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Objective.Around one-third of patients with juvenile idiopathic arthritis (JIA) fail to respond to first-line methotrexate (MTX) or anti-tumor necrosis factor (TNF) therapy, with even fewer achieving ≥ American College of Rheumatology Pediatric 70% criteria for response (ACRpedi70), though individual responses cannot yet be accurately predicted. Because change in serum S100-protein myeloid-related protein complex 8/14 (MRP8/14) is associated with therapeutic response, we tested granulocyte-specific S100-protein S100A12 as a potential biomarker for treatment response.Methods.S100A12 serum concentration was determined by ELISA in patients treated with MTX (n = 75) and anti-TNF (n = 88) at baseline and followup. Treatment response (≥ ACRpedi50 score), achievement of inactive disease, and improvement in Juvenile Arthritis Disease Activity Score (JADAS)-10 score were recorded.Results.Baseline S100A12 concentration was measured in patients treated with anti-TNF [etanercept n = 81, adalimumab n = 7; median 200, interquartile range (IQR) 133–440 ng/ml] and MTX (median 220, IQR 100–440 ng/ml). Of the patients in the anti-TNF therapy group, 74 (84%) were also receiving MTX. Responders to MTX (n = 57/75) and anti-TNF (n = 66/88) therapy had higher baseline S100A12 concentration compared to nonresponders: median 240 (IQR 125–615) ng/ml versus 150 (IQR 87–233) ng/ml, p = 0.021 for MTX, and median 308 (IQR 150–624) ng/ml versus 151 (IQR 83–201) ng/ml, p = 0.002, for anti-TNF therapy. Followup S100A12 could be measured in 44/75 MTX-treated patients (34/44 responders) and 39/88 anti-TNF-treated patients (26/39 responders). Responders had significantly reduced S100A12 concentration (MTX: p = 0.031, anti-TNF: p < 0.001) at followup versus baseline. Baseline serum S100A12 in both univariate and multivariate regression models for anti-TNF therapy and univariate analysis alone for MTX therapy was significantly associated with change in JADAS-10.Conclusion.Responders to MTX or anti-TNF treatment can be identified by higher pretreatment S100A12 serum concentration levels.

Objectives. In JIA there is an unmet need for biomarkers with which to identify patients who will respond well to MTX. The aim of this study was to define the prognostic value of baseline serum proteins and clinical variables in response to MTX to help inform the clinician at time of diagnosis whether the patient is likely to respond well to MTX. Methods. JIA patients were recruited into the Childhood Arthritis Response to Medication Study (CHARMS). Clinical data and venous blood were collected before administration of MTX and at followup. MRP8/14 and inflammatory cytokines were measured by ELISA and multiplex immunoassay, respectively. CRP and ESR were measured as part of routine clinical assessment. To explore which baseline factors might predict successful treatment, binary logistic regression models were fitted for outcome. Results. High disease activity (high serum MRP8/14, active joint count or physician’s score) pre-MTX was observed in a subgroup of patients with a better response to therapy. In a multivariable analysis, after accounting for MRP8/14 at baseline, no other factors were independently significantly associated with outcome. Patients with baseline MRP8/14 >3000 ng/ml were more likely to respond to MTX at ACR50 or better: odds ratio 16.07 (95% CI 2.00, 129.3). Conclusion. We have demonstrated that high levels of baseline serum MRP8/14 have prognostic value in predicting a subgroup of patients whose arthritis will improve on MTX. Routine collection of serum prior to the start of medication would be a valuable step in collaborative validation of such biomarkers.

Objective. The role of the adaptive immune system has not been explored in detail compared with the innate immune system in systemic JIA (sJIA) pathogenesis. The aim of this study was to examine the phenotype of circulating peripheral blood CD4 + T-cell subpopulations in a cross-sectional study of sJIA patients during disease remission on medication and during acute flare of the disease. Methods. Flow cytometry was used to examine the phenotype and cytokine production of IFNg-, IL-4and IL-17-producing CD4 + T cells in the peripheral blood of 10 sJIA patients with active disease, 9 sJIA with inactive disease, 14 JIA patients with oligoarticular onset, 10 adult control subjects and 10 agematched control subjects. In parallel, we examined the proportion of FoxP3 + Tregs. Results. IFNg- and IL-17-producing CD4 + T cells and IL-17-producing CD3 + CD4 T cells were present at higher proportions in the peripheral blood of sJIA patients, irrespective of their disease status. Our data also confirm the known increase of the proportions of IFNg-producing Th1 cells with increasing age and suggest an increase with age in the IL-17-producing CD4 + T-cell population. Conclusion. This study is the first to describe significantly higher proportions of Th1 and Th17 T helper cell subsets in the peripheral blood of sJIA patients. These proinflammatory cells may play a pathogenic role in sJIA. Our data also emphasize the importance of using paediatric age-matched control subjects when evaluating the T-cell cytokine profile in JIA.

Introduction Approximately 30 % of juvenile idiopathic arthritis (JIA) patients fail to respond to anti-TNF treatment. When clinical remission is induced, some patients relapse after treatment has been stopped. We tested the predictive value of MRP8/14 serum levels to identify responders to treatment and relapse after discontinuation of therapy. Methods Samples from 88 non-systemic JIA patients who started and 26 patients who discontinued TNF-blockers were analyzed. MRP8/14 serum levels were measured by in-house MRP8/14 ELISA and by Bühlmann Calprotectin ELISA at start of anti-TNF treatment, within 6 months after start and at discontinuation of etanercept in clinical remission. Patients were categorized into responders (ACRpedi ≥ 50 and/or inactive disease) and non-responders (ACRpedi

Item does not contain fulltext BACKGROUND: Analysis of myeloid-related protein 8 and 14 complex (MRP8/14) serum concentrations is a potential new tool to support the diagnosis of systemic-onset juvenile idiopathic arthritis (SJIA) in the presence of fever of unknown origin. OBJECTIVE: To test the ability of MRP8/14 serum concentrations to monitor disease activity in patients with SJIA and stratify patients at risk of relapse. METHODS: Serum concentrations of MRP8/14 in 52 patients with SJIA were determined by a sandwich ELISA. The monitoring of therapeutic regimens targeting interleukin 1 and tumour necrosis factor alpha, and methotrexate treatment was analysed and diagnostic power to predict flares was tested. RESULTS: MRP8/14 levels were clearly raised in active disease and decreased significantly in response to successful treatments. Serum concentrations of MRP8/14 increased significantly (p740 ng/ml predicted disease flares accurately (sensitivity 92%, specificity 88%). MRP8/14 levels correlated well with clinical disease activity, as assessed by physician's global assessment of disease activity (r=0.62), Childhood Health Assessment Questionnaire (r=0.56), active joint count (r=0.46) and with C-reactive protein (r=0.71) and erythrocyte sedimentation rate (r=0.72) (for all p

Background Methotrexate (MTX) is the first line of therapy for patients with juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM). The mechanisms of action of MTX in childhood autoimmunity are not fully elucidated. The primary target sites of inflammation of JIA and JDM i.e. joint and muscle, respectively do not represent sites from which samples can be easily obtained to monitor inflammatory markers. In contrast peripheral blood is accessible and can be obtained at time of routine clinical screen. We hypothesized that changes in peripheral blood of patients would be informative in monitoring disease and understanding inflammatory pathways that are modulated by MTX.

Standard management of Juvenile Idiopathic Arthritis (JIA) is heavily dependent on the use of methotrexate (MTX), which induces clinical benefit in about 65% of patients. We have previously demonstrated that children with high serum levels of MRP8/14 protein prior to starting MTX have a high chance of good response to MTX. However, among children whose MRP8/14 serum levels are moderate or low, prior to MTX, some respond well whilst others respond poorly to MTX. We have taken a proteomics approach to identify novel biomarkers present in serum prior to treatment that correlate with response or non response to MTX.

The nucleoside adenosine exerts regulatory functions prompting T cell anergy and preventing release of inflammatory cytokines. The main source of extracellular adenosine is AMP dephosphorylated by CD73. The resulting product can be taken up by the cell or further metabolized by ADA (Adenosine deaminase) expressed extracellularly when bound to the membrane via coupling to CD26 protein, a surrogate marker for ADA expression. We have shown that CD73 expression and its AMPase activity are reduced on JIA (juvenile idiopathic arthritis) SFMC (synovial fluid mononuclear cells), particularly on CD8+ T cells and CD19+ B cells; we hypothesise that this may lead to a defect in generation of anti inflammatory adenosine in JIA.

Background Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatological disease with an incidence of 1 in 1000. Methotrexate is the primary DMARD given to patients with JIA but approximately 30% of children fail to respond. The SPARKS CHARM study enrolls patients with JIA about to start MTX with the aim to discover predictors of response to MTX, to distinguish patients who will respond well to MTX from non-responders.

Background Methotrexate (MTX) is the standard disease modifying therapy for children with juvenile idiopathic arthritis (JIA), inducing remission in ~65% of cases. There are currently no known predictors which classify who will successfully respond to MTX therapy nor those who will remain well following MTX withdrawal. Mechanisms of MTX action in JIA are at present unclear: genetic and gene expression profiling would provide novel insights into the biology of this therapy.

The nucleotidases CD39 and CD73 are responsible for the catabolism of pro-inflammatory ATP to AMP, and the consequent dephosphorylation of this nucleotide to regulatory adenosine. CD39 protein has previously been observed to be elevated (1) on JIA (Juvenile Idiopathic Arthritis) SFMC (synovial fluid mononuclear cells) with a correspondent increase in ATPase activity, while CD73 has been found decreased on JIA SFMC, potentially affecting the cells ability to synthesize suppressive adenosine.