Clinical features, treatment and outcomes of Italian children with enthesitis-related arthritis and juvenile psoriatic arthritis: a cross-sectional cohort study.

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.

OMERACT International Consensus for Ultrasound Definitions of Tenosynovitis in Juvenile Idiopathic Arthritis: Systematic Literature Review and Delphi Process.

OBJECTIVE: Synovitis and tenosynovitis are present in juvenile idiopathic arthritis (JIA), both as joint pain and/or inflammation, making them difficult to detect on physical examination. Although ultrasonography (US) allows for discrimination of the 2 entities, only definitions and scoring of synovitis in children have been established. This study was undertaken to produce consensus-based US definitions of tenosynovitis in JIA. METHODS: A systematic literature search was performed. Selection criteria included studies focused on US definition and scoring systems for tenosynovitis in children, as well as US metric properties. Through a 2-step Delphi process, a panel of international US experts developed definitions for tenosynovitis components (step 1) and validated them by testing their applicability on US images of tenosynovitis in several age groups (step 2). A 5-point Likert scale was used to rate the level of agreement. RESULTS: A total of 14 studies were identified. Most used the US definitions developed for adults to define tenosynovitis in children. Construct validity was reported in 86% of articles using physical examination as a comparator. Few studies reported US reliability and responsiveness in JIA. In step 1, experts reached a strong group agreement (>86%) by applying adult definitions in children after one round. After 4 rounds of step 2, the final definitions were validated on all tendons and at all locations, except for biceps tenosynovitis in children <4 years old. CONCLUSION: The study shows that the definition of tenosynovitis used in adults is applicable to children with minimal modifications agreed upon through a Delphi process. Further studies are required to confirm our results.

Validity of ultrasonography in detecting enthesitis in children: A systematic literature review.

OBJECTIVE: A systematic review to assess the value of ultrasonography (US) for detecting enthesitis in juvenile idiopathic arthritis (JIA). METHODS: PubMed and Embase databases were searched for articles published from January 1966 to May 2021; we selected those meeting the inclusion criteria according to the US definition of enthesitis and metric properties studied. We assessed the clinical features of the population, study design, the type and number of entheses examined, the definition and scoring system of US enthesitis and metric properties according to the OMERACT filter (truth, discrimination and feasibility). The quality of the studies was evaluated with the Quality Assessment of Diagnostic Accuracy Studies 2. RESULTS: Five publications met the inclusion criteria (26 to 146 patients and 1 to 10 bilaterally examined entheses). All studies focused on lower-limb entheses. The elementary lesions included in the definition of adult enthesitis were generally assessed. Few studies reported US reliability and none evaluated sensitivity to change of US. US revealed entheseal abnormalities in 9.4 to 53% of JIA patients and 20 to 83% of enthesitis-related arthritis cases. No significant abnormalities were found in healthy children. US findings were poorly correlated with clinical examination. The overall quality of the studies was low, mainly because of the lack of a reference standard. CONCLUSION: US is a sensitive tool to detect entheseal abnormalities in JIA. The current evidence highlights that a standardized US definition of enthesitis in children is lacking and US criteria and discriminant validity have not been established.

Development and Initial Validation of the ONCOREUM Score to Differentiate Childhood Cancer with Arthropathy from Juvenile Idiopathic Arthritis.

OBJECTIVE: To develop and validate a weighted score, the ONCOREUM score, that aids physicians in differentiation of cancer with arthropathy from juvenile idiopathic arthritis (JIA). STUDY DESIGN: Data were extracted from the ONCOREUM Study, a multicenter, cross-sectional investigation aimed at comparing children with cancer and arthropathy to children with JIA. Three statistical approaches were applied to develop the ONCOREUM score and assess the role of each variable in the diagnosis of cancer with arthropathy, including 2 approaches based on multivariable stepwise selection (models 1 and 2) and 1 approach on a Bayesian model averaging method (model 3). The ß coefficients estimated in the models were used to assign score points. Considering that not missing a child with cancer is a mandatory clinical objective, discriminating performance was assessed by fixing sensitivity at 100%. Score performance was evaluated in both developmental and validation samples (representing 80% and 20% of the study population, respectively). RESULTS: Patients with cancer and arthropathy (49 with solid tumors and 46 with hematologic malignancies without peripheral blasts) and 677 patients with JIA were included. The highest area under the receiver operating characteristic (ROC) curve (AUC) in the validation data set was yielded by model 1, which was selected to constitute the ONCOREUM score. The score ranged from -18 to 21.8, and the optimal cutoff obtained through ROC analysis was -6. The sensitivity, specificity, and AUC of the cutoff in the validation sample were 100%, 70%, and 0.85, respectively. CONCLUSIONS: The ONCOREUM score is a powerful and easily applicable tool that may facilitate early differentiation of malignancies with articular complaints from JIA.

A novel magnetic resonance imaging scoring system for active and chronic changes in children and adolescents with juvenile idiopathic arthritis of the hip.

BACKGROUND: Hip involvement predicts severe disease in juvenile idiopathic arthritis (JIA) and is accurately assessed by MRI. However, a child-specific hip MRI scoring system has not been validated. OBJECTIVE: To test the intra- and interobserver agreement of several MRI markers for active and chronic hip changes in children and young adults with JIA and to examine the precision of measurements commonly used for the assessment of growth abnormalities. MATERIALS AND METHODS: Hip MRIs from 60 consecutive children, adolescents and young adults with JIA were scored independently by two sets of radiologists. One set scored the same MRIs twice. Features of active and chronic changes, growth abnormalities and secondary post-inflammatory changes were scored. We used kappa statistics to analyze inter- and intraobserver agreement for categorical variables and a Bland-Altman approach to test the precision of continuous variables. RESULTS: Among active changes, there was good intra- and interobserver agreement for grading overall inflammation (kappa 0.6-0.7). Synovial enhancement showed a good intraobserver agreement (kappa 0.7-0.8), while the interobserver agreement was moderate (kappa 0.4-0.5). Regarding acetabular erosions on a 0-3 scale, the intraobserver agreement was 0.6 for the right hip and 0.7 for the left hip, while the interobserver agreement was 0.6 for both hips. Measurements of joint space width, caput-collum-diaphyseal angle, femoral neck-head length, femoral width and trochanteric distance were imprecise. CONCLUSION: We identified a set of MRI markers for active and chronic changes in JIA and suggest that the more robust markers be included in future studies addressing clinical validity and long-term patient outcomes.

Procedures for the content, conduct and format of EULAR/PReS paediatric musculoskeletal ultrasound courses.

BACKGROUND: Despite the worldwide increasing request of education on paediatric musculoskeletal ultrasound (PedMSUS), content, conduct and format of PedMSUS courses have never been internationally agreed. OBJECTIVES: To produce educational procedures for the conduct, content and format of EULAR/PReS PedMSUS courses. METHODS: After a systemic literature review and expert opinion collection, a panel of items for the development of procedures on PedMSUS courses was identified. Agreement on the items was assessed through Delphi surveys among a taskforce of 24 members, which included 18 experts in PedMSUS (8 rheumatologists, 1 radiologist, 9 paediatric rheumatologists), 1 methodologist and rheumatologist expert in MSUS, 2 patient research partners, 1 health professional in rheumatology and 2 EMEUNET/EMERGE members, from 8 different European countries. Each item was assessed through a 5-point Likert scale (0, full disagreement; 5, full agreement); agreement was reached for >75% of answers rating 4-5. All items with agreement were included in the preliminary core set of educational procedures, which underwent external assessment by a broader Consensus group (Faculty and Tutors of previous EULAR PedMSUS courses and PReS Imaging Working Party members), through Delphi survey. RESULTS: Two Delphi surveys produced the preliminary core set of procedures for basic, intermediate, advanced and teach-the-teachers (TTT) PedMSUS courses. A Delphi survey within the Consensus group produced agreement on the proposed procedures. CONCLUSIONS: Shared EULAR/PReS procedures for the conduct, content and format of basic, intermediate, advanced and TTT PedMSUS courses were identified on international basis.

Pro Nerve Growth Factor and Its Receptor p75NTR Activate Inflammatory Responses in Synovial Fibroblasts: A Novel Targetable Mechanism in Arthritis.

We have recently provided new evidence for a role of p75NTR receptor and its preferential ligand proNGF in amplifying inflammatory responses in synovial mononuclear cells of chronic arthritis patients. In the present study, to better investigate how activation of the p75NTR/proNGF axis impacts synovial inflammation, we have studied the effects of proNGF on fibroblast-like synoviocytes (FLS), which play a central role in modulating local immune responses and in activating pro-inflammatory pathways. Using single cell RNA sequencing in synovial tissues from active and treatment-naïve rheumatoid arthritis (RA) patients, we demonstrated that p75NTR and sortilin, which form a high affinity receptor complex for proNGF, are highly expressed in PRG4pos lining and THY1posCOL1A1pos sublining fibroblast clusters in RA synovia but decreased in RA patients in sustained clinical remission. In ex vivo experiments we found that FLS from rheumatoid arthritis patients (RA-FLS) retained in vitro a markedly higher expression of p75NTR and sortilin than FLS from osteoarthritis patients (OA-FLS). Inflammatory stimuli further up-regulated p75NTR expression and induced endogenous production of proNGF in RA-FLS, leading to an autocrine activation of the proNGF/p75NTR pathway that results in an increased release of pro-inflammatory cytokines. Our data on the inhibition of p75NTR receptor, which reduced the release of IL-1ß, IL-6 and TNF-α, further confirmed the key role of p75NTR activation in regulating inflammatory cytokine production. In a set of ex vivo experiments, we used RA-FLS and cultured them in the presence of synovial fluids obtained from arthritis patients that, as we demonstrated, are characterized by a high concentration of proNGF. Our data show that the high levels of proNGF present in inflamed synovial fluids induced pro-inflammatory cytokine production by RA-FLS. The blocking of NGF binding to p75NTR using specific inhibitors led instead to the disruption of this pro-inflammatory loop, reducing activation of the p38 and JNK intracellular pathways and decreasing inflammatory cytokine production. Overall, our data demonstrate that an active proNGF/p75NTR axis promotes pro-inflammatory responses in synovial fibroblasts, thereby contributing to chronic synovial inflammation, and point to the possible use of p75NTR inhibitors as a novel therapeutic approach in chronic arthritis.

Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study.

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 by patients with Langerhans histiocytosis (16 [47%] of 34), leukaemia (189 [32%] of 582), soft-tissue sarcomas (16 [24%] of 68), and neuroblastoma (21 [19%] of 109). In the 324 patients with cancer and musculoskeletal symptoms, the most common complaints were joint pain (199 [61%]), followed by limb bone pain (112 [35%]). Joint involvement had a prevalent monoarticular pattern (100 [48%] of 207) and oligoarticular pattern (86 [42%] had 2-4 joints involved and 20 [10%] had >4 joints involved), with the most frequently involved joints being the hip (88 [43%] of 207) and knee (81 [39%]). On multivariable analysis, limb bone pain was the independent variable most strongly associated with cancer (odds ratio [OR] 87·80 [95% CI 18·89-408·12]), followed by weight loss (59·88 [6·34-565·53]), thrombocytopenia (12·67 [2·40-66·92]), monoarticular involvement (11·30 [4·09-31·19]), hip involvement (3·30 [1·13-9·61]), and male sex (2·40 [1·03-5·58]). Factors independently associated with juvenile idiopathic arthritis were morning stiffness (OR 0·04 [95% CI 0·01-0·20]), joint swelling (0·03 [0·01-0·09]), and involvement of the small hand joints (0·02 [0-1·05]). INTERPRETATION: Our study provides detailed information about presenting musculoskeletal manifestations of childhood cancers and highlights the clinical and laboratory features that are most helpful in the differential diagnosis with juvenile idiopathic arthritis. FUNDING: Associazione Lorenzo Risolo.

Age-Related Vascularization and Ossification of Joints in Children: An International Pilot Study to Test Multiobserver Ultrasound Reliability.

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.

Linking Joint Impairment and Gait Biomechanics in Patients with Juvenile Idiopathic Arthritis.

Juvenile Idiopathic Arthritis (JIA) is a paediatric musculoskeletal disease of unknown aetiology, leading to walking alterations when the lower-limb joints are involved. Diagnosis of JIA is mostly clinical. Imaging can quantify impairments associated to inflammation and joint damage. However, treatment planning could be better supported using dynamic information, such as joint contact forces (JCFs). To this purpose, we used a musculoskeletal model to predict JCFs and investigate how JCFs varied as a result of joint impairment in eighteen children with JIA. Gait analysis data and magnetic resonance images (MRI) were used to develop patient-specific lower-limb musculoskeletal models, which were evaluated for operator-dependent variability (< 3.6°, 0.05 N kg-1 and 0.5 BW for joint angles, moments, and JCFs, respectively). Gait alterations and JCF patterns showed high between-subjects variability reflecting the pathology heterogeneity in the cohort. Higher joint impairment, assessed with MRI-based evaluation, was weakly associated to overall joint overloading. A stronger correlation was observed between impairment of one limb and overload of the contralateral limb, suggesting risky compensatory strategies being adopted, especially at the knee level. This suggests that knee overloading during gait might be a good predictor of disease progression and gait biomechanics should be used to inform treatment planning.

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.

An image-based kinematic model of the tibiotalar and subtalar joints and its application to gait analysis in children with Juvenile Idiopathic Arthritis.

In vivo estimates of tibiotalar and the subtalar joint kinematics can unveil unique information about gait biomechanics, especially in the presence of musculoskeletal disorders affecting the foot and ankle complex. Previous literature investigated the ankle kinematics on ex vivo data sets, but little has been reported for natural walking, and even less for pathological and juvenile populations. This paper proposes an MRI-based morphological fitting methodology for the personalised definition of the tibiotalar and the subtalar joint axes during gait, and investigated its application to characterise the ankle kinematics in twenty patients affected by Juvenile Idiopathic Arthritis (JIA). The estimated joint axes were in line with in vivo and ex vivo literature data and joint kinematics variation subsequent to inter-operator variability was in the order of 1°. The model allowed to investigate, for the first time in patients with JIA, the functional response to joint impairment. The joint kinematics highlighted changes over time that were consistent with changes in the patient's clinical pattern and notably varied from patient to patient. The heterogeneous and patient-specific nature of the effects of JIA was confirmed by the absence of a correlation between a semi-quantitative MRI-based impairment score and a variety of investigated joint kinematics indexes. In conclusion, this study showed the feasibility of using MRI and morphological fitting to identify the tibiotalar and subtalar joint axes in a non-invasive patient-specific manner. The proposed methodology represents an innovative and reliable approach to the analysis of the ankle joint kinematics in pathological juvenile populations.

Microbiome Analytics of the Gut Microbiota in Patients With Juvenile Idiopathic Arthritis: A Longitudinal Observational Cohort Study.

OBJECTIVE: To assess the composition of gut microbiota in Italian and Dutch patients with juvenile idiopathic arthritis (JIA) at baseline, with inactive disease, and with persistent activity compared to healthy controls. METHODS: In a multicenter, prospective, observational cohort study, fecal samples were collected at baseline from 78 Italian and 21 Dutch treatment-naive JIA patients with <6 months of disease duration and compared to 107 geographically matched samples from healthy children. Forty-four follow-up samples from patients with inactive disease and 25 follow-up samples from patients with persistent activity were analyzed. Gut microbiota composition was determined by 16S ribosomal RNA-based metagenomics. Alpha- and ß-diversity were computed, and log ratios of relative abundance were compared between patients and healthy controls using random forest models and logistic regression. RESULTS: Baseline samples from Italian patients showed reduced richness compared to healthy controls (P < 0.001). Random forest models distinguished between Italian patient baseline samples and healthy controls and suggested differences between Dutch patient samples and healthy controls (areas under the curve >0.99 and 0.71, respectively). The operational taxonomic units (OTUs) of Erysipelotrichaceae (increased in patients), Allobaculum (decreased in patients), and Faecalibacterium prausnitzii (increased in patients) showed different relative abundance in Italian patient baseline samples compared to controls after controlling for multiple comparisons. Some OTUs differed between Dutch patient samples and healthy controls, but no evidence remained after controlling for multiple comparisons. No differences were found in paired analysis between Italian patient baseline and inactive disease samples. CONCLUSION: Our findings show evidence for dysbiosis in JIA patients. Only patient/control status, age, and geographic origin appear to be drivers of the microbiota profiles, regardless of disease activity stage, inflammation, and markers of autoimmunity.

Prediction of inactive disease in juvenile idiopathic arthritis: a multicentre observational cohort study.

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 <6 months was analysed. Potential predictors were baseline clinical variables, joint US, gut microbiota composition and a panel of inflammation-related compounds in blood plasma. Various algorithms were employed to predict inactive disease according to Wallace criteria at 6-month intervals in the first 2 years. Performance of the models was evaluated using the split-cohort technique. The cohort was analysed in its entirety, and separate models were developed for oligoarticular patients, polyarticular RF negative patients and ANA positive patients. Results: All models analysing the cohort as a whole showed poor performance in test data [area under the curve (AUC): <0.65]. The subgroup models performed better. Inactive disease was predicted by lower baseline juvenile arthritis DAS (JADAS)-71 and lower relative abundance of the operational taxonomic unit Mogibacteriaceae for oligoarticular patients (AUC in test data: 0.69); shorter duration of morning stiffness, higher haemoglobin and lower CXCL-9 levels at baseline for polyarticular RF negative patients (AUC in test data: 0.69); and shorter duration of morning stiffness and higher baseline haemoglobin for ANA positive patients (AUC in test data: 0.72). Conclusion: Inactive disease could not be predicted with satisfactory accuracy in the whole cohort, likely due to disease heterogeneity. Interesting predictors were found in more homogeneous subgroups. These need to be validated in future studies.

Predictors of Flare Following Etanercept Withdrawal in Patients with Rheumatoid Factor-negative Juvenile Idiopathic Arthritis Who Reached Remission while Taking Medication.

OBJECTIVE: To evaluate the rate of flare after etanercept (ETN) withdrawal in patients with juvenile idiopathic arthritis (JIA) who attained clinical remission while taking medication, and to identify predictors of flare. METHODS: Patients were included with oligo- (oJIA) and rheumatoid factor-negative polyarticular JIA (pJIA) who received a first course of ETN for at least 18 months, maintained clinically inactive disease (CID) for at least 6 months during treatment, and were followed for 12 months after ETN withdrawal. Demographic and clinical features were collected at onset, at baseline (initiation of ETN), and at time of disease flare. RESULTS: After ETN withdrawal, 66 of the 110 patients enrolled (60%) flared with arthritis (of whom 7 flared with concurrent anterior uveitis; none with uveitis alone). The median time to flare was 4.3 months (interquartile range 2.5-6.4) with no evident differences between oJIA and pJIA. The number and type of joints involved at baseline and characteristics of ETN treatment/discontinuation were not associated with flare. Patients who flared were more frequently males (p = 0.034), positive for antinuclear antibody (ANA; p = 0.047), and had higher values of C-reactive protein (CRP; p = 0.012) at baseline. These variables remained significantly associated with flare in a multivariate logistic analysis, a model accounting for only 14% of the variability of the occurrence of the flare. CONCLUSION: Our results show that a significant proportion of patients with JIA who maintain CID for at least 6 months experience a relapse after ETN withdrawal. Male sex, presence of ANA, and elevated CRP at baseline were associated with higher risk of flare.

Correction to: The Italian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The family name of author Francesco La Torre was incorrect in the published article. The correct family name should read as La Torre F.

Juvenile idiopathic arthritis - the role of imaging from a rheumatologist's perspective.

Alongside recent advances in treatment strategies for juvenile idiopathic arthritis (JIA), paediatric rheumatologists have taken increasing interest in the use of imaging. Magnetic resonance imaging (MRI) and musculoskeletal ultrasound, by providing more detailed information on disease activity than clinical examination and conventional radiography (CR), have become helpful diagnostic and managerial tools. The growing skeleton, however, with changing appearances over time, is still challenging in the establishment of valid scoring systems for pathological changes. Defining child- and age-specific reference standards is therefore a highly prioritized issue. The aim of this article is to raise awareness among radiologists of the substantial role that imaging can play to optimize the management of JIA patients and to describe the state-of-the-art validation process of imaging as an outcome measure. A closer collaboration between radiologists and pediatric rheumatologists is crucial to define a scheduled workflow for imaging in JIA.

Imaging of the hip in juvenile idiopathic arthritis.

Hip involvement is common and estimated to occur in approximately 35-63% of children with juvenile idiopathic arthritis (JIA). It is more prevalent in the aggressive systemic subtypes, with irreversible changes occurring as early as within 5 years of diagnosis. Whilst clinical parameters and joint examination can be useful for assessing disease severity, subclinical disease is known to exist and delayed treatment may herald a lifetime of disability and pain. Early recognition of JIA changes is therefore crucial in determining treatment options. Validated scoring systems in the radiologic assessment of the hip for clinical drug trials may inform treatment outcomes, although robust tools for analysis are still lacking. This review article details the modalities utilised for imaging the hip in children with JIA with particular efforts focused upon reliability and validity in their assessment of joint disease. We conclude with a short literature review on the potential future techniques being developed for hip joint imaging in JIA.

The Italian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

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 Health Related Quality of Life (HRQoL) 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.

Normative ultrasound references for the paediatric wrist; dorsal soft tissues.

OBJECTIVE: To report novel ultrasound (US) references for the healthy paediatric wrist. METHODS: Healthy children and adolescents had an US examination including Doppler, of the right wrist, using a mid-sagittal image through the radiocarpal (RC)/midcarpal (MC) joints. These features were noted: appearances and depth of the recess, with an additional measurement in the flexed position and number of Doppler signals within the recess in close proximity to the joint. In a second, blinded session, all images were reassessed by the same observer. RESULTS: In total, 116 subjects (59 girls) aged 6-16 years (mean 10 years and 11 months) were included. The RC recess was visible in 71, of which 60 were non-bulging and 11 were bulging. In flexion, the thickness decreased in 60 (84.5%), suggestive of joint fluid. Of the 54 visible MC recesses, 45 (83.3%) thinned in flexion. The mean depths of the RC and MC recesses were 0.4 mm (SD 0.5, range 0-2.9) and 0.5 mm (SD 0.6, range 0-2.4), respectively, with no differences according to sex, but with increasing depths by age.For the RC joints, at least one Doppler signal was seen in the recess in 9/116 joints (7.8%), whereas this was true for 3.5% of the MC recesses. There were no statistically significant association between the depth of the RC or MC recesses and number of hand active sport activities (P=0.733 and P=0.091, respectively). CONCLUSION: The appearances of the dorsal RC and MC recesses in healthy children may mimic pathology. Hence, findings should be interpreted carefully.