[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.
Arthritis research & therapy 11/2013; 15(6):R198. · 4.27 Impact Factor
[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.
Annals of the rheumatic diseases 02/2013; · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVE:: The primary aim of this systematic review was to examine the evidence for a pain-sleep relationship in children with persistent pain by reviewing studies using single and mixed pediatric persistent pain samples. METHODS:: Electronic searches of Medline, PubMed, the Cochrane Database of Systematic Reviews, and PsycINFO were conducted to identify all relevant empirical studies. Studies were included in the review if the majority of participants were between 0 and 17 years and from one of the following pediatric pain populations: juvenile idiopathic arthritis, sickle cell disease, migraine/headache, functional abdominal pain, juvenile fibromyalgia syndrome, chronic musculoskeletal pain, or mixed populations including the aforementioned conditions. RESULTS:: Research from single and mixed sample studies support the hypothesis that children and adolescents with persistent pain suffer from sleep impairment. Literature addressing factors that may influence or mediate the pain-sleep relationship and the functional outcomes of the pain-sleep relationship was reviewed, and a model of the interrelationships with pain and sleep was developed. CONCLUSION:: Findings from this review highlight the need to assess and treat sleep problems in children presenting with persistent pain. Health care providers should consider conducting routine sleep screenings, including a comprehensive description of sleep patterns and behaviors obtained through clinical interview, sleep diaries, and/or the use of standardized measures of sleep. Future research focusing on investigating the mechanisms associating sleep and pediatric persistent pain and on functional outcomes of poor sleep in pediatric pain populations is needed.
Journal of developmental and behavioral pediatrics: JDBP 02/2013; 34(2):120-128. · 2.27 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: To assess the relative effect of clinical factors and medications on pain intensity, physical function, and health status in juvenile idiopathic arthritis (JIA). METHODS: We conducted a retrospective cross-sectional study of data from children with JIA enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. We tested whether clinical characteristics of JIA were associated with pain intensity, physical function, and health status using multivariable linear and ordinal logistic regression. RESULTS: During the study period, 2571 subjects with JIA enrolled in the CARRA Registry. Ratings of pain intensity, physical function, and health status differed significantly between JIA categories. In comparison to other categories of JIA, subjects with enthesitis-related arthritis (ERA) reported worse pain and function. In multivariable analyses, higher active joint count and current use of nonsteroidal antiinflammatory drugs (NSAID), biologics, or corticosteroids were associated with worse scores on all patient-reported measures. ERA and older age were significantly associated with higher pain intensity and poorer health status. Systemic JIA and uveitis were significantly associated with worse health status. Enthesitis, sacroiliac tenderness, and NSAID use were independently associated with increased pain intensity in ERA. The correlation was low between physician global assessment of disease activity and patient-reported pain intensity, physical function, and health status. CONCLUSION: Significant differences in pain intensity, physical function, and health status exist among JIA categories. These results suggest that current treatments may not be equally effective for particular disease characteristics more common in specific JIA categories, such as enthesitis or sacroiliac tenderness in ERA.
The Journal of Rheumatology 10/2012; · 3.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: INTRODUCTION:: To examine in a randomize controlled feasibility clinical trial the efficacy of a cognitive-behavioral intervention designed to manage pain, enhance disease adjustment and adaptation and improve quality of life among female adolescents with systemic lupus erythematosus. METHODS:: Female adolescents (n = 53) ranging in age from 12 to 18 years were randomly assigned to 1 of 3 groups including a cognitive-behavioral intervention, an education-only arm and a no-contact control group. Participants were assessed at baseline, postintervention and at 3- and 6-month intervals after completion of the intervention. RESULTS:: No significant differences were revealed among the 3 treatment arms for any of the dependent measures at any of the assessment points. For the mediator variables, a posthoc secondary analysis did reveal increases in coping skills from baseline to postintervention among the participants in the cognitive-behavioral intervention group compared with both the no-contact control group and the education-only group. CONCLUSION:: Although no differences were detected in the primary outcome, a possible effect on coping of female adolescents with systemic lupus erythematosus was detected in this feasibility study. Whether the impact of training in the area of coping was of sufficient magnitude to generalize to other areas of functioning, such as adjustment and adaptation, is unclear. Future phase III randomized trials will be needed to assess additional coping models and to evaluate the dose of training and its influence on pain management, adjustment and health-related quality of life.
The American Journal of the Medical Sciences 10/2012; 344(4):274-282. · 1.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: The management of background corticosteroid therapy in rheumatology clinical trials poses a major challenge. We describe the consensus methodology used to design an algorithm to standardize changes in corticosteroid dosing during the Randomized Placebo Phase Study of Rilonacept in Systemic Juvenile Idiopathic Arthritis Trial (RAPPORT). METHODS: The 20 RAPPORT site principal investigators (PIs) and 4 topic specialists constituted an expert panel that participated in the consensus process. The panel used a modified Delphi Method consisting of an on-line questionnaire, followed by a one day face-to-face consensus conference. Consensus was defined as [GREATER-THAN OR EQUAL TO] 75% agreement. For items deemed essential but when consensus on critical values was not achieved, simple majority vote drove the final decision. RESULTS: The panel identified criteria for initiating or increasing corticosteroids. These included the presence or development of anemia, myocarditis, pericarditis, pleuritis, peritonitis, and either complete or incomplete macrophage activation syndrome (MAS). The panel also identified criteria for tapering corticosteroids which included absence of fever for [GREATER-THAN OR EQUAL TO] 3 days in the previous week, absence of poor physical functioning, and seven laboratory criteria. A tapering schedule was also defined. CONCLUSION: The expert panel established consensus regarding corticosteroid management and an algorithm for steroid dosing that was well accepted and used by RAPPORT investigators. Developed specifically for the RAPPORT trial, further study of the algorithm is needed before recommendation for more general clinical use.
[show abstract][hide abstract] ABSTRACT: This study utilized e-diaries to evaluate whether components of emotion regulation predict daily pain and function in children with juvenile idiopathic arthritis (JIA).
43 children ages 8-17 years and their caregivers provided baseline reports of child emotion regulation. Children then completed thrice daily e-diary assessments of emotion, pain, and activity involvement for 28 days. E-diary ratings of negative and positive emotions were used to calculate emotion variability and to infer adaptive emotion modulation following periods of high or low emotion intensity. Hierarchical linear models were used to evaluate how emotion regulation related to pain and function.
The attenuation of negative emotion following a period of high negative emotion predicted reduced pain; greater variability of negative emotion predicted higher pain and increased activity limitation. Indices of positive emotion regulation also significantly predicted pain.
Components of emotion regulation as captured by e-diaries predict important health outcomes in children with JIA.
Journal of Pediatric Psychology 07/2012; 37(1):43-52. · 2.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: Registries are a well-established mechanism for obtaining high quality, disease-specific data, but are often highly project-specific in their design, implementation, and policies for data use. In contrast to the conventional model of centralized data contribution, warehousing, and control, we design a self-scaling registry technology for collaborative data sharing, based upon the widely adopted Integrating Biology & the Bedside (i2b2) data warehousing framework and the Shared Health Research Information Network (SHRINE) peer-to-peer networking software. MATERIALS AND METHODS: Focusing our design around creation of a scalable solution for collaboration within multi-site disease registries, we leverage the i2b2 and SHRINE open source software to create a modular, ontology-based, federated infrastructure that provides research investigators full ownership and access to their contributed data while supporting permissioned yet robust data sharing. We accomplish these objectives via web services supporting peer-group overlays, group-aware data aggregation, and administrative functions. RESULTS: The 56-site Childhood Arthritis & Rheumatology Research Alliance (CARRA) Registry and 3-site Harvard Inflammatory Bowel Diseases Longitudinal Data Repository now utilize i2b2 self-scaling registry technology (i2b2-SSR). This platform, extensible to federation of multiple projects within and between research networks, encompasses >6000 subjects at sites throughout the USA. DISCUSSION: We utilize the i2b2-SSR platform to minimize technical barriers to collaboration while enabling fine-grained control over data sharing. CONCLUSIONS: The implementation of i2b2-SSR for the multi-site, multi-stakeholder CARRA Registry has established a digital infrastructure for community-driven research data sharing in pediatric rheumatology in the USA. We envision i2b2-SSR as a scalable, reusable solution facilitating interdisciplinary research across diseases.
Journal of the American Medical Informatics Association 06/2012; · 3.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pain in children with rheumatic conditions such as arthritis is common. However, there is currently no standardized method for the assessment of this pain in children presenting to pediatric rheumatologists. A more consistent and comprehensive approach is needed to effectively assess, treat and monitor pain outcomes in the pediatric rheumatology population. The objectives of this study were to: (a) develop consensus regarding a standardized pain assessment tool for use in pediatric rheumatology practice and (b) test the feasibility of three mediums (paper, laptop, and handheld-based applications) for administration.
In Phase 1, a 2-stage Delphi technique (pediatric rheumatologists and allied professionals) and consensus meeting (pediatric pain and rheumatology experts) were used to develop the self- and proxy-report pain measures. In Phase 2, 24 children aged 4-7 years (and their parents), and 77 youth, aged 8-18 years, with pain, were recruited during routine rheumatology clinic appointments and completed the pain measure using each medium (order randomly assigned). The participant's rheumatologist received a summary report prior to clinical assessment. Satisfaction surveys were completed by all participants. Descriptive statistics were used to describe the participant characteristics using means and standard deviations (for continuous variables) and frequencies and proportions (for categorical variables)
Completing the measure using the handheld device took significantly longer for youth (M = 5.90 minutes) and parents (M = 7.00 minutes) compared to paper (M = 3.08 and 2.28 minutes respectively p = 0.001) and computer (M = 3.40 and 4.00 minutes respectively; p < 0.001). There was no difference in the number of missed responses between mediums for children or parents. For youth, the number of missed responses varied across mediums (p = 0.047) with the greatest number of missed responses occurring with the handheld device. Most children preferred the computer (65%, p = 0.008) and youth reported no preference between mediums (p = 0.307). Most physicians (60%) would recommend the computer summary over the paper questionnaire to a colleague.
It is clinically feasible to implement a newly developed consensus-driven pain measure in pediatric rheumatology clinics using electronic or paper administration. Computer-based administration was most efficient for most users, but the medium employed in practice may depend on child age and economic and administrative factors.
[show abstract][hide abstract] ABSTRACT: Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.
[show abstract][hide abstract] ABSTRACT: The extent to which parent variables are associated with the level of disability experienced by children with persistent pain has been an area of increasing research.
To evaluate the extent to which parent perceptions of their child's vulnerability are associated with functioning and health care utilization among children with persistent pain. We also evaluated whether perceptions of child vulnerability contribute to an indirect relationship between parent distress and child functioning and/or child health care utilization.
The study sample comprised 87 patients aged 6-18 years and a parent attending a chronic pain clinic. Children completed questionnaires on functional limitations, and parents completed questionnaires on parent distress, perceptions of child vulnerability, and extent of the child's pain-related health care utilization. Hierarchical regression and bootstrapping mediation analyses were used to test study hypotheses.
Perceptions of child vulnerability were found to be clinically elevated in nearly half (46%) of parents/caregivers, and average child functional ability for the sample was substantially lower than healthy norms. Parent perceptions of greater child vulnerability were significantly associated with poorer child functioning and more child pain-related health care utilization regardless of child age, sex, and duration of persistent pain. Parent distress was found to be indirectly related to child health care utilization through parent perceptions of child vulnerability but directly related to child functioning.
Parent perceptions of child vulnerability appear important for understanding levels of child functional limitations and health care utilization among children with chronic pain.
Journal of pain and symptom management 01/2012; 43(5):953-60. · 2.42 Impact Factor
[show abstract][hide abstract] ABSTRACT: To define inactive disease (ID) and clinical remission (CR) and to delineate variables that can be used to measure ID/CR in childhood-onset systemic lupus erythematosus (cSLE).
Delphi questionnaires were sent to an international group of pediatric rheumatologists. Respondents provided information about variables to be used in future algorithms to measure ID/CR. The usefulness of these variables was assessed in 35 children with ID and 31 children with minimally active lupus (MAL).
While ID reflects cSLE status at a specific point in time, CR requires the presence of ID for >6 months and considers treatment. There was consensus that patients in ID/CR can have <2 mild nonlimiting symptoms (i.e., fatigue, arthralgia, headaches, or myalgia) but not Raynaud's phenomenon, chest pain, or objective physical signs of cSLE; antinuclear antibody positivity and erythrocyte sedimentation rate elevation can be present. Complete blood count, renal function testing, and complement C3 all must be within the normal range. Based on consensus, only damage-related laboratory or clinical findings of cSLE are permissible with ID. The above parameters were suitable to differentiate children with ID/CR from those with MAL (area under the receiver operating characteristic curve >0.85). Disease activity scores with or without the physician global assessment of disease activity and patient symptoms were well suited to differentiate children with ID from those with MAL.
Consensus has been reached on common definitions of ID/CR with cSLE and relevant patient characteristics with ID/CR. Further studies must assess the usefulness of the data-driven candidate criteria for ID in cSLE.