EULAR-PReS points to consider for the use of imaging in the diagnosis and management of juvenile idiopathic arthritis in clinical practice.

To develop evidence based points to consider the use of imaging in the diagnosis and management of juvenile idiopathic arthritis (JIA) in clinical practice. The task force comprised a group of paediatric rheumatologists, rheumatologists experienced in imaging, radiologists, methodologists and patients from nine countries. Eleven questions on imaging in JIA were generated using a process of discussion and consensus. Research evidence was searched systematically for each question using MEDLINE, EMBASE and Cochrane CENTRAL. Imaging modalities included were conventional radiography, ultrasound, MRI, CT, scintigraphy and positron emission tomography. The experts used the evidence obtained from the relevant studies to develop a set of points to consider. The level of agreement with each point to consider was assessed using a numerical rating scale. A total of 13 277 references were identified from the search process, from which 204 studies were included in the systematic review. Nine points to consider were produced, taking into account the heterogeneity of JIA, the lack of normative data and consequent difficulty identifying pathology. These encompassed the role of imaging in making a diagnosis of JIA, detecting and monitoring inflammation and damage, predicting outcome and response to treatment, use of guided therapies, progression and remission. Level of agreement for each proposition varied according to the research evidence and expert opinion. Nine points to consider and a related research agenda for the role of imaging in the management of JIA were developed using published evidence and expert opinion.

MRI versus conventional measures of disease activity and structural damage in evaluating treatment efficacy in juvenile idiopathic arthritis.

OBJECTIVE: To compare the American College of Rheumatology paediatric (ACRp) response criteria and conventional radiography with MRI findings in a cohort of patients with juvenile idiopathic arthritis. METHODS: Forty consecutive patients (30 girls, 10 boys; median age 10.8 years) with arthritis of the wrist starting treatment with disease-modifying antirheumatic drugs or biological agents were recruited. At 1-year follow-up the treatment response was assessed by ACRp criteria and radiographic progression using the adapted Sharp/van der Heijde method. Wrist MRIs were evaluated using both the paediatric-MRI and the OMERACT rheumatoid arthritis MRI scores. Sensitivity to change of clinical and imaging variables was assessed by standardised response mean (SRM) and relative efficiency (RE) was used to compare SRMs. RESULTS: ACRp90 responders showed a significantly higher decrease in MRI synovitis score (median change -4) than non-responders (median change 0), ACRp30-50 responders (median change 0) and ACRp70 responders (median change -1) (p=0.0006, Kruskal-Wallis test). Non-responders showed significantly higher radiographic progression than ACRp90 responders (pB=0.016). The MRI synovitis score showed a greater responsiveness to change (SRM 1.69) compared with the majority of ACR core set of variables. MRI erosion scores were less responsive than conventional radiography in detecting destructive changes (RE <1). MRI follow-up revealed no signs of inflammation in four out of 24 wrists with clinically inactive disease. CONCLUSION: Only ACRp90 responders showed a significant decrease in synovitis and the halting of structural damage, suggesting that levels of response higher than ACRp30 are more appropriate for assessing drug efficacy. The excellent responsiveness of MRI and its ability to detect subclinical synovitis make it a promising outcome measure.

Novel automated system for magnetic resonance imaging quantification of the inflamed synovial membrane volume in patients with juvenile idiopathic arthritis.

OBJECTIVE: To introduce a novel automated method for the quantification of the inflamed synovial membrane volume (SV) using magnetic resonance imaging (MRI), and to investigate its feasibility and validity in patients with juvenile idiopathic arthritis (JIA). METHODS: The tool was tested on 58 patients with JIA and wrist involvement. Thirty-six patients had a 1-year MRI followup. MRI of the clinically more affected wrist was performed using a 1.5T scanner and a Flex small coil. An algorithmic approach, based on supervised voxel classification for automatic estimation of SV in a 3-dimensional MRI, was developed. The SV was estimated as the number of positively classified voxels and then normalized by the patient's body surface (NSV). Validation procedures included the analysis of reliability, construct validity, responsiveness to change, discriminant validity, and the predictive value. RESULTS: The agreement between the automated estimation of NSV and the manual measurements was excellent (intraclass correlation coefficient 0.93, 95% confidence interval 0.79-0.98). The automatic NSV demonstrated good construct validity by yielding strong correlations with local signs of disease activity and a moderate correlation with global physician assessment of disease activity and with the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system synovitis score. NSV showed a strong responsiveness to clinical change (standardized response mean values >1) and satisfactory discriminant validity. High baseline NSV (>4.6) had high predictive value (100%) with respect to erosive progression. CONCLUSION: The proposed automated method allowed reliable quantification of NSV, which represents a promising imaging biomarker of disease activity in JIA. The automated system has the potential to improve the longitudinal assessment of JIA and to predict progressive joint destruction.

The paediatric wrist revisited: redefining MR findings in healthy children.

OBJECTIVES: During a multicentre study on juvenile idiopathic arthritis, wide variations were observed in bone shape, signal intensity and volume of joint fluid as shown by MRI which in part appeared to be unrelated to disease activity. A study was undertaken to examine these features in a cohort of healthy children. METHODS: 88 children of mean age 9.8 years (range 5-15) underwent MRI imaging (T1-weighted Spin Echo and Spectral Selection Attenuated Inversion Recovery (SPAIR)) of the left wrist. The number of bony depressions, distribution and amount of joint fluid and the presence of bone marrow changes were assessed. RESULTS: Bony depressions were present in all children, increasing with age from a mean of 4.0 in children aged 4-6 years to 9.2 in those aged 12-15 years (p<0.001)). 45 of 84 children (53.6%) had a high signal on SPAIR with a corresponding low signal on T1 in at least one bone. No associations were seen between bone marrow change (present or not) and sex (p=0.827) or sports club membership (p=0.616). All children had visible joint fluid in at least one of the joints assessed. No associations were seen between the presence of joint fluid and age group, except for the radius/scaphoid and capitate-scaphoid joints and a recess lateral to the hamate. CONCLUSIONS: It is important to be aware of the high prevalence of bony depressions, signal changes suggestive of bone marrow oedema and the volume of joint fluid seen in normal children. Such findings must be interpreted with care in children with suspected disease such as juvenile arthritis.

The Paediatric Rheumatology International Trials Organization (PRINTO).

In this review we describe an international project, conducted by the Paediatric Rheumatology International Trials Organization (PRINTO) that was aimed to identify, validate and promulgate core sets of measures and a definition of improvement for the evaluation of response to therapy in clinical trials and in daily clinical practice in patients with juvenile systemic lupus erythematosus (JSLE). The following clinical measures were included in the PRINTO core set of outcome measure for the evaluation of response to therapy: 1) physician's global assessment of disease activity; 2) global disease activity measure; 3) 24-hour proteinuria; 4) parent's global assessment of the overall patient's well-being; 5) health-related quality of life assessment. The measures included in the core set were found to be feasible and not redundant, to have good construct validity, discriminative ability, internal consistency, with fair responsiveness to clinically important change in disease activity, and to be associated strongly with treatment outcome. In order to be classified as responder to a given treatment, a patient should demonstrate at least 50% improvement from baseline in any two of the five core set measures with no more than one of the remaining worsening by more than 30%. This definition is now known as the 'PRINTO/American College of Rheumatology (ACR) provisional criteria for JSLE'. The proposed core set and definition of improvement incorporate clinically meaningful change in a composite endpoint for the evaluation of global response to therapy in JSLE. The definition is now proposed for use in JSLE clinical trials, and may help physicians to decide if a child with SLE has responded adequately to therapy.

Cyclosporine A in juvenile idiopathic arthritis. Results of the PRCSG/PRINTO phase IV post marketing surveillance study.

OBJECTIVE: To investigate the clinical use patterns, clinical effect and safety of cyclosporine A (CSA) in juvenile idiopathic arthritis (JIA) in the setting of routine clinical care. METHODS: An open-ended, phase IV post marketing surveillance study was conducted among members of the Pediatric Rheumatology Collaborative Study Group (PRCSG) and of the Paediatric Rheumatology International Trials Organisation (PRINTO) to identify patients with polyarticular course JIA who had received CSA during the course of their disease. RESULTS: A total of 329 patients, half of whom had systemic JIA, were collected in 21 countries. Data were collected during 1240 routine clinic visits. CSA was started at a mean of 5.8 years after disease onset and was given at a mean dose of 3.4 mg/kg/day. The drug was administered in combination with MTX in 61% and along with prednisone in 65% of the patients who were still receiving CSA. Among patients who were still receiving CSA therapy at the last reported visit, remission was documented in 9% of the patients, whereas in 61% of the patients the disease activity was rated as moderate or severe. The most frequent reason for discontinuation of CSA was insufficient therapeutic effect (61% of the patients); only 10% of the patients stopped CSA because of remission. In 17% of the patients, side effects of therapy was given as the primary reason for discontinuation. CONCLUSION: This survey suggests that CSA may have a less favourable efficacy profile than MTX and etanercept, whereas the frequency of side effects may be similar. The exact place of CSA in the treatment of JIA can only be established via controlled clinical trial.

Functional ability and physical and psychosocial well-being of hypermobile schoolchildren.

OBJECTIVE: To compare the functional ability and the physical and psychosocial well-being of children with joint hypermobility to those of age- and sex-matched non-hypermobile subjects. METHODS: 311 healthy Italian schoolchildren aged 6.3 to 19.3 years were examined for hypermobility of the joints. Functional ability was assessed through the Childhood Health Assessment Questionnaire (CHAQ) and the physical and psychosocial well-being through the Childhood Health Questionnaire (CHQ). The parent's assessment of the child's overall well-being and of the child's pain was measured on a visual analogue scale. RESULTS: The overall prevalence of articular hypermobility was 34% (106/311), with the median hypermobility score being 3 (interquartile range 1, 5). Although the hypermobility score of girls (median 3: interquartile range 2, 5) exceeded that of boys (median 2.5; interquartile range 0, 5), this difference was not statistically significant (p = 0.16). The level of hypermobile children's pain in the preceding weeks, as assessed by the parents, was comparable to that recorded in the non-hypermobile peers. There was a weak negative correlation between the hypermobility score and the age of the child (r = -0.14, p=0.01). All instrument scores were comparable between hypermobile and non-hypermobile subjects, with the sole exception of a borderline significant greater impairment of the Role/social limitations-physical subscale of the CHQ in the hypermobile group. The hypermobility score was not correlated with any instrument score. CONCLUSIONS: The presence of joint hypermobility does not affect the functional ability and the physical and psychosocial well being of otherwise healthy children. These results suggest that the physical functioning in everyday life and the general health status of hypermobile children are not impaired.

Cross-cultural adaptation and psychometric evaluation of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ) in 32 countries. Review of the general methodology.

The aim of this project was to cross-culturally adapt and validate the American English version of the Childhood Health Assessment Questionnaire (CHAQ) and of the Child Health Questionnaire (CHQ) in the 32 different member countries of the Paediatric Rheumatology International Trials Organisation (PRINTO). This effort forms part of an international study supported by the European Union to evaluate the health-related quality of life in children with juvenile idiopathic arthritis (JIA) as compared to their healthy peers. A total of 6,644 subjects were enrolled from 32 countries: Argentina, Austria, Belgium, Brazil, Bulgaria, Chile, Croatia, the Czech Republic, Denmark, Finland, France, Georgia, Germany, Greece, Hungary, Israel, Italy, Korea, Latvia, Mexico, the Netherlands, Norway, Poland, Portugal, Russia, Slovakia, Spain, Sweden, Switzerland, Turkey, the United Kingdom, and Yugoslavia. A total of 3,235 patients had JIA (20% systemic onset, 33% polyarticular onset, 17% extended oligoarticular subtype, and 30% persistent oligoarticular subtype) while 3,409 were healthy children. This introductory paper describes the methodology used by all the participants. The results and the translated version of both the CHAQ and the CHQ for each country are fully reported in the following papers. The results of the present study show that cross-cultural adaptation is a valid process to obtain reliable instruments for the different socio-economic and socio-demographic conditions of the countries participating in the project.

The Italian version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).

We report herein the results of the cross-cultural adaptation and validation into the Italian language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Italian CHAQ was already published in the literature and was therefore revalidated while the Italian CHQ was fully cross culturally adapted with 3 forward and 3 backward translations, and than validated. A total of 1,192 subjects were enrolled: 404 patients with JIA (16% systemic onset, 31% polyarticular onset, 21% extended oligoarticular subtype, and 32% persistent oligoarticular subtype) and 788 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Italian version of the CHAQ-CHQ are reliable, and valid tools for the functional, physical and psychosocial assessment of children with JIA.

Methotrexate as a possible trigger of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

Macrophage activation syndrome (MAS) is a potentially life threatening complication of chronic rheumatic diseases, particularly systemic juvenile idiopathic arthritis (JIA). A number of triggers have been related to the development of MAS, including viral infections, nonsteroidal antiinflammatory drug therapy, and gold salt injections. We describe a patient with systemic JIA who developed MAS shortly after receiving methotrexate, suggesting that this drug can be regarded as a potential trigger of MAS in children with JIA.