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Objectives: Limited information is available on the clinical features, treatment modalities and outcomes of the juvenile idiopathic arthritis (JIA) categories of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA). This study was aimed to describe the characteristics of Italian children with ERA and JPsA and to compare them with those of patients with the other categories of JIA. Methods: Patients were part of a multinational sample included in a study aimed to investigate the prevalence of disease categories, treatment approaches, and disease status in patients from across different geographical areas (EPOCA Study). All patients underwent a retrospective assessment, based on the review of clinical chart, and a cross-sectional evaluation, which included assessment of physician- and parent-reported outcomes and laboratory tests, and recording of ongoing therapies. Results: Of the 9081 children with JIA enrolled in the EPOCA Study, 1300 were recruited at 18 paediatric rheumatology centres in Italy. 45 (3.5%) had ERA and 49 (3.8%) had JPsA. Several remarkable differences in demographic features and frequency of articular and extra-articular manifestations, disease damage, impairment in physical function and health-related quality of life, school-related problems, comorbidities, and ongoing treatments were observed between ERA and JPsA and the other JIA categories. Conclusions: We described the characteristics of Italian children with ERA and JPsA and highlighted their peculiarities and their differences from the other JIA subsets. These data provide useful insights for future revisions of JIA classification and a benchmarking against which the features from other cohorts may be compared.

Background: Presenting symptoms of childhood cancers might mimic those of rheumatic diseases. However, the evidence available to guide differential diagnosis remains scarce. Preventing wrong or delayed diagnosis is therefore important to avoid incorrect administration of glucocorticoid or immunosuppressive therapy and worsening of prognosis. As such, we aimed to assess the prevalence and characteristics of presenting musculoskeletal manifestations in patients at cancer onset and to identify the factors that differentiate childhood malignancies with arthropathy from juvenile idiopathic arthritis. Methods: We did a multicentre, cross-sectional study at 25 paediatric haemato-oncology centres and 22 paediatric rheumatology centres in Italy. We prospectively recruited patients who were younger than 16 years that were newly diagnosed with cancer or juvenile idiopathic arthritis. We excluded patients with glucocorticoid pre-treatment (>1 mg/kg per day of oral prednisone or equivalent for ≥2 consecutive weeks). We collected data for patients with a new diagnosis of cancer or juvenile idiopathic arthritis using an electronic case report form on a web-based platform powered by the Cineca Interuniversity Consortium. The primary outcome was to describe the frequency and characteristics of musculoskeletal manifestations at cancer onset; and the secondary outcome was to identify factors that could discriminate malignancies presenting with arthropathy, with or without other musculoskeletal symptoms, from juvenile idiopathic arthritis using multivariable logistic regression analysis. Findings: Between May 1, 2015, and May 31, 2018, 1957 patients were eligible, of which 1277 (65%) had cancer and 680 (35%) had juvenile idiopathic arthritis. Musculoskeletal symptoms occurred in 324 (25% [95% CI 23·0–27·8]) of 1277 patients with cancer, of whom 207 had arthropathy. Patients with malignant bone tumours had the highest frequency of musculoskeletal symptoms (53 [80%] of 66), followed b

Objective: To determine the intra- and interobserver reliability of ultrasound (US)-detected age-related joint vascularization and ossification grading in healthy children. Methods: Following standardized image acquisition and machine setting protocols, 10 international US experts examined 4 joints (wrist, second metacarpophalangeal joint, knee, and ankle) in 12 healthy children (divided into 4 age groups: 2–4, 5–8, 9–12, and 13–16 years). Gray-scale was used to detect the ossification grade, and power Doppler ultrasound (PDUS) was used to detect physiologic vascularization. Ossification was graded from 0 (no ossification) to 3 (complete ossification). A positive PDUS signal was defined as any PDUS signal inside the joint. Kappa statistics were applied for intra- and interobserver reliability. Results: According to the specific joint and age, up to 4 solitary PDUS signals (mean 1.5) were detected within each joint area with predominant localization of the physiologic vascularization in specific anatomic positions: fat pad, epiphysis, physis, and short bone cartilage. The kappa values for ossification grading were 0.87 (range 0.85–0.91) and 0.58 for intra- and interobserver reliability, respectively. The bias-adjusted kappa values for intra- and interobserver reliability were 0.71 (range 0.44–1.00) and 0.69, respectively. Conclusion: Detection of normal findings (i.e., grading of physiologic ossification during skeletal maturation and identification of physiologic vessels) can be highly reliable by using clear definitions and a standardized acquisition protocol. These data will permit development of a reliable and standardized US approach for evaluating pediatric joint pathologies.

Background/Purpose: Musculoskeletal (MSK) symptoms are a common presenting complaint in pediatric primary care (estimated prevalence 25-50%) and may be the initial manifestation of cancer in rare cases. An articular involvement has been observed in about 20% of onset leukemias, with pictures that can mimic juvenile idiopathic arthritis (JIA) leading to inappropriate steroid or immunosuppressive therapy and diagnostic delay. The primary objective of this study is to assess the prevalence and features of MSK symptoms at the onset of pediatric tumors. The secondary objective is to identify predictors of malignancy comparing tumors with MSK symptoms at onset and new cases of JIA diagnosed in the same period Methods: The ONCOREUM is a multicenter, observational, cross-sectional study conducted between 2015 and 2018 by 25 Centers of the Italian Association of Pediatric Hematology and Oncology (AIEOP) and 22 Rheumatological Centers of the Italian Society of Pediatrics (SIP). A web based data collection within the AIEOP platform managed by CINECA was performed after local ethics committees approval and written informed consent. We analyzed clinical and laboratory data of patients (pts) < 16 years of age with new diagnosis of tumors or JIA. The data were compare dusing χ² for categorical variables and t-test, Welch’s test, or Mann-Whitney U test for continuous variables. Statistical analysis was performed by the open source statistical software R. Results: We considered eligible 1928 pts: 655 of them were affected by JIA and 1273 by tumor. MSK symptoms at onset were found in 25% of cases of tumors, articular involvement (arthritis and/or arthralgia) in 16% and arthritis in 8% (Fig. 1). An initial rheumatological diagnosis was suspected in 9% (29/322) of tumors with MSK symptoms and in 17% (17/102) of tumors with arthritis at onset. The highest frequency of initial rheumatic suspicion was found in neuroblastoma (5/21), Langerhans histiocytosis (3/16) and leukemia (17/188).

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

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 Italian 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 1296 JIA patients (7.2% systemic, 59.5% oligoarticular, 21.4% RF negative polyarthritis, 11.9% other categories) and 100 healthy children, were enrolled in 18 centres. The JAMAR components discriminated well healthy subjects from JIA patients except for the Paediatric Rheumatology Quality of Life (PRQL) Psychosocial Health (PsH) subscales. All JAMAR components revealed good psychometric performances. In conclusion, the Italian 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: To provide an update from the Outcome Measures in Rheumatology (OMERACT) Ultrasound Working Group on the progress for defining ultrasound (US) minimal disease activity threshold at joint level in rheumatoid arthritis (RA) and for standardization of US application in juvenile idiopathic arthritis (JIA). Methods: For minimal disease activity, healthy controls (HC) and patients with early arthritis (EA) who were naive to disease-modifying antirheumatic drugs were recruited from 2 centers. US was performed of the hands and feet, and scored semiquantitatively (0-3) for synovial hypertrophy (SH) and power Doppler (PD). Synovial effusion (SE) was scored a binary variable. For JIA, a Delphi approach and subsequent validation in static images and patient-based exercises were used to developed preliminary definitions for synovitis and a scoring system. Results: For minimal disease activity, 7% HC had at least 1 joint abnormality versus 30% in the EA group. In HC, the findings of SH and PD were predominantly grade 1 whereas all grades were seen in the EA cohort, but SE was rare. In JIA, synovitis can be diagnosed based on B-mode findings alone because of the presence of physiological vascularization. A semiquantitative scoring system (0-3) for synovitis for both B-mode and Doppler were developed in which the cutoff between Doppler grade 2 and grade 3 was 30%. Conclusion: The first step has been taken to define the threshold for minimal disease activity in RA by US and to define and develop a scoring system for synovitis in JIA. Further steps are planned for the continuous validation of US in these areas. The Journal of Rheumatology

Objective: Musculoskeletal ultrasonography (US) has the potential to be an important tool in the assessment of disease activity in childhood arthritides. To assess pathology, clear definitions for synovitis need to be developed first. The aim of this study was to develop and validate these definitions through an international consensus process. Methods: The decision on which US techniques to use and the components to be included in the definitions, as well as the final wording, were developed by 31 US experts in a consensus process. A Likert scale of 1–5 (where 1 = complete disagreement and 5 = complete agreement) was used. A minimum of 80% of the experts scoring 4 or 5 was required for final approval. The definitions were then validated on 120 standardized US images of the wrist, metacarpophalangeal joints, and tibiotalar joints, displaying various degrees of synovitis at various ages. Results: B-mode and Doppler should be used for assessing synovitis in children. A US definition of the various components (i.e., synovial hypertrophy, effusion, and Doppler signal within the synovium) was developed. The definition was validated on still images with a median of 89% of participants (range 80–100) scoring it as 4 or 5 on a Likert scale. Conclusion: US definitions of synovitis and its elementary components covering the entire pediatric age range were successfully developed through a Delphi process and validated in a web-based still-images exercise. These results provide the basis for the standardized US assessment of synovitis in clinical practice and research.

Objective: To identify which laboratory tests that change over time are most valuable for the timely diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA). Methods: A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of experts was first asked to evaluate 115 profiles of patients with MAS, which included the values of laboratory tests at the pre-MAS visit and at MAS onset, and the change in values between the two time points. The experts were asked to choose the 5 laboratory tests in which change was most important for the diagnosis of MAS and to rank the 5 selected tests in order of importance. The relevance of change in laboratory parameters was further discussed and ranked by the same experts at a consensus conference. Results: Platelet count was the most frequently selected test, followed by ferritin level, aspartate aminotransferase (AST), white cell count, neutrophil count, and fibrinogen and erythrocyte sedimentation rate. Ferritin was most frequently assigned the highest score. At the end of the process, platelet count, ferritin level and AST were the laboratory tests in which the experts found change over time to be most important. Conclusions: We identified the laboratory tests in which change over time is most valuable for the early diagnosis of MAS in sJIA. The dynamics of laboratory values during the course of MAS should be further scrutinised in a prospective study in order to establish the optimal cut-off values for their variation.

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from <1% for a score of <11 to >99% for a score of ≥123. A cutoff value of ≥60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

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/m2; 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 juve

Objective The Outcome Measures in Rheumatology Ultrasound Task Force has recently started to work on the validation and standardization of musculoskeletal ultrasound (MSUS) examination in children in order to improve its applicability to joint examination. Methods This was a prospective multicenter study performed by 4 experts in pediatric MSUS, who independently collected representative images using predefined scanning procedures of 4 joints (knee, ankle, wrist, and second metacarpophalangeal joint) in different predefined age groups. Researchers were allowed to use their own settings (B-mode and Doppler) in order to get the best quality image and highest sensitivity for low blood flow. Images were evaluated for quality parameters and an atlas was created with the best images. An equipment comparative study was performed by a single examiner using 2 different types of machines. Results Sixty-four healthy children were scanned. The quality of evaluated images, obtained by predefined scanning positions, was highly comparable among the examiners. The B-mode images clearly showed age-related variations of joint findings, while Doppler images showed the presence of blood flow, particularly within the epiphyseal cartilage of the children at a younger age. There was a high to good level of consistency between images obtained from the 2 different ultrasound machines. Conclusion The study shows a systematic method for ultrasound examination of children at different age groups. Additionally, a baseline collection of images was developed, showing blood vessels in the joints examined. The present study could provide a framework for ongoing MSUS studies as well as for clinical practice in pediatric rheumatology.

BACKGROUND: Data from routine clinical practice are needed to further define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). The aim of this analysis was to investigate the disease status, reasons for discontinuation and adverse events in Italian JIA patients treated with etanercept (ETN). METHODS: In 2013, all centers of the Italian Pediatric Rheumatology Study Group were asked to make a census of patients given ETN after January 2000. Patients were classified in three groups: group 1 = patients still taking ETN; group 2 = patients discontinued from ETN for any reasons; group 3 = patients lost to follow-up while receiving ETN. All three groups received a retrospective assessment; patients in group 1 also underwent a cross-sectional assessment. RESULTS: 1038 patients were enrolled by 23 centers: 422 (40.7%) were in group 1, 462 (44.5%) in group 2, and 154 (14.8%) in group 3. Median duration of ETN therapy was 2.5 years. At cross-sectional assessment, 41.8% to 48.6% of patients in group 1 met formal criteria for inactive disease, whereas 52.4% of patients in group 2 and 55.8% of patients in group 3 were judged in clinical remission by their caring physician at last visit. A relatively greater proportion of patients with systemic arthritis were discontinued or lost to follow-up. Parent evaluations at cross-sectional visit in group 1 showed that 52.4% of patients had normal physical function, very few had impairment in quality of life, 51.2% had no pain, 76% had no morning stiffness, and 82.7% of parents were satisfied with their child's illness outcome. Clinically significant adverse events were reported for 27.8% of patients and ETN was discontinued for side effects in 9.5%. The most common adverse events were new onset or recurrent uveitis (10.2%), infections (6.6%), injection site reactions (4.4%), and neuropsychiatric (3.1%), gastrointestinal (2.4%), and hematological disorders (2.1%). Ten patients developed an

Musculoskeletal ultrasound (US) now thrives as an established imaging modality for the investigation and management of chronic inflammatory arthritis. We summarize here results of the Outcome Measures in Rheumatology (OMERACT) US working group (WG) projects of the last 2 years. These results were reported at the OMERACT 12 meeting at the plenary session and discussed during breakout sessions. Topics included standardization of US use in rheumatic disease over the last decade and its contribution to understanding musculoskeletal diseases. This is the first update report of WG activities in validating US as an outcome measure in musculoskeletal inflammatory and degenerative diseases, including pediatric arthritis, since the OMERACT 11 meeting.