T-cell activation without proliferation in juvenile idiopathic arthritis

A study was done to determine if the differentiation and activation phenotype of T cells in synovial fluid (SF) from patients with juvenile idiopathic arthritis (JIA) is associated with T-cell proliferation in situ. Mononuclear cells were isolated from 44 paired samples of peripheral blood and SF. Differentiation and activation markers were determined on CD4 and CD8 T cells by flow cytometry. Cell-cycle analysis was performed by propidium iodide staining, and surface-marker expression was also assessed after culture of the T cells under conditions similar to those found in the synovial compartment. The majority of the T cells in the SF were CD45RO+CD45RBdull. There was greater expression of the activation markers CD69, HLA-DR, CD25 and CD71 on T cells from SF than on those from peripheral blood. Actively dividing cells accounted for less than 1% of the total T-cell population in SF. The presence or absence of IL-16 in T-cell cultures with SF or in a hypoxic environment did not affect the expression of markers of T-cell activation. T cells from the SF of patients with JIA were highly differentiated and expressed early and late markers of activation with little evidence of in situ proliferation. This observation refines and extends previous reports of the SF T-cell phenotype in JIA and may have important implications for our understanding of chronic inflammation

An association between the acute phase response and patterns of antigen induced T cell proliferation in juvenile idiopathic arthritis

The aim of this research was to determine whether all memory T cells have the same propensity to migrate to the joint in patients with juvenile idiopathic arthritis. Paired synovial fluid and peripheral blood mononuclear cell proliferative responses to a panel of antigens were measured and the results correlated with a detailed set of laboratory and clinical data from 39 patients with juvenile idiopathic arthritis. Two distinct patterns of proliferative response were found in the majority of patients: a diverse pattern, in which synovial fluid responses were greater than peripheral blood responses for all antigens tested; and a restricted pattern, in which peripheral blood responses to some antigens were more vigorous than those in the synovial fluid compartment. The diverse pattern was generally found in patients with a high acute phase response, whereas patients without elevated acute phase proteins were more likely to demonstrate a restricted pattern. We propose that an association between the synovial fluid T cell repertoire and the acute phase response suggests that proinflammatory cytokines may influence recruitment of memory T cells to an inflammatory site, independent of their antigen specificity. Additionally, increased responses to enteric bacteria and the presence of αEβ7 T cells in synovial fluid may reflect accumulation of gut associated T cells in the synovial compartment, even in the absence of an elevated acute phase response. This is the first report of an association between the acute phase response and the T cell population recruited to an inflammatory site

Medically significant infections are increased in patients with juvenile idiopathic arthritis treated with etanercept. Results from the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study.

OBJECTIVE: The association between anti–tumor necrosis factor therapy and increased rates of infection is widely documented in adults with rheumatoid arthritis. Findings in children with juvenile idiopathic arthritis (JIA) have been less well documented. The aims of this analysis were to compare the rates of medically significant infections (MSIs) in children with JIA treated with etanercept (ETN) versus methotrexate (MTX) and to compare the rates between combination therapy with ETN plus MTX and monotherapy with ETN. METHODS: A total of 852 ETN‐treated children and 260 MTX‐treated children had been recruited to the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study (BSPAR‐ETN). MSIs included infections that resulted in death or hospitalization or were deemed medically significant by the clinician. This on‐drug analysis followed the patients until the first MSI, treatment discontinuation, the last followup, or death. Cox proportional hazards models, which were adjusted using propensity deciles, were used to compare rates of MSI between cohorts. Sensitivity analyses were conducted specifically with regard to serious infections (SIs), which were defined as those requiring hospitalization or treatment with intravenous antibiotics/antivirals. RESULTS: The ETN‐treated cohort was older and had a longer disease duration, but the disease activity was similar between the cohorts. A total of 133 first MSIs were reported (109 with ETN and 24 with MTX). Patients receiving ETN had higher rates of MSI than did the controls (propensity decile adjusted hazard ratio 2.13 [95% confidence interval 1.22–3.74]). The risk of MSI was higher whether patients were receiving combination or monotherapy. Sensitivity analysis showed no between‐group difference in the rate of SIs, which were much less common. CONCLUSION: ETN therapy is associated with an increased risk of MSI; however, this increased risk disappears when considering only SIs, which suggests that either there were differences in the severity of infections and/or there was a possible reporting bias

Growth in children and adolescents with juvenile idiopathic arthritis over 2 years of treatment with etanercept: results from the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study

OBJECTIVES: Children with JIA can experience delayed and restricted growth. The objectives of this study were to investigate the influence of etanercept (ETN) on vertical growth and factors associated with improved growth in patients with JIA over the initial 2 years of treatment. METHODS: This analysis was restricted to ETN-treated patients in the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study with complete height data recorded at baseline, 1 and 2 years. Height z-scores were calculated using the World Health Organization growth standards for age and gender. Change in height z-score was evaluated over time. Multivariable linear regression was used to identify factors associated with change in height z-score from baseline. RESULTS: A total of 191 ETN-treated patients were included: 65% female, median baseline age 11.0 years [interquartile range (IQR) 7.3-12.9], median disease duration 3.5 years (IQR 1.7-7.1). At baseline mean height z-score was -0.74 (s.d. 1.4). After 2 years mean height z-score increased to -0.45 (1.4) (change +0.29; P <0.001). In multivariable analysis, factors associated with an improvement in height z-score included lower baseline height z-score [-0.110 per unit (95% CI -0.161, -0.059), P <0.001] and no oral corticosteroid use at baseline [-0.192 (95% CI -0.343, -0.040), P = 0.013]. CONCLUSION: ETN therapy was associated with an improvement in height z-score over the first 2 years of therapy in this real-world cohort of children with severe JIA. The lack of a strong association of improvements in height with improvements in disease activity warrants further exploration