[Show abstract][Hide abstract] ABSTRACT: Sleep is an emerging area of concern in children with juvenile idiopathic arthritis (JIA). Research shows the presence of poor sleep quality and related adverse outcomes in pediatric pain populations, including JIA, but few studies have examined the prospective patterns of association between sleep and associated outcomes. This prospective study evaluated the direction and magnitude of associations between subjective sleep characteristics (sleep quality, difficulty initiating sleep, and sleep duration), pain intensity, and functional limitations in children with JIA. We hypothesized that pain intensity would partially mediate the relationship between sleep and functional limitations.
Children and adolescents with JIA (n=59, age range=8-18) recruited during clinic visits, completed smartphone-based diaries for one month. Subjective sleep characteristics were reported each morning; pain and functioning were assessed three times daily.
As hypothesized, the associations between sleep quality and functional limitations and between difficulty initiating sleep and functional limitations were partially mediated by pain intensity, at any given moment (z=-3.27, P=0.001, z=2.70, P<0.05). Mediation was not detected in a model testing the association between sleep duration, pain intensity, and functional limitations (z=-0.58, P=0.56).
Results suggest that sleep is integral to understanding the momentary association between pain intensity and functioning in children with JIA.
Full-text · Article · Sep 2015 · The Clinical journal of pain
[Show abstract][Hide abstract] ABSTRACT: ᅟ
Avascular necrosis (AVN) occurs in several chronic illnesses, including systemic lupus erythematosus (SLE), but can also occur in healthy children. There are multiple theories to explain why and how AVN occurs, but an exact mechanism has yet to be unraveled. AVN in the pediatric lupus population is understudied. The Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, provides an excellent venue to conduct an exploratory analysis to assess associations between AVN and demographics, SLE disease activity and vitamin D deficiency. Herein we present a brief report describing our findings, as well as reviewing the literature on AVN in SLE and other entities.
ClinicalTrials.gov identifier: NCT00065806.
[Show abstract][Hide abstract] ABSTRACT: Objective:
To follow children with juvenile idiopathic arthritis (JIA) who had completed at least 6 months of the TRial of Early Aggressive Therapy (TREAT) clinical study for an additional 2 years, describing safety of early aggressive treatment, disease activity, function, and duration of clinical inactive disease (CID) during followup.
Children were treated as per provider's discretion. Physician, patient/parent, and laboratory measures of disease status as well as safety information were collected at clinic visits every 3 months for up to 2 years.
Forty-eight children were followed for a mean of 28 months (range 12-42) beyond the end of the TREAT study. Half of patients were in CID for > 50% of their followup time. Overall, 88% of patients achieved CID at > 1 study visit and 54% achieved clinical remission while taking medication. Six patients were in CID for the duration of the study, and, of those, 2 achieved a full year of clinical remission while not taking medication. Active disease was mild: mean physician's global assessment 2.4, active joint count 3.5, parent global evaluation 2.4, Childhood Health Assessment Questionnaire 0.32, erythrocyte sedimentation rate 19 mm/h, and morning stiffness 23 min. There were no serious adverse events or adverse events reported at grade 3 or higher of Common Terminology Criteria for Adverse Events.
Early aggressive therapy in this cohort of patients with polyarticular JIA who had high initial disease activity was associated with prolonged periods of CID in the majority of patients during followup. Those not in CID had low levels of disease activity.
No preview · Article · Sep 2014 · The Journal of Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Objective: Epidemiological associations suggest that vitamin D status may play a role in inflammation and progression of atherosclerosis. Using frozen serum, carotid intima medial thickness (CIMT) measurements and other existing data from the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, we assessed interactions between serum 25-hydroxyvitamin D (25(OH)D), atorvastatin randomisation and CIMT progression rate. Methods: Participants in the 3-year APPLE trial were randomised to placebo or atorvastatin and CIMT progression rate was measured. Baseline frozen serum was used to measure 25(OH)D concentrations. Mixed effect longitudinal models for CIMT progression at 3 years were used to evaluate interaction between vitamin D deficiency (serum 25(OH)D <20 ng/mL) at baseline and atorvastatin or placebo treatment, adjusting for key systemic lupus erythematosus disease variables and cardiovascular risk factors. Results: 201/221 APPLE participants had available samples and were included in this analysis; 61/201 (30%) had vitamin D deficiency at baseline. In adjusted longitudinal modelling, there was significant interaction between baseline vitamin D deficiency and atorvastatin randomisation in 3-year progression of mean-max CIMT. In four out of six carotid segments, there was a greater decrease in mean-max CIMT progression rate in subjects who were treated with atorvastatin compared with placebo if they had baseline serum 25(OH)D levels ≥20 ng/mL. Conclusions: Subjects with serum 25(OH)D ≥20 ng/mL had less mean-max CIMT progression following 3 years of atorvastatin treatment. Results from secondary analyses must be interpreted cautiously, but findings suggest that underlying vitamin D deficiency may be involved in response to atorvastatin in atherosclerosis prevention.
[Show abstract][Hide abstract] ABSTRACT: Objective Epidemiological associations suggest vitamin D may play a role in inflammation and atherosclerosis. Using frozen serum and data from the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, we assessed associations between 25-hydroxyvitamin D [25(OH)D] and measures of systemic lupus erythematosus (SLE) disease activity and cardiovascular risk.
Methods Baseline APPLE serum samples were used to measure 25(OH)D levels. Logistic regression models for vitamin D deficiency [25(OH)D levels <20 ng/mL] were constructed using baseline variables collected as part of the trial, including race, season, latitude, disease duration, disease activity, high-sensitivity C-reactive protein (hsCRP), proteinuria, fasting lipids and carotid intima medial thickness (CIMT).
Results Samples were available from 201 of 221 APPLE subjects; 61/201 (30%) had vitamin D deficiency at baseline. In univariable analysis, baseline vitamin D deficiency was associated with season (p<0.01), minority status (p<0.01), body mass index (p=0.04), duration of SLE (p<0.01), SLICC damage index (p=0.04), hsCRP (p<0.01), mean–max CIMT (p=0.01), LDL-cholesterol (p=0.03) and timed urine protein (p=0.03). In multivariable modelling, vitamin D deficiency was associated with age, latitude, season, minority status, proteinuria and hsCRP.
Conclusions Vitamin D deficiency is common in paediatric lupus and is independently associated with elevated hsCRP, a marker of inflammation that predicts cardiovascular disease risk. Although association is not proof of causation, this association is novel in the paediatric SLE population and suggests that vitamin D deficiency may contribute to heightened inflammation and cardiovascular risk in this population.
Trial register number NCT00065806.
[Show abstract][Hide abstract] ABSTRACT: To determine the elapsed time while receiving aggressive therapy to the first observation of clinically inactive disease (CID), total duration of CID and potential predictors of this response in a cohort of children with recent onset of polyarticular juvenile idiopathic arthritis (poly-JIA).
Eighty-five children were randomized blindly to methotrexate (MTX), etanercept, and rapidly tapered prednisolone (MEP) or MTX monotherapy and assessed for CID over 1 year of treatment. Patients who failed to achieve intermediary endpoints were switched to open-label MEP treatment.
Fifty-eight (68.2%) of the 85 patients achieved CID at 1 or more visits including 18 who received blinded MEP, 11 while receiving MTX monotherapy, and 29 while receiving open-label MEP. Patients starting on MEP achieved CID earlier and had more study days in CID compared to those starting MTX, but the differences were not significantly different. Patients given MEP (more aggressive therapy) earlier in the disease course were statistically more likely to have a higher proportion of followup visits in CID than those with longer disease course at baseline. Those who achieved American College of Rheumatology Pediatric 70 response at 4 months had a significantly greater proportion of followup visits in CID, compared to those who failed to achieve this improvement (p < 0.0001). Of the 32 patients who met criteria for CID and then lost CID status, only 3 fulfilled the definition of disease flare.
Shorter disease duration prior to treatment, a robust response at 4 months, and more aggressive therapy result in a higher likelihood and longer duration of CID in patients with poly-JIA. The original trial from which data for this analysis were obtained is registered on www.clinicaltrials.gov NCT 00443430.
No preview · Article · May 2014 · The Journal of Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Children with organic diseases may experience persistent pain in the presence of controlled disease, as evidenced by little or no measurable disease activity or inflammation. Historically, dualistic definitions of pain have informed standard diagnostic approaches to persistent pain; aggressive investigation and treatment targeting underlying disease, even in the absence of evidence indicating disease escalation. Evidence across disease populations, in children with inflammatory bowel disease, sickle cell disease, and juvenile idiopathic arthritis indicates that persistent pain in these conditions may be better conceptualized as functional in nature, potentially resulting from disordered somatosensory processing including central sensitization. Applying a biopsychosocial understanding of persistent pain and multidisciplinary functional pain management strategies may lead to improved health outcomes.
[Show abstract][Hide abstract] ABSTRACT: In 2009, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) established a longitudinal multi-center, multiple disease U.S. national registry (CARRA Registry) for pediatric rheumatology with the intent of providing a new framework to drive observational clinical research and best practices, evidence-based care. Simultaneously, recognizing that widely variable therapeutic approaches hinder the ability to conduct meaningful comparative effectiveness studies and pragmatic trials in pediatric rheumatic diseases, CARRA investigators convened expert groups to formulate new consensus-based treatment plans (CTPs) in 5 major pediatric rheumatic disease areas. As the CTP approaches are adopted, it is important to establish baseline treatment variability across pediatric rheumatic diseases and clinical sites in the CARRA network. Using longitudinal data from the CARRA Registry, we provide a first description of variability of care across the network.
We examine variations of medication usage across 55 clinical sites in the treatment of 8 rheumatic conditions, including juvenile idiopathic arthritis (JIA), SLE and mixed connective tissue disease (MCTD), juvenile dermatomyositis (JDM), localized scleroderma, systemic sclerosis, juvenile primary fibromyalgia syndrome (JPFS), sarcoidosis, and vasculitis. Management of uveitis in JIA patients was also assessed. Study participants include all CARRA registry subjects enrolled in May 2010 through December 2013. Medications were categorized into 4 major classes: biologics, DMARDs, steroids and NSAIDs. We compare the percentage of patients exposed to each medication class at each; care variations were quantified using dispersion measures of standard deviation and range. A subgroup analysis was conducted to assess care variations among the largest group of subjects with similar characteristics of and low disease activity (JIA subjects with an average active joint count of 0 to 1 averaged over the enrolment period), where treatment were hypothesized to be most similar.
8,869 subjects were included in data analysis. Therapeutic approaches were highly variable for all 8 rheumatic diseases (Table 1, Fig 1). Subgroup analysis for JIA showed persistence of variability (Fig 2).
We quantify a substantial degree of therapeutic practice variability across sites, persisting across disease-severity-matched cohorts. Although enrollment bias is a significant limitation, the magnitude of the variability for the largest cohort (JIA) and persistence across multiple diseases and subtypes supports a widespread effect. This baseline quantification and methods developed for assessing variability will support ongoing efforts to monitor new consensus treatment protocol-based standardization efforts across the CARRA network.
No preview · Article · Mar 2014 · Arthritis and Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Background/Purpose:Consensus treatment plans (CTPs) serve as an alternative strategy to randomized controlled trials for assessing treatment effects. The CTPs for induction therapy of childhood proliferative lupus nephritis (cLN) were developed for use in clinical care; they are based on best available evidence and endorsed by CARRA Pediatric Rheumatologists. They specify two options for immunosuppressive therapy (IV Cyclophosphamide (CP) and oral Mycophenolate (MMF)) and three options for steroid therapy (primarily oral regimen, primarily IV regimen and mixed oral/IV regimen).The purpose of this pilot study was to assess the use of and adherence to the cLN-CTPs, and to estimate rates of renal response and safety and tolerability. Preliminary results are presented here.Methods:Providers at 14 participating CARRA sites agreed to utilize the induction cLN-CTPs for eligible patients. Eligible patients were <20 years old and had biopsy-proven newly diagnosed proliferative cLN; however the CTPs were not intended for patients with concurrent infections, pregnancy or other severe SLE manifestations that would dictate specific therapies different from the cLN-CTPs. Patients were invited to enroll in the CARRA registry for periodic collection of standard clinical SLE and renal outcome measures.Results:To date, 71 potential SLE patients with newly diagnosed proliferative cLN were cared for at 13 sites (87% female, mean age 14.6 yrs, mixed ethnicity [37% Hispanic] and race [41% Caucasian, 30% African American, 9% Asian, 20% other/unknown]). 41 (58%) patients were enrolled in the CARRA registry, a prerequisite for study participation. Reasons for non-enrollment in the registry included failure of being approached in a timely fashion (34%), patients/parents declined participation (4%), and failure to complete consent due to not speaking English (1%). Among the 41 patients who were enrolled in the registry, 29 (43%) were treated according to one of the cLN-CTPs. For induction immunosuppressive therapy, providers selected the CP CTP for 61%, and the MMF CTP for 39% of patients. For induction steroid therapy, providers selected the primarily IV regimen for 43%, mixed IV/oral regimen for 35%, and primary oral regimen for 17% of the patients. Reasons for not using one of the options specified in the CTPs included patients not meeting eligibility characteristics for their use (35%), providers choosing not to use the cLN-CTP (13%), treatment initiated at another institution (7%), and the prescribing physician being unaware of the cLN-CTPs (1.5%).Conclusion:A minority of patients with newly diagnosed proliferative cLN received therapy according to the cLN-CTPs, which are considered the best therapeutic regimen based on available scientific evidence and expert opinion. Important outcome data from many patients was missed by patients not being approached for enrollment in the registry. This suggests that additional efforts are necessary to promote implementation of the cLN-CTPs as we endeavor to perform comparative effectiveness studies and improve the prognosis for children with cLN.
No preview · Article · Mar 2014 · Arthritis and Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Background Avascular necrosis (AVN) can result in significant morbidity. Previous studies suggest that AVN is associated with systemic lupus erythematosus (SLE) and corticosteroid treatment. Hypovitaminosis D has been postulated to play a role in bisphosphonate-associated osteonecrosis of the jaw. Using frozen serum and demographic data from the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial, we conducted an exploratory analysis to assess associations between AVN and demographics, SLE disease activity and vitamin D deficiency, defined as serum 25-hydroxyvitamin D [25(OH)D] < 20 ng/mL.
Methods APPLE trial participants were randomised to placebo or atorvastatin. Frozen serum collected at baseline was used to measure 25(OH)D levels by chemiluminescent assay (IDS, LTD). Univariable analysis of APPLE data at baseline to 3 years was performed using chi- squared test for categorical baseline variables and Wilcoxon signed rank test for continuous variables.
Results Samples were available for 201/221 APPLE participants. 17/201 (8.4%) either had a history of (n = 9) or developed AVN during the study period (n = 8). Vitamin D deficiency, minority status, southern latitude, elevated triglycerides, and a history of hypertension and/or glomerulonephritis were associated with the presence or development of AVN (table). Body mass index, presence of antiphospholipid antibodies, SLEDAI, SLE disease duration and corticosteroid use were not associated with AVN.
Conclusion This is the first report of vitamin D deficiency associated with AVN in paediatric lupus. There was a trend towards lower vitamin D levels in subjects who developed AVN during the 3 years of the trial, but this was not statistically significant likely due to low numbers. AVN has devastating consequences, and its pathogenesis is likely multi-factorial. Unlike other studies, no association was seen between steroid use and AVN. This association does not prove causation, but suggests future avenues of study and may suggest a method of prevention for AVN.
Preview · Article · Mar 2014 · Arthritis and Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Objective Epidemiological associations suggest that vitamin D status may play a role in inflammation and progression of atherosclerosis. Using frozen serum, carotid intima medial thickness (CIMT) measurements and other existing data from the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, we assessed interactions between serum 25-hydroxyvitamin D (25(OH)D), atorvastatin randomisation and CIMT progression rate.
Methods Participants in the 3-year APPLE trial were randomised to placebo or atorvastatin and CIMT progression rate was measured. Baseline frozen serum was used to measure 25(OH)D concentrations. Mixed effect longitudinal models for CIMT progression at 3 years were used to evaluate interaction between vitamin D deficiency (serum 25(OH)D <20 ng/mL) at baseline and atorvastatin or placebo treatment, adjusting for key systemic lupus erythematosus disease variables and cardiovascular risk factors.
Results 201/221 APPLE participants had available samples and were included in this analysis; 61/201 (30%) had vitamin D deficiency at baseline. In adjusted longitudinal modelling, there was significant interaction between baseline vitamin D deficiency and atorvastatin randomisation in 3-year progression of mean-max CIMT. In four out of six carotid segments, there was a greater decrease in mean-max CIMT progression rate in subjects who were treated with atorvastatin compared with placebo if they had baseline serum 25(OH)D levels ≥20 ng/mL.
Conclusions Subjects with serum 25(OH)D ≥20 ng/mL had less mean-max CIMT progression following 3 years of atorvastatin treatment. Results from secondary analyses must be interpreted cautiously, but findings suggest that underlying vitamin D deficiency may be involved in response to atorvastatin in atherosclerosis prevention.
Trial registration number NCT00065806.
Preview · Article · Mar 2014 · Arthritis and Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Background/Purpose:Childhood-onset lupus (cSLE) is a chronic autoimmune disease and its effect on health-related quality of life (HRQoL) has not been systematically established. The Patient Reported Outcomes Measurement Information System (PROMIS™, http://nihpromis.org) is a publicly available system to measure patient reported outcomes that features electronic data collection. Although several validated legacy QoL measures exist for cSLE, each is longer than the PROMIS™ Pediatric Short Forms (Short Forms). The objective of this study was to investigate the feasibility, construct and discriminant validity of the Short Forms in cSLE in a clinical setting.Methods:In this ongoing study at two sites, 98 of 100 projected patients completed the Pediatric PROMIS™ Short Forms (Anger, Anxiety, Depressive, Fatigue, Mobility, Upper Extremity, Pain Interference, Peer Relations) and legacy QoL measures (Pediatric Quality of Life Inventory™ Generic Core [GC] & Rheumatology Modules [RM], Simple Measure Of Impact Of Lupus Erythematosus In Youngsters [SMILEY], Childhood Health Assessment Questionnaire [CHAQ], Child Health Questionnaire [CHQ], pain and well-being visual analog scales [VAS]). Questionnaire scores were compared and Spearman correlation analysis was performed in support of the construct validity of the Short Forms when used in cSLE. The discriminant validity was supported by analysis of PROMIS™ and legacy QoL score change at sequential visits and relationship of change was made with Spearman correlation analysis (to be shown).Results:Participants (78% female; 41% White, 44% Black, 6% Asian) had a mean age of 16 yrs (SD 3) and mean SLEDAI score of 6.07 (SD 5.99). There were no problems with completion of any of the PROMIS™ Short Forms (mean score = 50, clinically relevant difference = 10) which required 5–10 minutes in total (legacy QoL tools >15 min. each). On average, cSLE patients scored importantly worse in the Short Form assessing upper extremity function and mobility than the healthy children, while the other QoL domains were less affected (Table 1). This is also supported by the scores of the CHQ–PHS. Concurrent validity of the Short Forms is supported by moderate correlations with the scores of various legacy measures (to be shown).Table 1. Comparative scores for HRQoL in cSLE*PROMIS Short forms‡CHAQPedsQL-GCPedsQL-RMSMILEYCHQ-P50Values are means (standard deviations).aThe PROMIS™ short forms use T score distributions (50 represents the average for the US general population, with a standard deviation of 10. High scores represent more of the concept being measured (for negatively-worded concepts like pain, fatigue, and anxiety, a 60 is one standard deviation worse than average; for positively-worded concepts like physical or peer relationships, a 60 is one standard deviation better than average).Anger52.0 (4.3) Emotional74.1 (21.1)Worry70.0 (27.6)Effect63.3 (19.9)Behavior (BE)83.4 (15.9)Anxiety49.6 (3.8) Treatment80.8 (15.0)Burden60.1 (17.4)Mental Health (MH)77.5 (15.9)Depression51.9 (3.2) Self-esteem (SE)81.8 (15.5)Fatigue53.5 (3.4) Role/Social Limits-Physical (RP)87.5 (25.8)Mobility42.8 (3.5)Walk0.3 (0.6)Physical74.0 (20.3)Activity87.0 (17.7)Limitation68.2 (17.0)Physical Function (PF)78.2 (30.5) Arise0.4 (0.6) Hygiene0.3 (0.7) Play0.7 (0.9) Upper Extremity Function46.1 (3.9)Dress & Groom0.3 (0.7) Physical Summary (PHS)43.0 (13.2) Eat0.3 (0.7) Reach0.5 (0.8) Grip0.4 (0.7) Pain52.7 (3.1) Pain66.1 (28.2) Bodily Pain/Discomfort (BP)65.7 (29.7)Peer Relations46.7 (3.5) Social82.4 (20.0) Social72.8 (18.6)Social & Emotional Limits (REB)86.0 (29.3) General Health Perception (GH)56.6 (14.9) School66.0 (20.3)Communicate71.6 (27.6) Psychosocial Summary (PSS)52.8 (7.9)Completed by ChildCompleted by ParentConclusion:This pilot study supports QoL measurement using the PROMIS™ Short Forms as feasible and concurrently valid. PROMIS™ measures can now be utilized by clinicians treating cSLE for a more efficient patient reported health outcomes measure, taking advantage of their easy interpretation of scores and changes in scores, thereby, reducing respondent burden and making QoL assessment feasible in both research and clinical care settings.
No preview · Article · Mar 2014 · Arthritis and Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Objective:
To use electronic diaries (e-diaries) to determine whether pain, stiffness, and fatigue continue to be common, disabling symptoms in children with juvenile idiopathic arthritis (JIA) despite the use of aggressive treatments in contemporary medical management.
Fifty-nine children with JIA (ages 8-18 years) provided ratings of pain, stiffness, and fatigue intensity and functional limitations using a smartphone e-diary 3 times each day for 1 month. Medication information was collected via parent report and checked for accuracy by chart review. Descriptive analyses were conducted to determine typical symptom intensity, frequency, and variability. Multilevel modeling was used to analyze associations between symptoms and functional outcomes and between medication use and symptom intensity.
Children reported moments of pain in 66% of e-diary entries. No children were entirely pain-free across the reporting period. In 31% of all e-diary entries the visual analog scale score for pain was >40 (high pain intensity), with 86% of children reporting a high level of pain at least once during the study period. The mean ratings of pain, stiffness, and fatigue intensity were in the mild-to-moderate range. Medication class was not a reliable predictor of differences in symptom intensity, even though 79% of children were prescribed a disease-modifying antirheumatic drug and 47% were prescribed a biologic agent. Moments of higher pain intensity and higher stiffness intensity were each uniquely predictive of higher concurrent functional limitations.
Self-reported pain, stiffness, and fatigue continue to be common in children with JIA, despite contemporary advances in treatment strategies, including use of biologic agents. These findings are surprisingly consistent with previous results from research using daily paper diaries in the pre-biologics era. There remains a pressing and ongoing need to optimize pain and symptom management in JIA.
Full-text · Article · Feb 2014 · Arthritis & Rheumatology
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Nov 2013 · Arthritis research & therapy
[Show abstract][Hide abstract] ABSTRACT: The proven effectiveness of biologics and other immunomodulatory products in inflammatory rheumatic diseases has resulted in their widespread use as well as reports of potential short- and long-term complications such as infection and malignancy. These complications are especially worrisome in children who often have serial exposures to multiple immunomodulatory products. Post-marketing surveillance of immunomodulatory products in juvenile idiopathic arthritis (JIA) and pediatric systemic lupus erythematosus is currently based on product-specific registries and passive surveillance, which may not accurately reflect the safety risks for children owing to low numbers, poor long-term retention, and inadequate comparators. In collaboration with the US Food and Drug Administration (FDA), patient and family advocacy groups, biopharmaceutical industry representatives and other stakeholders, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the Duke Clinical Research Institute (DCRI) have developed a novel pharmacosurveillance model (CARRA Consolidated Safety Registry [CoRe]) based on a multicenter longitudinal pediatric rheumatic diseases registry with over 8000 participants. The existing CARRA infrastructure provides access to much larger numbers of subjects than is feasible in single-product registries. Enrollment regardless of medication exposure allows more accurate detection and evaluation of safety signals. Flexibility built into the model allows the addition of specific data elements and safety outcomes, and designation of appropriate disease comparator groups relevant to each product, fulfilling post-marketing requirements and commitments. The proposed model can be applied to other pediatric and adult diseases, potentially transforming the paradigm of pharmacosurveillance in response to the growing public mandate for rigorous post-marketing safety monitoring.
[Show abstract][Hide abstract] ABSTRACT: Children with systemic lupus erythematosus (SLE) have a high prevalence of antiphospholipid (aPL) antibodies and are at increased risk for aPL-related thrombosis. We investigated the association between annexin A5 anticoagulant activity and antibodies to the domain I portion of β2-glycoprotein I (anti-DI antibodies), and propose a potential mechanism for the pathogenesis of aPL-related thrombosis. Using samples from 183 children with SLE collected during the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, we examined resistance to the anticoagulant effects of annexin A5, using the annexin A5 resistance (A5R) assay, and evaluated for anti-DI IgG antibodies. Children with SLE had higher frequency of anti-D1 antibodies (p = 0.014) and significantly reduced A5R compared to pediatric controls: mean A5R = 172 ± 30% versus 242 ± 32% (p < 0.0001). Children with SLE and positive anti-DI antibodies had significantly lower mean A5R levels compared to those with negative anti-DI antibodies: mean A5R = 155 ± 24% versus 177 ± 30% (p < 0.0001). In multivariate analysis, anti-DI antibodies (p = 0.013) and lupus anticoagulant (LA) (p = 0.036) were both independently associated with reduced A5R. Children with SLE have significantly reduced annexin A5 anticoagulant activity that is associated with the presence of LA and anti-DI antibodies.
[Show abstract][Hide abstract] ABSTRACT: Objective 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.
Methods 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.
Results 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.
Conclusions 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.
ClinicalTrials.gov identifier: NCT00065806.
No preview · Article · Feb 2013 · Annals of the rheumatic diseases