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Objective Determine the pharmacokinetics (PK) and exposure–response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).Methods We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach.Results Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults.Conclusions We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes.Trial registration number NCT04358302.

Introduction Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.Methods Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and dissemination Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration number ClinicalTrials.gov Registry (NCT04358302).

Pediatric rheumatic diseases (PRDs) are a heterogeneous group of diseases that can have a chronic unpredictable disease course that can negatively affect mood, functioning, and quality of life. Given the range of difficulties faced in managing PRDs, as well as the psychosocial issues youth with these diseases experience, pediatric psychologists can be well suited to address concerns that arise in care for youth with PRDs including adherence, cognitive assessment, pain management, functional disability, and mood. Potential ways that pediatric psychologists can address these concerns and be embedded within an interdisciplinary treatment plan for youth with PRDs are described., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pediatric rheumatic diseases (PRDs) are a heterogeneous group of diseases that can have a chronic unpredictable disease course that can negatively affect mood, functioning, and quality of life. Given the range of difficulties faced in managing PRDs, as well as the psychosocial issues youth with these diseases experience, pediatric psychologists can be well suited to address concerns that arise in care for youth with PRDs including adherence, cognitive assessment, pain management, functional disability, and mood. Potential ways that pediatric psychologists can address these concerns and be embedded within an interdisciplinary treatment plan for youth with PRDs are described., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To evaluate safety and effectiveness of adalimumab (ADA) in polyarticular-course juvenile idiopathic arthritis (JIA) in the STRIVE registry., Methods: STRIVE enrolled patients with polyarticular-course JIA into 2 arms based on treatment with methotrexate (MTX) alone or ADA with/without MTX (ADA ± MTX). Adverse events (AEs) per 100 patient-years of observation time were analyzed by registry arm. Patients who entered the registry within 4 weeks of starting MTX or ADA ± MTX, defined as new users, were evaluated for change in disease activity assessed by the 27-joint Juvenile Arthritis Disease Activity Score with the C-reactive protein level (JADAS-27 CRP )., Results: At the 7-year cutoff date (June 1, 2016), data from 838 patients were available (MTX arm n = 301, ADA ± MTX arm n = 537). The most common AEs were nausea (10.3%), sinusitis (4.7%), and vomiting (4.3%) in the MTX arm and arthritis (3.9%), upper respiratory tract infection (3.5%), sinusitis, tonsillitis, and injection site pain (3.0% each) in the ADA ± MTX arm. Rates of serious infection were 1.5 events/100 patient-years in the MTX arm and 2.0 events/100 patient-years in the ADA ± MTX arm. AE and serious AE rates were similar in patients receiving ADA with versus without MTX. No deaths or malignancies were reported. New users in the ADA ± MTX arm showed a trend toward lower mean JADAS-27 CRP compared with new users in the MTX arm in the first year of STRIVE., Conclusion: The STRIVE registry 7-year interim results support the idea that ADA ± MTX is well tolerated by most children. Registry median ADA exposure was 2.47 (interquartile range 1.0-3.6) years, with 42% of patients continuing ADA at the 7-year cutoff date., (© 2019 AbbVie Inc. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Purpose of Review: Primary immunodeficiency disorders (PIDs) are no longer defined by infections alone. First clinical sign or sequelae of PID may include autoimmunity, such as cytopenias, arthritis or enteropathy. This review addresses the latest in multidisciplinary approaches for expanding clinical phenotypes of PIDs with autoimmunity, including new presentations of known entities and novel gene defects. We also discuss diagnostic tools for identifying the distinct changes in immune cells subsets and autoantibodies, mechanistic understanding of the process, and targeted treatment and indications for hematopoietic stem-cell transplantation (HSCT)., Recent Findings: In the past years, increased awareness and use of genetic screening, confirmatory functional studies and immunological biomarkers opened the door for early recognition of PIDs among patients with autoimmunity. Large cohort studies detail the clinical spectrum and treatment outcome of PIDs with autoimmunity with specific immune genes (e.g., CTLA4, LRBA, PI3Kδ, NFKB1, RAG). The benefit of early recognition is initiation of targeted therapies with precise re-balancing of the dysregulated immune pathways (e.g., biologicals) or definitive therapy (e.g., HSCT)., Summary: Clinical presentation of patients with PID and autoimmunity is highly variable and requires in-depth diagnostics and precision medicine approaches.

Objective: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA)., Methods: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data., Results: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features., Conclusions: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed., Competing Interests: Competing interests: VES reports personal fees from Novartis. GD reports personal fees from Novartis. SC reports personal fees from Novartis and grants from AB2 Bio. GS reports personal fees from Novartis. KB reports personal fees from Novartis. RQC is co-PI of an investigator-initiated clinical trial funded by SOBI. RD reports personal fees from Boehringer Ingelheim, other from NowVitals, personal fees and other from Triple Endoscopy, other from Earables, and NowVitals with patents and lung-related device development. AAG reports grants and personal fees from Novartis and grants from NovImmune. SL reports personal fees from Novartis. RS reports personal fees from Novartis, NovImmune and SOBI. SS reports personal fees from Novartis. MLS reports personal fees from Novartis. LRY reports other from Up-To-Date and other from Boehringer Ingelheim, outside the submitted work. EDM reports grants from Novartis., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The anti-interleukin-6 receptor-alpha antibody tocilizumab was approved for intravenous (IV) injection in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years based on results of a randomized controlled phase 3 trial. Tocilizumab treatment in systemic juvenile idiopathic arthritis (sJIA) patients younger than 2 was investigated in this open-label phase 1 trial and compared with data from the previous trial in patients aged 2 to 17 years., Methods: Patients younger than 2 received open-label tocilizumab 12 mg/kg IV every 2 weeks (Q2W) during a 12-week main evaluation period and an optional extension period. The primary end point was comparability of pharmacokinetics during the main evaluation period to that of the previous trial (in patients aged 2-17 years), and the secondary end point was safety; pharmacodynamics and efficacy end points were exploratory. Descriptive comparisons for pharmacokinetics, pharmacodynamics, safety, and efficacy were made with sJIA patients aged 2 to 17 years weighing < 30 kg (n = 38) who received tocilizumab 12 mg/kg IV Q2W in the previous trial (control group)., Results: Eleven patients (mean age, 1.3 years) received tocilizumab during the main evaluation period. The primary end point was met: tocilizumab exposures for patients younger than 2 were within the range of the control group (mean [±SD] μg/mL concentration at the end-of-dosing interval [C min ]: 39.8 [±14.3] vs 57.5 [±23.3]; maximum concentration [C max ] postdose: 288 [±40.4] vs 245 [±57.2]). At week 12, pharmacodynamic measures were similar between patients younger than 2 and the control group; mean change from baseline in Juvenile Arthritis Disease Activity Score-71 was - 17.4 in patients younger than 2 and - 28.8 in the control group; rash was reported by 14.3 and 13.5% of patients, respectively. Safety was comparable except for the incidence of serious hypersensitivity reactions (27.3% in patients younger than 2 vs 2.6% in the control group)., Conclusions: Tocilizumab 12 mg/kg IV Q2W provided pharmacokinetics, pharmacodynamics, and efficacy in sJIA patients younger than 2 comparable to those in patients aged 2 to 17 years. Safety was comparable except for a higher incidence of serious hypersensitivity events in patients younger than 2 years., Classification: Juvenile idiopathic arthritis., Trial Registration: ClinicalTrials.gov, NCT01455701 . Registered, October 20, 2011, Date of enrollment of first participant: October 26, 2012.

Bone health in children with rheumatic conditions may be compromised due to several factors related to the inflammatory disease state, delayed puberty, altered life style, including decreased physical activities, sun avoidance, suboptimal calcium and vitamin D intake, and medical treatments, mainly glucocorticoids and possibly some disease-modifying anti-rheumatic drugs. Low bone density or even fragility fractures could be asymptomatic; therefore, children with diseases of high inflammatory load, such as systemic onset juvenile idiopathic arthritis, juvenile dermatomyositis, systemic lupus erythematosus, and those requiring chronic glucocorticoids may benefit from routine screening of bone health. Most commonly used assessment tools are laboratory testing including serum 25-OH-vitamin D measurement and bone mineral density measurement by a variety of methods, dual-energy X-ray absorptiometry as the most widely used. Early disease control, use of steroid-sparing medications such as disease-modifying anti-rheumatic drugs and biologics, supplemental vitamin D and calcium, and promotion of weight-bearing physical activities can help optimize bone health. Additional treatment options for osteoporosis such as bisphosphonates are still controversial in children with chronic rheumatic diseases, especially those with decreased bone density without fragility fractures. This article reviews common risk factors leading to compromised bone health in children with chronic rheumatic diseases and discusses the general approach to prevention and treatment of bone fragility.

Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation and arthritis. Monocytes are implicated in sJIA pathogenesis, but their role in disease is unclear. The response of sJIA monocytes to IFN may be dysregulated. We examined intracellular signaling in response to IFN type I (IFNα) and type II (IFNγ) in monocytes during sJIA activity and quiescence, in 2 patient groups. Independent of disease activity, monocytes from Group 1 (collected between 2002 and 2009) showed defective STAT1 phosphorylation downstream of IFNs, and expressed higher transcript levels of SOCS1, an inhibitor of IFN signaling. In the Group 2 (collected between 2011 and 2014), monocytes of patients with recent disease onset were IFNγ hyporesponsive, but in treated, quiescent subjects, monocytes were hyperresponsive to IFNγ. Recent changes in medication in sJIA may alter the IFN hyporesponsiveness. Impaired IFN/pSTAT1 signaling is consistent with skewing of sJIA monocytes away from an M1 phenotype and may contribute to disease pathology., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: To describe grey-scale sonographic findings in lower extremity entheses in healthy children., Methods: Healthy patients referred to Orthopedic Surgery or Adolescent Medicine outpatient clinics or their siblings ages 5-18 years were recruited. Grey-scale ultrasound was performed on 3 entheseal sites bilaterally, the proximal patellar ligament insertion (PPL), distal patellar ligament insertion (DPL), and Achilles tendon insertion (AT). Entheseal thickness and quality were recorded. Comparison of thickness between contralateral sites was evaluated to determine within subject site variability., Results: 702 entheses were examined in 117 children. Age had a weak positive correlation with thickness with large variability. Weight had the strongest correlation to thickness. Contralateral sites are comparable in thickness; a difference of 28%, 26%, and 18% between bilateral PPL, DPL, and AT, respectively, falls within the 95th percentile of the healthy pediatric population in this study. The patellar ligament contour evolved with age from a curved to linear contour., Conclusions: Weight is the best predictor of entheseal thickness in children although there is a large degree of variability. Contralateral entheses are comparable in thickness. A difference below 28%, 26%, and 18% between bilateral PPL, DPL, and AT, respectively, falls within the 95(th) percentile.

Objective: Few data are available regarding the rates of serious adverse events (SAEs) and important medical events (IMEs) outside of product-based registries and clinical trials for juvenile idiopathic arthritis (JIA). The Enhanced Drug Safety Surveillance Project (EDSSP) was developed to pilot a novel system to collect SAEs/IMEs in children with JIA. This analysis reports the results from this 4-year (2008-2012) EDSSP., Methods: Participating physicians were surveyed monthly to ascertain whether their JIA patients experienced an SAE or IME. Sites were surveyed every 6 months to determine the number of unique JIA patients seen at each site during that 6-month period. Reporting rates were calculated per 100 person-years and 95% confidence intervals (95% CIs) were calculated based on a Poisson distribution., Results: Thirty-seven Childhood Arthritis and Rheumatology Research Alliance sites with 115 physicians participated. The mean response rate to the monthly surveys was 65%. There were 147 total SAEs and 145 total IMEs. The largest proportion of SAEs and IMEs occurred in children with polyarticular JIA (39% and 37%, respectively). The majority of SAEs and IMEs were reported for patients receiving therapy with biologic agents (76% and 69%, respectively). The total event rate for SAEs and IMEs combined was 1.07 events per 100 person-years (95% CI 0.95-1.19). The rates for SAEs and IMEs were 0.54 per 100 person-years (95% CI 0.45-0.63) and 0.53 per 100 person-years (95% CI 0.49-0.62), respectively., Conclusion: The EDSSP provided a simple tool for SAE/IME reporting within an established research network and resulted in a similar range of reported events as captured by a traditional product-based registry., (Copyright © 2015 by the American College of Rheumatology.)

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., Methods: 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., Results: 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., Conclusion: 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.

Objective: To assess the efficacy and safety of rilonacept, an interleukin-1 inhibitor, in a randomized, double-blind, placebo-controlled trial., Methods: An initial 4-week double-blind placebo phase was incorporated into a 24-week randomized multicenter design, followed by an open-label phase. Seventy-one children who had active arthritis in ≥2 joints were randomized (1:1) to the 2 arms of the study. Patients in the rilonacept arm received rilonacept (loading dose 4.4 mg/kg followed by 2.2 mg/kg weekly, subcutaneously) beginning on day 0. Patients in the placebo arm received placebo for 4 weeks followed by a loading dose of rilonacept at week 4 followed by weekly maintenance doses. The primary end point was time to response, using the adapted American College of Rheumatology Pediatric 30 criteria coupled with the absence of fever and taper of the dosage of systemic corticosteroids, using prespecified criteria., Results: The time to response was shorter in the rilonacept arm than in the placebo arm (χ(2) = 7.235, P = 0.007). The secondary analysis, which used the same response criteria, showed that 20 (57%) of 35 patients in the rilonacept arm had a response at week 4 compared with 9 (27%) of 33 patients in the placebo arm (P = 0.016). Exacerbation of systemic juvenile idiopathic arthritis (JIA) was the most common severe adverse event. More patients in the rilonacept arm had elevated liver transaminase levels (including levels more than 3 times the upper limit of normal) compared with those in the placebo arm. Adverse events were similar in the 2 arms of the study., Conclusion: Rilonacept was generally well tolerated and demonstrated efficacy in active systemic JIA., (Copyright © 2014 by the American College of Rheumatology.)

Background: Magnetic resonance imaging (MRI) is often used to diagnose and monitor treatment effects of juvenile spondyloarthropathy (SpA). Our objective was to describe MRI findings in juvenile SpA and determine predictors of active sacroiliitis and response to treatment., Methods: Children who had MRI of the sacroiliac (SI) joints and were referred to the pediatric rheumatology clinic from 2009 to 2012 were retrospectively studied. The clinical parameters, laboratory studies and findings on MRI were collected and a composite score ratio (CR) was calculated for both SI joints on each MRI study based on a semi-quantitative scale that included evaluation of bone marrow edema (BME), synovial enhancement (SE), and erosions (ER). The findings on MRI were correlated with clinical and laboratory values., Results: 50 subjects who underwent 76 MRI for suspected or known SpA were included in the study. Sacroiliitis was seen in 48 MRIs in 32 subjects. Of the subjects with sacroiliitis, mean age ± standard deviation was 13.7 ± 2.6 years, 71% were male and 41% were HLA B27 positive. SE without BME was seen in 31% cases of sacroiliitis. In subjects with sacroiliitis, 79% also had hip arthritis and 41% had enthesitis of the pelvic region on MRI. In 38% of subjects with sacroiliitis, physical exam was not indicative of sacroiliitis or hip arthritis. Longitudinal data were available for 13 subjects. Sacroiliitis on MRI improved in 9 subjects with the greatest improvement in MRI composite score ratio after initiation of etanercept therapy. CR improvement was due to improvement of BME and SE components, while the ER score remained the same or worsened in all but 1 subject., Conclusion: History, physical exam or laboratory data may not predict sacroiliitis in children. Magnetic resonance imaging plays a valuable role in the initial evaluation and later treatment monitoring of children with spondyloarthropathy. Synovial enhancement is significantly reduced after treatment, and unlike adults, synovial enhancement may be detected without accompanying bone marrow edema, which suggests gadolinium contrast may be an important component in the assessment of children with spondyloarthropathy.

Objective: 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)., Methods: 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., Results: 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., Conclusion: 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.

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 ≥ 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 ≥ 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.

Objective: There is wide variation in therapeutic approaches to systemic juvenile idiopathic arthritis (JIA) among North American rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available for treatment of systemic JIA can result in better health outcomes. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans and standardized assessment schedules for use in clinical practice to facilitate such studies., Methods: Case-based surveys were administered to CARRA members to identify prevailing treatments for new-onset systemic JIA. A 2-day consensus conference in April 2010 employed modified nominal group technique to formulate preliminary treatment plans and determine important data elements for collection. Followup surveys were employed to refine the plans and assess clinical acceptability., Results: The initial case-based survey identified significant variability among current treatment approaches for new-onset systemic JIA, underscoring the utility of standardized plans to evaluate comparative effectiveness. We developed 4 consensus treatment plans for the first 9 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The 4 treatment regimens included glucocorticoids only, or therapy with methotrexate, anakinra, or tocilizumab, with or without glucocorticoids. This approach was approved by >78% of the CARRA membership., Conclusion: Four standardized treatment plans were developed for new-onset systemic JIA. Coupled with data collection at defined intervals, use of these treatment plans will create the opportunity to evaluate comparative effectiveness in an observational setting to optimize initial management of systemic JIA., (Copyright © 2012 by the American College of Rheumatology.)

Objective: To determine whether aggressive treatment initiated early in the course of rheumatoid factor (RF)-positive or RF-negative polyarticular juvenile idiopathic arthritis (JIA) can induce clinical inactive disease within 6 months., Methods: Between May 2007 and October 2010, a multicenter, prospective, randomized, double-blind, placebo-controlled trial of 2 aggressive treatments was conducted in 85 children ages 2-16 years with polyarticular JIA of <12 months' duration. Patients received either methotrexate (MTX) 0.5 mg/kg/week (maximum 40 mg) subcutaneously, etanercept 0.8 mg/kg/week (maximum 50 mg), and prednisolone 0.5 mg/kg/day (maximum 60 mg) tapered to 0 by 17 weeks (arm 1), or MTX (same dosage as arm 1), etanercept placebo, and prednisolone placebo (arm 2). The primary outcome measure was clinical inactive disease at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous clinical inactive disease) at 12 months., Results: By 6 months, clinical inactive disease had been achieved in 17 (40%) of 42 patients in arm 1 and 10 (23%) of 43 patients in arm 2 (χ(2) = 2.91, P = 0.088). After 12 months, clinical remission on medication was achieved in 9 patients in arm 1 and 3 patients in arm 2 (P = 0.053). There were no significant interarm differences in adverse events., Conclusion: Although this study did not meet its primary end point, early aggressive therapy in this cohort of children with recent-onset polyarticular JIA resulted in clinical inactive disease by 6 months and clinical remission on medication within 12 months of treatment in substantial proportions of patients in both arms., (Copyright © 2012 by the American College of Rheumatology.)

Systemic juvenile idiopathic arthritis (SJIA) is a chronic arthritis of children characterized by a combination of arthritis and systemic inflammation. There is usually non-specific laboratory evidence of inflammation at diagnosis but no diagnostic test. Normalized volumes from 89/889 2-D protein spots representing 26 proteins revealed a plasma pattern that distinguishes SJIA flare from quiescence. Highly discriminating spots derived from 15 proteins constitute a robust SJIA flare signature and show specificity for SJIA flare in comparison to active polyarticular juvenile idiopathic arthritis or acute febrile illness. We used 7 available ELISA assays, including one to the complex of S100A8/S100A9, to measure levels of 8 of the15 proteins. Validating our DIGE results, this ELISA panel correctly classified independent SJIA flare samples, and distinguished them from acute febrile illness. Notably, data using the panel suggest its ability to improve on erythrocyte sedimentation rate or C-reactive protein or S100A8/S100A9, either alone or in combination in SJIA F/Q discriminations. Our results also support the panel's potential clinical utility as a predictor of incipient flare (within 9 wk) in SJIA subjects with clinically inactive disease. Pathway analyses of the 15 proteins in the SJIA flare versus quiescence signature corroborate growing evidence for a key role for IL-1 at disease flare., (Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

PURPOSE: Systemic juvenile idiopathic arthritis is a chronic pediatric disease. The initial clinical presentation can mimic other pediatric inflammatory conditions, which often leads to significant delays in diagnosis and appropriate therapy. SJIA biomarker development is an unmet diagnostic/prognostic need to prevent disease complications. EXPERIMENTAL DESIGN: We profiled the urine peptidome to analyze a set of 102 urine samples, from patients with SJIA, Kawasaki disease (KD), febrile illnesses (FI), and healthy controls. A set of 91 plasma samples, from SJIA flare and quiescent patients, were profiled using a customized antibody array against 43 proteins known to be involved in inflammatory and protein catabolic processes. RESULTS: We identified a 17-urine-peptide biomarker panel that could effectively discriminate SJIA patients at active, quiescent, and remission disease states, and patients with active SJIA from confounding conditions including KD and FI. Targeted sequencing of these peptides revealed that they fall into several tight clusters from seven different proteins, suggesting disease-specific proteolytic activities. The antibody array plasma profiling identified an SJIA plasma flare signature consisting of tissue inhibitor of metalloproteinase-1 (TIMP1), interleukin (IL)-18, regulated upon activation, normal T cell expressed and secreted (RANTES), P-Selectin, MMP9, and L-Selectin. CONCLUSIONS AND CLINICAL RELEVANCE: The urine peptidomic and plasma protein analyses have the potential to improve SJIA care and suggest that SJIA urine peptide biomarkers may be an outcome of inflammation-driven effects on catabolic pathways operating at multiple sites. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12014-010-9058-8) contains supplementary material, which is available to authorized users.

This study was undertaken to assess the contribution of protein adsorption and cell growth to increases in electrode impedance that occur immediately following implantation of cochlear implant electrodes and other neural stimulation devices. An in vitro model of the electrode-tissue interface was used. Radiolabelled albumin in phosphate buffered saline was added to planar gold electrodes and electrode impedance measured using a charge-balanced biphasic current pulse. The polarization impedance component increased with protein adsorption, while no change to access resistance was observed. The maximum level of protein adsorbed was measured at 0.5 µg cm(-2), indicating a tightly packed monolayer of albumin molecules on the gold electrode and resin substrate. Three cell types were grown over the electrodes, macrophage cell line J774, dissociated fibroblasts and epithelial cell line MDCK, all of which created a significant increase in electrode impedance. As cell cover over electrodes increased, there was a corresponding increase in the initial rise in voltage, suggesting that cell cover mainly contributes to the access resistance of the electrodes. Only a small increase in the polarization component of impedance was seen with cell cover.

Neonatal tetanus is a severe, often fatal disease caused by the toxin Clostridium tetani. Neonatal tetanus is a generalized tetanus, which occurs in a neonate between 3-28 days of life. The findings indicated that tetanus in a newborn of an unvaccinated mother occurred after the application of non-sterile clay to the umbilical cord. This case was a seven-day-old male baby with progressive difficulty in feeding, trismus, hypertonicity, opisthotonos, and heart murmur. The patient was afebrile and eupneic, and had a history of non-sterile home delivery. In the past, the area of Bujanovac, Medvedja and Presevo had been exposed to mass immigration (especially due to the war in the territory of former Yugoslavia), which caused a serious problem for general practitioners, who had to be vigilant and ensure that all patients registered in their practice were fully immunized. This case has provided a clear indication of the necessity for strategies of both vaccination and ensuring hygienic conditions throughout pregnancy and delivery to prevent neonatal tetanus.

Juvenile idiopathic arthritis (JIA) refers to a group of chronic childhood arthropathies of unknown etiology, currently classified into subtypes primarily on the basis of clinical features. Research has focused on the hypothesis that these subtypes arise through distinct etiologic pathways. In this Review, we discuss four subtypes of JIA: persistent oligoarticular, extended oligoarticular, rheumatoid-factor-positive polyarticular and rheumatoid-factor-negative polyarticular. These subtypes differ in prevalence between ethnic groups and are associated with different HLA alleles. Non-HLA genetic risk factors have also been identified, some of which reveal further molecular differences between these subtypes, while others suggest mechanistic overlap. Investigations of immunophenotypes also provide insights into subtype differences: adaptive immunity seems to have a prominent role in both polyarticular and oligoarticular JIA, and the more-limited arthritis observed in persistent oligoarticular JIA as compared with extended oligoarticular JIA may reflect more-potent immunoregulatory T-cell activity in the former. Tumor necrosis factor seems to be a key mediator of both polyarticular and oligoarticular JIA, especially in the extended oligoarticular subtype, although elevated levels of other cytokines are also observed. Limited data on monocytes, dendritic cells, B cells, natural killer T cells and neutrophils suggest that the contributions of these cells differ across subtypes of JIA. Within each subtype, however, common pathways seem to drive joint damage.