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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.

Made available in DSpace on 2019-10-05T16:54:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-04-01 IRCCS Istituto Giannina Gaslini Background To our knowledge, the characteristics and burden of childhood arthritis have never been studied on a worldwide basis. We aimed to investigate, with a cross-sectional study, the prevalence of disease categories, treatment methods, and disease status in patients from across different geographical areas and from countries with diverse wealth status. Methods In this multinational, cross-sectional, observational cohort study, we asked international paediatric rheumatologists from specialised centres to enrol children with a diagnosis of juvenile idiopathic arthritis, according to International League of Associations for Rheumatology criteria, who were seen consecutively for a period of 6 months. Each patient underwent retrospective and cross-sectional assessments, including measures of disease activity and damage and questionnaires on the wellbeing and quality of life of the children. We qualitatively compared the collected data across eight geographical areas, and we explored an association between disease activity and damage and a country's gross domestic product (GDP) with a multiple logistic regression analysis. Findings Between April 4, 2011, and Nov 21, 2016, 9081 patients were enrolled at 130 centres in 49 countries, grouped into eight geographical areas. Systemic arthritis (125 [33.0%] of 379 patients) and enthesitis-related arthritis (113 [29.8%] of 379) were more common in southeast Asia, whereas oligoarthritis was more prevalent in southern Europe (1360 [56.7%] of 2400) and rheumatoid factor-negative polyarthritis was more frequent in North America (165 [31.5%] of 523) than in the other areas. Prevalence of uveitis was highest in northern Europe (161 [19.1%] of 845 patients) and southern Europe (450 [18.8%] of 2400) and lowest in Latin America (54 [6.4%] of 849), Africa and Middle East (71 [5.9%] of 1209), and southeast Asia (19 [5.0%] of 379). Median age at disease onset was lower in southern Europe (3.5 years, IQR 1.9-7.3) than in other regions. Biological, disease-modifying antirheumatic drugs were prescribed more frequently in northern Europe and North America than in other geographical settings. Patients living in countries with lower GDP had greater disease activity and damage than those living in wealthier countries. Damage was associated with referral delay. Interpretation Our study documents a variability in prevalence of disease phenotypes and disparities in therapeutic choices and outcomes across geographical areas and wealth status of countries. The greater disease burden in lowerresource settings highlights the need for public health efforts aimed at improving equity in access to effective treatments and care for juvenile idiopathic arthritis. Copyright (C) 2019 Elsevier Ltd. All rights reserved. Univ Genoa, Ist Giannina Gaslini, IRCCS, Clin Paediat & Rheumatol, Genoa, Italy Univ Genoa, Ist Giannina Gaslini, IRCCS, Epidemiol & Biostat Serv, Genoa, Italy Univ Genoa, Ist Giannina Gaslini, IRCCS, Sci Directory, Genoa, Italy Univ Genoa, PRINTO, IRCCS, Ist Giannina Gaslini, Genoa, Italy Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet & Maternal, Genoa, Italy Wilhelmina Childrens Hosp, Dept Pediat Immunol & Rheumatol, Utrecht, Netherlands Sanjay Gandhi Postgrad Inst Med Sci, Lucknow, Uttar Pradesh, India Univ Hosp 12 Octubre, Dept Pediat Rheumatol, Madrid, Spain Alfaisal Univ, Dept Pediat Rheumatol, King Faisal Specialist Hosp, Riyadh, Saudi Arabia Alfaisal Univ, Res Ctr, Riyadh, Saudi Arabia Western Univ Childrens Hosp, Hlth Sci Ctr, London, ON, Canada Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway Oslo Univ Hosp, Med Fac, Oslo, Norway Univ Oslo, Oslo, Norway Oslo Univ Hosp, Norwegian Natl Advisory Unit Rheumat Dis Children, Oslo, Norway Univ Hosp Munster, Dept Pediat Rheumatol & Immunol, Munster, Germany Hosp Sor Maria Ludovica, Rheumatol Serv, La Plata, Buenos Aires, Argentina Bucharest Emergency Hosp, Cluj Napoca, Romania Childrens Emergency Hosp, Cluj Napoca, Romania Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, Cincinnati, OH 45229 USA Alberta Childrens Prov Gen Hosp, Div Pediat Rheumatol, Dept Pediat, Calgary, AB, Canada Sofiamed, Pediat Dept, Sofia, Bulgaria Rigshosp, Juliane Marie Ctr, Paediat Rheumatol Unit, Copenhagen, Denmark Natl Inst Rheumatism & Physiotherapy, Clin Immunol Adult & Paediat Rheumatol Dept, Budapest, Hungary Univ Latvia, Pediat Dept, Riga, Latvia Univ Latvia, Univ Childrens Hosp, Riga, Latvia Univ Estadual Paulista, Botucatu Fac Med, Botucatu, SP, Brazil Shariati Hosp, Rheumatol Res Ctr, Dept Pediat & Rheumatol, Tehran, Iran Inst Rheumatol Belgrade, Div Pediat Rheumatol, Belgrade, Serbia Thessaloniki Univ, Dept Pediat 1, Hippokrat Gen Hosp, Sch Med, Thessaloniki, Greece Univ Estadual Paulista, Botucatu Fac Med, Botucatu, SP, Brazil

Background: The characteristics and burden of childhood arthritis have never been studied on a worldwide basis. We aimed to investigate prevalence of disease categories, treatment modalities and disease status across different geographic areas. Methods: International paediatric rheumatologists were asked to enrol a consecutive sample of children with juvenile idiopathic arthritis. Each patient underwent retrospective and cross-sectional assessments, including parent-reported outcomes. Level of disease activity and damage were correlated with wealth of the country, expressed as gross domestic product per capita. Findings: Between 2011 and 2016, 9,081 patients were enrolled at 130 centres in 49 countries, grouped in 8 geographic areas. A wide difference in the prevalence of disease categories across areas was seen, with systemic arthritis and oligoarthritis being relatively more common in Southeast Asia (33%) and Southern Europe (56·7%), respectively, and rheumatoid-factor negative polyarthritis and enthesitis related arthritis being relatively more frequent in North America (31·5%) and Southeast Asia (29·8%), respectively. Prevalence of uveitis was highest in Northern Europe and Southern Europe (19·2% and 19%, respectively) and lowest in Latin America (6·5%), Africa & Middle East (6·1%), and Southeast Asia (5·1%). Median age at disease onset was lower in Southern Europe (3·5 years) than in other regions (4·7-7·4 years). Biologic disease-modifying anti-rheumatic drugs (DMARDs) were prescribed more frequently in Western countries (30·5-46%) than in other geographic settings (21·1- 25·1%). Patients living in lower-income countries had greater disease activity and damage than patients cared for in wealthier countries. Damage was associated with referral delay. Interpretation: Our study documents a variability in prevalence of disease phenotypes and disparities in therapeutic choices and outcomes across geographic areas. The greater disease burden in lower-resource settings highlights the need for public health efforts aimed to improve equity in access to effective treatments and structure and process of care. Funding Statement: IRCCS Istituto Giannina Gaslini, Genoa, Italy. Declaration of Interests: Dr. Bovis reports personal fees from Biogen, Novartis, outside the submitted work. Dr. Foell reports grants from Novartis, Pfizer; personal fees from Novartis, Pfizer, Sobi, Chugai-Roche, during the conduct of the study. Dr. Shafaie reports grants from IRCCS Istituto Giannina Gaslini, during the conduct of the study. Dr. Lazar reports grants from IRCCS Istituto Giannina Gaslini, during the conduct of the study; non- financial support from Abbvie; personal fees from ROCHE, outside the submitted work. Dr. Lovell reports other funding from Astra-Zeneca Pharm, Wyeth Pharm, Amgen, Abbott, Pfizer, Hoffman-La Roche, Novartis, UBC, Takeda, Janssen, GSK, Boehringer Ingelheim, Celgene, Novartis, Roche, Bristol Myers Squibb, Abbvie, Pfizer, Roche, Forest Research, outside the submitted work. Dr. Martini reports grants from Abbvie, Boehringer, Novartis, R-Pharm, BMS, Hoffman-La Roche, Janssen, Novartis, Pfizer, Sobi, outside the submitted work; personal fees from Abbvie, Astrazeneca, Novartis, Pfizer, Roche, R-Pharm, Sanofi, UCB, outside the submitted work. Dr. Ravelli reports personal fees from AbbVie, BMS, Pfizer, Hoffman LaRoche, Novartis, Centocor, "Francesco Angelini" and Reckitt Benckiser, outside the submitted work. Dr. Ruperto reports personal fees from Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Baxalta Biosimilars, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono, Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Rewind Arms, R-Pharma, Sanofi Aventis, Servier, Sinergie, Takeda, Vertex, UCB Biosciences GmbH, outside the submitted work; grants from Abbott, BMS, "Francesco Angelini", GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth, outside the submitted work. Dr. Trachana reports personal fees from IRCCS Istituto Giannina Gaslini, during the conduct of the study; personal fees from Novartis, Pfizer, IRCCS Istituto Giannina Gaslini, outside the submitted work. Dr. Aggarwal, Dr. Al-Mayouf, Dr. Alongi, Dr. Consolaro, Dr. de Inocencio, Dr. Demirkaya, Dr. Flato, Dr. Garay, Dr. Giancane, Dr. Miettunen, Dr. Mihaylova, Dr. Montobbio, Dr. Nielsen, Dr. Orban, Dr. Pistorio, Dr. Rumba-Rozenfelde, Dr. Saad-Magalhaes, Dr. Susic, Dr. van Dijkhuizen and Dr. Wulffraat have nothing to disclose. Ethics Approval Statement: All participating centres obtained the approval of the study protocol by their local Ethics Committee, according to national laws. The parents or guardians of all patients and healthy children provided written informed consent to participation in the study.

Summary Background Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy. Methods We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m 2 ; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. Findings Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. Interpretation Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. Funding Italian Agency of Drug Evaluation.

Objectives To predict the occurrence of inactive disease in JIA in the first 2 years of disease. Methods An inception cohort of 152 treatment-naïve JIA patients with disease duration

Background Methotrexate (MTX) is an effective and safe drug in the treatment of juvenile idiopathic arthritis (JIA). Despite its safety, MTX-related gastrointestinal adverse effects before and after MTX administration, termed MTX intolerance, occur frequently, leading to non-compliance and potentially premature MTX termination. The aim of this study was to construct a risk model to predict MTX intolerance. Methods In a prospective JIA cohort, clinical variables and single nucleotide polymorphisms were determined at MTX start. The Methotrexate Intolerance Severity Score was employed to measure MTX intolerance in the first year of treatment. MTX intolerance was most prevalent at 6 or 12 months after MTX start, which was defined as the outcome for the prediction model. The model was developed in 152 patients using multivariable logistic regression analysis and subsequently internally validated using bootstrapping. Results The prediction model included the following predictors: JIA category, antinuclear antibody, parent/patient assessment of pain, Juvenile Arthritis Disease Activity Score-27, thrombocytes, alanine aminotransferase and creatinine. The model classified 77.5% of patients correctly, and 66.7% of patients after internal validation by bootstrapping. The lowest predicted risk of MTX intolerance was 18.9% and the highest predicted risk was 85.9%. The prediction model was transformed into a risk score (range 0–17). At a cut-off of ≥6, sensitivity was 82.0%, specificity 56.1%, positive predictive value was 58.7% and negative predictive value 80.4%. Conclusions This clinical prediction model showed moderate predictive power to detect MTX intolerance. To develop into a clinically usable tool, it should be validated in an independent cohort and updated with new predictors. Such an easy-to-use tool could then assist clinicians in identifying patients at risk to develop MTX intolerance, and in turn to monitor them closely and intervene timely in order to prevent the development of MTX intolerance. Trial registration ISRCTN register, www.isrctn.com, ISRCTN13524271