Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis: does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial.

BACKGROUND: Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial. METHODS: 92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m2/week. RESULTS: 32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4-10), median 10 months (7-16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6-9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group. CONCLUSIONS: Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety. TRIAL REGISTRATION: Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585 .

Reliability assessment of the OMERACT whole-body magnetic resonance imaging scoring system for juvenile idiopathic arthritis.

Inter-reader reliability of a new scoring system for evaluating joint inflammation and enthesitis in whole body MRI (WBMRI) in juvenile idiopathic arthritis was tested. The scoring system grades 732 item-region combinations of bone marrow and soft tissue changes for commonly involved joints and entheseal sites. Five radiologists rated 17 WBMRI scans through an online rating platform. Item-wise reliability was calculated for 117 items with non-zero scores in >10 % of readings. Interquartile ranges of the five-reader Kappa reliability coefficients were 0.58-0.73 (range: 0.36-0.88) for the joints, 0.65-0.81 (range: 0.39-0.95) for the entheses, and 0.62-0.75 (range: 0.60-0.76) for chronic nonbacterial osteomyelitis-like lesions.

Developing standards for MRI evaluation of joints in children with juvenile idiopathic arthritis utilizing the temporomandibular joint as a model.

The treatment of a patient with juvenile idiopathic arthritis (JIA) is best monitored with standardized and validated tools to measure joint changes over time. Treatment approaches are best indicated if the clinicians are aware of the structural status of the joint at a given time, especially in anatomically deep joints for which clinical assessment is limited. Magnetic resonance imaging (MRI) is of utmost importance for assessment of deep joints and extra-articular soft tissue of the entire body for which ultrasound may be suboptimal. Because the distinction between pathologic and physiologic joint changes on MRI is key for proper diagnosis and treatment of patients with arthropathies, a comprehensive standardized approach is needed to effectively measure outcomes of growing joints of children with JIA. Such an approach is essential for both clinical assessment and to conduct clinical trials in patients with JIA treated in different centers around the world. To meet this need, several international imaging collaborative research groups have been developing MRI scales over the past years, including the MRI in JIA (JAMRI) special interest group within the Outcome Measures in Rheumatology (OMERACT) research network. This manuscript reviews the efforts of the OMERACT JAMRI working group to generate and validate pediatric MRI scoring systems for different joints in children with JIA that can have ubiquitous utilization anywhere in the world. In particular, it describes the different steps of development and validation of an MRI scale using the TMJ as a model.

Systematic calibration reduces sources of variability for the preliminary OMERACT juvenile idiopathic arthritis MRI- sacroiliac joint score (OMERACT JAMRIS-SIJ).

OBJECTIVE: To determine whether systematic calibration enhances scoring proficiency of the OMERACT juvenile idiopathic arthritis MRI-Sacroiliac Joint score (JAMRIS-SIJ) and whether contrast-enhancement enhances its performance. METHODS: MRI SIJ scans of 50 cases with juvenile spondyloarthritis were scored by 7 raters after calibration with 3 different knowledge transfer tools. RESULTS: Calibrated readers achieved greater reliability for scoring certain inflammatory and structural lesions. Sensitivity and reliability for scoring inflammatory lesions was greater on fluid-sensitive compared to contrast-enhanced sequences. CONCLUSION: Systematic calibration should be implemented prior to the use of JAMRIS-SIJ for clinical trials. It is unlikely that contrast-enhanced MRI will improve the performance of this method.

Significant pain decrease in children with non-systemic Juvenile Idiopathic Arthritis treated to target: results over 24 months of follow up.

BACKGROUND: The aim of this study was to compare pain-scores in three targeted treatment-strategies in JIA-patients and to identify characteristics predicting persistent pain. METHODS: In the BeSt-for-Kids-study 92 DMARD-naïve JIA-patients were randomized in 3 treatment-strategies: 1) initial sequential DMARD-monotherapy 2) initial methotrexate (MTX)/prednisolone-bridging or 3) initial MTX/etanercept. Potential differences in VAS pain scores (0-100 mm) over time between treatment-strategies were compared using linear mixed models with visits clustered within patients. A multivariable model was used to assess the ability of baseline characteristics to predict the chance of high pain-scores during follow-up. RESULTS: Pain-scores over time reduced from mean 55.3 (SD 21.7) to 19.5 (SD 25.3) mm after 24 months. On average, pain-scores decreased significantly with ß -1.37 mm (95% CI -1.726; -1.022) per month. No significant difference was found between treatment-strategies (interaction term treatment arm*time (months) ß (95% CI) arm 1: 0.13 (-0.36; 0.62) and arm 2: 0.37 (-0.12; 0.86) compared to arm 3). Correction for sex and symptom duration yielded similar results. Several baseline characteristics were predictive for pain over time. Higher VAS pain [ß 0.44 (95% CI 0.25; 0.65)] and higher active joint count [0.77 (0.19; 1.34)] were predictive of higher pain over time, whereas, low VAS physician [ -0.34 (-0.55; -0.06)], CHQ Physical [ -0.42 (-0.72; -0.11)] and Psychosocial summary Score [ -0.42 (-0.77; -0.06)] were predictive of lower pain. CONCLUSIONS: Treatment-to-target seems effective in pain-reduction in non-systemic JIA-patients irrespective of initial treatment-strategy. Several baseline-predictors for pain over time were found, which could help to identify patients with a high risk for development of chronic pain. TRIAL REGISTRATION: Dutch Trial Registry number 1574.

Somatic symptoms, pain, catastrophizing and the association with disability among children with heritable connective tissue disorders.

The aim of the present study was to investigate the nature and prevalence of nonspecific somatic symptoms, pain and catastrophizing in children with Heritable Connective Tissue Disorders (HCTD), and to determine their association with disability. This observational, multicenter study included 127 children, aged 4-18 years, with Marfan syndrome (MFS) (59%), Loeys-Dietz syndrome (LDS) (8%), Ehlers-Danlos syndromes (EDS) (12%) and hypermobile Ehlers-Danlos syndrome (hEDS) (23%). The assessments included the Children's Somatization Inventory or parent proxy (CSI, PCSI), pain visual-analogue scale (VAS), SUPERKIDZ body diagram, Pain Catastrophizing Scale Child or parent proxy (PCS-C, PCS-P) and Childhood Health Assessment Questionnaire (CHAQ-30). Data from children aged ≥8 years were compared to normative data. In children ≥ 8 years (n = 90), pain was present in 59%, with a median of 4 (IQR = 3-9) pain areas. Compared to normative data, the HCTD group reported significantly higher on the CSI (p ≤ 0.001, d = 0.85), VAS pain intensity (p ≤ 0.001, d = 1.22) and CHAQ-30 (p ≤ 0.001, d = 1.16) and lower on the PCS-C (p = 0.017, d = -0.82) and PCS-P (p ≤ 0.001, d = -0.49). The intensity of nonspecific somatic symptoms and pain explained 45% of the variance in disability (r2 = 0.45 F(2,48) = 19.70, p ≤ 0.001). In children ≤ 7 years (n = 37), pain was present in 35% with a median of 5(IQR = 1-13) pain areas. The mean(SD) VAS scores for pain intensity was 1.5(2.9). Functional disability was moderately correlated to the number of pain areas (r = 0.56, p ≤ 0.001), intensity of nonspecific somatic symptoms (r = 0.63, p ≤ 0.001) and pain (r = 0.83, p ≤ 0.001). In conclusion, this study supports the need for comprehensive assessment of nonspecific somatic symptoms, pain, and disability in children with HCTD to allow tailored treatment.

Pediatric joint hypermobility: a diagnostic framework and narrative review.

BACKGROUND: Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are debilitating conditions. Diagnosis is currently clinical in the absence of biomarkers, and criteria developed for adults are difficult to use in children and biologically immature adolescents. Generalized joint hypermobility (GJH) is a prerequisite for hEDS and generalized HSD. Current literature identifies a large proportion of children as hypermobile using a Beighton score ≥ 4 or 5/9, the cut off for GJH in adults. Other phenotypic features from the 2017 hEDS criteria can arise over time. Finally, many comorbidities described in hEDS/HSD are also seen in the general pediatric and adolescent population. Therefore, pediatric specific criteria are needed. The Paediatric Working Group of the International Consortium on EDS and HSD has developed a pediatric diagnostic framework presented here. The work was informed by a review of the published evidence. OBSERVATIONS: The framework has 4 components, GJH, skin and tissue abnormalities, musculoskeletal complications, and core comorbidities. A Beighton score of ≥ 6/9 best identifies children with GJH at 2 standard deviations above average, based on published general population data. Skin and soft tissue changes include soft skin, stretchy skin, atrophic scars, stretch marks, piezogenic papules, and recurrent hernias. Two symptomatic groups were agreed: musculoskeletal and systemic. Emerging comorbid relationships are discussed. The framework generates 8 subgroups, 4 pediatric GJH, and 4 pediatric generalized hypermobility spectrum disorders. hEDS is reserved for biologically mature adolescents who meet the 2017 criteria, which also covers even rarer types of Ehlers-Danlos syndrome at any age. CONCLUSIONS: This framework allows hypermobile children to be categorized into a group describing their phenotypic and symptomatic presentation. It clarifies the recommendation that comorbidities should be defined using their current internationally accepted frameworks. This provides a foundation for improving clinical care and research quality in this population.

Determination of Relative Weightings for Sacroiliac Joint Pathologies in the OMERACT Juvenile Arthritis Magnetic Resonance Imaging Sacroiliac Joint Score.

This study aims to determine the relative weights (point value) of items of the juvenile idiopathic arthritis magnetic resonance imaging-sacroiliac joint scoring system (JAMRIS-SIJ). An adaptive multicriteria decision analysis was performed using the 1000Minds web application to determine the relative weights of the items in the JAMRIS-SIJ inflammation and damage domains. Experts in imaging and rheumatology independently completed a conjoint analysis survey (CAS) to determine the point value of the measurement items of the JAMRIS-SIJ. Each CAS survey question asked the expert to compare two hypothetical patient profiles, which were otherwise similar but different at two items at a time, and to select which item showed a more severe stage of inflammation or osteochondral damage. In addition, experts ranked 14 JAMRIS-SIJ grade only or image + grade patient vignettes while blinded to the CAS-derived weights. The validity of the weighted JAMRIS-SIJ was tested by comparing the expert CAS-weighted score and the image + grade ranking method. Seventeen experts completed the CAS (11 radiologists and 6 rheumatologists). Considering the point value for inflammation domain items, osteitis (24.7%) and bone marrow edema (24.3%) had higher group-averaged percentage weights compared to inflammation in erosion cavity (16.9%), joint space enhancement (13.1%), joint space fluid (9.1%), capsulitis (7.3%), and enthesitis (4.6%). Similarly, concerning the damage domain, ankylosis (41.3%) and erosion (25.1%) showed higher group-averaged weights compared to backfill (13.9%), sclerosis (10.7%), and fat metaplasia lesion (9.1%). The Spearman correlation coefficients of the CAS-weighted vignette order and unweighted JAMRIS-SIJ grade only order vignettes for all experts were 0.79 for inflammation and 0.80 for damage. The correlations of image vignettes among imaging experts to CAS were 0.75 for inflammation and 0.90 for damage. The multicriteria decision analysis identified differences in relative weights among the JAMRIS-SIJ measurement items. The determination of the relative weights provided expert-driven score scaling and face validity for the JAMRIS-SIJ, enabling the future evaluation of its longitudinal construct validity.

Physical activity and physical fitness in children with heritable connective tissue disorders.

Objectives: Health problems in patients with heritable connective tissue disorders (HCTD) are diverse and complex and might lead to lower physical activity (PA) and physical fitness (PF). This study aimed to investigate the PA and PF of children with heritable connective tissue disorders (HCTD). Methods: PA was assessed using an accelerometer-based activity monitor (ActivPAL) and the mobility subscale of the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT). PF was measured in terms of cardiovascular endurance using the Fitkids Treadmill Test (FTT); maximal hand grip strength, using hand grip dynamometry (HGD) as an indicator of muscle strength; and motor proficiency, using the Bruininks-Oseretsky Test of Motor Proficiency-2 (BOTMP-2). Results: A total of 56 children, with a median age of 11.6 (interquartile range [IQR], 8.8-15.8) years, diagnosed with Marfan syndrome (MFS), n = 37, Loeys-Dietz syndrome (LDS), n = 6, and genetically confirmed Ehlers-Danlos (EDS) syndromes, n = 13 (including classical EDS n = 10, vascular EDS n = 1, dermatosparaxis EDS n = 1, arthrochalasia EDS n = 1), participated. Regarding PA, children with HCTD were active for 4.5 (IQR 3.5-5.2) hours/day, spent 9.2 (IQR 7.6-10.4) hours/day sedentary, slept 11.2 (IQR 9.5-11.5) hours/day, and performed 8,351.7 (IQR 6,456.9-1,0484.6) steps/day. They scored below average (mean (standard deviation [SD]) z-score -1.4 (1.6)) on the PEDI-CAT mobility subscale. Regarding PF, children with HCTD scored well below average on the FFT (mean (SD) z-score -3.3 (3.2)) and below average on the HGD (mean (SD) z-score -1.1 (1.2)) compared to normative data. Contradictory, the BOTMP-2 score was classified as average (mean (SD) z-score.02 (.98)). Moderate positive correlations were found between PA and PF (r(39) = .378, p < .001). Moderately sized negative correlations were found between pain intensity and fatigue and time spent actively (r(35) = .408, p < .001 and r(24) = .395 p < .001, respectively). Conclusion: This study is the first to demonstrate reduced PA and PF in children with HCTD. PF was moderately positively correlated with PA and negatively correlated with pain intensity and fatigue. Reduced cardiovascular endurance, muscle strength, and deconditioning, combined with disorder-specific cardiovascular and musculoskeletal features, are hypothesized to be causal. Identifying the limitations in PA and PF provides a starting point for tailor-made interventions.

Patterns of clinical joint inflammation in juvenile idiopathic arthritis.

OBJECTIVES: We studied patterns of joint inflammation in juvenile idiopathic arthritis (JIA) to assess whether joint activity recurs locally in the same joints. METHODS: Joints of 91 patients of the BeSt for Kids study, a treat-to-target trial for children with recent-onset oligoarticular, rheumatoid factor-negative polyarticular and psoriatic JIA, were clinically assessed during 2 years (10 study visits). The association between joint inflammation at baseline and later inflammation in the same joint was assessed using a multilevel mixed-effects logistic regression model at joint level. With a Poisson model, the association between baseline joint inflammation and the number of study visits at which the same joint was recurrently inflamed was tested. RESULTS: Of the 6097 joints studied, 15% (897) was clinically inflamed at baseline. In 42% (377/897) of those joints, inflammation recurred during follow-up. Joint inflammation at baseline was statistically significantly associated with joint inflammation during follow-up in the same joint (OR 3.9, 95% CI 3.5 to 4.4) and specifically with the number of episodes of recurrent joint inflammation (IRR 1.6, 95% CI 1.2 to 2.1). CONCLUSION: In JIA, joint inflammation has the tendency to recur multiple times in joints that are clinically inflamed at disease onset. This indicates that local factors might play a role in the processes contributing to the occurrence of JIA flares.

Discrete Choice Experiment on a Magnetic Resonance Imaging Scoring System for Temporomandibular Joints in Juvenile Idiopathic Arthritis.

OBJECTIVE: To determine the relative importance weights of items and grades of a newly developed additive outcome measure called the juvenile idiopathic arthritis (JIA) magnetic resonance imaging (MRI) scoring system for the temporomandibular joint (TMJ) (JAMRIS-TMJ). METHODS: An adaptive partial-profile, discrete choice experiment (DCE) survey using the 1000Minds platform was independently completed by members of an expert group consisting of radiologists and non-radiologist clinicians to determine the group-averaged relative weights for the JAMRIS-TMJ. Subsequently, an image-based vignette ranking exercise was done, during which experts individually rank ordered 14 patient vignettes for disease severity while blinded to the weights and unrestricted to JAMRIS-TMJ assessment criteria. Validity of the weighted JAMRIS-TMJ was tested by comparing the consensus-graded, DCE-weighted JAMRIS-TMJ score of the vignettes with their unrestricted image-based ranks provided by the experts. RESULTS: Nineteen experts completed the DCE survey, and 21 completed the vignette ranking exercise. Synovial thickening and joint enhancement showed higher weights per raw score compared to bone marrow items and effusion in the inflammatory domain, while erosions and condylar flattening showed nonlinear and higher weights compared to disk abnormalities in the damage domain. The weighted JAMRIS-TMJ score of the vignettes correlated highly with the ranks from the unrestricted comparison method, with median Spearman's ρ of 0.92 (interquartile range [IQR] 0.87-0.95) for the inflammation and 0.93 (IQR 0.90-0.94) for the damage domain. CONCLUSION: A DCE survey was used to quantify the importance weights of the items and grades of the JAMRIS-TMJ. The weighted score showed high convergent validity with an unrestricted, holistic vignette ranking method.

Reliability of the Preliminary OMERACT Juvenile Idiopathic Arthritis MRI Score (OMERACT JAMRIS-SIJ).

This study reports the reliability of the juvenile idiopathic arthritis magnetic resonance imaging scoring system (JAMRIS-SIJ). The study comprised of eight raters-two rheumatologists and six radiologists-and 30 coronal T1 and Short-Tau Inversion Recovery (STIR) MRI scans of patients with enthesitis-related juvenile spondylarthritis. The median age of patients was 15 years with a mean disease duration of 5 years and 22 (73.3%) of the sample were boys. The inter-rater agreement of scores for each of the JAMRIS-SIJ items was calculated using a two-way random effect, absolute agreement, and single rater intraclass correlation coefficient (ICC 2.1). The ICC was interpreted together with kurtosis, since the ICC is also affected by the distribution of scores in the sample. The eight-rater, single measure inter-rater ICC (and kurtosis) values for JAMRIS-SIJ inflammation and damage components were the following: bone marrow edema (BME), 0.76 (1.2); joint space inflammation, 0.60 (1.8); capsulitis, 0.58 (9.2); enthesitis, 0.20 (0.1); ankylosis, 0.89 (35); sclerosis, 0.53 (4.6); erosion, 0.50 (6.5); fat lesion, 0.40 (21); backfill, 0.38 (38). The inter-rater reliability for BME and ankylosis scores was good and met the a priori set ICC threshold, whereas for the other items it was variable and below the selected threshold. Future directives should focus on refinement of the scores, definitions, and methods of interpretation prior to validation of the JAMRIS-SIJ through the assessment of its measurement properties.

Assessing the Reliability of the OMERACT Juvenile Idiopathic Arthritis Magnetic Resonance Scoring System for Temporomandibular Joints (JAMRIS-TMJ).

Contrast-enhanced magnetic resonance imaging (MRI) remains the most comprehensive modality to assess juvenile idiopathic arthritis (JIA)-related inflammation and osteochondral damage in the temporomandibular joints (TMJ). This study tested the reliability of a new JIA MRI scoring system for TMJ (JAMRIS-TMJ) and the impact of variations in calibration and reader specialty. Thirty-one MRI exams of bilateral TMJs were scored independently using the JAMRIS-TMJ by 20 readers consisting of radiologists and non-radiologist clinicians in three reading groups, with or without a calibrating atlas and/or tutorial. The inter-reader reliability in the multidisciplinary cohort assessed by the generalizability coefficient was 0.61-0.67 for the inflammatory and 0.66-0.74 for the damage domain. The atlas and tutorial did not improve agreement within radiologists, but improved the agreement between radiologist and non-radiologist groups. Agreements between different calibration levels were 0.02 to 0.08 lower by the generalizability coefficient compared to agreement within calibration levels; agreement between specialty groups was 0.04 to 0.10 lower than within specialty groups. Averaging two radiologists raised the reliability above 0.8 for both domains. Therefore, the reliability of JAMRIS-TMJ was moderate-to-good depending on the presence of specialty and calibration differences. The atlas and tutorial are necessary to improve reliability when the reader cohort consists of multiple specialties.

Consensus-driven conceptual development of a standardized whole body-MRI scoring system for assessment of disease activity in juvenile idiopathic arthritis: MRI in JIA OMERACT working group.

OBJECTIVES: Whole body-MRI is helpful in directing diagnostic and treatment approaches, and as a research outcome measure. We describe our initial consensus-driven phase towards developing a whole body-MRI scoring system for juvenile idiopathic arthritis. METHODS: An iterative approach using three rounds of anonymous Delphi surveys followed by a consensus meeting was used to draft the structure of the whole body-MRI scoring system, including the relevant anatomic joints and entheses for assessment, diagnostic item selection, definition and grading, and selection of appropriate MRI planes and sequences. The surveys were completed independently by an international expert group consisting of pediatric radiologists and rheumatologists. RESULTS: Twenty-two experts participated in at least one of three rounds of Delphi surveys and a concluding consensus meeting. A first iteration scoring system was developed which ultimately included the assessment of 100 peripheral, 23 chest, and 76 axial joints, and 64 entheses, with 2-4 diagnostic items graded in each of the items, using binary (presence/absence) and 2-3-level ordinal scores. Recommendations on anatomic MRI planes and sequences were specified as the minimally necessary imaging protocol for the scoring system. CONCLUSION: A novel whole body-MRI scoring system for juvenile idiopathic arthritis was developed by consensus among members of MRI in JIA OMERACT working group. Further iterative refinements, reliability testing, and responsiveness are warranted in upcoming studies.

Improving domain definition and outcome instrument selection: Lessons learned for OMERACT from imaging.

OBJECTIVES: Imaging is one of the most rapidly evolving fields in medicine. Unfortunately, many imaging technologies have been applied as measurement instruments without rigorous evaluation of the evidence supporting their truth, discriminatory capability and feasibility for that context of use. The Outcome Measures in Rheumatology (OMERACT) Filter 2.1 Instrument Selection Algorithm (OFISA) is used to evaluate such evidence for use of an instrument in a research setting. The objectives of this work are to: [1] define and describe the key conceptual aspects that are essential for the evaluation of imaging as an outcome measurement instrument and [2] describe how these aspects can be assessed through OFISA. METHODS: Experts in imaging and/or methodology met to formalize concepts and define key steps. These concepts were discussed with a team of patient research partners with interest in imaging to refine technical and methodological aspects into comprehensible information. A workshop was held at OMERACT2020 and feedback was incorporated into existing OMERACT process for domain and instrument selection. RESULTS: Three key lessons were identified: (1) a clear definition of the domain we want to measure is a necessary prerequisite to the selection of a good instrument, (2) the sources of variability that can directly influence the instrument should be clearly identified, (3) incorporating these first two lessons into OFISA improves the quality of every instrument selection process. CONCLUSIONS: The incorporation of these lessons in the updated OMERACT Filter (now 2.2) will improve the quality of the selection process for all types of outcome measurement instruments.

Toward Developing a Semiquantitative Whole Body-MRI Scoring for Juvenile Idiopathic Arthritis: Critical Appraisal of the State of the Art, Challenges, and Opportunities.

With powerful new therapies available for management of juvenile idiopathic arthritis (JIA), early diagnosis leading to appropriate treatment may prevent long-term structural joint damage. Although magnetic resonance imaging (MRI) is typically used to assess individual body parts, indications for whole body (WB) MRI are increasing. Its utility as a diagnostic and monitoring tool has already been widely investigated in adult rheumatology patients, but less so in pediatric rheumatologic patients. This paper is a comprehensive review of scoring systems and a proposal for the conceptual development of a WB-MRI scoring system for the evaluation of JIA. In this review we identify, summarize, and critically appraise the available literature on the use of WB-MRI in inflammatory arthritis, addressing relevant considerations on components of a classification system that can lead to the development of a future pediatric WB-MRI scoring system for use in children with JIA. We also discuss advantages and challenges of developing such a WB-MRI scoring system for assessment of JIA and outline next steps toward the conceptual development of this scoring system.

Psychometric Properties of the Pediatric Patient-Reported Outcomes Measurement Information System Item Banks in a Dutch Clinical Sample of Children With Juvenile Idiopathic Arthritis.

OBJECTIVE: To assess the psychometric properties of 8 pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) item banks in a clinical sample of children with juvenile idiopathic arthritis (JIA). METHODS: A total of 154 Dutch children (mean ± SD age 14.4 ± 3.0 years; range 8-18 years) with JIA completed 8 pediatric version 1.0 PROMIS item banks (anger, anxiety, depressive symptoms, fatigue, pain interference, peer relationships, physical function mobility, physical function upper extremity) twice and the Pediatric Quality of Life Inventory (PedsQL) and the Childhood Health Assessment Questionnaire (C-HAQ) once. Structural validity of the item banks was assessed by fitting a graded response model (GRM) and inspecting GRM fit (comparative fit index [CFI], Tucker-Lewis index [TLI], and root mean square error of approximation [RMSEA]) and item fit (S-X2 statistic). Convergent validity (with PedsQL/C-HAQ subdomains) and discriminative validity (active/inactive disease) were assessed. Reliability of the item banks, short forms, and computerized adaptive testing (CAT) was expressed as the SE of theta (SE[θ]). Test-retest reliability was assessed using intraclass correlation coefficients (ICCs) and smallest detectable change. RESULTS: All item banks had sufficient overall GRM fit (CFI >0.95, TLI >0.95, RMSEA <0.08) and no item misfit (all S-X2 P > 0.001). High correlations (>0.70) were found between most PROMIS T scores and hypothesized PedsQL/C-HAQ (sub)domains. Mobility, pain interference, and upper extremity item banks were able to discriminate between patients with active and inactive disease. Regarding reliability, PROMIS item banks outperformed legacy instruments. Post hoc CAT simulations outperformed short forms. Test-retest reliability was strong (ICC >0.70) for all full-length item banks and short forms, except for the peer relationships item bank. CONCLUSION: The pediatric PROMIS item banks displayed sufficient psychometric properties for Dutch children with JIA. PROMIS item banks are ready for use in clinical research and practice for children with JIA.

Establishing an Updated Core Domain Set for Studies in Juvenile Idiopathic Arthritis: A Report from the OMERACT 2018 JIA Workshop.

OBJECTIVE: The current Juvenile Idiopathic Arthritis (JIA) Core Set used in randomized controlled trials (RCT) and longitudinal observational studies (LOS) was developed without the input of patients/parents. At the Outcome Measures in Rheumatology (OMERACT) 2016, a special interest group voted to reconsider the core set, incorporating broader input. We describe subsequent work culminating in an OMERACT 2018 plenary and consensus voting. METHODS: Candidate domains were identified through literature review, qualitative surveys, and online discussion boards (ODB) held with patients with JIA and parents in Australia, Italy, and the United States. A Delphi process with parents, patients, healthcare providers, researchers, and regulators served to edit the domain list and prioritize candidate domains. After the presentation of results, OMERACT workshop participants voted, with consensus set at > 70%. RESULTS: Participants in ODB were 53 patients with JIA (ages 15-24 yrs) and 55 parents. Three rounds of Delphi considering 27 domains were completed by 190 (response rate 85%), 201 (84%), and 182 (77%) people, respectively, from 50 countries. There was discordance noted between domains prioritized by patients/parents compared to others. OMERACT conference voting approved domains for JIA RCT and LOS with 83% endorsement. Mandatory domains are pain, joint inflammatory signs, activity limitation/physical function, patient's perception of disease activity (overall well-being), and adverse events. Mandatory in specific circumstances: inflammation/other features relevant to specific JIA categories. CONCLUSION: Following the OMERACT methodology, we developed an updated JIA Core Domain Set. Next steps are to identify and systematically evaluate best outcome measures for these domains.

Treat to target (drug-free) inactive disease in DMARD-naive juvenile idiopathic arthritis: 24-month clinical outcomes of a three-armed randomised trial.

QUESTION: Which is the best strategy to achieve (drug-free) inactive disease in juvenile idiopathic arthritis (JIA)? METHODS: In a randomised, single-blinded, study in disease-modifying anti-rheumatic drug (DMARD)-naive patients with JIA, three treatment-strategies were compared: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX +etanercept. Treatment-to-target entailed 3-monthly DMARD/biological adjustments in case of persistent disease activity, with drug tapering to nil in case of inactive disease.After 24 months, primary outcomes were time-to-inactive-disease and time-to-flare after DMARD discontinuation. Secondary outcomes were adapted ACRPedi30/50/70/90 scores, functional ability and adverse events. RESULTS: 94 children (67 % girls) aged median (IQR) 9.1 (4.6-12.9) years were enrolled: 32 in arms 1 and 2, 30 in arm 3. At baseline visual analogue scale (VAS) physician was mean 49 (SD 16) mm, VAS patient 53 (22) mm, erythrocyte sedimentation rate 12.8 (14.7), active joints median 8 (5-12), limited joints 2.5 (1-4.8) and Childhood Health Assessment Questionnaire score mean 1.0 (0.6).After 24 months, 71% (arm 1), 70% (arm 2) and 72% (arm 3) of patients had inactive disease and 45% (arm 1), 31% (arm 2) and 41% (arm 3) had drug-free inactive disease. Time-to-inactive-disease was median 9.0 (5.3-15.0) months in arm 1, 9.0 (6.0-12.8) months in arm 2 and 9.0 (6.0-12.0) months in arm 3 (p=0.30). Time-to-flare was not significantly different (overall 3.0 (3.0-6.8) months, p=0.7). Adapted ACR pedi-scores were comparably high between arms. Adverse events were similar. CONCLUSION: Regardless of initial specific treatments, after 24 months of treatment-to-target aimed at drug-free inactive disease, 71% of recent-onset patients with JIA had inactive disease (median onset 9 months) and 39% were drug free. Tightly controlled treatment-to-target is feasible. TRIAL REGISTRATION NUMBER: 1574.

Participation in a single-blinded pediatric therapeutic strategy study for juvenile idiopathic arthritis: are parents and patient-participants in equipoise?

BACKGROUND: Genuine uncertainty on superiority of one intervention over the other is called equipoise. Physician-investigators in randomized controlled trials (RCT) need equipoise at least in studies with more than minimal risks. Ideally, this equipoise is also present in patient-participants. In pediatrics, data on equipoise are lacking. We hypothesize that 1) lack of equipoise at enrolment among parents may reduce recruitment; 2) lack of equipoise during participation may reduce retention in patients assigned to a less favoured treatment-strategy. METHODS: We compared preferences of parents/patients at enrolment, documented by a questionnaire (phase 1), with preferences developed during follow-up by an interview-study (phase 2) to investigate equipoise of child-participants and parents in the BeSt-for-Kids-study (NTR 1574). This trial in new-onset Juvenile Idiopathic Arthritis-patients consists of three strategies. One strategy comprises initial treatment with a biological disease-modifying-antirheumatic-drug (DMARD), currently not standard-of-care. Semi-structured interviews were conducted with 23 parents and 7 patients, median 11 months after enrolment. RESULTS: Initially most parents and children were not in equipoise. Parents/patients who refused participation, regularly declined due to specific preferences. Many participating families preferred the biological-first-strategy. They participated to have a chance for this initial treatment, and would even consider stopping trial-participation when not randomized for it. Their conviction of superiority of the biological-first strategy was based on knowledge from internet and close relations. According to four parents, the physician-investigator preferred the biological-first-strategy, but the majority (n = 19) stated that she had no preferred strategy. In phase 2, preferences tended to change to the treatment actually received. CONCLUSIONS: Lack of equipoise during enrolment did not reduce study recruitment, mainly due to the fact that preferred treatment was only available within the study. Still, when developing a trial it is important to evaluate whether the physicians' research question is in line with preferences of the patient-group. By exploring so-called 'informed patient-group'-equipoise, successful recruitment may be enhanced and bias avoided. In our study, lack of equipoise during trial-participation did not reduce retention in those assigned to a less favoured option. We observed a change for preference towards treatment actually received, possibly explained by comparable outcomes in all three arms.