Blood brain barrier permeability and astrocyte-derived extracellular vesicles in children with juvenile idiopathic arthritis: a cross-sectional study.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most prevalent rheumatic disease in children, and the inflammatory process is widely studied, primarily characterized by its impact on joint health. Emerging evidence suggests that JIA may also affect the central nervous system (CNS). This study investigates the potential CNS involvement in JIA by analyzing the presence of astrocyte-derived extracellular vesicles (EVs) and the S100B protein in plasma, both of which are indicative of astrocyte activity and blood-brain barrier (BBB) integrity. METHODS: EDTA plasma from 90 children diagnosed with JIA and 10 healthy controls, matched by age and gender, was analyzed for extracellular vesicles by flow cytometric measurement. Astrocyte-derived EVs were identified using flow cytometry with markers for aquaporin 4 (AQP-4) and glial fibrillary acidic protein (GFAP). Levels of the S100B protein were measured using a commercial ELISA. Disease activity was assessed using the Juvenile Arthritis Disease Activity Score (JADAS27, 0-57), and pain levels were measured using a visual analogue scale (VAS, 0-10 cm). RESULTS: Our analyses revealed a significantly higher concentration of astrocyte-derived EVs in the plasma of children with JIA compared with healthy controls. Furthermore, children with JADAS27 scores of 1 or higher exhibited notably higher levels of these EVs. The S100B protein was detectable exclusively in the JIA group. CONCLUSION: The elevated levels of astrocyte-derived EVs and the presence of S100B in children with JIA provide evidence of BBB disruption and CNS involvement, particularly in those with higher disease activity. These findings underscore the importance of considering CNS health in the comprehensive management of JIA. Further research is required to elucidate the mechanisms behind CNS engagement in JIA and to develop treatments that address both joint and CNS manifestations of the disease.

A Pilot Study Investigating Faecal Microbiota After Two Dietary Interventions in Children with Juvenile Idiopathic Arthritis.

There is evidence for an impact of the gut microbiota on the immune system, which has consequences for inflammatory diseases. Exclusive enteral nutrition (EEN) and the specific carbohydrate diet (SCD) have been demonstrated as effective anti-inflammatory treatments for children with Crohn's disease. We have previously shown an anti-inflammatory effect from these nutritional treatments in children with juvenile idiopathic arthritis (JIA). The aim of this study was to investigate if improved clinical symptoms after EEN or SCD treatment in children with JIA could be linked to changes in faecal microbiota. We included sixteen patients with JIA (age 7-17 years), six for treatment with EEN and ten with SCD. EEN was given for 3-5 weeks and SCD for 4-5 weeks, with clinical and laboratory status assessed before and after treatment. Faecal samples were analysed for microbiota diversity and composition using 16S rRNA gene sequencing. Analyses of the faecal microbiota showed an effect on the overall composition with both interventions; the most striking result was a decreased relative abundance of the genus Faecalibacterium from EEN and of Bifidobacterium from SCD. The α-diversity decreased significantly from SCD (P = 0.04), but not from EEN (P = 0.22). Despite the study cohorts being small, both EEN and SCD were shown to impact the faecal microbiota. Future larger studies with a focus on metagenomics or metabolomics could possibly reveal a link and clarify the clinical effects of those nutritional regimens.

Fecal microbiota in children with juvenile idiopathic arthritis treated with methotrexate or etanercept.

BACKGROUND: Alterations in the composition of the fecal microbiota in children with juvenile idiopathic arthritis (JIA) have been observed in several studies, but it has not been determined whether the standard treatment for JIA changes the composition or function of the microbiota. The first-line disease-modifying anti-rheumatic drug for treatment of JIA is usually methotrexate, followed or supplemented by anti-tumor necrosis factor alpha drugs, such as etanercept. The aim of this study was to investigate the effects of methotrexate and etanercept treatments on the fecal microbiota and the fecal short-chain fatty acids (SCFAs) in children with JIA. METHODS: In this multicenter study, the composition of fecal microbiota from 45 treatment-naïve children with JIA was compared with that from 29 children treated with methotrexate and 12 children treated with etanercept. We also made pairwise comparisons of 15 children sampled before and during methotrexate treatment and 7 children sampled before and during etanercept treatment. The microbiota was determined using sequencing amplicons from the V3 and V4 regions of the 16S rRNA gene. Alpha-diversity, community composition, and relative abundances of bacterial taxa were analyzed in all comparisons. Analyses of fecal SCFAs, using a high-performance liquid chromatograph, were performed for the pairwise comparisons. RESULTS: We did not find any significant differences in α-diversity or community composition of microbiota. However, principal coordinate analysis indicated a change in community composition in 7 of the 15 paired samples before and during methotrexate and 2 of the 7 paired samples before and during etanercept. Comparisons of the relative abundance of taxa revealed minor differences before and during treatment with methotrexate or etanercept, but they were not significant after correction for multiple analyses, and the unpaired and paired analyses did not show similar changes. There were no significant differences in levels of fecal SCFAs before and during treatment with methotrexate or etanercept. CONCLUSIONS: Treatment with methotrexate or etanercept had minor, but no significant or consistent changes either on composition of microbiota or on levels of SCFAs, suggesting that these changes are not related to the therapeutic effects of methotrexate or etanercept.

Fecal Microbiota in Untreated Children With Juvenile Idiopathic Arthritis: A Comparison With Healthy Children and Healthy Siblings.

OBJECTIVE: Changes in the composition of gut microbiota have been suggested to be associated with juvenile idiopathic arthritis (JIA). The objective in this study was to investigate if the diversity and composition of the fecal microbiota differed between children with JIA and healthy controls (HCs), and if the microbiota differed between children with JIA and their healthy siblings. METHODS: In this multicenter, case-control study, fecal samples were collected from 75 children with JIA and 32 HCs. Eight of the HCs were siblings to 8 children with JIA, and they were compared only pairwise with their siblings. The microbiota was determined using sequencing amplicons from the V3 and V4 regions of the 16S rRNA gene. Alpha diversity, community composition of microbiota, and relative abundances of taxa were compared between children with JIA and healthy unrelated controls as well as between children with JIA and healthy siblings. RESULTS: Our data revealed no significant differences in α-diversity or community composition of microbiota between children with JIA, healthy unrelated controls, or healthy siblings. Analyses of relative abundances of phyla, families, and genera identified trends of differing abundances of some taxa in children with JIA, in comparison with both HCs and healthy siblings, but none of these findings were significant after adjustment for multiple comparisons. CONCLUSION: There were no significant differences in the composition of fecal microbiota in children with JIA compared with HCs. The composition of microbiota in children with JIA did not differ significantly from that in their healthy siblings.

Evaluation of screening for coeliac disease in children with juvenile idiopathic arthritis.

AIM: To study the prevalence of coeliac disease (CD) in children with Juvenile idiopathic arthritis (JIA), by screening a population-based cohort of children with JIA using autoantibodies against tissue transglutaminase (anti-TG2). METHODS: All children diagnosed with JIA in three Swedish counties, with disease onset between 2007 and 2014, were included prospectively. Serum levels of IgA anti-TG2 antibodies, IgG anti-TG2 antibodies, and total IgA were analysed. Children with positive levels of IgA anti-TG2 antibodies and children with IgA deficiency in combination with positive levels of IgG anti-TG2 antibodies were referred to the paediatric gastroenterology unit for gastroscopy and small intestine biopsy. RESULTS: A total of 216 children were included, and analysis of IgA and IgG anti-TG2 antibodies was performed in 213 children. Three children were diagnosed with CD prior to the diagnosis of JIA, and three additional children were found through screening, resulting in a CD point prevalence of 2.8% (95% CI 0.6-5.0%). CONCLUSION: We found a point prevalence of CD close to previous described prevalence in the general population of Swedish children. Therefore, general screening for CD in children with JIA is not supported by our data. However, this study shows that asymptomatic CD in children with JIA may be found by screening.

Up regulated complement and fc receptors in juvenile idiopathic arthritis and correlation with disease phenotype.

PURPOSE: The progress in identifying immunological mechanisms in juvenile idiopathic arthritis (JIA) has partly been hampered by the fact that the disease is heterogeneous. Here we have investigated complement and Fc receptors, as part of the inflammatory process, in two subgroups of JIA. METHODS: Blood from 26 patients with oligoarticular or polyarticular course type JIA and 21 healthy age and sex-matched controls were investigated by FACS and immunoassays. RESULTS: Increased numbers of monocytes and augmented plasma levels of C-reactive protein, C3a and IgG were found in both JIA subgroups. However, only polyarticular patients exhibited increased expression of Fc gamma receptor (FcγR) II and III and complement receptor (CR) 1 on monocytes along with enhanced CR1 expression on B cells. A correlation was observed between degree of receptor expression and C3a levels in the patients. CONCLUSIONS: Complement and Fc receptors are up regulated in children with multiple joint involvements, thus highlighting these pathways in the pathogenesis of polyarticular JIA.