Systemic lupus erythematosus (SLE) is characterized by increased cardiovascular risk in adult-onset and childhood-onset SLE (cSLE). Type I interferons (IFNs) appear to play a prominent role in premature vascular damage in adult SLE, at least in part, by inducing impairments in the phenotype and function of endothelial progenitor cells (EPCs), thereby hampering vascular repair. It is not clear if EPC dysfunction is present in cSLE in association with a type I IFN signature.
Phenotype and numbers of EPCs were quantified in patients with cSLE, juvenile idiopathic arthritis (JIA), and matched healthy controls (HC). In a separate cohort of cSLE subjects, markers of subclinical atherosclerosis and endothelial dysfunction were quantified using standardized protocols, and analyzed for associations with type I IFN serum activity.
EPC numbers and function were significantly decreased in cSLE as compared to JIA and HC. cSLE serum impaired HC EPC differentiation into mature endothelial cells, an effect blocked by type I IFN pathway inhibition. Type I IFN serum activity was not significantly associated with subclinical atherosclerosis and endothelial function in cSLE.
As in adults, cSLE is characterized by phenotypic and functional EPC abnormalities, likely triggered by type I IFNs. While cross-sectional analysis detected no global association between type I IFN signatures and vascular measures of subclinical atherosclerosis, longitudinal assessments are needed to evaluate if progression of vascular damage in cSLE is associated with type I IFNs as in the adult population.
interferons; pediatric SLE; atherosclerosis; biomarker
To evaluate the influence of ethnicity on self-reported health related quality of life (HRQOL) in the Canadian childhood-onset systemic lupus Erythematosus (cSLE) population.
Patients with cSLE at 4 pediatric centers were consecutively enrolled. Sociodemographics and multiple disease activity measures were collected. The Child Health Questionnaire (CHQ) was administered and analysed by ethnicity.
We enrolled 213 cSLE patients, and complete data from 196 patients with these ethnicities were analysed: White (33%), Asian (32%), South Asian (16%), Black (11%), Latino/Hispanic (5%), and Aboriginal (4%). Compared to healthy children, cSLE patients rated their HRQOL significantly more poorly in 9 of 10 individual domains, and in 4 of 10 domains when compared to a cohort of juvenile arthritis. Within the cSLE cohort, CHQ scores were lower in 5 of 10 domains in white patients versus nonwhite ethnicities (p<0.05 for each). Physical summary scores (PhS) were lower for white patients compared to the other ethnicities aggregated together (46.0 ± 11.9 vs. 50.4 ± 10.1, p = 0.009); however, psychosocial summary scores (PsS) were similar among the groups (40.5 ± 14.6 vs. 42.8 ± 12.7, p = 0.26). Disease activity measures, including Systemic Lupus Disease Activity Index, Systemic Lupus Activity Measure and physician global visual analogue scale were similar across ethnicities. However, patient reported Systemic Lupus Activity Questionnaire symptom scores were greater in patients of white ethnicity compared to those of Asian ethnicity (8.2 ± 5.8 vs. 4.5 ± 4.7, p=0.004).
The self- and parent-reported health status of Canadian cSLE patients differed across ethnicities, with white patients reporting lower HRQOL, despite similar and overall low disease activity.
child; adolescent; pediatric; health status; spydergram; autoimmune disease; chronic illness; systemic lupus erythematosus; child health questionnaire
To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA).
This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) <30 kg; 8 mg/kg for BW ≥30 kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab.
In part 1, 188 patients received tocilizumab (<30 kg: 10 mg/kg (n=35) or 8 mg/kg (n=34); ≥30 kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: −0.21; 95% CI −0.35 to −0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY).
Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis.
Trial registration number:
DMARDs (biologic); Juvenile Idiopathic Arthritis; Treatment
Key Clinical Message
Systemic lupus erythematosus should be included in the differential diagnosis of every adolescent with pancytopenia. An accurate diagnosis with the appropriate therapy is vital and can cause lasting reversal of this condition.
Systemic lupus erythematosus should be included in the differential diagnosis of every adolescent with pancytopenia. An accurate diagnosis with the appropriate therapy is vital and can cause lasting reversal of this condition.
Aplastic anemia; pancytopenia; systemic lupus erythematosus
Participants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy.
Subgroups were prespecified and defined by age (> or ≤15.5 years), systemic lupus erythematosus (SLE) duration (> or ≤24 months), pubertal status (Tanner score ≥4 as post-pubertal or <4 as pre-pubertal), low density lipoprotein cholesterol (LDL) (≥ or <110 mg/dl) and high-sensitivity C reactive protein (hsCRP) (≥ or <1.5 mg/l). A combined subgroup (post-pubertal and hsCRP≥1.5 mg/l) was compared to all others. Longitudinal linear mixed-effects models were developed using 12 CIMT and other secondary APPLE outcomes (lipids, hsCRP, disease activity and damage, and quality of life). Three way interaction effects were assessed for models.
Significant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures.
Pubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy.
Systemic lupus erythematosus (SLE) is a multisystem disease with significant morbidity and even mortality. Cytomegalovirus (CMV) is a ubiquitous herpesvirus that, similar to SLE, can also lead to significant morbidity and mortality in the immunocompromised host. The relationship between SLE and CMV is complex, with observations suggesting that CMV induces the autoimmunity of SLE in addition to occurring in the immunocompromised host with known SLE. In this article, we first consider CMV infection in the immunocompetent host, and further examine how this infection differs in the patient with SLE. We focus on disease mechanisms, CMV detection and treatment. We review the differences between CMV infection, syndrome and disease, as identifying the correct state will determine the appropriate treatment. We propose guidelines for the screening and management of CMV infection in childhood-onset SLE, and recognize that further study in this population is required to increase our understanding of the interplay between these disease entities.
childhood; CMV; complication; Cytomegalovirus; detection; guidelines; infection; lupus; pediatric
To determine the influence of ethnicity and sociodemographic factors on disease characteristics of the Canadian Pediatric Lupus population.
Childhood-onset SLE (cSLE) patients at four pediatric centers in Halifax, Montreal, Toronto and Vancouver were consecutively recruited. Sociodemographics and disease data were collected. Patients were categorized by their primary self-selected ethnicity, and exploratory cluster analyses were examined for disease expression by ethnicity.
We enrolled 213 cSLE patients, and ethnicity data were available for 206 patients: White (31%), Asian (30%), South Asian (15%), Black (10%), Latino/Hispanic (4%), Aboriginal (4%) and Arab/Middle Eastern (3%). The frequency of clinical classification criteria (malar rash, arthritis, serositis and renal disease) and autoantibodies significantly differed among ethnicities. Medications were prescribed equally across ethnicities: 76% were taking prednisone, 86% anti-malarials, and 56% required additional immunosuppressants. Cluster analysis partitioned three main groups – mild (N = 50), moderate (N = 82) and severe (N = 68) disease clusters. Only 20% of White patients were in the severe cluster compared to 51% of Asian and 41% of Black patients (p=0.03). However, disease activity indices and damage scores were similar across ethnicities.
Canadian cSLE patients reflect our multi-ethnic population, with differences in disease manifestations, autoantibody profiles and severity of disease expression by ethnicity.
child; adolescent; race; socioeconomic status; sociodemographics; autoimmune disease; chronic illness; systemic lupus erythematosus; paediatric
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.
The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE).
We 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.
There 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.
These 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.
Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB.
We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18–22.6 weeks gestation). Using human fetal hearts (20–22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305–319 of the extracellular loop linking transmembrane segments S5–S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells.
Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets.
Following the introduction of the ILAR criteria for juvenile idiopathic arthritis, juvenile psoriatic arthritis (JPsA) has become a better recognized category within the inflammatory arthritides of childhood. There are fewer reports describing the characteristics and long-term outcome of patients with JPsA than other subtypes of JIA.
The aim of our study was to determine the long-term outcome and clinical course of patients with juvenile psoriatic arthritis (JPsA) and to define subgroups of JPsA.
Clinical records of all patients meeting criteria for JPsA were reviewed and divided into 4 groups depending on their clinical features and onset type. Patient characteristics and clinical features at onset and during follow-up were determined.
The cohort consisted of 119 patients: 65 with oligoarticular-onset (55%; persistent 44 and extended 21), 34 (29%) with RF(-) and 4 (3%) RF(+) polyarticular and 16 (13%) enthesitis-related arthritis (ERA). At diagnosis patients with ERA were oldest and more commonly male (p=0.001 and =0.01 respectively). Patients with a polyarticular course had more involvement of small joints of the hands and wrist when compared to patients with persistent oligoarticular and ERA (p<0.001) while patients with ERA had more hip and sacroiliac arthritis (p<0.001 for both). Nail changes were seen in 66 patients (57%) and were associated with DIP involvement (p=0.0034).
Outcome: Time to first inactive disease on, but not off, therapy was significantly longer among patients with polyarticular course when compared to oligoarticular and ERA (p=0.016 and p=0.48 respectively). Patients with polyarticular course more frequently had contractures during follow-up than other groups (p=0.01).
The long-term outcome of with JPsA was generally good. Patients with JPsA did not appear to form distinct sub-group of patients but rather resembled JIA patients with onset types without psoriasis.
To formulate consensus treatment plans (CTPs) for induction therapy of newly-diagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (jSLE).
A structured consensus formation process was employed by the members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) after considering the existing medical evidence and current treatment approaches.
After an initial Delphi survey (response rate 70%), a 2-day consensus conference, and two follow-up Delphi surveys (response rates 63–79%), consensus was achieved for a limited set of CTPs addressing the induction therapy of proliferative LN. These CTPs were developed for prototypic patients defined by eligibility characteristics, and included immunosuppressive therapy with either mycophenolic acid orally twice per day, or intravenous cyclophosphamide once per month at standardized doses for six months. Additionally, the CTPs describe three options for standardized use of glucocorticoids; including a primarily oral, a mixed oral/intravenous, and a primarily intravenous regimen. There was consensus on measures of effectiveness and safety of the CTPs. The CTPs were well accepted by the pediatric rheumatology providers treating children with LN, and up to 300 children per year in North America are expected to be candidates for the treatment with the CTPs.
CTPs for induction therapy of proliferative LN in jSLE based on the available scientific evidence and pediatric rheumatology group experience have been developed. Consistent use of the CTPs may improve the prognosis of proliferative LN, and support the conduct of comparative effectiveness studies aimed at optimizing therapeutic strategies for proliferative LN in jSLE.
children; SLE; lupus nephritis; induction therapy; consensus
The goal of the study was to determine the predictive validity of neutrophil gelatinase-associated lipocalin (NGAL) in anticipating worsening of global and renal childhood-onset SLE (cSLE) disease activity.
111 patients with cSLE were enrolled in a longitudinal, prospective study with quarterly study visits and had at least three study visits. At each visit global disease activity was measured using three external standards: numerically converted BILAG index, SLEDAI-2K and physician assessment score. Renal and extrarenal disease activity were measured by the respective domain scores. The disease course over time was categorized at the most recent visit (persistently active, persistently inactive, improved or worsening). Plasma and urinary NGAL levels were measured by ELISA, and urinary NGAL was standardized to urinary creatinine. The longitudinal changes in NGAL levels were compared to the changes in SLE disease activity using mixed effects models.
Significant increases in standardized urinary NGAL levels of up to 104% were detected up to three months before worsening of lupus nephritis (as measured by all three external standards). Plasma NGAL levels increased significantly by as much as 20% up to three months before worsening of global SLE disease activity as measured by all three external standards. Plasma NGAL levels increased significantly by 26% as early as three months prior to worsening of lupus nephritis as measured by the renal BILAG domain score.
Serial measurement of urinary and plasma NGAL levels may be valuable in predicting impending worsening of global and renal cSLE disease activity.
Childhood-onset systemic lupus erythematosus; lupus nephritis; neutrophil gelatinase-associated lipocalin (NGAL); renal biomarker
Lupus nephritis (LN) is among the main determinants of poor prognosis in systemic lupus erythematosus (SLE). The objective of this study was to 1) isolate and identify proteins contained in the LN urinary protein signature (PS) of children with SLE; 2) assess the usefulness of the PS-proteins for detecting activity of LN over time. Using surface-enhanced or matrix assisted laser desorption/ionization time of flight mass spectrometry, the proteins contained in the LN urinary PS were identified. They were transferrin (Tf), ceruloplasmin (Cp), α1-acid-glycoprotein (AGP), lipocalin-type prostaglandin-D synthetase (L-PGDS), albumin and albumin-related fragments. Serial plasma and urine samples were analyzed using immunonephelometry or ELISA in 98 children with SLE (78% African-American) and 30 controls with juvenile idiopathic arthritis. All urinary PS-proteins were significantly higher with active versus inactive LN or in patients without LN (all p<0.005), and their combined area under the receiver operating characteristic curve was 0.85. As early as 3 months before a clinical diagnosis of worsening LN, significant increases of urinary Tf, AGP (both p < 0.0001) and L-PGDS (p < 0.01) occurred, indicating that these PS-proteins are biomarkers of LN activity and may help anticipate the future course of LN.
To evaluate risk factors of sub-clinical atherosclerosis in a pediatric SLE population.
A prospective multicenter cohort of 221 patients underwent baseline measurements of carotid intima medial thickening (CIMT) as part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. SLE disease measures, medications, and traditional risk factors for atherosclerosis were assessed. A standardized protocol was used to assess thickness of the bilateral common carotids and mean maximal IMT of 12 segments. Univariable analysis identified potential associations with CIMT that were examined in multivariable linear regression modeling.
Based on mean-mean common or mean-max CIMT as the dependent variable, univariable analysis showed significant associations with increased CIMT: increasing age, longer SLE duration, minority status, higher BMI, male sex, increased creatinine clearance, higher Lp(a), proteinuria, azathioprine use, and prednisone dose. Azathioprine use (P=0.005 for mean-mean common; P=0.102 for mean-max model) and male sex (P< 0.001) were both associated with increases in mean-max CIMT. Moderate dose prednisone (0.15–0.4 mg/kg/day) was associated with decreases in mean-max CIMT (P=0.024) while high or low dose prednisone was associated with mean-mean common CIMT (P=0.021) or mean-max CIMT (P=0.064), respectively. BMI (P<0.001) and creatinine clearance (P=0.031), remained associated with increased mean-mean common CIMT, while increasing age (P<0.001) and increasing Lp(a) (P=0.005) were associated with increased mean-max CIMT.
Traditional as well as non-traditional risk factors are associated with increased CIMT in pediatric SLE patients in this cohort. Azathioprine treatment was associated with increased CIMT. The relationship of CIMT with prednisone dose may not be linear.
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility.
Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 genes on chromosome 2 were genotyped using Illumina platform as a part of extensive association study in a large collection of 9923 lupus cases and controls from different racial groups. DNA from patients and controls was obtained from peripheral blood. Principal component analyses and population based case-control association analyses were performed and the p values, FDR q values and Odds ratios with 95% confidence intervals (95% CIs) were calculated.
We observed strong genetic associations with SLE and multiple SNPs located within the STAT4 gene in different ethnicities (Fisher combined p= 7.02×10−25). In addition to strong confirmation of the association in the 3rd intronic region of this gene reported previously, we identified additional haplotypic association across STAT4 gene and in particular a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to the proximity to STAT4.
Our findings indicate that the STAT4 gene is likely to be a crucial component in SLE pathogenesis among multiple racial groups. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets.
To assess the long-term efficacy and safety of infliximab plus methotrexate in juvenile rheumatoid arthritis (JRA).
Patients eligible for the open-label extension (OLE, weeks 52–204) received infliximab 3–6 mg/kg every 8 weeks plus methotrexate.
Of the 78/122 (64%) children entering the OLE, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (eight patients) or patient/physician/sponsor requirement (eight patients). Infliximab (mean dose 4.4 mg/kg per infusion) was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At week 204, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24% and 13%, respectively.
In the limited population of JRA patients remaining in the study at 4 years, infliximab was safe and effective but associated with a high patient discontinuation rate.
Clinical trials registration number NCT00036374.
The first case of Kawasaki syndrome presenting as acute severe hepatitis with coagulopathy, in association with an acute Epstein-Barr virus infection is reported. This case supports the hypothesis that Epstein-Barr virus may play a role in the etiology of Kawasaki syndrome and serves as a reminder that a diagnosis of Kawasaki syndrome should be considered for a persistently febrile child, even in the face of an atypical presentation.
Coagulopathy; Hepatitis; Kawasaki syndrome