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Objective. To report the efficacy and safety of TNF-a inhibitors (etanercept and adalimumab) in a cohort of patients with JIA treated in a single paediatric rheumatological centre. Methods. Patients with JIA under the age of 18 years, treated with TNF-a blockers at the Paediatric Rheumatologic Centre of the National Institute of Rheumatology and Physiotherapy (Budapest, Hungary) from 2002, were enrolled in an open, observational study. At baseline, patient and disease characteristics were registered. Disease activity was evaluated (before the start of the treatment and after every 3 months) according to the JIA core set of the ACR paediatric definition of improvement (ACR Pedi). Adverse events (AEs) were documented. Results. In all, 72 patients were evaluated. Mean (S.D.) age at onset was 5.5 (3.8) years, mean disease duration was 7.4 (3.9) years. All disease activity parameters improved significantly in the first 3 months of treatment. After 3 and 12 months of treatment, 88 and 76% of patients, respectively, achieved the criteria of the ACR Pedi 30. AEs were uncommon. After 12 months, >85% of patients continued the therapy. Conclusion. Anti-TNF-a agents (etanercept and adalimumab) are effective, safe and well tolerated in JIA patients. Extension of this study for a longer follow-up period and to the patients with JIA after the age of 18 years (with validated and comparable disease activity parameters) is needed to evaluate the long-term effectiveness and safety of the TNF-a inhibitors.

Hereby, we report the case of a 12-year-old girl developing oligoarthritis and progressing into a polyarticular form. Rheumatoid factor was positive, and juvenile idiopathic arthritis (JIA) was diagnosed. After a poor response to DMARDs, an anti-TNF agent (infliximab) was initiated, but to be discontinued due to an allergic reaction. The same complication was observed with the fully human derivative, adalimumab. At the age of 22, the patient presented septicemia with severe anemia and subsequent development of leukopenia, myocarditis with heart failure, and ANA, aSm, aSS-A, aCL positives, and nephrotic syndrome. These new clinical manifestations fulfilled the classification criteria for the diagnosis of systemic lupus erythematosus. Due to the poor therapeutic responses for both diseases, alternative medical options have to be considered, such as targeted therapy with anti-CD20 or interleukin-6 receptor antagonist monoclonal antibodies. This patient may also be a candidate for autologous hemopoietic stem cell transplantation.

The standardization of the criteria to evaluate improvement in rheumatic diseases has been a goal of numerous research groups. This work led to establishment of definition of response in rheumatoid arthritis (1), juvenile arthritis (2–4), systemic lupus erythematosus (SLE) both in adults (5–7) and children (8–10). The International Myositis Outcome Assessment and Clinical Studies (IMACS) group proposed a core set of outcome variables for inclusion in clinical trials in adult and juvenile inflammatory myopathies and defined the degree of change in each core set variables that is clinically meaningful, as well as guidelines for performing clinical trials (11–14). However, until now these proposals have not yet been formally validated in the context of external prospective pediatric studies or clinical trials. Although children/adolescents and adults with DM share many signs and symptoms of disease, they differ in the clinical features and outcome (15–17), and treatment approaches should consider the peculiarities of juvenile patients as well as their longer life expectancy. Therefore, all outcome measures developed for adults need to be subjected to a critical evidence-based evaluation of their measurement properties in children and adolescents. To help standardize the conduct and reporting of juvenile dermatomyositis (JDM) clinical trials and enhance identification of new therapeutic agents, the Pediatric Rheumatology International Trials Organization (PRINTO) (18), in collaboration with the Pediatric Rheumatology Collaborative Study Group (PRCSG) and with the support of the European Union and the U.S. National Institutes of Health, undertook in year 2000 a multinational effort to develop, and promulgate a core set of outcome variables and a definition of clinical improvement to evaluate response to therapy in patients with JDM and in juvenile SLE. The first two phases of the project, previously published (8;19), led to the development of a prospectively evidence-based validated core set of six variables for the evaluation of response to therapy that is now known as the provisional PRINTO/American College of Rheumatology/European League Against Rheumatism Disease Activity Core Set for the evaluation of response to therapy in JDM (PRINTO/ACR/EULAR JDM core set) (Table 1). Table 1 Final domains and suggested variables included in the final PRINTO/ACR EULAR core set for the evaluation of response to therapy in JDM (adapted from ref. (19)). In this paper we report the results of the third phase of the project, which was aimed at developing a provisional validated definition of improvement to aid in the classification of individual patients in future therapeutic trials and in current clinical practice as either improved or not improved.

The authors present case reports with juvenile idiopathic arthritis being associated with functional constipation but not with inflammatory bowel disease. The cause of megacolon was only cleared in one case in the form of Hirschprung’s disease. The skeletal symptoms could be classified as seronegative spondylathropathy. Surgical treatment resulted in the remission of arthritis in one case and a possible pathogenic explanation is discussed. Common genetic predisposition is a plausible explanation, but fecal stasis leading to increased permeability to macromolecules, increased exposure to microbial and dietary antigens, loss of tolerance to own bacterial flora and host susceptibility to the increased antigenic load may stand in the background of this infrequent and not yet described association between juvenile idiopathic arthritis and functional constipation.

Objective To assess the long-term efficacy and safety of infliximab plus methotrexate in juvenile rheumatoid arthritis (JRA). Methods Patients eligible for the open-label extension (OLE, weeks 52–204) received infliximab 3–6 mg/kg every 8 weeks plus methotrexate. Results Of the 78/122 (64%) children entering the OLE, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (eight patients) or patient/physician/sponsor requirement (eight patients). Infliximab (mean dose 4.4 mg/kg per infusion) was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At week 204, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24% and 13%, respectively. Conclusions In the limited population of JRA patients remaining in the study at 4 years, infliximab was safe and effective but associated with a high patient discontinuation rate. Clinical trials registration number NCT00036374.

Objective.To investigate the possible association between polymorphisms of the mannose-binding lectin gene (MBL2) and susceptibility to juvenile idiopathic arthritis (JIA).Methods.We performed a case-control association study including 118 Hungarian patients with JIA and 118 sex-matched healthy controls. MBL genotyping for the 3 mutant structural alleles at codons 54 (B), 57 (C), and 52 (D) in exon 1 and the promoter polymorphisms at position −550 (HL) and −221 (YX) were carried out by real-time PCR allelic discrimination. Serum level of MBL was determined by ELISA.Results.Variant allele frequencies of both codon 52 and 57 polymorphisms in the MBL2 gene were significantly overrepresented in JIA (p = 0.001 and p = 0.004, respectively). The frequency of low MBL genotypes (XA/XA, YA/YO, XA/YO, and YO/YO) in JIA was higher than that in healthy controls (p = 0.001). Serum MBL concentrations were found to be significantly lower in JIA patients versus control subjects (p = 0.001). The 2 promoter polymorphisms and codon 54 SNP of the MBL2 gene were not associated with JIA.Conclusion.Our findings suggest that genetically determined low MBL levels may predispose children to JIA in a Hungarian population. These data warrant further research to investigate the role of the lectin-dependent complement system in the pathogenesis of JIA.

To identify preliminary core sets of outcome variables for disease activity and damage assessment in juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM).Two questionnaire surveys were mailed to 267 physicians from 46 different countries asking each member to select and rank the response variables used when assessing clinical response in patients with JSLE or JDM. Next, 40 paediatric rheumatologists from 34 countries met and, using the nominal group technique, selected the domains to be included in the disease activity and damage core sets for JSLE and JDM.A total of 41 response variables for JSLE and 37 response variables for JDM were selected and ranked through the questionnaire surveys. In the consensus conference, domains selected for both JSLE and JDM activity or damage core sets included the physician and parent/patient subjective assessments and a global score tool. Domains specific for JSLE activity were the immunological tests and the kidney function parameters. Concerning JDM, functional ability and muscle strength assessments were indicated for both activity and damage core sets, whereas serum muscle enzymes were included only in the activity core set. A specific paediatric domain called 'growth and development' was introduced in the disease damage core set for both diseases and the evaluation of health-related quality of life was advised in order to capture the influence of the disease on the patient lifestyle.We developed preliminary core sets of measures for disease activity and damage assessment in JSLE and JDM. The prospective validation of the core sets is in progress.

Objectives Juvenile idiopathic arthritis (JIA) is a chronic inflammatory joint disease affecting children. Even if remission is successfully induced, about half of the patients experience a relapse after stopping anti-inflammatory therapy. The present study investigated whether patients with JIA at risk of relapse can be identified by biomarkers even if clinical signs of disease activity are absent. Methods Patients fulfilling the criteria of inactive disease on medication were included at the time when all medication was withdrawn. The phagocyte activation markers S100A12 and myeloid-related proteins 8/14 (MRP8/14) were compared as well as the acute phase reactant high-sensitivity C reactive protein (hsCRP) as predictive biomarkers for the risk of a flare within a time frame of 6 months. Results 35 of 188 enrolled patients experienced a flare within 6 months. Clinical or standard laboratory parameters could not differentiate between patients at risk of relapse and those not at risk. S100A12 and MRP8/14 levels were significantly higher in patients who subsequently developed flares than in patients with stable remission. The best single biomarker for the prediction of flare was S100A12 (HR 2.81). The predictive performance may be improved if a combination with hsCRP is used. Conclusions Subclinical disease activity may result in unstable remission (ie, a status of clinical but not immunological remission). Biomarkers such as S100A12 and MRP8/14 inform about the activation status of innate immunity at the molecular level and thereby identify patients with unstable remission and an increased risk of relapse.

OBJECTIVES: To compare health-related quality of life (HRQL) and to identify clinical determinants for poor HRQL of patients with juvenile idiopathic arthritis (JIA) coming from three geographic areas.METHODS: The HRQL was assessed through the Child Health Questionnaire (CHQ). A total of 30 countries were included grouped in three geographic areas: 16 countries in Western Europe; 10 in Eastern Europe; and four in Latin America. Potential determinants of poor HRQL included demographic data, physician's and parent's global assessments, measures of joint inflammation, disability as measured by Childhood Health Assessment Questionnaire (CHAQ) and erythrocyte sedimentation rate. Poor HRQL was defined as a CHQ physical summary score (PhS) or psychosocial summary score (PsS)

Objective. To evaluate the safety and efficacy of infliximab in the treatment of juvenile rheumatoid arthritis (JRA). Methods. This was an international, multicenter, randomized, placebo-controlled, double-blind study. One hundred twenty-two children with persistent polyarticular JRA despite prior methotrexate (MTX) therapy were randomized to receive infliximab or placebo for 14 weeks, after which all children received infliximab through week 44. Patients received MTX plus infliximab 3 mg/kg through week 44, or MTX plus placebo for 14 weeks followed by MTX plus infliximab 6 mg/kg through week 44. Results. Although a higher proportion of patients in the 3 mg/kg infliximab group than in the placebo group had achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement at week 14 (63.8% and 49.2%, respectively), the between-group difference in this primary efficacy end point was not statistically significant (P = 0.12). By week 16, after the crossover from placebo to infliximab 6 mg/kg when all patients were receiving infliximab, an ACR Pedi 30 response was achieved in 73.2% of all patients. By week 52, ACR Pedi 50 and ACR Pedi 70 responses had been reached in 69.6% and 51.8%, respectively, of patients. Infliximab was generally well tolerated, but the safety profile of infliximab 3 mg/kg appeared less favorable than that of infliximab 6 mg/kg, with more frequent occurrences of serious adverse events, infusion reactions, antibodies to infliximab, and newly induced antinuclear antibodies and antibodies to double-stranded DNA observed with the 3 mg/kg dose. Conclusion. While infliximab at 3 mg/kg and 6 mg/kg showed durable efficacy at 1 year, achievement of the primary efficacy end point at 3 months did not differ significantly between infliximab-treated and placebo-treated patients. Safety data indicated that the 6-mg/kg dose may provide a more favorable risk/benefit profile. These results warrant further investigation in children with JRA. © 2007, American College of Rheumatology.

JIA affected sibling pairs present high correlation for ANA and ILAR category G Filocamo, C Malattia, I Foeldvari, V Stanevicha, S Nielsen, T Herlin, C Pruunsild, F Zulian, Z Balogh, F Dressler, I Rumba, MG Alpigiani, E Cortis, F Falcini, R Trauzeddel, G Calcagno, L Lepore, M Alessio, DN Glass, SD Thompson, A Martini, N Ruperto, for the Paediatric Rheumatology International Trials Organisation (PRINTO)