Translation and validation in Italian of the methotrexate intolerance severity score for children and adults with arthritis.

OBJECTIVES: Methotrexate (MTX) is the most used drug to treat children and adults with arthritis and its use is burdened by adverse effects. The MTX intolerance severity score (MISS) was developed in English to identify patients who are intolerant to MTX. The aim of this study was to translate and validate the MISS in Italian. METHODS: The Italian version of the MISS was developed following the "guidelines for process of cross-cultural adaptation of self-reported measures". The Italian version of the MISS was validated in 125 patients with juvenile idiopathic arthritis (JIA) followed at the Rheumatology Unit of Bambino Gesù Children Hospital. We assessed the construct validity and calculated the internal consistency of the Italian MISS. We performed ROC analysis to assess the overall performance of the Italian MISS. RESULTS: We translated and adapted the MISS to the Italian language. The Italian MISS showed a very good internal consistency as shown by a Cronbach α of 0.87 (95% CI, 0.84-0.90) and a composite reliability of 0.89 (95% CI, 0.83-0.91).The Cohen's κ was 0.81 (95% CI, 0.71-0.91), suggesting a very good construct validity. The ROC analysis showed an area under the curve (AUC) of 0.97 (95% CI, 0.93-0.99). A threshold of 6 to define intolerant patients, showed a sensitivity of 98.3% and specificity of 81.2%. CONCLUSIONS: We developed the Italian version of the MISS and showed its validity and reliability to identify patients intolerant to MTX in clinical practice and in a research setting.

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.

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.

Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial.

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 juvenile idiopathic arthritis. FUNDING: Italian Agency of Drug Evaluation.

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.

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.

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.

Imaging in juvenile idiopathic arthritis - international initiatives and ongoing work.

Imaging is increasingly being integrated into clinical practice to improve diagnosis, disease control and outcome in children with juvenile idiopathic arthritis. Over the last decades several international groups have been launched to standardize and validate different imaging techniques. To enhance transparency and facilitate collaboration, we present an overview of ongoing initiatives.

TCR repertoire sequencing identifies synovial Treg cell clonotypes in the bloodstream during active inflammation in human arthritis.

OBJECTIVES: The imbalance between effector and regulatory T (Treg) cells is crucial in the pathogenesis of autoimmune arthritis. Immune responses are often investigated in the blood because of its accessibility, but circulating lymphocytes are not representative of those found in inflamed tissues. This disconnect hinders our understanding of the mechanisms underlying disease. Our goal was to identify Treg cells implicated in autoimmunity at the inflamed joints, and also readily detectable in the blood upon recirculation. METHODS: We compared Treg cells of patients with juvenile idiopathic arthritis responding or not to therapy by using: (i) T cell receptor (TCR) sequencing, to identify clonotypes shared between blood and synovial fluid; (ii) FOXP3 Treg cell-specific demethylated region DNA methylation assays, to investigate their stability and (iii) flow cytometry and suppression assays to probe their tolerogenic functions. RESULTS: We found a subset of synovial Treg cells that recirculated into the bloodstream of patients with juvenile idiopathic and adult rheumatoid arthritis. These inflammation-associated (ia)Treg cells, but not other blood Treg cells, expanded during active disease and proliferated in response to their cognate antigens. Despite the typical inflammatory-skewed balance of immune mechanisms in arthritis, iaTreg cells were stably committed to the regulatory lineage and fully suppressive. A fraction of iaTreg clonotypes were in common with pathogenic effector T cells. CONCLUSIONS: Using an innovative antigen-agnostic approach, we uncovered a population of bona fide synovial Treg cells readily accessible from the blood and selectively expanding during active disease, paving the way to non-invasive diagnostics and better understanding of the pathogenesis of autoimmunity.

A circulating reservoir of pathogenic-like CD4+ T cells shares a genetic and phenotypic signature with the inflamed synovial micro-environment.

OBJECTIVES: Systemic immunological processes are profoundly shaped by the micro-environments where antigen recognition occurs. Identifying molecular signatures distinctive of such processes is pivotal to understand pathogenic immune responses and manipulate them for therapeutic purposes. Unfortunately, direct investigation of peripheral tissues, enriched in pathogenic T cells, is often impossible or imposingly invasive in humans. Conversely, blood is easily accessible, but pathogenic signatures are diluted systemically as a result of the strict compartmentalisation of immune responses. In this work, we aimed at defining immune mediators shared between the bloodstream and the synovial micro-environment, and relevant for disease activity in autoimmune arthritis. METHODS: CD4(+) T cells from blood and synovium of patients with juvenile idiopathic arthritis (JIA) were immunophenotyped by flow cytometry. The TCR repertoire of a circulating subset showing similarity with the synovium was analysed through next-generation sequencing of TCR ß-chain CDR3 to confirm enrichment in synovial clonotypes. Finally, clinical relevance was established by monitoring the size of this subset in the blood of patients with JIA and rheumatoid arthritis (RA). RESULTS: We identified a small subset of circulating CD4(+) T cells replicating the phenotypical signature of lymphocytes infiltrating the inflamed synovium. These circulating pathogenic-like lymphocytes (CPLs) were enriched in synovial clonotypes and they exhibited strong production of pro-inflammatory cytokines. Importantly, CPLs were expanded in patients with JIA, who did not respond to therapy, and also correlated with disease activity in patients with RA. CONCLUSIONS: CPLs provide an accessible reservoir of pathogenic cells recirculating into the bloodstream and correlating with disease activity, to be exploited for diagnostic and research purposes.

Current state of musculoskeletal ultrasound in paediatric rheumatology: results of an international survey.

OBJECTIVE: The aim of this study was to investigate the current use of musculoskeletal US (MSUS) and the most relevant areas of interest for this imaging modality in paediatric rheumatology. METHODS: A questionnaire was developed by the paediatric subgroup of the OMERACT US task force and e-mailed to the members of the main international paediatric rheumatology networks and societies. Responses were entered in an electronic database. Results were analysed quantitatively or summarized qualitatively in the case of open questions. RESULTS: The overall response rate was 36% (262/719). The use of MSUS varied among members of the various networks/societies. MSUS was considered of high relevance for improvement of diagnostic skills, for the guidance of joint injections and for the assessment of specific joints, namely the hip, ankle, midfoot and wrist. It was considered useful for early detection of synovitis and in determining disease activity and disease remission. CONCLUSION: Although at present MSUS is not widely used by paediatric rheumatologists, there is considerable interest in this imaging technology among members of the international networks. The results of this survey suggest that the next objective in the research agenda should be the standardization of the assessment of joints in healthy children. This will then help differentiate pathological (i.e. synovitic) joints from normal joints. The initial target joints should be the hip, ankle, midfoot and wrist. MSUS training focused on the assessment of paediatric patients might be very important in implementing the use of this technique in clinical practice and research.

Clinical overview and outcome in a cohort of children with polyarteritis nodosa.

OBJECTIVES: Polyarteritis nodosa (PAN) is a rare vasculitis in childhood and poor information is known about its long-term outcome. Our aim was to describe the clinical features, at onset and during the disease course, of childhood-onset PAN and identify a potential correlation with persistent organ damage and worse outcome in a cohort of paediatric patients with a confirmed diagnosis of PAN. METHODS: A retrospective collection of demographic and clinical data of 52 Caucasian children diagnosed with PAN, fulfilling the EULAR/PRES diagnostic criteria, recruited from eight paediatric rheumatologic centres and one transition unit, was performed. A statistical correlation was made between clinical involvement at onset or during the overall disease course and patients' final outcome. RESULTS: Data from 52 patients (31 males, 21 females) were collected: their mean age at onset was 7.9 years (median 6.3) and mean follow-up period was 6.2 years (median 5.4). At the last follow-up visit, 27 patients (51.9%) were off therapy in clinical remission, 17 (32.7%) were in clinical remission while on medication, and 6 (11.6%) had a persistent or relapsing disease course. Two patients (3.8%) deceased because of severe cerebral involvement. Cranial nerve palsy during the disease course was significantly correlated with a worse prognosis (p=0.011). The presence of nephrogenic hypertension at onset and seizures during the disease course were significantly associated with the development of irreversible organ damage (p= 0.040 and 0.011, respectively). CONCLUSIONS: Childhood PAN is a severe disease with substantial risk of long-term morbidities. In our cohort of patients the worst outcome was significantly correlated with renal and neurological involvement.

Development and validation of a pediatric internationally agreed ultrasound knee synovitis protocol (PIUS-knee) by the PReS imaging working party.

OBJECTIVES: To identify an optimal pediatric musculoskeletal ultrasound (MSUS) protocol for the detection of knee arthritis in patients with juvenile idiopathic arthritis (JIA) including a comparison with existing protocols. Secondary aims were to correlate MSUS-identified B-Mode (BM) and Power Doppler-Mode (PD) synovitis with clinical findings. METHODS: Consecutive JIA patients with confirmed knee arthritis after clinical examination underwent a thorough MSUS study protocol which included views identified and consented by the Pediatric Rheumatology european Society (PReS) Imaging Working Party for the detection of synovitis. In total eight views including measurement of the suprapatellar recess were included. Scoring of synovitis followed the pediatric OMERACT criteria (BM and PD severity grading 0 to 3). Interobserver reliability of BM and PD was tested before study begin. Previously published MSUS protocols for knee synovitis were also identified from the literature and their scan protocols compared to identify differences in sensitivity for synovitis according to the number and specific type of views included. Finally, a clinically applicable MSUS protocol for knee synovitis could be proposed. RESULTS: In 114 patients with clinically active knee inflammation, BM positivity (grading ≥ 1) was most frequently detected in the suprapatellar longitudinal and transverse scans performed in any positioning (frequency 97-99% in suprapatellar longitudinal in 30° or neutral respectively). PD positivity was however higher in these views performed in 30° flexion compared to neutral. Intrasynovial PD positivity (grading ≥ 1) was most frequently detected in the lateral parapatellar (69%, sensitivity 0.68, specificity 0.98), medial parapatellar (frequency 67%, sensitivity 0.67, specificity 1.0), the longitudinal lateral (68%, sensitivity 0.67, specificity 0.98) and suprapatellar transverse in 30° (frequency 64%, sensitivity 0.64, specificity 1.0). A combination of five views was the most sensitive for BM and PD synovitis. The suprapatellar recess size was analyzed by age and gender. For each group, the recess was wider in knees with arthritis than without (p < 0.001). Interobserver reliability of BM and PD positivity showed 85% agreement, with kappa 0.74 (very good). Three published studies with knee synovitis MSUS protocols were identified, which included a range of 1-3 views. Evaluation of the sensitivity of positive PD findings of each of these protocols reached a range of 53-83%; the highest sensitivity (91%) was achieved with the 5 views as identified by this study. These five views were therefore combined to form the Pediatric Internationally agreed Ultrasound (PIUS) knee protocol. CONCLUSION: BM and PD positivity reliably correlated with the identification of pathological findings in knees of patients with JIA. From an internationally agreed protocol of eight images, a combination of five showed the greatest sensitivity for synovitis. This protocol, termed 'PIUS-Knee' performed well when compared to existing protocols.

Ultrasound-detected synovial abnormalities are frequent in clinically inactive juvenile idiopathic arthritis, but do not predict a flare of synovitis.

OBJECTIVES: To investigate whether children with juvenile idiopathic arthritis (JIA) in clinical remission have subclinical synovial disease on ultrasound, and whether ultrasound abnormalities predict an early flare of synovitis. METHODS: Thirty-nine consecutive children who had clinically defined inactive disease (ID) for a minimum of 3 months underwent ultrasound assessment of 52 joints. All joints were scanned for synovial hyperplasia, joint effusion, power Doppler (PD) signal and tenosynovitis. Patients were then followed clinically for up to 2 years until a flare of synovitis occurred in one or more joints, or until the 2-year visit if the disease remained in clinical remission. RESULTS: Synovial hyperplasia, joint effusion, PD signal and tenosynovitis in at least one joint were detected in 76.9%, 66.7%, 33.3% and 15.4% of patients, respectively. During the 2-year follow-up, 24 patients (61.5%) experienced sustained ID, whereas 15 patients (38.5%) had a flare of synovitis in a total of 45 joints after a median of 10.6 months (range 6.3-13.7 months). At study entry, the rate of synovial hyperplasia, joint effusion and tenosynovitis was comparable between patients with persistent ID and patients with synovitis flare, whereas patients with persistent ID had a greater frequency of PD signal than patients with synovitis flare. Only 17 of the 45 flared joints had ultrasound abnormalities at study entry. CONCLUSION: The authors found that ultrasound-detected synovial abnormalities are common in children with JIA in clinical remission. However, the presence of ultrasound pathology did not predict an early flare of synovitis in the affected joints.

Towards a role of ultrasound in children with juvenile idiopathic arthritis.

US is a powerful tool for the assessment of joint synovitis in children with JIA and has been shown to be more accurate than clinical examination in detecting synovial disease. Recent studies have documented the presence of US-detected synovial pathology in children with JIA in clinical remission. US assessment enables the differentiation of joint synovitis from tenosynovitis, may help detect enthesitis and is valuable for capturing cartilage damage and early bone erosions. Guidance to local injection therapy represents an important application of US in routine care. Although US has a great potential for diffusion among paediatric rheumatologists, several issues need to be addressed. In particular, a thorough knowledge of US anatomy of joints in growing children is necessary to interpret US findings in JIA patients. The present review examines the potential role of US in the assessment of joint disease in children with JIA.

Remission, minimal disease activity, and acceptable symptom state in juvenile idiopathic arthritis: defining criteria based on the juvenile arthritis disease activity score.

OBJECTIVE: To determine cutoff values for defining remission, minimal disease activity, and parent and child acceptable symptom state in juvenile idiopathic arthritis (JIA) using the Juvenile Arthritis Disease Activity Score (JADAS). METHODS: For the selection of cutoff values, data from a clinical database including 609 children with JIA were used. Optimal cutoff values were determined against external criteria by calculating the 75th percentile of cumulative score distribution and through receiver operating characteristic curve analysis. External criteria included formal definitions of inactive disease and minimal disease activity, subjective rating of remission by physicians, parents, and children, and rating of acceptable symptom state by parents and children. The choice of cutoffs was made based on clinical and statistical grounds. Cross-validation was performed using 4 JIA patient samples that included a total of 1,323 patients, and was based on assessment of construct, discriminant, and predictive validity. RESULTS: With all versions of the JADAS, the cutoff score for classifying a patient as having inactive disease was 1, whereas the cutoff for classification of minimal disease activity was 2 for oligoarticular JIA and 3.8 for polyarticular JIA. Cutoffs for physicians', parents', and children's subjective rating of remission ranged from 2 to 2.3. Cutoffs for acceptable symptom state ranged from 3.2 to 5.4 for parents and from 3 to 4.5 for children. Results of cross-validation analyses strongly supported the selected cutoff values. CONCLUSION: Cutoff values for classifying various disease states in JIA using the JADAS were developed. In cross-validation analyses, they proved to have good construct and discriminant validity and ability to predict disease outcome.

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.