A Meta-Analysis to Estimate the Placebo Effect in Randomized Controlled Trials in Juvenile Idiopathic Arthritis.

OBJECTIVE: To estimate the placebo effect in juvenile idiopathic arthritis (JIA) through a meta-analysis of phase III clinical trials with placebo comparator. METHODS: A systematic literature search was carried out up to December 2014. For parallel design studies the outcome was evaluated as a single 1-dimensional (1-D) variable or as a composite score; outcomes of withdrawal studies were evaluated only as composite scores. RESULTS: We included 26 of 224 trials (12%). In trials with parallel study design and a 1-D outcome, the placebo effect was 0.35 (95% confidence interval [95% CI] 0.27-0.43). Among trials with parallel study design and a composite score outcome, the placebo rate response was higher in trials that included patients with nonsystemic JIA (0.35 [95% CI 0.29-0.42]) than in trials that included only patients with systemic JIA (0.17 [95% CI 0.10-0.30]). In the withdrawal design trials, the percentages of patients receiving placebo who had disease flares during the double-blind phase were lower in trials that included patients with nonsystemic JIA (0.55 [95% CI 0.47-0.64]) than in trials that included only patients with systemic JIA (0.68 [95% CI 0.33-0.90]). CONCLUSION: In trials with a parallel study design a sizable number of patients seem to benefit from a placebo effect, although this effect is smaller in patients with systemic JIA. In trials with a withdrawal design the inverse placebo effect is similar among the different JIA categories. This placebo effect should be considered when evaluating the effectiveness of proposed interventions and for future calculations of sample size.

Performance of Birmingham Vasculitis Activity Score and disease extent index in childhood vasculitides.

OBJECTIVES: To evaluate the performance of the Birmingham Vasculitis Activity Score (BVAS) v3 and the Disease Extent Index (DEI) for the assessment of disease activity in 4 primary childhood (c-) systemic vasculitides. METHODS: Patients fulfilling the EULAR/PRINTO/PRES (Ankara) c-vasculitis classification criteria for Henoch-Schönlein purpura (HSP), childhood (c) polyarteritis nodosa (c-PAN), c-Wegener's granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) with disease duration at the time of diagnosis ≤3 months were extracted from the PRINTO database. The performance of the BVAS and DEI were examined by assessing convergent validity, the pattern of disease involvement, and responsiveness. We also evaluated alternative unweighted scoring methods for both tools. RESULTS: The analysis set included 796 patients with 669 HSP, 80 c-PAN, 25 c-WG and 22 c-TA. The median age at diagnosis was 6.9 years (6.6-12) and median delay in making the diagnosis from the onset of signs/symptoms was 0.01 (0.003-0.027) years. A strong correlation was found between the BVAS and DEI (rs=0.78) while correlation with the physician global assessment was moderate (rs=0.48) with BVAS and poor with DEI (rs=0.25). Both the BVAS and DEI sub-scores and total scores were able to descrive the disease involvement in the 4 childhood vasculitides. Responsiveness was large (>1.5) for both tools. The performance characteristics of the BVAS and DEI with the unweighted methods were comparable. CONCLUSIONS: This study demonstrates that both the BVAS and DEI are valid tools for the assessment of the level of disease activity in a large cohort of childhood acute and chronic vasculitides.

Clinical significance of rare copy number variations in epilepsy: a case-control survey using microarray-based comparative genomic hybridization.

OBJECTIVE: To perform an extensive search for genomic rearrangements by microarray-based comparative genomic hybridization in patients with epilepsy. DESIGN: Prospective cohort study. SETTING: Epilepsy centers in Italy. PATIENTS: Two hundred seventy-nine patients with unexplained epilepsy, 265 individuals with nonsyndromic mental retardation but no epilepsy, and 246 healthy control subjects were screened by microarray-based comparative genomic hybridization. MAIN OUTCOME MEASURES: Identification of copy number variations (CNVs) and gene enrichment. RESULTS: Rare CNVs occurred in 26 patients (9.3%) and 16 healthy control subjects (6.5%) (P = .26). The CNVs identified in patients were larger (P = .03) and showed higher gene content (P = .02) than those in control subjects. The CNVs larger than 1 megabase (P = .002) and including more than 10 genes (P = .005) occurred more frequently in patients than in control subjects. Nine patients (34.6%) among those harboring rare CNVs showed rearrangements associated with emerging microdeletion or microduplication syndromes. Mental retardation and neuropsychiatric features were associated with rare CNVs (P = .004), whereas epilepsy type was not. The CNV rate in patients with epilepsy and mental retardation or neuropsychiatric features is not different from that observed in patients with mental retardation only. Moreover, significant enrichment of genes involved in ion transport was observed within CNVs identified in patients with epilepsy. CONCLUSIONS: Patients with epilepsy show a significantly increased burden of large, rare, gene-rich CNVs, particularly when associated with mental retardation and neuropsychiatric features. The limited overlap between CNVs observed in the epilepsy group and those observed in the group with mental retardation only as well as the involvement of specific (ion channel) genes indicate a specific association between the identified CNVs and epilepsy. Screening for CNVs should be performed for diagnostic purposes preferentially in patients with epilepsy and mental retardation or neuropsychiatric features.

Development and initial validation of composite parent- and child-centered disease assessment indices for juvenile idiopathic arthritis.

OBJECTIVE: To develop and validate a parent-centered and a child-centered composite disease assessment index for juvenile idiopathic arthritis (JIA): the Juvenile Arthritis Parent Assessment Index (JAPAI) and the Juvenile Arthritis Child Assessment Index (JACAI), respectively. METHODS: The JAPAI and the JACAI include 4 measures: parent/child rating of overall well-being, pain, physical function, and health-related quality of life (HRQOL). Validation analyses were conducted on nearly 5,000 patients and included assessment of construct validity, discriminant validity, responsiveness to change, and reliability. Besides the 4-item version, a 3-item version of both indices, which did not include HRQOL, was tested. RESULTS: The JAPAI and the JACAI demonstrated good construct validity, yielding high correlations with the Juvenile Arthritis Disease Activity Score and moderate correlations with physician global rating and joint counts. Correlations obtained for the JAPAI and the JACAI and for the 4-item and the 3-item versions were comparable. Factorial analysis by principal component analysis showed that both indices are monodimensional. Both the JAPAI and JACAI discriminated well between different disease states and courses and between different levels of American College of Rheumatology Pediatric criteria in a clinical trial, and revealed fair responsiveness to clinical change. Internal consistency was satisfactory, with a Cronbach's alpha of >0.80 in all but 1 of the patient samples tested. CONCLUSION: The JAPAI and the JACAI were found to be valid instruments for assessment of disease status in JIA and suitable surrogates of physicians' evaluations. Both indices are potentially applicable in clinical practice, observational studies, and therapeutic trials.

Outcome and predicting factors of single and multiple intra-articular corticosteroid injections in children with juvenile idiopathic arthritis.

OBJECTIVES: To investigate the efficacy of IA CS (IAC) therapy in single and multiple joints in children with JIA and to seek for predictors of synovitis flare. METHODS: The clinical charts of patients who received their first IAC injection between January 2002 and December 2008 were reviewed. The CS used was triamcinolone hexacetonide for large joints and methylprednisolone acetate for small or difficult to access joints. Patients were stratified as follows: one joint injected; two joints injected; and three or more joints injected. Predictors included sex, age at disease onset, JIA category, age and disease duration, ANA status, iridocyclitis, general anaesthesia, number and type of injected joints, acute-phase reactants and concomitant MTX therapy. RESULTS: The cumulative probability of survival without synovitis flare for patients injected in one, two, or three or more joints was 70, 45 and 44%, respectively, at 1 year; 61, 32 and 30%, respectively, at 2 years; and 37, 22 and 19%, respectively, at 3 years. On Cox regression analysis, positive CRP, negative ANA and injection in the ankle were the strongest predictors for synovitis flare. The only significant side effect was skin hypopigmentation or s.c. atrophy, which occurred in <2% of patients. CONCLUSION: IAC therapy-induced sustained remission of synovitis in a substantial proportion of patients injected either in single or multiple joints, with a good safety profile. The risk of synovitis flare was higher in patients who had positive CRP, negative ANA and were injected in the ankle.

Antinuclear antibody-positive patients should be grouped as a separate category in the classification of juvenile idiopathic arthritis.

OBJECTIVE: We undertook this study to test the hypothesis that in the International League of Associations for Rheumatology (ILAR) classification of juvenile idiopathic arthritis (JIA), patients with similar characteristics can be classified into different categories. We sought to investigate whether antinuclear antibody (ANA)-positive patients having disease in the ILAR categories of oligoarthritis, rheumatoid factor-negative polyarthritis, psoriatic arthritis, and undifferentiated arthritis share homogeneous features and to compare these features with those of ANA-negative patients having the same categories of disease. METHODS: We identified JIA patients who had been followed up during a 22-year period. ANA positivity was defined as ≥2 positive results at a titer of ≥1:160. Demographic and clinical features were recorded retrospectively and compared between ANA-positive and ANA-negative patients. RESULTS: Of a total of 971 patients, 711 were ANA positive, 149 were ANA negative, and 111 had an indeterminate ANA status. Patients with indeterminate ANA status were excluded. ANA-positive patients in the different ILAR categories were similar in terms of age at disease presentation, female-to-male ratio, and frequency of asymmetric arthritis and iridocyclitis. Compared with ANA-positive patients, the ANA-negative group was older at disease presentation and had a lower prevalence of females, a lower frequency of iridocyclitis and asymmetric arthritis, a greater number of affected joints over time, and a different pattern of arthritis. The close relationship between the presence of ANAs and younger age at disease presentation, female predominance, asymmetric arthritis, development of iridocyclitis, lower number of affected joints over time, and lack of hip involvement was also confirmed by multivariate and multiple correspondence analysis. CONCLUSION: Our findings substantiate the hypothesis that ANA-positive patients classified into different JIA categories by current ILAR criteria constitute a homogeneous patient population.

Evaluation of 21-numbered circle and 10-centimeter horizontal line visual analog scales for physician and parent subjective ratings in juvenile idiopathic arthritis.

OBJECTIVE: To evaluate the measurement properties of 21-numbered circle visual analog scales (VAS) and traditional 10-cm horizontal line VAS for physician and parent subjective ratings in children with juvenile idiopathic arthritis (JIA). METHODS: We studied 2 patient samples in whom physician global rating of overall disease activity, parent global rating of the child's overall well-being, and parent rating of intensity of child's pain were performed using traditional 10-cm horizontal line VAS (n = 397) or 21-numbered circle VAS (n = 471). The measurement performances of the 2 VAS formats were examined by assessing construct validity, score distribution, responsiveness to change over time, and minimal clinically important difference (MCID). RESULTS: Most Spearman correlations with other JIA outcome measures yielded by 21-numbered circle VAS were greater than those obtained with 10-cm horizontal line VAS, revealing that the circle VAS format has better construct validity. Ceiling effects (i.e., score = 0) for physician and parent global ratings were 43.7% and 32.9%, respectively, on 21-numbered circle VAS, and 31.6% and 35.3%, respectively, on 10-cm horizontal line VAS. Responsiveness of 21-numbered circle VAS was good (standardized response mean > 0.8) or moderate (standardized response mean > 0.6) among patients classified as improved or worsened, respectively, by the physician or the parent. Overall, MCID values for 21-numbered circle VAS tended to be greater for worsening than for improvement. CONCLUSION: The 21-numbered circle VAS are a suitable alternative to the 10-cm horizontal line VAS and may facilitate incorporation of physician and parent subjective ratings in standard clinical practice.

A new short and simple health-related quality of life measurement for paediatric rheumatic diseases: initial validation in juvenile idiopathic arthritis.

OBJECTIVE: To develop and validate a new short and simple measure of health-related quality of life (HRQL) in children with juvenile idiopathic arthritis (JIA). METHODS: The Paediatric Rheumatology Quality of Life Scale (PRQL) is a 10-item questionnaire that explores HRQL in two domains: physical health (PhH) and psychosocial health (PsH). Validation of the parent proxy report and child self-report versions of the instrument was accomplished by evaluating 472 JIA patients and approximately 800 healthy children. Validation analyses included assessment of feasibility, face and content validity; construct and discriminative ability; internal structure and consistency; test-retest reliability; responsiveness to clinical change; and minimal clinically important difference. RESULTS: The PRQL was found to be feasible and to possess both face and content validity. The PRQL score correlated in the predicted range with most of the other JIA outcome measures, thereby demonstrating good construct validity, and discriminated well between different levels of disease severity. Assessment of internal structure (factor analysis) revealed that the PhH and PsH subscales identify two unambiguously separated domains. The internal consistency (Cronbach's alpha) was 0.86. The intraclass correlation coefficient for test-retest reliability was 0.91. The PRQL revealed fair responsiveness, with a standardized response mean of 0.67 in improved patients. Overall, the PRQL appeared to be more able to capture physical HRQL than psychosocial HRQL. CONCLUSION: The PRQL was found to possess good measurement properties and is, therefore, a valid instrument for the assessment of HRQL in children with JIA. This tool is primarily proposed for use in standard clinical care.

Informática na educação: perspectivas de inclusão / Computer Literacy in Education - The Perspectives of Inclusion

O presente artigo tem como objetivo analisar as perspectivas de mudanças na abordagem educacional de uma escola de Educação Especial a partir de um projeto de Informática na Educação. Para tanto faz-se um resgate cronológico das etapas de implantação do projeto de informática e as modificações que ocorreram na abordagem educacional. Como marco inicial encontramos as propostas de formação de professores e a informática como recurso possível para construção de conhecimento de pessoas com necessidades especiais decorrentes de deficiência física. As mudanças ocorridas ao longo desta trajetória são explicitadas a analisadas por meio dos projetos de trabalho, postura de alunos e professores, reflexões sobre as práticas emergentes, reformulações na gestão, bem como análise de atitudes rumo à construção de autonomia dos alunos com necessidades educativas especiais, enquanto pessoas conscientes de suas limitações, porém com possibilidades para caminhar rumo ao desenvolvimento de competências. Desta forma foi desenvolvido um processo de formação continuada para que o professor encontrasse respostas a indagações surgidas neste caminho e que mostraram tão presentes em seu cotidiano. O eixo central que sustentou as diferentes indagações permeou as questões curriculares e a formação de professores. Os resultados desta investigação evidenciaram quanto o recurso da informática potencializa mudanças na educação com vistas a inclusão, porém nos apontou a importância dos demais elementos do processo educacional para construir uma pedagogia diferenciada e uma nova proposta educacional, que valorize todos os protagonistas do processo apresentando uma visão de escola democrática, que privilegie: formação do cidadão e construção de competências, possibilitando assim que as pessoas com necessidades educativas especiais possa ser efetivamente incluída na sociedade do conhecimento.