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OBJECTIVE: To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. METHODS: Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]-negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0). RESULTS: A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator-activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well. CONCLUSION: Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether peripheral blood mononuclear cells (PBMCs) from children with recent-onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures. METHODS: Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second-line medications, such as methotrexate or biologic agents. RNA was extracted from isolated mononuclear cells, fluorescence labeled, and hybridized to commercial gene expression microarrays (Affymetrix HG-U133 Plus 2.0). Data were analyzed using analysis of variance at a 5% false discovery rate threshold after robust multichip analysis preprocessing and distance-weighted discrimination normalization. RESULTS: Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA patients and healthy controls. Hierarchical clustering of these probe sets distinguished 3 subgroups within the polyarticular JIA group. Prototypical patients within each subgroup were identified and used to define subgroup-specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor beta-inducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets. CONCLUSION: Gene expression signatures in PBMCs from patients with recent-onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease. [ABSTRACT FROM AUTHOR]

Objective: To report pharmacokinetics (PK), immunogenicity, clinical effect, and safety of intravenous (IV) golimumab in children with active polyarticular-course juvenile idiopathic arthritis (pcJIA) who participated in A Study to Evaluate the Pharmacokinetics, Efficacy and Safety of Intravenous Golimumab in Pediatric Participants With Active Polyarticular Course Juvenile Idiopathic Arthritis Despite Methotrexate Therapy (GO-VIVA)'s open-label, long-term extension (LTE) through week 252., Methods: GO-VIVA participants who continued IV golimumab (80 mg/m 2 every 8 weeks) after week 52 were included. PK and safety were assessed through week 244 (last dose) and week 252, respectively, and clinical response through week 116. Clinical outcomes included JIA-American College of Rheumatology (ACR) responses and clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10). Binary outcomes used nonresponder imputation, and other descriptive analyses used observed data., Results: Of 112/127 (88.2%) participants entering the LTE, 69 completed the week 252 visit. Median steady-state trough golimumab concentrations were generally maintained from week 52 through week 244 (range 0.3-0.6 μg/mL). Antigolimumab antibody rates were consistent through week 52 (39.2% [49/125]) and week 244 (44.8% [56/125]). Week 52 JIA-ACR 30/50/70/90 response rates (75.6% [96/127], 74% [94/127], 65.4% [83/127], and 48.8% [62/127], respectively) were generally maintained through week 116 (72.4% [92/127], 71.7% [91/127], 63.8% [81/127], and 50.4% [64/127], respectively), when the median cJADAS10 was 1.6 and 56.7% (72/127) of participants achieved cJADAS10 ≤ 5 (minimal disease activity). Rates (per 100 patient-years) of serious adverse events and serious infections through week 252 were 7.7 and 3.9, respectively., Conclusion: GO-VIVA LTE participants experienced adequate PK exposure and stable safety and immunogenicity. The majority of participants experienced no more than minimal residual disease activity. Data suggest IV golimumab treatment provided durable clinical response through week 116, with an acceptable risk-benefit profile., (Copyright © 2024 by the Journal of Rheumatology.)

Objective: The physician global assessment of disease activity (PhGA) is a tool used nearly ubiquitously by pediatric rheumatologists for the assessment of patient disease activity status. However, this tool lacks standardization in its scoring. This survey aimed to identify score influencing factors, along with inclusion or exclusion of extra-articular manifestations and imaging, when scoring the PhGA in juvenile idiopathic arthritis (JIA)., Methods: Electronic surveys were sent to Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Care and Outcomes Improvement Network members who completed a previous survey on scoring of the PhGA. Respondents were asked to rank their top seven factors for inclusion in the PhGA for nonsystemic JIA (nsJIA) and systemic JIA (sJIA), along with ranking extra-articular manifestations and imaging for inclusion. Frequency and percentage of rank and Likert responses were analyzed, and geographic regions as well as level of experience were compared using the chi-square test and Fisher's test., Results: A total of 276 respondents from 54 countries and six continents participated. For nsJIA, factors selected by >50% included number of swollen joints, active uveitis, duration of morning stiffness, and number of tender joints. For sJIA, factors selected by >50% were presence and duration of fever, laboratory tests, number of swollen joints, serositis, rash, hepatomegaly, lung disease, and lymphadenopathy. Agreement on the inclusion of extra-articular factors, such as uveitis, macrophage activation syndrome, and sJIA-associated lung disease, had >70% moderate or strong agreement for inclusion, whereas psoriasis had only 50.5% agreement for inclusion and imaging had 64.7% agreement for inclusion. Variations in rank between different geographic regions or level of experience were minor., Conclusion: This survey identifies factors that pediatric rheumatology providers find important for PhGA scoring of disease activity, documents varying agreement on inclusion of extra-articular manifestations of disease, and lays the framework for further consensus work., (© 2024 American College of Rheumatology.)

Introduction: The Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) is a North American learning health network focused on improving outcomes of children with juvenile idiopathic arthritis (JIA). JIA is a chronic autoimmune disease that can lead to morbidity related to persistent joint and ocular inflammation. PR-COIN has a shared patient registry that tracks twenty quality measures including ten outcome measures of which six are related to disease activity. The network's global aim, set in 2021, was to increase the percent of patients with oligoarticular or polyarticular JIA that had an inactive or low disease activity state from 76% to 80% by the end of 2023., Methods: Twenty-three hospitals participate in PR-COIN, with over 7,200 active patients with JIA. The disease activity outcome measures include active joint count, physician global assessment of disease activity, and measures related to validated composite disease activity scoring systems including inactive or low disease activity by the 10-joint clinical Juvenile Arthritis Disease Activity Score (cJADAS10), inactive or low disease activity by cJADAS10 at 6 months post-diagnosis, mean cJADAS10 score, and the American College of Rheumatology (ACR) provisional criteria for clinical inactive disease. Data is collated to measure network performance, which is displayed on run and control charts. Network-wide interventions have included pre-visit planning, shared decision making, self-management support, population health management, and utilizing a Treat to Target approach to care., Results: Five outcome measures related to disease activity have demonstrated significant improvement over time. The percent of patients with inactive or low disease activity by cJADAS10 surpassed our goal with current network performance at 81%. Clinical inactive disease by ACR provisional criteria improved from 46% to 60%. The mean cJADAS10 score decreased from 4.3 to 2.6, and the mean active joint count declined from 1.5 to 0.7. Mean physician global assessment of disease activity significantly improved from 1 to 0.6., Conclusions: PR-COIN has shown significant improvement in disease activity metrics for patients with JIA. The network will continue to work on both site-specific and collaborative efforts to improve outcomes for children with JIA with attention to health equity, severity adjustment, and data quality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Harris, Bingham, Vora, Yildirim-Toruner, Batthish, Bullock, Burnham, Fair, Ferraro, Ganguli, Gilbert, Gottlieb, Halyabar, Hazen, Laxer, Lee, Liu, Lovell, Mannion, Oberle, Pan, Shishov, Weiss and Morgan.)

Objective: The OMERACT Juvenile Idiopathic Arthritis (JIA) Working Group (WG) aimed to reach agreement on a consensus-based definition and description of the core domain related to patient perception of overall well-being and disease activity., Methods: A committee of patient research partners, clinicians, methodologists, and researchers drafted working definitions and descriptions. The WG conducted two iterative electronic stakeholder surveys to obtain consensus on domain description, definition, and the distinction between patient perception of overall well-being and disease activity. These definitions were then presented at the OMERACT 2023 Special Interest Group (SIG) session for agreement., Results: Forty-five participants, from 7 countries and 4 continents, were comprised of six patients, 18 caregivers, and 21 healthcare providers. The consensus threshold (70%) was exceeded on all survey questions from both stakeholder groups (patients/caregivers, all others). Agreement was obtained on the new definition, description, and domain title, along with agreement on separate assessments of two target domains, patient perception of overall well-being as it relates to disease and patient perception of disease activity., Conclusion: Through an iterative consensus process and achieving agreement from the OMERACT SIG session attendees, the JIA WG has created a detailed definition and description for the two target domains in the patient perception of overall well-being related to disease core domain of the JIA mandatory core domain set. The next phase of this work will be instrument selection using the OMERACT filter 2.2., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Erin Balay-Dustrude reports travel was provided by Omeract - Outcome Measures in Rheumatology. Ben Horgan reports travel was provided by Omeract - Outcome Measures in Rheumatology. Grayson Shultz reports travel was provided by Omeract - Outcome Measures in Rheumatology. Alessandro Consolaro reports a relationship with Pfizer that includes: funding grants and speaking and lecture fees. Joost F. Swart reports a relationship with Amgen Inc that includes: consulting or advisory. Esi M Morgan reports a relationship with Pfizer that includes: funding grants. Esi M Morgan reports a relationship with Agency for Healthcare Research and Quality that includes: funding grants. Esi M Morgan reports a relationship with American College of Rheumatology that includes: speaking and lecture fees and travel reimbursement. Esi M Morgan reports a relationship with Pediatric Rheumatology Care and Outcomes Improvement Network that includes: board membership., (Copyright © 2023. Published by Elsevier Inc.)

Objective: To describe the selection, development, and implementation of quality measures (QMs) for juvenile idiopathic arthritis (JIA) by the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN), a multihospital learning health network using quality improvement methods and leveraging QMs to drive improved outcomes across a JIA population since 2011., Methods: An American College of Rheumatology-endorsed multistakeholder process previously selected initial process QMs. Clinicians in PR-COIN and parents of children with JIA collaboratively selected outcome QMs. A committee of rheumatologists and data analysts developed operational definitions. QMs were programmed and validated using patient data. Measures are populated by registry data, and performance is displayed on automated statistical process control charts. PR-COIN centers use rapid-cycle quality improvement approaches to improve performance metrics. The QMs are revised for usefulness, to reflect best practices, and to support network initiatives., Results: The initial QM set included 13 process measures concerning standardized measurement of disease activity, collection of patient-reported outcome assessments, and clinical performance measures. Initial outcome measures were clinical inactive disease, low pain score, and optimal physical functioning. The revised QM set has 20 measures and includes additional measures of disease activity, data quality, and a balancing measure., Conclusion: PR-COIN has developed and tested JIA QMs to assess clinical performance and patient outcomes. The implementation of robust QMs is important to improve quality of care. PR-COIN's set of JIA QMs is the first comprehensive set of QMs used at the point-of-care for a large cohort of JIA patients in a variety of pediatric rheumatology practice settings., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: To assess the heterogeneity in factors affecting physician's global assessment of disease activity (PhGA) and in PhGA scoring of multiple JIA patient's case scenarios., Methods: An electronic web-based questionnaire of factors potentially considered in PhGA was sent worldwide to members of PRINTO and the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN). The respondents were asked to rate from 0 to 100 the relevance of 17 factors possibly affecting PhGA scoring and to derive a PhGA score of 17 detailed JIA patient cases. The median and interquartile range was used to measure the heterogeneity in the scoring. To demonstrate the consistency among the PhGA scores of the patient cases provided by multiple physicians, we assessed the inter-rater reliability using intra-class correlation., Results: The questionnaire was completed by 491 respondents. A large individual variation was observed in the impact of different factors on PhGA when assessing JIA. For non-systemic JIA the presence of fever had the largest variation and swollen joint count had the smallest. For sJIA, the largest variation was seen in the presence of erosions and the smallest in the presence of fever. The intra-class correlation of the group for PhGA scoring of patient cases was 0.53 (95% CI 0.38, 0.72)., Conclusions: In a sample of worldwide respondents, the scoring of the PhGA is divergent. Consensus on PhGA scoring guidelines is required to obtain a consistent assessment of patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Aim: To assess safety of COVID-19 vaccination in paediatric patients with immune-mediated inflammatory disease (IMID)., Methods: Subjects of 5-21 years of age with IMID who received at least one COVID-19 vaccine completed electronic surveys after each vaccine to assess side effects within 1 week of vaccination, current medications and COVID-19 testing after vaccination. Charts were reviewed for COVID-19 polymerase chain reaction and IgG response to SARS-CoV-2 spike protein results and for disease flare during the study period., Results: Among 190 enrolled subjects, 71% were female, with median age 17 (range 6-21) years. The most common diagnosis was juvenile idiopathic arthritis/rheumatoid arthritis (55%). 78% of subjects were taking immunosuppressive medication. At least one side effect was reported in 65% of subjects after any dose of the vaccine; with side effects in 38%, 53% and 55% of subjects after the first, second and third vaccine doses, respectively. The most common side effects were injection site pain (59%), fatigue (54%) and headache (39%). No anaphylaxis or myocarditis was reported. Three subjects (2%) experienced disease flare., Conclusion: In our cohort of paediatric patients with IMID, observed side effects were found to be mild and disease flare rates were found to be low following COVID-19 vaccination., (© 2022 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objectives: Immunosuppressed paediatric patients with rheumatic disease (RD) may be at risk for severe or critical disease related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Data remain scarce on coronavirus disease 2019 (COVID-19) outcomes in paediatric RD patients. The aim of this study was to determine the seroprevalence of SARS-CoV-2 IgG and to describe COVID-19 outcomes in immunosuppressed paediatric RD patients., Methods: Patients diagnosed with RD before age 18 years and treated with at least one immunosuppressive medication for at least 3 months were enrolled from a tertiary paediatric rheumatology practice in New York and also underwent routine SARS-CoV-2 IgG testing from May to November 2020. A total of 571 patients were screened and 262 were enrolled. SARS-CoV-2 IgG-positive subjects were assessed for symptoms of COVID-19 infection. SARS-CoV-2 PCR results were recorded where available. Demographic, diagnostic, medication and outcome data were collected., Results: Of 262 subjects (186 female), 35 (13%) were SARS-CoV-2 IgG positive; 17 (49%) had symptoms suggestive of COVID-19. Of the 17 patients who had SARS-CoV-2 PCR testing, 11 (65%) were PCR positive, 7 of whom were IgG positive. Most SARS-CoV-2 IgG-positive subjects were not PCR tested. The most common symptoms in IgG- and/or PCR-positive subjects were fever, fatigue and cough. No SARS-CoV-2 IgG- or PCR-positive subject developed severe or critical COVID-19 or required hospitalization., Conclusions: This is the first report of clinical outcomes of SARS-CoV-2 infection and seroprevalence of SARS-CoV-2 IgG in a large cohort of paediatric RD patients. Most SARS-CoV-2 IgG-positive subjects had no symptoms of COVID-19 infection. Symptomatic subjects all had mild COVID-19 symptoms, suggesting that the risk of severe or critical COVID-19 in immunosuppressed paediatric RD patients is minimal., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA)., Methods: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal., Results: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36)., Conclusion: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare., (© 2018, American College of Rheumatology.)

Objective: To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti-tumor necrosis factor (anti-TNF) therapy in children with polyarticular forms of juvenile idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease., Methods: In 16 centers 137 patients with clinically inactive JIA who were receiving anti-TNF therapy (42% of whom were also receiving methotrexate [MTX]) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti-TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life-table analysis, t-tests, chi-square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare., Results: Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti-TNF therapy for the initial 6 months and were included in the phase of the study in which anti-TNF therapy was stopped. Stopping anti-TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05)., Conclusion: Over one-third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti-TNF therapy. Several predictors of lower likelihood of flare were identified., (© 2018, American College of Rheumatology.)

Objective: Nonadherence is currently an underrecognized and potentially modifiable obstacle to care in juvenile idiopathic arthritis (JIA). The purpose of our study was to design and implement a standardized approach to identifying adherence barriers for youth with JIA across 7 pediatric rheumatology clinics through the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) and to assess the frequency of adherence barriers in patients and their caregivers across treatment modalities., Methods: An iterative process using coproduction among parents and providers of patients with JIA was used to design the Barriers Assessment Tool to screen for adherence barriers across 4 treatment modalities (i.e., oral medications, injectable medications, infusions, and physical/occupational therapy). This tool was implemented in 7 rheumatology clinics across the United States and patient responses were collected for analysis., Results: Data were collected from 578 parents and 99 patients (n = 44 parent-child dyads). Seventy-seven percent (n = 444) of caregivers and 70% (n = 69) of patients reported at least 1 adherence barrier across all treatment components. The most commonly reported adherence barriers included worry about future consequences of therapy, pain, forgetting, side effects, and embarrassment related to the therapy. There was no significant difference between endorsement of barriers between parents and adolescents., Conclusion: Implementing a standardized tool assessing adherence barriers in the JIA population across multiple clinical settings is feasible. Systematic screening sheds light on the factors that make adherence difficult in JIA and identifies targets for future adherence interventions in clinical practice.

Objective: The nuclear oncoprotein DEK is an autoantigen associated with juvenile idiopathic arthritis (JIA), especially the oligoarticular subtype. DEK is a secreted chemotactic factor. Abundant levels of DEK and DEK autoantibodies are found in inflamed synovium in JIA. We undertook this study to further characterize the nature of DEK autoantibodies in screening serum samples from 2 different cohorts that consisted mostly of patients with JIA., Methods: DEK autoantibody levels were analyzed in sera from 33 JIA patients, 13 patients with other inflammatory conditions, and 11 healthy controls, as well as in 89 serum samples from JIA patients receiving anti-tumor necrosis factor (anti-TNF) therapy. Recombinant His-tagged full-length DEK protein (1-375 amino acids [aa]) and the 187-375-aa and 1-350-aa His-tagged DEK fragments made in a baculovirus system were used for enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The C-terminal 25-aa fragment of DEK was expressed in a glutathione S-transferase-tagged vector. ELISA results were calculated as area under the curve by the trapezoidal rule., Results: DEK autoantibody levels were significantly higher in patients with polyarticular JIA than in those with oligoarticular JIA, and were higher in patients with polyarticular JIA who had more active disease after cessation of anti-TNF therapy. Immunoblotting against the C-terminal 25-aa fragment of DEK confirmed that this section of the DEK molecule is the most immunogenic domain., Conclusion: DEK autoantibody levels are higher in patients with polyarticular JIA than in those with oligoarticular JIA, and higher in patients who have disease flares after cessation of anti-TNF therapy. The C-terminal 25-aa fragment is the most immunogenic portion of DEK. These findings are significant with respect to the nature of DEK autoantibodies, their contribution to JIA pathogenesis, and their implications for JIA management., (© 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: To identify targets for improving mental healthcare of adolescents with systemic lupus erythematosus (SLE) by assessing current practices and perceived barriers for mental health intervention by pediatric rheumatology clinicians., Methods: Members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) completed a Web-based survey assessing current mental health practices, beliefs, and barriers. We examined associations between provider characteristics and the frequency of barriers to mental health screening and treatment using multivariable linear regression., Results: Of the 375 eligible CARRA members, 130 responded (35%) and 119 completed the survey. Fifty-two percent described identification of depression/anxiety in adolescents with SLE at their practice as inadequate, and 45% described treatment as inadequate. Seventy-seven percent stated that routine screening for depression/anxiety in pediatric rheumatology should be conducted, but only 2% routinely used a standardized instrument. Limited staff resources and time were the most frequent barriers to screening. Respondents with formal postgraduate mental health training, experience treating young adults, and practicing at sites with very accessible mental health staff, in urban locations, and in Canada reported fewer barriers to screening. Long waitlists and limited availability of mental health providers were the most frequent barriers to treatment. Male clinicians and those practicing in the Midwest and Canada reported fewer barriers to treatment., Conclusion: Pediatric rheumatology clinicians perceive a need for improved mental healthcare of adolescents with SLE. Potential strategies to overcome barriers include enhanced mental health training for pediatric rheumatologists, standardized rheumatology-based mental health practices, and better integration of medical and mental health services.

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: This study aimed to assess long-term safety and developmental data on juvenile idiopathic arthritis (JIA) patients treated in routine clinical practice with celecoxib or nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs)., Methods: Children aged ≥2 to <18 years with rheumatoid-factor-positive or -negative polyarthritis, persistent or extended oligoarthritis, or systemic arthritis were enrolled into this prospective, observational, multicenter standard-of-care registry. Eligible patients were newly or recently prescribed (≤6 months) an nsNSAID or celecoxib. Enrolled patients were followed to the end of the study, whether they remained on the original NSAID, switched, or discontinued therapy altogether. All adverse events (AEs) regardless of severity were captured in the database., Results: A total of 274 patients (nsNSAID, n = 219; celecoxib, n = 55) were observed for 410 patient-years of observation. Naproxen, meloxicam, and nabumetone were the most frequently used nsNSAIDs. At baseline, the celecoxib group was older, had a numerically longer median time since diagnosis, and a numerically higher proportion of patients with a history of gastrointestinal-related NSAID intolerance. AEs reported were those frequently observed with NSAID treatment and were similar across groups (nsNSAIDs: 52.0%; celecoxib: 52.9%). Twelve unique patients experienced a total of 18 serious AEs; the most frequent were infections, and none was attributed to NSAID use., Conclusions: The safety profile of celecoxib and nsNSAIDs appears similar overall. The results from this registry, ongoing pharmacovigilance, and the phase 3 trial that led to the approval of celecoxib for children with JIA provide evidence that the benefit-risk for celecoxib treatment in JIA remains positive., Trial Registration: ClinicalTrials.gov identifier NCT00688545.

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.

Purpose of Review: To present a case-based approach of three common scenarios which often present to the primary care physician. The approach to these cases and the differential diagnosis are discussed for these common rheumatologic diseases., Recent Findings: Numerous healthy children and adolescents are referred to pediatric rheumatologists for the evaluation of suspected rheumatologic diseases. Often, general rheumatologic laboratory tests are sent which are not necessarily specific to the clinical situation. There is a high false-positive rate associated with many of these tests and undue anxiety and referrals result from these. Directed laboratory studies based on history and exam findings are more prudent and useful in the evaluation of these children. Routine antinuclear antibody testing, for example, is not recommended without supportive symptoms or signs., Summary: A practical approach for primary care physicians is described for the evaluation of patients suspected of having some of the more common pediatric rheumatologic symptoms and diseases.

Juvenile idiopathic arthrithis (JIA) is the most common rheumatic disease of childhood.JIA is a chronic disease that is associated with periods of disease flares and periods of disease inactivity.Early, aggressive treatment with nonsteroidal anti-inflammatory drugs, intra-articular corticosteroid injections, or methotrexate, has significantly improved the outcome of most children who have JIA. Biologics have been shown to be both safe and effective for the treatment of more aggressive forms of arthritis and for uveitis. Long-term safety data of biologics is still uncertain. In the near future, it is hoped that genetic testing will allow earlier diagnosis of JIA as well as help predict the disease course of children who have JIA. Genetic analysis also may allow physicians to target therapies more effectively. It is hoped that development of more specific therapies will decrease overall immunosuppression and other associated toxicities.

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.)

Objective: The ability to assess quality of care is a necessary component of continuous quality improvement. The assessment typically is accomplished by determination of compliance with a defined set of quality measures (QMs). The objective of this effort was to establish a set of QMs for the assessment of the process of care in juvenile idiopathic arthritis (JIA)., Methods: A 12-member working group composed of representatives from the American College of Rheumatology, American Academy of Pediatrics, American Board of Pediatrics, and Association of Rheumatology Health Professionals was assembled to guide the project. Delphi questionnaires were sent to 237 health professionals involved in the care of children with JIA. A total of 471 items in 23 domains were identified. The working group met via 4 live e-meetings during which results from the Delphi questionnaires were distilled to a reduced draft set. Each working group member selected a proposed QM to investigate and present evidence from the literature as to its attributes and appropriateness for inclusion into the set. Nominal group technique was used to come to consensus on a proposed set of QMs., Results: The proposed set contains 12 QMs within 4 health care domains. Each QM consists of a statement of 1) the assessment to be completed, 2) when the first assessment should be completed and a suggested frequency of assessment during followup, 3) recommendations of appropriate tools or methods of assessment, and 4) initial performance goals., Conclusion: Implementation of the proposed QM set will improve the process of care, facilitate continuous quality improvement, and eventuate in improved health outcomes of children with JIA., (Copyright © 2011 by the American College of Rheumatology.)

Objective: Systemic juvenile idiopathic arthritis (JIA) is frequently associated with the development of macrophage activation syndrome. This study was undertaken to better understand the relationship between systemic JIA and macrophage activation syndrome., Methods: Gene expression profiles were examined in 17 patients with untreated new-onset systemic JIA, 5 of whom showed evidence of subclinical macrophage activation syndrome (of whom 2 eventually developed overt macrophage activation syndrome). Peripheral blood mononuclear cells (PBMCs) were separated on Ficoll gradients, and purified RNA was analyzed using Affymetrix GeneChip expression arrays. A fraction of the PBMCs were used for flow cytometry to define the cellular composition of the samples., Results: Two hundred twenty-five differentially expressed genes (P < 0.05) that distinguished patients with systemic JIA from healthy controls (n = 30) were identified. Clustering analysis indicated that expression patterns correlated with serum ferritin levels. Three main clusters distinguished systemic JIA patients with highly elevated ferritin levels (including those with subclinical macrophage activation syndrome) from those with normal or only moderately elevated ferritin levels. The first cluster comprised genes involved in the synthesis of hemoglobins and structural proteins of erythrocytes. This transcriptional profile was consistent with immature nucleated red blood cells, likely reflective of high red blood cell turnover. Also included were transcripts indicating immature granulocytes. The second cluster was enriched for genes involved in cell cycle regulation. The third cluster was enriched for genes involved in innate immune responses, including those involved in the negative regulation of Toll-like receptor/interleukin-1 receptor-triggered inflammatory cascades and markers of the alternative pathway of macrophage differentiation. Additional differentially expressed genes of interest were those involved in the cytolytic pathway, including SH2D1A and Rab27a., Conclusion: These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.

Objective: To describe the development and test the efficacy of a cognitive-behavioral intervention (CBT) for juvenile fibromyalgia., Method: Sixty-seven children with fibromyalgia and their parents were recruited to participate in an 8-week intervention that included modules of pain management, psychoeducation, sleep hygiene, and activities of daily living. Children were taught techniques of cognitive restructuring, thought stopping, distraction, relaxation, and self-reward. Additionally, they kept daily pain and sleep diaries. Children completed questionnaires of pre- and post-treatment measuring physical status and psychological functioning., Results: Following CBT, children reported significant reductions (p < .006) in pain, somatic symptoms, anxiety, and fatigue, as well as improvements in sleep quality. Additionally, children reported improved functional ability and had fewer school absences., Conclusion: Children with fibromyalgia can be taught CBT strategies that help them effectively manage this chronic and disabling musculoskeletal pain disorder.

Objective: To compare patients with juvenile rheumatoid arthritis (JRA) injected with triamcinolone hexacetonide (TH) or triamcinolone acetonide (TA) with respect to time to relapse., Methods: This was a retrospective chart review of 85 patients: 51 patients with JRA who had received a joint injection with TH during the period June 2000-April 2001 and 48 patients who had received a joint injection with TA during the period May 2001-March 2002 who were followed for a minimum of 15 months, after an intraarticular steroid injection., Results: The primary endpoint variable for the study was the time to relapse of the arthritis in the affected joint following an intraarticular injection. A total of 227 joints were injected, 114 with TH and 113 with TA. In the TH group the mean time to relapse (+/- SE) was 10.14 +/- 0.49 months compared to the TA group at 7.75 +/- 0.49 months (p < 0.0001) using the log-rank test. A proportional hazards (Cox) regression analysis revealed no statistical association between sex, duration of illness, or type of arthritis and relapse time. An analysis was performed on the first intraarticular injection for each patient, with the average time to relapse for all joints injected of 10.36 +/- 0.72 months for TH compared to 8.45 +/- 0.78 months for TA (p < 0.02). A further analysis of the first knee injections showed a relapse time in the TH group of 11.11 +/- 0.81 months compared to 7.95 +/- 0.95 months for TA (p < 0.008)., Conclusion: TH offers an advantage to TA, as there is a longer duration of action leading to an improved prolonged response rate in weight-bearing joints, particularly the knees. The results suggest that TH should be the intraarticular steroid of choice, particularly for the knee joint, in patients with JRA.

Kawasaki disease (KD) is a multisystem vasculitis of unknown etiology, with coronary artery aneurysms occurring in 25% of untreated cases. With conventional treatment of intravenous immunoglobulin (i.v.IG) and high dose aspirin (ASA) only 4% of patients develop coronary artery aneurysms. Children who are unresponsive present a challenge. Tumor necrosis factor-alpha levels peak during the acute and subacute phase of KD, especially in children who develop coronary artery aneurysms. We describe a 3-year-old male with KD and giant coronary artery aneurysms, unresponsive to multiple doses of i.v.IG and methylprednisolone, who was treated with infliximab. After the first dose he defervesced and his laboratory measures improved.

Objective: Children with juvenile rheumatoid arthritis (JRA) treated with methotrexate (MTX) were examined for their course after the discontinuation of the drug to define the relapse and remission rates and to identify predictors of relapse., Methodology: A retrospective chart review of all patients with JRA was conducted in two pediatric rheumatology centers. A total of 101 patients being treated with MTX were identified. Dose, response to the drug, and length of time until reaching a state of complete control were noted. The outcome of patients with a complete response in whom the drug was discontinued was examined with regards to length of time to relapse or continued remission., Results: In 25 patients, MTX was discontinued after reaching complete control of the disease. There were no statistically significant predictors of response to MTX identified. Of 25 whose MTX was discontinued, relapse occurred in 13 (52%) after a mean of 11 months after discontinuation. There was no significant difference among patients who relapsed or those who remained in remission as to sex, subtype of JRA, number of months to complete control, or number of months in complete control until discontinuing MTX. Patients younger than 41/2 years at diagnosis were found to be more likely to relapse than patients diagnosed at a later age. In 10 of the patients who relapsed, complete control was induced within a mean of 7 months after restarting MTX., Conclusion: The optimal time for discontinuing MTX in children with JRA who have achieved complete control is unknown. Relapse occurred in approximately half of the patients in whom MTX was discontinued. Because response to reinstitution of the drug is good, it is reasonable to discontinue MTX after prolonged complete control. It remains to be seen whether the relapse rate can be improved by waiting for longer periods of time in complete control before its discontinuation.

Wegener granulomatosis traditionally has been treated with glucocorticoids and cyclophosphamide. Both the disease and its treatments are associated with significant morbidity and mortality rates. There has been an effort to find effective but less toxic alternative treatments. We describe three children with Wegener granulomatosis who responded well to treatment with glucocorticoids and methotrexate, similar to a regimen used in adults.

Compared the effectiveness of several response exaggeration techniques. Socially anxious college males (N = 34) were instructed to exaggerate some component of social anxiety onset. One group exaggerated their attending to manifestations of their anxiety, two groups exaggerated either a relevant or irrelevant anxiety response, a fourth group imagined an exaggerated consequence of their anxiety, and a fifth group served as a placebo control. All groups reported a greater willingness to initiate and maintain an interaction with a female and displayed less anxiety in a role-playing situation; no differential treatment effects were found. These findings fail to support results from other studies that attested to the efficacy of response exaggeration techniques.

Thrombocytopenia and haemolysis in intraoperative autotransfusion result mainly from extravascular tissue contact and therefore are not correctable by mechanical improvements in the autotransfusion apparatus. Instead, attention must be directed towards prevention of blood 'recognition' of extravascular tissue or stabilization of blood components against this damage. Methylprednisolone is shown to be effective in alleviating red cell and platelet damage induced by intraoperative autotransfusion in the canine model.