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Objectives: CLIPPER2 was an 8-year, open-label extension of the phase 3b, 2-year CLIPPER study on the safety and efficacy of etanercept in patients with JIA, categorized as extended oligoarticular arthritis (eoJIA), enthesitis-related arthritis (ERA) or PsA., Methods: Participants with eoJIA (2-17 years old), ERA or PsA (each 12-17 years old) who received ≥1 etanercept dose (0.8 mg/kg weekly; maximum 50 mg) in CLIPPER could enter CLIPPER2. Primary end point was occurrence of malignancy. Efficacy assessments included proportions achieving JIA ACR 30/50/70/90/100 criteria and ACR inactive disease criteria, and clinical remission (ACR criteria) or Juvenile Arthritis DAS (JADAS) ≤1., Results: Overall, 109/127 (86%) CLIPPER participants entered CLIPPER2 [n = 55 eoJIA, n = 31 ERA, n = 23 PsA; 99 (78%) on active treatment]; 84 (66%) completed 120 months' follow-up [32 (25%) on active treatment]. One malignancy (Hodgkin's disease in 18-year-old patient with eoJIA treated with methotrexate for 8 years) was reported; there were no cases of active tuberculosis or deaths. Numbers and incidence rates (events per 100 patient-years) of TEAEs (excluding infections/ISRs) decreased from 193 (173.81) in Year 1 to 9 (27.15) in Year 10; TE infections and serious infections also decreased. Over 45% of participants (n = 127) achieved JIA ACR50 responses from Month 2 onwards; 42 (33%) and 34 (27%) participants achieved JADAS and ACR clinical remission, respectively., Conclusions: Etanercept treatment up to 10 years was well tolerated, consistent with the known safety profile, with durable response in the participants still on active treatment. The benefit-risk assessment of etanercept in these JIA categories remains favourable., Trial Registration: ClinicalTrials.gov IDs: CLIPPER (NCT00962741); CLIPPER2 (NCT01421069)., (© The Author(s) 2023. 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 develop and validate new Juvenile Arthritis Disease Activity Score 10 (JADAS10) and clinical JADAS10 (cJADAS10) cutoffs to separate the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with oligoarthritis and with rheumatoid factor-negative polyarthritis, based on subjective disease assessment by the treating pediatric rheumatologist., Methods: The cutoffs definition cohort was composed of 1,936 patients included in the multinational Epidemiology, Treatment and Outcome of Childhood Arthritis (EPOCA) study. Using the subjective physician rating as an external criterion, 4 methods were applied to identify the cutoffs: mapping, Youden index, 90% specificity, and maximum agreement. The validation cohort included 4,014 EPOCA patients, patients from 2 randomized trials, and 88 patients from the PharmaChild registry. Cutoff validation was conducted by assessing discriminative and predictive ability., Results: The JADAS10 cutoffs were 1.4, 4, and 13, respectively, for oligoarthritis and 2.7, 6, and 17, respectively, for polyarthritis. The cJADAS10 cutoffs were 1.1, 4, and 12, respectively, for oligoarthritis and 2.5, 5, and 16, respectively, for polyarthritis. The cutoffs discriminated strongly among different levels of pain and morning stiffness, between patients who were and those who were not prescribed a new medication, and between different levels of improvement in clinical trials. Achievement of ID and MiDA according to the new JADAS cutoffs at least twice in the first year of disease predicted better outcome at 2 years., Conclusion: The 2021 JADAS and cJADAS cutoffs revealed good metrologic properties in both definition and validation samples, and are therefore suitable for use in clinical trials and routine practice., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To revise the current juvenile idiopathic arthritis (JIA) International League of Associations for Rheumatology (ILAR) classification criteria with an evidence-based approach, using clinical and routine laboratory measures available worldwide, to identify homogeneous clinical groups and to distinguish those forms of chronic arthritis typically seen only in children from the childhood counterpart of adult diseases., Methods: The overall project consists of 4 steps. This work represents Step 1, a Delphi Web-based consensus and Step 2, an international nominal group technique (NGT) consensus conference for the new provisional Pediatric Rheumatology International Trials Organization JIA classification criteria. A future large data collection of at least 1000 new-onset JIA patients (Step 3) followed by analysis and NGT consensus (Step 4) will provide data for the evidence-based validation of the JIA classification criteria., Results: In Step 1, three Delphi rounds of interactions were implemented to revise the 7 ILAR JIA categories. In Step 2, forty-seven questions with electronic voting were implemented to derive the new proposed criteria. Four disorders were proposed: (a) systemic JIA; (b) rheumatoid factor-positive JIA; (c) enthesitis/spondylitis-related JIA; and (d) early-onset antinuclear antibody-positive JIA. The other forms were gathered under the term "others." These will be analyzed during the prospective data collection using a list of descriptors to see whether the clustering of some of them could identify homogeneous entities., Conclusion: An international consensus was reached to identify different proposed homogeneous chronic disorders that fall under the historical term JIA . These preliminary criteria will be formally validated with a dedicated project.

Recent therapeutic advances in juvenile idiopathic arthritis (JIA) have made remission an achievable goal for most patients. Reaching this target leads to improved outcomes. The objective was to develop recommendations for treating JIA to target. A Steering Committee formulated a set of recommendations based on evidence derived from a systematic literature review. These were subsequently discussed, amended and voted on by an international Task Force of 30 paediatric rheumatologists in a consensus-based, Delphi-like procedure. Although the literature review did not reveal trials that compared a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated development of recommendations. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasise the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target. All items were agreed on by more than 80% of the members of the Task Force. A research agenda was formulated. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research. These recommendations can inform various stakeholders about strategies to reach optimal outcomes for JIA., Competing Interests: Competing interests: AR has received grant support and/or speaking or consultant fees from AbbVie, Bristol-Myers Squibb, Novartis, Pfizer, Roche and Johnson & Johnson; AC reports personal fees from AbbVie and non-financial support from Pfizer; GH has received research funds, advisory board membership and honorary fees from AbbVie, Pfizer and Roche; RML has been consultant and/or participated in advisory boards for AbbVie, Eli Lilly, Novartis, Sanofi and Sobi; DJL reports grants/research support from the National Institutes of Health, NIAMS, and received consultancy fees from AstraZeneca, Bristol-Myers Squibb, AbbVie, Pfizer, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Biogen, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Celgene and Janssen, and speaker bureaus from Genentech; NMW reports research grants and/or consultant fees from AbbVie and Novartis; JDA has received consultant fees from Pfizer; SMA-M does not report competing interests; JA reports grant support and/or personal fees from AbbVie, Gebro, Pfizer, Novartis, Roche and Sobi; TA has received speaking and/or consultant fees from AbbVie, Boehringer Ingelheim and Pfizer; RAB does not report competing interests; MWB does not report competing interests; RB-V does not report competing interests; RC has received consultant fees from AbbVie, Alfa Wassermann and Novartis; FDB reports grants from Hoffmann-La Roche, Bristol-Myers Squibb, Novimmune, Novartis, Abbott, Pfizer and Sobi; ED does not report competing interests; DF reports grant support and/or personal fees from Pfizer, Novartis, Roche and Sobi; YI does not report competing interests; PL has received grant support from AbbVie; EMM does not report competing interests; PQ has received speakers' fees from AbbVie, Novartis, Pfizer, Roche and Sobi, grants from AbbVie, Pfizer and Novartis, and personal fees for consultancy from AbbVie, Novartis, Novimmune and Sanofi; NR reports personal fees from AbbVie, Amgen, Biogen Idec, Alter, AstraZeneca, Baxalta Biosimilars, Boehringer, Bristol-Myers Squibb, Celgene, CrescendoBio, EMD Serono, Hoffmann-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi-Aventis, Servier, Takeda and UCB Biosciences, and other financial relationships from Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-La Roche, Novartis, Pfizer, Sanofi-Aventis, Schwarz Biosciences, Abbott, Francesco Angelini SPA, Sobi and Merck Serono; RR does not report competing interests; CS-M does not report competing interests; SSa does not report competing interests; CS does not report competing interests; SSh has received speaking and advisory board fees from Novartis; JFS does not report competing interests; YU reports grant support and/or personal fees and/or non-financial support from AbbVie, Janssen, Novartis, Pfizer and Roche; SJV reports grant support from Sobi; JSS has received grant support from and/or provided expert advice to AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Celltrion, Gilead, Glaxo, Janssen, Lilly, Pfizer, MSD, Roche, Samsung, Novartis-Sandoz and UCB., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Slovene language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the 3 Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 100 JIA patients (7.0% systemic, 47.0% oligoarticular, 22.0% RF negative polyarthritis, 24.0% other categories) and 120 healthy children, were enrolled. The JAMAR components discriminated well healthy subjects from JIA patients, except for the Health-Related Quality of Life, Psychosocial Health subscales. All JAMAR components revealed good psychometric performances. In conclusion, the Slovene version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Objective: The main objective was to determine the 2-year clinical benefit and safety of etanercept (ETN) in children with the juvenile idiopathic arthritis (JIA) categories of extended oligoarthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA)., Methods: CLIPPER was a 96-week, phase IIIb, open-label, multicenter study. Patients with eoJIA, ERA, or PsA received ETN 0.8 mg/kg once weekly (50 mg max) for up to 96 weeks. The proportions of patients reaching the JIA American College of Rheumatology (ACR) 30/50/70/90/100 and inactive disease responses at Week 96 were calculated. Adverse events (AE) were collected throughout the study (intention-to-treat sample)., Results: There were 127 patients (eoJIA n = 60, ERA n = 38, PsA n = 29) who received ≥ 1 dose of ETN. The mean disease duration was 31.6 (eoJIA), 23.0 (ERA), and 21.8 (PsA) months. At Week 96, JIA ACR 30/50/70/90/100/inactive disease responses (95% CI) were achieved by 84.3% (76.7, 90.1), 83.5% (75.8, 89.5), 78.7% (70.6, 85.5), 55.1% (46.0, 63.9), 45.7% (36.8, 54.7), and 27.6% (20.0, 36.2) of patients, respectively. The most common AE (no. events, events per 100 patient-yrs) overall were headache (23, 10.7), pyrexia (12, 5.6), and diarrhea (10, 4.6). The most common infections were upper respiratory tract infection (83, 38.6), pharyngitis (50, 23.2), gastroenteritis (22, 10.2), bronchitis (19, 8.8), and rhinitis (17, 7.9). No cases of malignancy, active tuberculosis, demyelinating disorders, or death were reported., Conclusion: Over 96 weeks of therapy, ETN demonstrated sustained efficacy at treating the clinical symptoms of all 3 JIA categories, with no major safety issues.

Objective: To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA)., Methods: A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA-associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference., Results: Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ = 0.76)., Conclusion: We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies., (© 2015, American College of Rheumatology.)

Objective: To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA)., Methods: In this multinational, multicenter study, pediatric rheumatologists and hemato-oncologists entered patient data collected retrospectively into a web-based database., Results: A total of 362 patients, 22% of whom had MAS at the onset of systemic JIA, were included in the study by 95 investigators from 33 countries. The most frequent clinical manifestations were fever (96%), hepatomegaly (70%), and splenomegaly (58%). Central nervous system dysfunction and hemorrhages were recorded in 35% and 20% of the patients, respectively. Platelet count and liver transaminase, ferritin, lactate dehydrogenase, triglyceride, and d-dimer levels were the sole laboratory biomarkers showing a percentage change of >50% between the pre-MAS visit and MAS onset. Evidence of macrophage hemophagocytosis was found in 60% of the patients who underwent bone marrow aspiration. MAS occurred most frequently in the setting of active underlying disease, in the absence of a specific trigger. Nearly all patients were given corticosteroids, and 61% received cyclosporine. Biologic medications and etoposide were given to 15% and 12% of the patients, respectively. Approximately one-third of the patients required admission to the intensive care unit (ICU), and the mortality rate was 8%., Conclusion: This study provides information on the clinical spectrum and current management of systemic JIA-associated MAS through the analysis of a very large patient sample. MAS remains a serious condition, as a sizeable proportion of patients required admission to the ICU or died., (Copyright © 2014 by the American College of Rheumatology.)

Objectives: Influenza vaccination in children with rheumatic diseases is often recommended, but not frequently performed. Our aim was to assess the safety and efficacy of annual influenza vaccination in a longitudinal follow-up study of an unselected group of children with juvenile idiopathic arthritis (JIA)., Methods: Thirty-one children with stable JIA (10 boys, 21 girls, mean age 11.0 years) receiving various therapies and 14 children in a control group (10 boys, 4 girls, mean age 11.9 years) were vaccinated with the annual influenza vaccine Begrivac® 2008/2009. The children in both groups were followed for adverse events and infections 6 months after vaccination. Autoantibodies production and antibody titers against three vaccine viruses were determined in serial samples taken before, 1 and 6 months after vaccination., Results: Eleven (35%) children with JIA and 5 (36%) children in the control group reported short-term adverse events. A JIA flare was observed one month after vaccination in 4 (13%) patients, and in the following five months in 7 (23%) patients. The response to vaccination after one month was significant in the control and study groups as a whole, but not in a subgroup of 4 children receiving anti-TNF-α therapy. After six months, no significant differences in the protective titers against vaccine viruses among the patient and control groups were observed. Changes in the mean values of autoantibodies after vaccination were found only for IgG aCL in the JIA group., Conclusions: No long-term adverse events were reported after influenza vaccination in JIA and control group. Thirty-five percent of children with JIA experienced flare of the disease after vaccination. Protective antibodies against at least 2 vaccine viruses 6 months after vaccination were detected in all patients.

We describe 3 patients who presented with features of macrophage activation syndrome (MAS) at the time of presentation of systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis, and Kawasaki disease. Immunohistochemical studies in the patient with SLE demonstrated extensive expression of CD163 on hemophagocytic macrophages, suggesting a possible role as a marker of MAS.

Nasal septal perforation has been well recognized in patients with various rheumatic diseases. To our knowledge, this condition has not been reported in children with systemic juvenile idiopathic arthritis (SJIA) or patients with adult onset Still's disease (AOSD). We describe 3 patients with persistent SJIA/AOSD who developed nasal septal perforation during the course of their disease. As illustrated by these cases, nasal septal perforation may develop as a rare complication of SJIA/AOSD and can be considered as part of the clinical spectrum of the disease. In one case the nasal septal perforation was associated with vasculitis.

Background: Antibodies against cyclic citrullinated peptide (anti-CCP) are considered to be specific for rheumatoid arthritis (RA)., Objective: To assess the clinical significance of anti-CCP in a cohort of patients with juvenile idiopathic arthritis (JIA)., Methods: Anti-CCP were tested by an enzyme linked immunosorbent assay (ELISA) in serum samples from 109 patients with JIA (30 boys, 79 girls), with a mean age of 8.7 years (range 0.6-20.3) and mean disease duration of 3.6 years (range 3 months to 15.6 years). As control groups, anti-CCP were also tested in sera of 30 healthy children, 25 patients with juvenile onset systemic lupus erythematosus (SLE), and 50 adult patients (30 with RA, 20 with SLE)., Results: Positive anti-CCP values were found in sera of two patients with JIA (2%), one with polyarthritis, and one with oligoarthritis. Statistical analysis showed that anti-CCP were not associated with the presence of antinuclear antibodies, raised erythrocyte sedimentation rate, or erosions. In the control groups, none of the patients with juvenile onset SLE and only one of 20 adults with SLE were positive for anti-CCP, but 19/30 (63%) adults with RA showed anti-CCP positivity., Conclusions: Anti-CCP can be detected in children with JIA, but are less frequently present than in adults with RA.

Objective: Anticardiolipin antibodies (aCL) have been frequently detected in juvenile idiopathic arthritis (JIA), but have not been associated with disease activity or clinical features of the antiphospholipid syndrome (APS). Our aim was to determine aCL and anti-beta2 glycoprotein I (anti-beta2GPI) antibody levels and lupus anticoagulant (LA) in serial samples from children with JIA and to investigate the clinical significance of these antibodies., Methods: The values of aCL, anti-beta2GPI and LA were prospectively followed in 28 children with JIA from disease onset. aCL and anti-beta2GPI were assayed by an ELISA method. Two monoclonal beta2GPI-dependent aCL (HCAL and EY2C9) were used as calibrators. LA was determined by a modified dilute Russell viper venom time test., Results: Thirteen (46.4%) children with JIA were already positive for aCL at their first referral to our center. During the follow-up, the frequency of aCL decreased from 46.4% to 28.6%; however, it remained significantly higher compared with healthy children. In contrast, for anti-beta2GPI the difference in the frequency between the children with JIA and healthy children was not statistically significant. Serial determination of aPL levels in JIA patients revealed frequent fluctuations. Positive aCL persisted over time in 6 (21.4%) children with JIA, 6 (21.4%) children were initially positive for aCL, but became later negative, and 3 (10.7%) children were initially negative for aCL and became later positive. Persistently positive anti-beta2GPI were observed during the follow-up only in one patient, while none of the patients was persistently positive for LA. No association between aCL, anti-beta2GPI or LA and disease activity could be established. No patient with positive aCL, anti-beta2GPI or LA showed any clinical feature of APS., Conclusion: The discrepancy between the presence of aCL and anti-beta2GPI might indicate that the production of aCL in JIA is associated with an infectious trigger. Furthermore, the low frequency of anti-beta2GPI and LA could explain the limited prothrombotic potential of aPL observed in JIA. However, we found a distinct group of JIA patients with persistently positive aCL, the clinical implications of which are at the present time unknown.