusionsThis study demonstrated a high prevalence of AD in families of children with SLE, although a family history of AD did not correlate with more severe SLE in subjects. Future larger studies are necessary to elucidate patterns of familial inheritance and baseline patient characteristics that may affect severity of disease in pediatric SLE.

Long-term education and employment outcomes in pediatric-onset systemic lupus erythematosus

Methods Data derive from the 2007 cycle of the LOS, an annual longitudinal telephone survey of diverse English-speaking subjects with confirmed SLE. Only subjects of working age (22-50 years) were included in the analysis (N=326). Subjects were classified as juvenile-onset if age at diagnosis was < 18 years (N=70). Outcome variables included completion of a bachelor’s degree and current employment status. We used logistic regression to compare pSLE and aSLE with and without adjustment for other characteristics that could affect educational attainment and employment outcomes. Age, gender, ethnicity and the presence of renal disease were included as predictors of educational attainment. Predictors of employment included age, gender, ethnicity, renal disease, completion of a bachelor’s degree, self-reported disease

Measurement of autoantibodies in pediatric- and adolescent-onset systemic lupus erythematosus and their significant relationship with disease-associated manifestations

Purpose Pediatric-onset systemic lupus erythematosus (SLE) patients are prone to develop major organ involvement and a more severe disease course than adult-onset SLE. Early management of the disease is necessary to prevent further complications, which can partly be accomplished by monitoring autoantibody levels and understanding their significance in the disease process. We evaluated an autoantibody profile in pediatric- and adolescentonset systemic lupus erythematosus (SLE) patients to determine the clinical and statistical associations with disease-related manifestations. Methods Sera from 53 SLE patients and 22 healthy individuals were collected. Antibodies to C1q, histone, chromatin, ribosomal P, double stranded (ds) DNA, and high avidity (HA) dsDNA were measured by enzyme-linked immunosorbent assays. Patient records were evaluated for clinical and laboratory associations. Results SLE patients exhibited significantly elevated levels of all measured autoantibodies when compared to healthy individuals (p<0.05). The most prevalent autoantibody measured in the SLE cohort was anti-C1q antibodies, found in 58% of SLE patients. Anti-C1q antibodies correlated significantly with proteinuria, fever, urinary casts, and decreased complement levels (p<0.05). Anti-C1q antibodies were significantly elevated in SLE patients with active disease (127U) compared to patients who were inactive (63U) (p<0.05). Anti-C1q antibodies and antihistone antibodies were significantly elevated in patients with class III/IV nephritis compared to class I/II/V nephritis (p<0.05). SLE patients with active nephritis at the time of sample collection demonstrated significantly elevated levels of anti-C1q antibodies compared to those without active nephritis (191U v. 80U, p<0.05), also exhibiting 100% specificity for active nephritis, proteinuria, and urinary casts. Chart-documented anti-dsDNA antibodies were positive in 28 SLE patients, INOVA antidsDNA antibodies in 21 patients, and HA anti-dsDNA antibodies in 8 patients. However, measuring HA antidsDNA antibodies rather than conventional anti-dsDNA antibodies may prove more accurate by eliminating low avidity, weakly bound antibodies detected by traditional assays. Anti-histone antibodies correlated significantly with leukopenia, hemolytic anemia, and anti-dsDNA and HA anti-dsDNA antibodies (p<0.05).