Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype.

OBJECTIVES: Little is known about the mechanisms of efficacy of methotrexate (MTX) in childhood arthritis, or genetic influences upon response to MTX. The aims of this study were to use gene expression profiling to identify novel pathways/genes altered by MTX and then investigate these genes for genotype associations with response to MTX treatment. METHODS: Gene expression profiling before and after MTX treatment was performed on 11 children with juvenile idiopathic arthritis (JIA) treated with MTX, in whom response at 6 months of treatment was defined. Genes showing the most differential gene expression after the treatment were selected for single nucleotide polymorphism (SNP) genotyping. Genotype frequencies were compared between nonresponders and responders (ACR-Ped70). An independent cohort was available for validation. RESULTS: Gene expression profiling before and after MTX treatment revealed 1222 differentially expressed probes sets (fold change >1.7, P<0.05) and 1065 when restricted to full responder cases only. Six highly differentially expressed genes were analyzed for genetic association in response to MTX. Three SNPs in the SLC16A7 gene showed significant association with MTX response. One SNP showed validated association in an independent cohort. CONCLUSION: This study is the first, to our knowledge, to evaluate gene expression profiles in children with JIA before and after MTX, and to analyze genetic variation in differentially expressed genes. We have identified a gene, which may contribute to genetic variability in MTX response in JIA, and established as proof of principle that genes that are differentially expressed at mRNA level after drug administration may also be good candidates for genetic analysis.

Mothers' reports of the difficulties that their children experience in taking methotrexate for Juvenile Idiopathic Arthritis and how these impact on quality of life.

BACKGROUND: Children who take methotrexate for juvenile idiopathic arthritis may experience side effects, including nausea and vomiting, leading to anticipatory nausea in some children, and fear of injections or blood tests. The aim of this study was to examine the prevalence and extent of these difficulties and their impact on quality of life. METHODS: Participants were mothers of children with JIA who were currently taking methotrexate (MTX). Mothers completed a questionnaire about MTX that was developed for the study, two questions from the treatment subscale of the Pediatric Quality of Life Inventory (PedsQL) Rheumatology scale to assess needle-related problems and the Child Health Questionnaire 50-item parent version (CHQ-PF50) to assess health-related quality of life (HRQoL). RESULTS: 171 mothers participated in the study. More than half of children were reported to have experienced one or more of: nausea or vomiting after taking MTX, anticipatory nausea, fear of blood tests or fear of injections. There was no significant difference in reported rates of sickness or needle-related problems between MTX responders (ACR70 or above), partial responders (ACR30 or ACR50) and non-responders. In multivariate analyses, variables that were significant independent predictors of one or more MTX-related difficulties included younger age, taking MTX subcutaneously and having a larger number of currently active joints. Feeling sick after taking MTX was a significant independent predictor of poorer scores on the physical summary scale of the CHQ-PF50. Anxiety about injections and feeling sick after taking MTX were significant independent predictors of poorer scores on the psychosocial summary scale. CONCLUSIONS: Difficulties in taking MTX are experienced by a significant proportion of children with JIA and these may have an adverse impact on HRQoL. Approaches to help minimize these difficulties are required.

Do mothers and fathers hold similar views about their child's arthritis?

OBJECTIVE: Evaluations of the well-being of children with juvenile idiopathic arthritis (JIA) typically rely on parents as proxy respondents. An assumption of several studies appears to be that mothers' and fathers' ratings are interchangeable, as reports do not always specify which parent completed the assessments nor, in repeated measures, whether they were completed by the same parent. The aim of this study was to examine the level of agreement between mothers' and fathers' ratings of their child's quality of life (QOL) and to identify possible predictors of disagreement. METHODS: Mothers and fathers (n = 82) of children with JIA completed ratings of their child's symptoms, QOL, and measures of their mood and beliefs about their child's illness and treatment. The number of active and limited joints and the physician's global assessment were also recorded. RESULTS: Intraclass correlation coefficients between mothers' and fathers' ratings of physical and psychosocial QOL were high (0.824 and 0.755, respectively). However, calculation of difference scores revealed that 70.6% and 65.9%, respectively, were classified as discordant. Where parents differed, the direction of difference was not systematic. Discordance in parents' mood states and in their illness and treatment beliefs explained a small amount of the variance in discordance in QOL. CONCLUSION: It should not be assumed that proxy ratings of a child's well-being can be generalized from one parent to the other. Studies that take repeated assessments should ensure that the same parent completes assessments at all time points. Other factors that may explain discordance between parents' ratings need to be explored.