Juvenile Idiopathic Arthritis Subgroups Research Articles

Alteration of Fecal Microbiota Profiles in Juvenile Idiopathic Arthritis. Associations with HLA-B27 Allele and Disease Status.

Alteration of gut microbiota is involved in several chronic inflammatory and autoimmune diseases, including rheumatoid arthritis, and gut microbial “pro-arthritogenic” profiles have been hypothesized. Intestinal inflammation may be involved in spondyloarthropathies and in a subset of patients affected by Juvenile Idiopathic Arthritis (JIA), the most common chronic rheumatic disease of childhood. We compared the fecal microbiota composition of JIA patients with healthy subjects (HS), evaluating differences in microbial profiles between sub-categories of JIA, such as enthesitis-related arthritis (JIA-ERA), in which inflammation of entheses occurs, and polyarticular JIA, non-enthesitis related arthritis (JIA-nERA). Through taxon-level analysis, we discovered alteration of fecal microbiota components that could be involved in subclinical gut inflammation, and promotion of joint inflammation. We observed abundance in Ruminococcaceae in both JIA categories, reduction in Clostridiaceae and Peptostreptococcaceae in JIA-ERA, and increase in Veillonellaceae in JIA-nERA, respectively, compared with HS. Among the more relevant genera, we found an increase in Clostridium cluster XIVb, involved in colitis and arthritis, in JIA-ERA patients compared with HS, and a trend of decrease in Faecalibacterium, known for anti-inflammatory properties, in JIA-nERA compared with JIA-ERA and HS. Differential abundant taxa identified JIA patients for the HLA-B27 allele, including Bilophila, Clostridium cluster XIVb, Oscillibacter, and Parvimonas. Prediction analysis of metabolic functions showed that JIA-ERA metagenome was differentially enriched in bacterial functions related to cell motility and chemotaxis, suggesting selection of potential virulence traits. We also discovered differential microbial profiles and intra-group variability among active disease and remission, suggesting instability of microbial ecosystem in autoimmune diseases with respect to healthy status. Similarly to other chronic autoimmune and inflammatory diseases, different microbial profiles, as observed among different JIA subgroups compared to HS, and potential functional acquisition related to migration, could promote inflammation and contribute to the disease pathogenesis.

High mobility group box protein 1-A prognostic marker for structural joint damage in 10-year follow-up of patients with juvenile idiopathic arthritis.

High mobility group box protein 1 (HMGB1) is an important pro-inflammatory mediator in adult rheumatoid arthritis. The diagnostic utility of HMGB1 in Juvenile Idiopathic Arthritis (JIA) is still unclear. The aim was to examine whether serum HMGB1 levels are associated with inflammation, radiological disease progression, and long-term prognosis in JIA. We included 131 children with JIA from a population-based prevalence study; 38 of them were prospectively followed up for 10 years. Clinical and laboratory disease characteristics at study entry and after 10 years as well as radiological progression over 10 years were recorded. HMGB1 levels were analyzed by an ELISA. The HMGB1 levels were similar in children with different JIA subgroups and in children with established (53%) or newly diagnosed (47%) disease. HMGB1 levels did not differ between groups at entry into the study or at 10 years, by sex, or by the presence or absence of RF or ANA antibodies. HMGB1 levels at the study entry correlated with HMGB1 levels at 10 years and with blood neutrophil count. Most importantly, children with destructive arthritis at 10 years had a tendency toward higher HMGB1 levels at study entry (median 1.2 vs 0.6ng/ml, ns) and displayed 4-fold higher circulating HMGB1 levels (median 3.4 vs 0.8ng/ml, p = 0.0014) than children without radiological destructions. Our results suggest that HMGB1 is a marker of inflammatory activity in children with JIA. Higher serum HMGB1 levels are related to more destructive JIA and could be used as a negative prognostic marker at the disease start. Clinicaltrials.gov NCT01905319. Registered July 16, 2013.

Wnt/β-catenin signaling plays a key role in the development of spondyloarthritis.

Spondyloarthritis (SpA) is a group of diseases consisting of psoriatic arthritis (PsA), reactive arthritis, arthritis related to inflammatory bowel disease (a subgroup of juvenile idiopathic arthritis), and ankylosing spondylitis (the prototype of SpA). Axial bone formation and the combination of concurrent erosion and new bone formation are specific characteristics of SpA disease. The use of antiproinflammatory cytokines, such as inhibitors of tumor necrosis factor α (TNF-α), appears to be the greatest advance in the treatment of SpA over the past 20 years. However, TNF-α blockers do not halt new bone formation. Recent clinical observations and animal studies demonstrate that Wnt signaling proteins and natural Wnt inhibitors, such as DKK1 and sclerostin, are likely to play important roles in the process of ankylosis in SpA, and could potentially serve as therapeutic targets for the treatment of SpA.

Somatic NOD2 mosaicism in Blau syndrome

Somatic NOD2 mosaicism in Blau syndrome

FRI0548 Costs of Early Juvenile Idiopathic Arthritis (JIA)

BackgroundJIA is the most common chronic inflammatory rheumatic disease in childhood. It carries a high risk for life-long morbidity and disability. Longitudinal cost-of-illness studies are crucial, given the availability of...

FRI0534 Immunization Status of Vaccine-Preventable Diseases in Children with Juvenile Idiopathic Arthritis

BackgroundImmunization is the least invasive and most cost-effective approach to reduce the incidence of infections and morbidity and mortality in children. Since patients with juvenile idiopathic arthritis (JIA) are at...

Synovial membrane protein expression differs between juvenile idiopathic arthritis subtypes in early disease

IntroductionJuvenile idiopathic arthritis (JIA) is the most common rheumatological disease of childhood with a prevalence of around 1 in 1,000. Without appropriate treatment it can have devastating consequences including permanent disability from joint destruction and growth deformities. Disease aetiology remains unknown. Investigation of disease pathology at the level of the synovial membrane is required if we want to begin to understand the disease at the molecular and biochemical level. The synovial membrane proteome from early disease-stage, treatment naive JIA patients was compared between polyarticular and oligoarticular subgroups.MethodsProtein was extracted from 15 newly diagnosed, treatment naive JIA synovial membrane biopsies and separated by two dimensional fluorescent difference in-gel electrophoresis. Proteins displaying a two-fold or greater change in expression levels between the two subgroups were identified by matrix assisted laser desorption ionization-time of flight mass spectrometry with expression further verified by Western blotting and immunohistochemistry.ResultsAnalysis of variance analysis (P ≤ 0.05) revealed 25 protein spots with a two-fold or greater difference in expression levels between polyarticular and oligoarticular patients. Hierarchical cluster analysis with Pearson ranked correlation revealed two distinctive clusters of proteins. Some of the proteins that were differentially expressed included: integrin alpha 2b (P = 0.04); fibrinogen D fragment (P = 0.005); collagen type VI (P = 0.03); fibrinogen gamma chain (P = 0.05) and peroxiredoxin 2 (P = 0.02). The identified proteins are involved in a number of different processes including platelet activation and the coagulation system.ConclusionsThe data indicate distinct synovial membrane proteome profiles between JIA subgroups at an early stage in the disease process. The identified proteins also provide insight into differentially perturbed pathways which could influence pathological events at the joint level.

Natural killer cell activity and frequency of killer cell immunoglobulin‐like receptors in children with different forms of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) has three major onset types with widely varying clinical features: systemic, polyarticular and pauciarticular. We assessed natural killer (NK) cell function and killer cell immunoglobulin-like receptor (KIR) genotypes in patients with different JIA subtypes. Peripheral blood samples from 72 children with active JIA (systemic, 25; polyarticular, 24; pauciarticular, 23) and 25 controls were used for flow cytometric assessments of NK cell count, cytotoxicity, perforin, granzyme B, interferon (IFN)-γ and tumour necrosis factor (TNF)-α. Samples from 220 children with JIA (systemic, 84; polyarticular, 72; pauciarticular, 64) and 150 controls were used for KIR2DS2, KIR2DS4, KIR3DS1, KIR2DL1, KIR2DL2, KIR2DL3 and KIR3DL1 typing by polymerase chain reaction with sequence-specific oligonucleotide probes. Compared with the controls, the patients with systemic JIA showed lower NK cell counts, cytotoxicity and perforin and granzyme B expression (p<0.05), while the patients with pauci- and polyarticular JIA showed higher perforin and granzyme B expression (p<0.05). NK cells produced higher level of TNF-α while lower level of IFN-γ in the pauci- and polyarticular JIA groups than in the systemic JIA group (p<0.05). No significant differences in KIR gene frequencies were found between the JIA subgroups and healthy controls, except for the positive frequency and locus frequency of KIR2DS4, which were lower in the systemic JIA group. Compared with poly- and pauciarticular JIA, systemic JIA is associated with decreased NK cell function, more IFN-γ and less TNF-α secretion of NK cell and lower KIR2DS4 frequency.

AB1187 Autoantibodies recognizing carbamylated proteins (anti-carp) in sera of patients with JIA

BackgroundAnti-citrullinated protein antibodies (ACPA) have a low prevalence in Juvenile Idiopathic Arthritis (JIA). Autoantibodies recognizing carbamylated protein (anti-CarP) are a promising new serological marker for ACPA negative Rheumatoid Arthritis and...

FRI0350 Quality of life of juvenile idiopathic arthritis cohort at adulthood in a transition program

BackgroundHealth Related Quality of Life (HRQoL) is affected in Juvenile idiopathic arthritis (JIA) because of pain, functional impairment and joint destruction. The main quality of life score used in JIA...

THU0329 OPG/RANK/RANKL in pathogenesis of osteoporosis of juvenile idiopathic arthritis (JIA) subtypes

BackgroundA decrease in bone mass has been described in a high percentage with increased risk of osteoporosis in JIA subtypes. The pathogenesis of bone loss in active JIA is complex,...

SAT0482 Overweight Prevalence in Children and Adolescents with Juvenile Idiopathic Arthritis in Dependence on Health and Lifestyle Aspects

BackgroundOverweight is a serious problem of relevance to health policy. Patients with chronic diseases might be a risk group. Juvenile idiopathic arthritis (JIA) leads to functional restrictions limiting physical activity...

FRI0324 Experience with adalimumab in 123 patients with juvenile idiopathic arthritis (JIA)

BackgroundAdalimumab is a fully human anti-TNF monoclonal antibody approved for the treatment of resistant polyarticular juvenile idiopathic arthritis at a dosage of 24 mg/kg/m2. every other week in children below...

FRI0339 Prevelance of MEFV gene mutations in chidren with juvenil idiopathic arthritis

BackgroundMutations of the MEFV gene, which encodes pyrin protein, a negative regulator of inflammation, leads to Familial Mediterranean Fever (FMF). Recent studies with adults suggest that MEFV gene mutations may...

MEFV gene mutations in Turkish children with juvenile idiopathic arthritis

Mutations of the Mediterranean fever (MEFV) gene, which encodes pyrin protein, leads to familial Mediterranean fever (FMF) and a connection between MEFV mutations and rheumatic diseases has been suggested. The aim of this study was to explore the frequency and clinical significance of MEFV mutations in children with juvenile idiopathic arthritis (JIA). In this study, children with JIA, who had no typical symptoms of FMF, were screened for the mutations in exons 2 and 10 of the MEFV gene by direct sequencing. A total of 96 children, 56 girls (58.3%), with a median age of 11 years (2-18 years) were included. Patients were classified according to JIA subgroups as oligoarthritis in 43 (44.8%), rheumatoid factor-negative polyarthritis in 22 (22.9%), rheumatoid factor-positive polyarthritis in 2 (2.1%), systemic arthritis in 12 (12.5%) patients, enthesitis-related arthritis in 16 (16.7%), and psoriatic arthritis 1 (1.04%). A total of 31 children (32.3%) had MEFV mutations: 25 heterozygous, 2 homozygous, and 4 compound heterozygous. There were 22 (11.4%) exon 10 mutations (M694V, R761H, K695R, V726A, R653H) and 15 (7.8%) exon 2 mutations (E148Q, G304R, E148V, T267I). The allele frequencies of MEFV mutations were found to be 19.27%, which is higher than the general population [p = 0.03, (odds ratio (OR):1.93, 95% confidence interval (CI): 1.09-3.41)]. MEFV mutation carrier rates were significantly higher in antinuclear antibody (ANA) negative than in ANA positive patients [p = 0.01, (OR: 0.25, 95% CI: 0.085-0.74)] and in males than in females [p = 0.001, (OR: 0.197, 95% CI: 0.078-0.495)]. Also, there was a statistically significant difference between the MEFV mutation carrier rates and the subgroups of JIA (p = 0.005). These findings suggest that mutations of the MEFV gene may be responsible for rheumatic diseases other than FMF, and patients with JIA especially males, ANA negatives, and ERA subgroups should be screened for MEFV gene mutations in countries where FMF is frequent.

Espondiloartritis

Spondyloarthritis is a group of diseases related but different clinical expression: psoriatic arthritis, arthritis of inflammatory bowel disease, reactive arthritis, a subgroup of juvenile idiopathic arthritis and ankylosing spondylitis (the prototypic and best studied). In the last five years there have been significant advances in several areas to help better recognition of spondyloarthritis as a clinical entity and its classification. A better understanding of the pathophysiological mechanisms and genetic factors related to inflammation and structural damage. In addition, new clinical and imaging results are allowing a better assessment of treatment options. These continue to highlight biological therapies, especially the blocking tumor necrosis factor alpha and therapeutic breakthrough, however the exact role of physiotherapy, treatment with NSAIDs and other biological treatments are still not known intimately.The main challenges with direct application to clinical practice for the next decade are the development of tools for early diagnosis of treatment can modulate (or inhibit) the progression of structural damage and induce long-term remissions without treatment.

Up Regulated Complement and Fc Receptors in Juvenile Idiopathic Arthritis and Correlation with Disease Phenotype

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. 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. 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. Complement and Fc receptors are up regulated in children with multiple joint involvements, thus highlighting these pathways in the pathogenesis of polyarticular JIA.

The IL-1 Receptor Antagonist Gene Polymorphism in Turkish Patients with Juvenile Idiopathic Arthritis

Objective: Interleukin-1 receptor antagonist (IL-1Ra) gene (IL-1RN) polymorphism is associated with disease susceptibility and activity in several inflammatory diseases. The aim of this study was to investigate IL1RN genotype and its associations with different subtypes of juvenile idiopathic arthritis ( JIA) in a group of Turkish patients. Methods: A total of 273 subjects were included in this cross sectional study. Genomic DNA was obtained from the peripheral blood of 76 patients with juvenile idiopathic arthritis and 197 reference subjects. A variable number tandem repeat (VNTR) polymorphism in the second intron of the IL-1RN gene was detected by PCR-based methods. Probing pocket depth, clinical attachment loss, plaque accumulation and bleeding on probing (BOP) were recorded. The data were analyzed by the χ2 test, logistic regression and Mann-Whitney U test. Results: The frequency and carriage rate of IL1RN*2 were significantly increased in JIA patients compared with the controls. The high representation of IL1RN*2 in 34.3% of the 16 patients with systemic onset JIA, 27.5% of the 20 patients with polyarticular JIA, and 31.4% of the 11 patients with enthesitis-related arthritis was found. Conclusion: This study showed genetic associations between the IL-1Ra gene and the systemic subtype of JIA. These finding give a better understanding of the underlying etiological cause of subgroup of JIA and could lead to different therapeutic approaches each subgroups of JIA.

IgA Transglutaminase Levels in Children with Juvenile Idiopathic Arthritis

Several studies have indicated that adult patients with spondyloarthritis (SpA) have elevated levels of antibodies associated with celiac disease (CD). This has not been studied in children, and none of the studies corrected for total IgA levels. We measured total IgA and IgA against tissue transglutaminase (TTG) levels in 42 children with Juvenile Idiopathic Arthritis (JIA), of whom 11 had SpA, along with 10 non-inflammatory control subjects. Median (IQR) TTG IgA levels were elevated among children with ERA (8.8, 4.6 - 21) compared to 'JIA controls' (JIA subgroups other than ERA) (2.8, 1.5 - 5.9) and a healthy non-inflammatory control group (1.5, 0.82 - 12), p = 0.017, Kruskal-Wallis. There was no correlation between TTG IgA levels and measures of disease activity or with medicine use. None of the children were diagnosed endoscopically with celiac disease. Patients with ERA likewise had elevated total IgA level compared to the other groups (p = 0.001), and total IgA levels correlated highly with TTG IgA (r = 0.599, p<0.001). These findings suggest that elevations in TTG IgA may reflect increased polyclonal IgA production, rather than a specific intestinal inflammatory process.

γδT cells in Juvenile Idiopathic Arthritis: Higher Percentages of Synovial Vδ1+ and Vγ9+ T Cell Subsets Are Associated with Milder Disease

To analyze γδT cell subsets in peripheral blood (PB) and synovial fluid (SF) of patients with juvenile idiopathic arthritis (JIA), and to correlate γδT cell subsets with clinical characteristics. γδT cell subsets as percentages of CD3+ T cells in samples of PB (n = 25) and SF (n = 93) were analyzed by flow cytometry in 93 JIA patients. The percentage of Vγ9+ γδT cells after 10 days of in vitro expansion with either interleukin 2 (IL-2) or isopentenyl pyrophosphate (IPP) plus IL-2 was determined. Both Vδ1+ and Vγ9+ γδT cell subsets were detected in SF of all patients, but only the percentage of Vδ1+ cells was higher in SF compared to PB (p < 0.01). The distribution of γδT cell subsets was similar in different JIA subgroups, whereas antinuclear antibody (ANA)-positive patients had a higher percentage of SF Vδ1+ T cells than ANA-negative patients (p < 0.01). The percentage of SF Vδ1+ T cells was inversely associated with age at onset, recurrence of synovitis, and erythrocyte sedimentation rate; and that of SF Vγ9+ T cells was inversely correlated with age at onset and was higher in patients who recovered from disease (n = 15). IPP-induced expansion of SF Vγ9+ T cells correlated with disease remission, whereas the expansion of SF Vγ9+ T cells in media with IL-2 alone was significantly greater in patients with uveitis. The percentage of Vδ1+ and Vγ9+ γδT cells among the SF T cells and their ability to respond to IPP or IL-2 correlated with specific outcomes of JIA, suggesting their role in the immunopathogenesis of this disease.