Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium.

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry.

OBJECTIVE: To evaluate genetic, demographic and clinical features in patients with cryopyrin-associated periodic syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and predictive disease severity markers. METHODS: A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included. RESULTS: 136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss. CONCLUSIONS: Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.

The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.

OBJECTIVE: To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/EUROTRAPS international registry. METHODS: A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease. RESULTS: Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years. CONCLUSIONS: In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation.

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.

Breaking down the fences among registries on autoinflammatory diseases: the E-Merge project.

BACKGROUND: Among the various numbers of different autoinflammatory diseases (AIDs), the absolute majority of them remains rare, with a single representative in large populations. This project, endorsed by PRES, supported by the EMERGE fellowship program, and performed in line with the Metadata registry for the ERN RITA (MeRITA), has the objective of performing a data synchronization attempt of the most relevant research questions regarding clinical features, diagnostic strategies, and optimal management of autoinflammatory diseases. RESULTS: An analysis of three large European registries: Eurofever, JIR-cohort and AID-Net, with a total coverage of 7825 patients from 278 participating centers from different countries, was performed in the context of epidemiological and clinical data merging. The data collected and evaluated in the registries does not cover only pediatric patients, but also adults with newly diagnosed AIDs. General aspects of the existing epidemiological data have been discussed in the context of patient global distribution, potential diagnostic delays, access to genetic testing, and the availability of the treatment. CONCLUSIONS: In general, the results indicate a great potential for upcoming collaborative work using existing data in cohorts that enhance the quality of medical care performed for patients with autoinflammatory diseases.

International consensus for a definition of disease flare in lupus.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: "A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment." The LFA proposes this definition for lupus flare on the basis of its high face validity.

Does removal of aids/devices and help make a difference in the Childhood Health Assessment Questionnaire disability index?

OBJECTIVE: To assess whether the removal of aids/devices and/or help from another person in the Childhood Health Assessment Questionnaire (C-HAQ) leads to a significant change in the disability index (DI) score and responsiveness in juvenile idiopathic arthritis (JIA). METHODS: Changes in the C-HAQ DI score in a cross-sectional sample of 2663 children with JIA and in 530 active patients with JIA in a trial of methotrexate (MTX) were compared. RESULTS: Patients in the MTX trial had higher disease activity and disability than the cross-sectional sample. The frequency of aids/devices (range 1.2-10.2%) was similar between the two samples, while help (range 5.3-38.1%) was more frequently used in the MTX group. Correlation between disease severity variables and the two different C-HAQ DI scoring methods did not change substantially. There was a decrease in the C-HAQ DI score for both the cross-sectional (mean score from 0.64 with the original method to 0.54 without aids/devices and help, p<0.0001) and the MTX sample (mean score from 1.23 to 1.07, p<0.0001). A linear regression analysis of the original C-HAQ DI score versus the score without aids/devices and help demonstrated the substantial overlap of the different scoring methods. Responsiveness in the responders to MTX treatment did not change with the different C-HAQ DI scoring methods (range 0.86-0.82). CONCLUSION: The removal of aids/devices and help from the C-HAQ does not alter the interpretation of disability at a group level. The simplified C-HAQ is a more feasible and valid alternative for the evaluation of disability in patients with JIA.

Impact of involvement of individual joint groups on subdimensions of functional ability scales in juvenile idiopathic arthritis.

OBJECTIVE: To investigate the influence of arthritis in individual joint groups on subdimensions of functional ability questionnaires in children with juvenile idiopathic arthritis (JIA). METHODS: 206 patients were included who had the Childhood Health Assessment Questionnaire (C-HAQ) and the Juvenile Arthritis Functionality Scale (JAFS) completed simultaneously by a parent and received a detailed joint assessment. In each patient, joint involvement (defined as presence of swelling, pain on motion/tenderness and/or restricted motion) was classified in 3 topographic patterns: Pattern 1 (hip, knee, ankle, subtalar and foot joints); Pattern 2 (wrist and hand joints); Pattern 3 (elbow, shoulder, cervical spine and temporomandibular joints). Frequency of reported disability in each instrument subdimension was evaluated for each joint pattern, present either isolatedly or in mixed form. RESULTS: Among patients with Pattern 1, the JAFS revealed the greatest ability to capture and discriminate functional limitation, whereas impairment in the C-HAQ was more diluted across several subdimensions. Both C-HAQ and JAFS appeared to be less reliable in detecting functional impairment in the hand and wrist (Pattern 2) than in other body areas. Overall, the JAFS revealed a superior ability to discriminate the relative functional impact of impairment in individual joint groups among patients with mixed joint patterns. CONCLUSION: In children with JIA, a functional measure focused to assess the function of individual joint groups (the JAFS) may detect with greater precision the functional impact of arthritis in specific body areas than does a standard questionnaire based on the assessment of activities of daily living (the C-HAQ).

Methotrexate improves the health-related quality of life of children with juvenile idiopathic arthritis.

OBJECTIVES: To examine the change in health-related quality of life (HRQOL) and its determinants in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX). METHODS: Patients were extracted from the PRINTO clinical trial which aimed to evaluate the efficacy and safety profile of MTX administered in standard, intermediate or higher doses (10, 15 and 30 mg/m(2)/week respectively). Children with polyarticular-course JIA, who were less than 18 years and had a complete HRQOL assessment were included. RESULTS: A total of 521 children were included. At baseline, patients with JIA showed poorer HRQOL (p<0.01) than healthy children. In 207/412 (50%) and 63 (15%) children, HRQOL values were 2 standard deviations below the mean of healthy controls in the physical and psychosocial summary scale, respectively. After 6 months of treatment with standard dose MTX, there was a statistically significant improvement in all HRQOL health concepts, particularly the physical ones. Similar improvements were observed in those who did not respond to a standard dose of MTX and were subsequently randomised to a higher dose. The presence of marked disability at baseline was associated with a fivefold increased risk of retaining poor physical health after 6 months of active treatment with standard dose MTX. Other less important determinants of retaining poor physical well-being were the baseline level of systemic inflammation, pain intensity and an antinuclear-antibody-negative status. CONCLUSIONS: MTX treatment produces a significant improvement across a wide range of HRQOL components, particularly in the physical domains, in patients with JIA.

Preliminary evidence that etanercept may reduce radiographic progression in juvenile idiopathic arthritis.

OBJECTIVE: To investigate the rate of radiographic progression, as measured with the carpo-metacarpal ratio (Poznanski score), during etanercept (ETN) therapy in children with polyarticular juvenile idiopathic arthritis (JIA). METHODS: Patients included in the Italian ETN registry who had a standard radiograph of both hands and wrists in the posteroanterior view made at start of treatment and after 1 year were included in the study. The clinical response was assessed by means of the ACR Pediatric definition of improvement. Radiographic progression was determined by calculating the change in the Poznanski score between the baseline and the 1-year radiographs. RESULTS: A total of 40 patients were studied. The frequency of ACR pediatric 30, 50, and 70 response at 1 year was 77%, 72%, and 50%, respectively. The median change in the Poznanski score between baseline and 1 year was + 0.3 units, meaning that, on average, patients experienced improvement in radiographic progression. CONCLUSION: Our pilot study provides evidence that ETN is potentially capable of reducing the progression of radiographic joint damage in JIA. This finding deserves confirmation in a controlled trial.

Network in pediatric rheumatology: the example of pediatric rheumatology international trials organisation.

The pediatric rheumatic diseases (PRD) are rare conditions associated with important sequelae on the quality of life and long term outcome. The research aimed at studying new therapeutic approaches is difficult because of logistic, methodological and ethical problems. To face these problems 2 international networks; the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organization (PRINTO) have been founded. The 2 networks have the goal to promote, facilitate and conduct high quality research for the PRD. In particular they have been able to standardize the evaluation of response to therapy in juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus, and juvenile dermatomyositis, to draft clinical remission criteria in JIA, and to provide cross-cultural adapted and validated quality of life instruments like the Childhood Health Assessment Questionnaire, and the Child Health Questionnaire, into 32 different languages. In this paper we reviewed how the creation of large international trial networks such as PRINTO and PRCSG, the definition of internationally recognized and standardized outcome measures and definitions of improvement, the validation of quality of life instruments, the adoption of adequate legislative measures (pediatric rule), have created the basic premises for the best future assessment of the PRD. This progress now offers children with PRD the same opportunities as adults to be treated with drugs whose safety and efficacy have been assessed through legitimate scientifically valid investigations.

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.

Responsiveness of clinical measures to flare of disease activity in juvenile idiopathic arthritis.

OBJECTIVE: To compare the responsiveness of clinical measures in the assessment of disease flare in patients with juvenile idiopathic arthritis (JIA). METHODS: The clinical records of all consecutive patients with JIA who were diagnosed between 1995 and 2000 were retrospectively reviewed. In each patient, all visits made during follow-up were analyzed and those meeting the criteria for disease flare were recorded. The definition of flare was based on the therapeutic alterations made by the attending physician. Responsiveness of JIA clinical measures to relevant increase in disease activity (a flare) was evaluated by assessing the score change of each measure from a visit made 6 (+/- 3) months before a flare and the flare visit. Responsiveness statistics included the standardized response mean (SRM) and the effect size (ES). RESULTS: A total of 115 patients, who were followed for 0.5 to 6.2 years (mean 2.8 years), were studied. During follow-up, 51 patients (44%) experienced 1 or more disease flares, with the total number of flares being 75. Strong responsiveness (ES and SRM > or = 0.8) to increase in disease activity was demonstrated by the physician's and parent's global assessments, the global articular severity score, and the morning stiffness. The active, swollen and painful joint counts, the swelling, pain on motion/tenderness and limited range of motion (LROM) scores, and the erythrocyte sedimentation rate revealed moderate responsiveness (ES and SRM > or = 0.5). The poorest performances (ES and/or SRM < 0.5) were provided by the parent's assessment of pain, the functional ability tool, the number of joints with LROM, the LROM score, the C-reactive protein, the white blood cell and platelet count, and the hemoglobin level. CONCLUSION: Our analysis suggests that the swollen or painful joint counts are better suited than the count of joints with LROM for the assessment of disease flare in patients with JIA.

The Hungarian 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 Hungarian 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 Hungarian CHAQ CHQ were fully validated with 3 forward and 3 backward translations. A total of 127 subjects were enrolled: 67 patients with JIA (13.5% systemic onset, 42% polyarticular onset, 13.5% extended oligoarticular subtype, and 31% persistent oligoarticular subtype) and 60 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 Hungarian version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

The Georgian 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 Georgian 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 Georgian CHAQ CHQ were fully validated with 3 forward and 3 backward translation. A total of 115 subjects were enrolled: 54 patients with JIA (44% systemic onset, 28% polyarticular onset, 7.5% extended oligoarticular subtype, and 20.5% persistent oligoarticular subtype) and 61 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 Georgian version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

The Croatian 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 Croatian 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 Croatian CHAQ-CHQ were fully validated with 3 forward and 3 backward translations. A total of 139 subjects were enrolled: 75 patients with JIA (19% systemic onset, 20% polyarticular onset, 17% extended oligoarticular subtype, and 44% persistent oligoarticular subtype) and 64 healthy children. CHAQ clinically discriminated between healthy subjects and JIA patients, with the 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 polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Croatian version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

The Danish 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 Danish 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 Danish CHAQ-CHQ were fully validated with 3 forward and 3 backward translations. A total of 139 subjects were enrolled: 76 patients with JIA (25% systemic onset, 30% polyarticular onset, 19% extended oligoarticular subtype, and 26% persistent oligoarticular subtype) and 63 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 Danish version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

The Czech 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 Czech 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 Czech CHAQ-CHQ were fully validated with 3 forward and 3 backward translations. A total of 150 subjects were enrolled: 81 patients with JIA (14% systemic onset, 44% polyarticular onset, 10% extended oligoarticular subtype, and 32% persistent oligoarticular subtype) and 69 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 Czech version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

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.

Efficacy of folinic acid in reducing methotrexate toxicity in juvenile idiopathic arthritis.

OBJECTIVE: To investigate the efficacy of folinic acid in reducing the side effects associated with methotrexate (MTX) therapy in children with juvenile idiopathic arthritis (JIA) and to determine whether folate supplementation may reduce the benefit of MTX administration. METHODS: This was a retrospective, non-controlled study. Inclusion criteria were: 1) diagnosis of JIA according to the Durban 1997 criteria; 2) treatment with low to intermediate doses of MTX (10-20 mg/m2/week) as the sole second-line agent for at least 6 mos.; and 3) supplementation with folinic acid (2.5-7.5 mg) in a single weekly dose 24 hrs after MTX administration. All patients were started on folinic acid only after the development of a side effect. Exclusion criteria were: treatment with higher doses of MTX (> 20 mg/m2/week). The outcomes investigated were: hepatotoxicity (liver transaminase increase), gastrointestinal toxicity, disease flare, and clinical remission. The number of episodes per patient-year of MTX treatment of each outcome before and after folinic acid supplementation was compared by the Wilcoxon matched pairs test. RESULTS: A total of 43 children with JIA were included in the study. The mean duration of treatment before and after folinic acid supplementation was 1.1 years and 1.8 years, respectively. After the start of folinic acid supplementation, the mean number of episodes per patient-year of hepatotoxicity and gastrointestinal toxicity decreased from 2.30 to 0.32 (p < 0.001) and from 1.09 to 0.29 (p = 0.002), respectively. The mean number of disease flares and clinical remissions per patient-year did not change significantly. CONCLUSION: In our JIA patients, folinic acid supplementation resulted in a significant reduction in the most common side effects of MTX, without affecting the clinical efficacy of the drug.