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1.  Osteoblastogenesis from synovial fluid-derived cells is related to the type and severity of juvenile idiopathic arthritis 
Arthritis Research & Therapy  2012;14(3):R139.
Juvenile idiopathic arthritis (JIA) is characterized by synovial inflammation, followed by hyperplastic changes of the synovium, and destruction of articular cartilage along with underlying bone. This hyperplastic process is the result of inflammation-induced activation of NF-κB, which may be accompanied by decreased osteogenic differentiation of synovial mesenchymal progenitors and contribute to bone resorption. We aimed to explore osteoblast differentiation of synovial fluid (SF)-derived mesenchymal progenitors and correlate it with intensity of inflammation in patients with JIA.
Peripheral blood from 18 patients with oligoarticular (o)JIA, 22 patients with polyarticular (p)JIA and 18 controls was collected along with SF from 18 patients with oJIA and 9 patients with pJIA. SF-derived cells were cultured to assess osteoblastogenesis, using alkaline phosphatase histochemical staining and colorimetric activity assay. The expression of osteoblast-related genes, Runt-related transcription factor 2 (Runx2), Osteoprotegerin (OPG), Receptor activator of nuclear factor κB ligand (RANKL) and arthritis-related cytokine/chemokine genes, Tumor necrosis factor alpha (TNF-α, Fas, Fas ligand (FasL), Interleukin (IL)-1β, IL-4, IL-6, IL-17, IL-18, CC chemokine ligand (CCL)-2, CCL3, CCL4 was evaluated. Osteoblastogenesis was correlated with systemic and local inflammatory indicators. Expression of osteoblast genes was also analyzed in peripheral blood mononuclear cells (PBMC) and total SF-derived cells from patients with JIA. Additionally, we assessed the inhibitory effect of SF from patients with JIA on differentiation of human bone marrow (hBM)-derived osteoblasts.
Osteoblastogenesis from SF-derived progenitors was decreased in patients with pJIA compared to those with oJIA. Osteoblastogenesis from primary SF-derived cells negatively correlated with erythrocyte sedimentation rate (ρ = -0.391, P = 0.05), C-reactive protein concentration (ρ = -0.527, P<0.01) and synovial concentration of IL-17 (ρ = -0.552, P = 0.01). SF-derived osteoblasts from pJIA patients expressed more CCL2 and CCL3 genes than in oJIA (P = 0.04 and P = 0.03, respectively; Mann-Whitney test). Expression of Fas was significantly higher in osteoblasts from patients with pJIA than those with oJIA (P = 0.03, Mann-Whitney test). SF-derived cells from patients with pJIA expressed higher levels of RANKL than in oJIA (P = 0.05, Mann-Whitney test). PBMCs from patients with JIA expressed less OPG than healthy control patients (P = 0.05, Kruskal-Wallis test). SF from all tested JIA patients inhibited differentiation of hBM-derived osteoblasts (P = 0.04, Kruskal-Wallis test).
Osteoblast differentiation was decreased in patients with severe forms of JIA and accompanied by altered cytokine/chemokine expression pattern. Development of therapeutic interventions targeting synovial mesenchymal or osteoblast lineage cells in JIA would contribute to alleviating both bone destruction and inflammation in severe forms of the disease.
PMCID: PMC3446522  PMID: 22687048
2.  Comparison of soluble adhesion molecules in juvenile idiopathic arthritis between the active and remission stages 
Chen, C | Tsao, C | Ou, L | Yang, M | Kuo, M | Huang, J
Annals of the Rheumatic Diseases  2002;61(2):167-170.
Objective: To determine the serum levels of soluble adhesion molecules in patients with juvenile idiopathic arthritis (JIA), and to determine whether the levels of these molecules differ between active disease and remission in the same JIA subtype, and whether differences in these levels exist between controls and the three JIA subtypes.
Methods: The serum levels of soluble E-selectin (sE-selectin) and soluble intercellular adhesion molecule-1 (sICAM-1) were determined by enzyme linked immunosorbent assay (ELISA) in 40 patients with JIA (12 systemic, 13 polyarticular, and 15 oligoarticular) who had active disease or were in clinical remission and 16 healthy controls. Differences in the levels of adhesion molecules of the same JIA subtype during different disease activity were determined by the pairedt test, and differences between the disease and control groups were calculated by one way analysis of variance. A value p<0.01 was considered significant.
Results: During the same disease stage (active or in remission), systemic JIA was associated with a significantly higher sE-selectin level than the oligoarticular JIA subtype, whereas this was not found for sICAM-1. Although the mean levels of sE-selectin and sICAM-1 in active systemic and polyarticular JIA were higher than those in remission, this did not reach statistical significance. The levels of sE-selectin and sICAM-1 of the three JIA subtypes, in both the active stage and clinical remission, were still significantly higher than in normal controls.
Conclusions: Systemic JIA is associated with a higher sE-selectin level than oligoarticular JIA both in active disease and in clinical remission. This may explain why the morbidity of systemic JIA is greater than that of oligoarticular JIA—namely, owing to increased endothelial cell activation. As significantly higher levels of sE-selectin and sICAM-1 were found in the active and remission stages of the three JIA subtypes compared with those in the control group, JIA may recur even when clinical remission has been achieved.
PMCID: PMC1753987  PMID: 11796405
3.  Biologic similarities based on age at onset in oligoarticular and polyarticular subtypes of juvenile idiopathic arthritis 
Arthritis and rheumatism  2010;62(11):3249-3258.
To explore biologic correlates to age at onset in patients with juvenile idiopathic arthritis (JIA) using peripheral blood mononuclear cell (PBMC) gene expression analysis.
PBMCs were isolated from 56 healthy controls and 104 patients with recent-onset JIA (39 with persistent oligoarticular JIA, 45 with rheumatoid factor–negative polyarticular JIA, and 20 with systemic JIA). RNA was amplified and labeled using NuGEN Ovation, and gene expression was assessed with Affymetrix HG-U133 Plus 2.0 GeneChips.
A total of 832 probe sets revealed gene expression differences (false discovery rate 5%) in PBMCs from children with oligoarticular JIA whose disease began before age 6 years (early-onset disease) compared with those whose disease began at or after age 6 years (late-onset disease). In patients with early-onset disease, there was greater expression of genes related to B cells and less expression of genes related to cells of the myeloid lineage. Support vector machine analyses identified samples from patients with early- or late-onset oligoarticular JIA (with 97% accuracy) or from patients with early- or late-onset polyarticular JIA (with 89% accuracy), but not from patients with systemic JIA or healthy controls. Principal components analysis showed that age at onset was the major classifier of samples from patients with oligoarticular JIA and patients with polyarticular JIA.
PBMC gene expression analysis reveals biologic differences between patients with early-and late-onset JIA, independent of classification based on the number of joints involved. These data suggest that age at onset may be an important parameter to consider in JIA classification. Furthermore, pathologic mechanisms may vary with age at onset, and understanding these processes may lead to improved treatment of JIA.
PMCID: PMC3018072  PMID: 20662067
4.  Race and other risk markers in juvenile idiopathic arthritis-associated uveitis in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry 
The Journal of rheumatology  2013;40(12):2088-2096.
To characterize the epidemiology and clinical course of children with juvenile idiopathic arthritis-associated uveitis (JIA-U) in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry and explore differences between African American (AA) and Non-Hispanic White (NHW) children.
There were 3,967 NHW and AA children with JIA enrolled in the CARRA Registry. Demographic and disease-related data were collected from time of diagnosis to enrollment. Children with JIA alone were compared to those with JIA-U. Children with JIA-U were then compared by race.
Mean age of children with JIA-U was 11.4 years (±4.5), 76.9% were female and 2.8% were AA. Children with JIA-U were younger at arthritis onset, female, required more medications, had <5 joints involved, had oligoarticular JIA, and ANA (+), RF (−) and anti-CCP (−). AA children with JIA-U had decreased uveitis frequency, were older at arthritis onset and more frequently diagnosed with enthesitis-related JIA. Predictors of uveitis development include female gender, early age of arthritis onset, and oligoarticular persistent and extended JIA classification, whereas polyarticular RF-positive JIA was protective.
The prevalence of JIA-U in AA and NHW children is 11.6% in the CARRA registry. Known risk markers (ANA, age at arthritis onset, and oligoarticular JIA) were more frequent in our JIA-U cohort. AA children had a lower frequency of JIA-U. There were significant differences in age of arthritis onset and JIA subtype between NHW and AA children, although the ANA, RF and HLA-B27 were similar. Exploration of race as a risk factor should be considered.
PMCID: PMC4117408  PMID: 24187099
juvenile idiopathic arthritis; uveitis; risk markers; outcomes
5.  Evidence of fibrinogen as a target of citrullination in IgM rheumatoid factor-positive polyarticular juvenile idiopathic arthritis 
Several studies have noted the significance of measuring anti-cyclic citrullinated peptide (CCP) antibodies in juvenile idiopathic arthritis (JIA) as an important indicator for destructive disease, as is the case in rheumatoid arthritis (RA). While the role of anti-CCP antibodies in RA and JIA has become better understood, the identity of the target proteins of this modification has remained elusive. In this study, we evaluated serum from patients with various subtypes of JIA to investigate the presence of anti-deiminated (citrullinated) fibrinogen and anti-citrullinated α-enolase antibodies, and their association with RF and anti-CCP antibody isotypes.
Sera were obtained from 96 JIA patients, 19 systemic lupus erythematosus (SLE) patients, and 10 healthy children. All sera were measured for antibodies against citrullinated and native fibrinogen and α-enolase by an enzyme linked immunosorbent assay (ELISA). In addition, all sera were assayed for anti-CCP antibody isotypes and rheumatoid factor (RF) isotypes by ELISA. The relationship between anti-citrullinated fibrinogen and anti-α-enolase antibodies and disease activity and joint damage were also investigated. All results were correlated with clinical and laboratory parameters using Spearman's rho correlation coefficient. Multiple logistic regression analysis was utilized to identify which variables were associated with joint erosions and diagnosis of JIA.
Thirty-one JIA patients (32%) demonstrated reactivity to citrullinated fibrinogen and 9 (9%) to citrullinated α-enolase. Reactivity to citrullinated fibrinogen and α-enolase was predominantly found in IgM RF-positive polyarthritis patients. Fourteen JIA patients reacted with native α-enolase and a higher percentage of SLE patients reacted with citrullinated α-enolase when compared to JIA patients. Anti-citrullinated fibrinogen antibodies correlated with the presence of IgG anti-CCP antibodies and IgA and IgM RF. The presence of anti-citrullinated α-enolase antibodies correlated with IgA anti-CCP antibodies. IgG anti-CCP antibodies were significantly associated with joint damage and anti-citrullinated fibrinogen antibodies were strongly associated with JIA when compared to control groups. Anti-citrullinated fibrinogen antibodies demonstrated high sensitivity (81%) for IgM RF-positive polyarticular JIA. IgG anti-CCP antibodies had the highest specificity (95%) for JIA, with anti-citrullinated fibrinogen antibodies, IgA anti-CCP antibodies and IgA RF all following at 84%.
JIA patient sera exhibited strong reactivity to anti-citrullinated fibrinogen antibodies and demonstrated high sensitivity and specificity for JIA, primarily in IgM RF-positive polyarthritis patients. Fibrinogen is one of several protein targets for citrullination in JIA.
PMCID: PMC3071779  PMID: 21439056
6.  Bone Density, Structure, and Strength in Juvenile Idiopathic Arthritis 
Arthritis and rheumatism  2008;58(8):2518-2527.
To identify determinants of musculoskeletal deficits (muscle cross-sectional area [mCSA], trabecular volumetric bone mineral density [vBMD], and cortical bone strength [section modulus]) in patients with juvenile idiopathic arthritis (JIA) and to determine if cortical bone strength is appropriately adapted to muscle forces.
Peripheral quantitative computed tomography (pQCT) of the tibia was performed in 101 patients with JIA (79% female; 24 with oligoarticular JIA, 40 with polyarticular JIA, 18 with systemic JIA, and 19 with spondylarthritis [SpA]) and 830 healthy control subjects; all were ages 5–22 years. Outcomes of pQCT were expressed as sex- and race-specific Z scores. Multivariable linear regression models assessed mCSA and bone status in JIA patients compared with controls and identified factors associated with musculoskeletal deficits in JIA.
The median duration of JIA was 40 months; 29% of the JIA patients had active arthritis, and 28% had received glucocorticoid therapy during the previous year. Compared with the controls, the mCSA and section modulus Z scores were significantly lower in patients with polyarticular JIA and those with SpA. Trabecular vBMD Z scores were significantly lower in patients with polyarticular JIA, those with systemic JIA, and those with SpA. Significant predictors of musculoskeletal deficits included active arthritis in the previous 6 months (mCSA), temporomandibular joint disease (mCSA and section modulus), functional disability (mCSA and vBMD), short stature (vBMD), infliximab exposure (vBMD), and JIA duration (section modulus). The section modulus was significantly reduced relative to mCSA in patients with JIA after adjustment for age and limb length.
Marked deficits in vBMD and bone strength occur in JIA in association with severe and longstanding disease. Contrary to the findings of previous studies, bone deficits were greater than expected relative to the mCSA, which illustrates the importance of adjusting for age and bone length.
PMCID: PMC2705769  PMID: 18668565
7.  Oligoarticular and polarticular JIA: epidemiology and pathogenesis 
Nature reviews. Rheumatology  2009;5(11):616-626.
Juvenile idiopathic arthritis (JIA) refers to a group of chronic childhood arthropathies, currently classified into subtypes primarily on the basis of clinical features. Research has focused on the hypothesis that these subtypes arise through distinct etiologic pathways. In this Review, we discuss four subtypes of JIA: persistent oligoarticular, extended oligoarticular, rheumatoid-factor positive polyarticular and rheumatoid-factor-negative polyarticular. These subtypes differ in prevalence between ethnic groups and are associated with different HLA alleles. Non-HLA genetic risk factors have also been identified, some of which reveal further molecular differences between these subtypes, while others suggest mechanistic overlap. Investigations of immunophenotypes also provide insights into subtype differences: adaptive immunity appears to have a prominent role in both polyarticular and oligoarticular JIA, and the more-limited arthritis observed in persistent oligoarticular JIA as compared with extended oligoarticular JIA may reflect more-potent immunoregulatory T-cell activity in the former. Tumor necrosis factor seems to be a key mediator of both polyarticular and oligoarticular JIA, especially in the extended oligoarticular subtype, although elevated levels of other cytokines also are observed. Limited data on monocytes, dendritic cells, B cells, natural killer T cells, and neutrophils suggest that the contributions of these cells differ across subtypes of JIA. Within each subtype, however, common pathways appear to drive joint damage.
PMCID: PMC4159935  PMID: 19806151
8.  Synovial Fluid Proteins Differentiate Between the Subtypes of Juvenile Idiopathic Arthritis 
Arthritis and rheumatism  2010;62(6):1813-1823.
Juvenile Idiopathic Arthritis (JIA) is a heterogeneous group of inflammatory of diseases and there no clinically useful prognostic markers to predict disease outcome in these children. Synovial fluid is likely a reflection of the proteins present in the inflamed synovium. The purpose of this study was to delineate the synovial fluid proteome and determine whether there are differences in the protein expression in subtypes of JIA.
Synovial fluid from children with oligoarticular, polyarticular and systemic JIA were compared. Two dimensional gel electrophoresis for protein separation and Matrix associated laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) and Quadripole time of flight mass spectrometry (Q-TOF-MS) for protein identification were used for this study. Synovial fluid cells were analyzed by PCR for the presence of haptoglobin mRNA.
The synovial fluid proteome of the samples was delineated. The majority of proteins showed overexpression in JIA synovial fluid as compared to non-inflammatory controls. There were 24 statistically significant differentially expressed spots (> 2 fold change and p<.05) between the subtypes of JIA. PCR analysis revealed haptoglobin mRNA suggesting that haptoglobin is locally produced in an inflamed joint in JIA.
Despite similar histological appearance of inflamed joints in subtypes of JIA, there are differences in protein expression in the subtypes of JIA. Haptoglobin is differentially expressed between the subtypes of JIA and is locally produced in an inflamed joint in JIA. Haptoglobin and other differentially expressed proteins may be potential biomarkers in JIA.
PMCID: PMC2918379  PMID: 20222116
9.  The Role of Transforming Growth Factor β Signaling in Fibroblast-like Synoviocytes From Patients With Oligoarticular Juvenile Idiopathic Arthritis 
This study was designed to investigate the pathogenic contributions of fibroblast-like synoviocytes (FLS) to juvenile idiopathic arthritis (JIA) by identifying pathways with dysregulated gene expression in FLS from patients with oligoarticular JIA.
FLS were derived from synovial fluid obtained by arthrocentesis from patients with JIA undergoing intraarticular steroid injections and from orthopedic control patients. Gene expression profiles of the JIA and control FLS were obtained using the Affymetrix platform, with application of Ingenuity Pathway Analysis and Gene Set Enrichment Analysis software to define gene sets in dysregulated pathways and networks of potential pathologic relevance in this disease. Biologically relevant differentially expressed genes were confirmed by RNA and protein analysis.
Exploration of global gene expression profiles of the JIA FLS revealed important dysregulated pathways, including the transforming growth factor β (TGFβ) signaling, as well as endochondral bone formation, cartilage formation, and β-catenin networks. Importantly, bone morphogenetic protein 4 (BMP-4) was significantly overexpressed in the JIA FLS. FLS from patients with oligoarticular JIA exhibit a chondrocyte phenotype, as evidenced by expression of type II collagen and aggrecan.
Dysregulation of the pathways involved in the pathogenesis of oligoarticular JIA were revealed through gene expression profiling. JIA FLS displayed dysregulated TGFβ signaling and exhibited a hypertrophic chondrocyte phenotype. These characteristics, along with contributions from the β-catenin network may have implications for endochondral bone formation and local growth disturbances in oligoarticular JIA. Overexpression of BMP-4 in FLS from patients with oligoarticular JIA in particular may play an important role in disease pathogenesis, with a direct effect on functional outcome and with implications for future treatment.
PMCID: PMC4108350  PMID: 24782191
10.  Assessment of the clinical significance of gelatinase activity in patients with juvenile idiopathic arthritis using quantitative protein substrate zymography 
Annals of the Rheumatic Diseases  2005;65(4):501-507.
To measure gelatinase activities in paired synovial fluid (SF) and serum of patients with juvenile idiopathic arthritis (JIA), and to assess how these activities relate to clinical and laboratory measures of disease activity.
A quantitative protein substrate zymography method was adapted and validated for use with serum and SF. Bands of activity were measured by densitometry and correlated with standard laboratory indicators of inflammation: erythrocyte sedimentation rate and platelet count.
Gelatinase activity was found consistently in patients with JIA, with reproducible, quantified bands of activity corresponding to pro‐matrix metalloproteinase‐9 (pro‐MMP‐9), including the neutrophil associated lipocalin complex, and pro‐ and active forms of MMP‐2. Both active MMP‐2 and pro‐MMP‐9 were higher in JIA serum than in controls, though no differences were seen between patients grouped according to age, disease duration, or JIA subtype. However, SF MMP‐9 correlated significantly with the laboratory indicators of inflammation, as did the relative level of active MMP‐2.
Both MMP‐2 and MMP‐9 gelatinolytic activities are raised during active JIA and associated with inflammatory activity regardless of age and disease duration, supporting a role for MMPs in the breakdown of joint components from early in disease. These MMPs may be specific markers of active joint destruction linked to inflammatory JIA, MMP‐9 as a product of infiltrating cells, and the activation of MMP‐2 produced within the joint.
PMCID: PMC1798108  PMID: 16150790
gelatinase; matrix metalloproteinases; zymogram; juvenile idiopathic arthritis; cartilage
11.  Meta-analysis confirms association between TNFA-G238A variant and JIA, and between PTPN22-C1858T variant and oligoarticular, RF-polyarticular and RF-positive polyarticular JIA 
Although more than 100 non-HLA variants have been tested for associations with juvenile idiopathic arthritis (JIA) in candidate gene studies, only a few have been replicated. We sought to replicate reported associations of single nucleotide polymorphisms (SNPs) in the PTPN22, TNFA and MIF genes in a well-characterized cohort of children with JIA.
We genotyped and analyzed 4 SNPs in 3 genes: PTPN22 C1858T (rs2476601), TNFA G-308A, G-238A (rs1800629, rs361525) and MIF G-173C (rs755622) in 647 JIA cases and 751 healthy controls. We tested for association between each variant and JIA as well as JIA subtypes. We adjusted for multiple testing using permutation procedures. We also performed a meta-analysis that combined our results with published results from JIA association studies.
While the PTPN22 variant showed only modest association with JIA (OR = 1.29, p = 0.0309), it demonstrated a stronger association with the RF-positive polyarticular JIA subtype (OR = 2.12, p = 0.0041). The MIF variant was not associated with the JIA as a whole or with any subtype. The TNFA-238A variant was associated with JIA as a whole (OR 0.66, p = 0.0265), and demonstrated a stronger association with oligoarticular JIA (OR 0.33, p = 0.0006) that was significant after correction for multiple testing. TNFA-308A was not associated with JIA, but was nominally associated with systemic JIA (OR = 0.33, p = 0.0089) and enthesitis-related JIA (OR = 0.40, p = 0.0144). Meta-analyses confirmed significant associations between JIA and PTPN22 (OR 1.44, p <0.0001) and TNFA-238A (OR 0.69, p < 0.0086) variants. Subtype meta-analyses of the PTPN22 variant revealed associations between RF-positive, RF-negative, and oligoarticular JIA, that remained significant after multiple hypothesis correction (p < 0.0005, p = 0.0007, and p < 0.0005, respectively).
We have confirmed associations between JIA and PTPN22 and TNFA G-308A. By performing subtype analyses, we discovered a statistically-significant association between the TNFA-238A variant and oligoarticular JIA. Our meta-analyses confirm the associations between TNFA-238A and JIA, and show that PTPN22 C1858T is associated with JIA as well as with RF-positive, RF-negative and oligoarticular JIA.
PMCID: PMC3874734  PMID: 24160187
Genetics; Juvenile idiopathic arthritis; Association; Replication
12.  Network analysis identifies protein clusters of functional importance in juvenile idiopathic arthritis 
Arthritis Research & Therapy  2014;16(3):R109.
Our objective was to utilise network analysis to identify protein clusters of greatest potential functional relevance in the pathogenesis of oligoarticular and rheumatoid factor negative (RF-ve) polyarticular juvenile idiopathic arthritis (JIA).
JIA genetic association data were used to build an interactome network model in BioGRID 3.2.99. The top 10% of this protein:protein JIA Interactome was used to generate a minimal essential network (MEN). Reactome FI Cytoscape 2.83 Plugin and the Disease Association Protein-Protein Link Evaluator (Dapple) algorithm were used to assess the functionality of the biological pathways within the MEN and to statistically rank the proteins. JIA gene expression data were integrated with the MEN and clusters of functionally important proteins derived using MCODE.
A JIA interactome of 2,479 proteins was built from 348 JIA associated genes. The MEN, representing the most functionally related components of the network, comprised of seven clusters, with distinct functional characteristics. Four gene expression datasets from peripheral blood mononuclear cells (PBMC), neutrophils and synovial fluid monocytes, were mapped onto the MEN and a list of genes enriched for functional significance identified. This analysis revealed the genes of greatest potential functional importance to be PTPN2 and STAT1 for oligoarticular JIA and KSR1 for RF-ve polyarticular JIA. Clusters of 23 and 14 related proteins were derived for oligoarticular and RF-ve polyarticular JIA respectively.
This first report of the application of network biology to JIA, integrating genetic association findings and gene expression data, has prioritised protein clusters for functional validation and identified new pathways for targeted pharmacological intervention.
PMCID: PMC4062926  PMID: 24886659
13.  Economic impact of juvenile idiopathic arthritis and familial Mediterranean fever 
Rheumatology International  2011;32(7):1955-1962.
The aim of the study was to determine the economical impact of juvenile idiopathic arthritis (JIA) and familial Mediterranean fever (FMF) in Turkey. A total of 100 patients (69 F/31 M) with JIA and 100 with FMF (68 F/32 F) who were consecutively seen in the outpatient clinic of the pediatric rheumatology department at Cerrahpasa Medical School between August 2008 and January 2009 were studied. Cost data were collected through a questionnaire filled out by the parents. The mean age (JIA: 11 ± 5 years; FMF:12 ± 4 years) and mean disease duration (JIA:5 ± 3 years; FMF: 4 ± 3 years) of the patients were similar. JIA patients were assigned to 5 subtypes (polyarticular: n = 45, oligoarticular: n = 30, systemic onset: n = 13, psoriatic: n = 6, and enthesopathy-related JIA: n = 6). Forty-nine percent of the patients with JIA were treated with anti-TNF drugs and 61% with DMARDs. All patients with FMF were using colchicine. The total annual cost of JIA (€3,994 ± 4,101) was considerably higher than that of FMF (€162 ± 77) (P < 0.001). Medication fee was the major determinant of total costs in both diseases constituting 85% in JIA and 39% in FMF. Among the subtypes of JIA, total annual costs were the highest among patients with polyarticular type (€6,045 ± 4,078). Medications especially anti-TNF drugs were the major contributor among all determinants of costs in JIA. The low costs of health care system and prominent changes in the health care policies for the last 5 years in Turkey might have played role in our findings.
PMCID: PMC3382642  PMID: 21461856
Juvenile idiopathic arthritis; Familial Mediterranean fever; Cost of illness study; Direct costs; Indirect costs; Etanercept; Anti-TNF agents; Turkey
14.  Evaluation of anti-citrullinated type II collagen and anti-citrullinated vimentin antibodies in patients with juvenile idiopathic arthritis 
To determine the prevalence and significance of anti-citrullinated vimentin and anti-citrullinated type II collagen antibodies and elucidate their role in the disease process of juvenile idiopathic arthritis (JIA).
Sera were obtained from 95 patients with various subtypes of JIA, 19 systemic lupus erythematosus (SLE) patients, and 10 healthy children. Antibodies were measured in the sera against citrullinated and native type II collagen and vimentin (vim1-16 and vim 59-74) by enzyme-linked immunosorbent assay. Samples were compared to anti-cyclic citrullinated peptide (anti-CCP) antibody and rheumatoid factor (RF) isotypes, and our previously measured anti-citrullinated fibrinogen and α-enolase antibodies on the same patient population, in addition to erythrocyte sedimentation rate and C-reactive protein. The relationship between the anti-citrullinated antibody profile and disease activity and joint damage were also investigated.
Twenty-three JIA patients (24%) demonstrated reactivity to anti-citrullinated type II collagen. Ten JIA patients (10.5%) demonstrated reactivity to anti-citrullinated vimentin 1–16 antibodies and 7 (7.4%) to anti-citrullinated vimentin 59–74 antibodies. One IgM RF-positive polyarticular patient was positive for all 5 of the citrullinated autoantibodies tested. Thirty-seven different subsets of patients were identified based on their anti-citrullinated autoantibody and RF isotype profile. No significant associations were noted with anti-citrullinated type II collagen and anti-citrullinated vimentin antibodies with joint damage or disease activity. Anti-citrullinated vimentin 59–74 antibodies demonstrated the highest overall specificity at 89.7%, with anti-citrullinated vimentin 1–16 and anti-citrullinated type II collagen antibodies at 86.2%.
This study demonstrates that antibodies to multiple citrullinated epitopes are present in the sera of patients with various subtypes of JIA. It also demonstrates the frequent occurrence of anti-citrullinated type II collagen and anti-citrullinated fibrinogen antibodies. The presence of autoantibodies to citrullinated antigens in JIA patients is highly diverse.
PMCID: PMC3765710  PMID: 23987731
Juvenile idiopathic arthritis; Anti-cyclic citrullinated peptide antibodies; Type II collagen; Vimentin
15.  Autoinflammatory gene polymorphisms and susceptibility to UK juvenile idiopathic arthritis 
To investigate the autoinflammatory hereditary periodic fever syndrome genes MVK and TNFRSF1A, and the NLRP1 and IL1 genes, for association with juvenile idiopathic arthritis (JIA).
For MVK, TNFRSF1A and NLRP1 pair-wise tagging SNPs across each gene were selected and for IL1A SNPs from a prior meta-analysis were included. 1054 UK Caucasian JIA patients were genotyped by Sequenom iPlex MassARRAY and allele and genotype frequencies compared with 5380 unrelated healthy UK Caucasian controls.
Four SNPs were significantly associated with UK JIA: rs2071374 within intron 4 of IL1A (ptrend=0.006), rs2228576 3’ of TNFRSF1A (ptrend=0.009) and 2 SNPs, rs11836136 and rs7957619, within MVK (ptrend=0.006, ptrend=0.005 respectively). In all cases the association appeared to be driven by the systemic-onset JIA (SoJIA) subtype. Genotype data for the two MVK SNPs was available in a validation cohort of 814 JIA (oligoarticular and RF negative polyarticular) cases and 3058 controls from the US. Replication was not confirmed, however, further suggesting that this association is specific to SoJIA.
These findings extend the observations of the relevance of studying monogenic loci as candidates for complex diseases. We provide novel evidence of association of MVK and TNFRSF1A with UK JIA, specifically driven by association with SoJIA and further confirm that the IL1A SNP association with SoJIA is subtype specific. Replication is required in independent cohorts.
PMCID: PMC3621775  PMID: 23547563
Autoinflammatory genes; Juvenile idiopathic arthritis; MVK; TNFRSF1A; IL1A
16.  Physician assessment of disease activity in JIA subtypes. Analysis of data extracted from electronic medical records 
Although electronic medical records (EMRs) have facilitated care for children with juvenile idiopathic arthritis (JIA), analyses of treatment outcomes have required paper based or manually re-entered data. We have started EMR discrete data entry for JIA patient visits, including joint examination and global assessment, by physician and patient. In this preliminary study, we extracted data from the EMR to Xenobase™ (TransMed Systems, Inc., Cupertino, CA), an application permitting cohort analyses of the relationship between global assessment to joint examination and subtype.
During clinic visits, data were entered into discrete fields in ambulatory visit forms in the EMR (EpicCare™, Epic Systems, Verona, WI). Data were extracted using Clarity Reports, then de-identified and uploaded for analyses to Xenobase™. Parameters included joint examination, ILAR diagnostic classification, physician global assessment, patient global assessment, and patient pain score. Data for a single visit for each of 160 patients over a 2 month period, beginning March, 2010, were analyzed.
In systemic JIA patients, strong correlations for physician global assessment were found with pain score, joint count and patient assessment. In contrast, physician assessment for patients with persistent oligoarticular and rheumatoid factor negative patients showed strong correlation with joint counts, but only moderate correlation with pain scores and patient global assessment. Conversely, for enthesitis patients, physician assessment correlated strongly with pain scores, and moderately with joint count and patient global assessment. Rheumatoid factor positive patients, the smallest group studied, showed moderate correlation for all three measures. Patient global assessment for systemic patients showed strong correlations with pain scores and joint count, similar to data for physician assessment. For polyarticular and enthesitis patients, correlation of patient global assessment with pain scores was strong. Moderate correlations were found between patient global assessment and joint count in oligoarticular and polyarticular patients.
Data extraction from the EMR is feasible and useful to evaluate JIA patients for indicators of treatment responsiveness. In this pilot study, we found correlates for physician global assessment of arthritis differed, according to disease subtype. Further data extraction and analyses will determine if these findings can be confirmed, and will assess other outcome measures, compare longitudinal responses to treatment, and export extracted data to multi-center databases.
PMCID: PMC3089777  PMID: 21492466
17.  Tocilizumab: The evidence for its place in the treatment of juvenile idiopathic arthritis 
Core evidence  2010;4:181-189.
Juvenile idiopathic arthritis (JIA) is one of the most common chronic diseases with childhood onset. It comprises different subtypes of which the systemic onset subtype is often resistant to treatment. With the advent of biological treatment with tumor necrosis factor-α (TNFα)-inhibitors, the clinical outcome of JIA has improved considerably, but only for subtypes other than systemic JIA. Substantial evidence shows that the proinflammatory cytokine interleukin-6 (IL-6) plays a pivotal role in systemic JIA. The blockage of IL-6 action by tocilizumab, a humanized anti-IL-6-receptor monoclonal antibody, could therefore be an effective treatment of systemic JIA.
The purpose of this article was to review the clinical trials of tocilizumab and to discuss its place in the treatment of JIA with the focus on the systemic onset of disease.
Evidence review:
Two phase II studies and one phase III clinical trial of tocilizumab demonstrating the clinical efficacy and safety in systemic onset JIA have been published. Within those studies, sustained and high response rates of clinical improvement have been achieved with American College of Rheumatology Pediatric criteria (ACRPed) 30, 50, and 70 observed in 98%, 94%, and 90% of patients, respectively, after 48 weeks. One study regarding the clinical efficacy of tocilizumab for the treatment of oligo- and polyarticular JIA has been presented only as a conference abstract.
Place in therapy:
The very promising results seen so far in patients with severe systemic JIA and acceptable tolerability gives tocilizumab a central role in the future therapy in controlling this disease. No other biological therapy has achieved similar high response rates when treating with tocilizumab 8 mg/kg every two weeks to patients with systemic onset JIA, but direct comparison of the efficacy of different biological agents are not yet available.
PMCID: PMC2899792  PMID: 20694074
tocilizumab; anti-IL-6-receptor antibody; biologics; systemic; juvenile idiopathic arthritis
18.  Serum S100A12 and Temporomandibular Joint Magnetic Resonance Imaging in Juvenile Idiopathic Arthritis Egyptian Patients: Acase Control Study 
This study aimed to measure serum levels of the proinflammatory protein S100A12, investigate clinical as well as contrast enhanced magnetic resonance imaging findings of temporomandibular joint inflammation among juvenile idiopathic arthritis patients and to find out the correlation between each of them, moreover with different disease parameters as temporomandibular joint inflammation may occur without clinical manifestations; it is in need for thorough evaluation and S100A12 may be a future anti-inflammatory treatment in JIA. Twenty patients with Juvenile Idiopathic Arthritis (JIA) and 10 healthy control subjects underwent measurement of S100A12 serum concentrations by sandwich ELISA. Temporomandibular Joints (TMJs); clinical and post contrast Magnetic Resonance Imaging (MRI) examinations were performed. MRI findings were scored. Results showed that TMJ arthritis was detected in 80% of JIA patients using MRI. Serum S100A12 levels were significantly increased in patients compared to controls. Serum concentrations of S100A12 and total MRI scores were significantly higher in JIA patients with active disease compared to those without activity. Systemic and polyarticular JIA patients showed significant increase in S100A12 levels and total MRI scores compared to those with oligoarticular JIA. The MRI TMJ abnormalities revealed significant association with clinical signs of TMJ inflammation but not with symptoms. A significant correlation was found between serum S100A12 concentrations and MRI score as well as between each of them and different clinical, laboratory disease parameters. Serum S100A12 levels showed significant positive correlation with synovial enhancement score. To conclude TMJ arthritis could be detected in most cases of JIA patients using contrast enhanced MRI. Increased S100A12 levels may point to synovial inflammation. Clinical signs of TMJ arthritis may be used as filter for MRI examination. Further studies on larger scale of JIA patients are needed for monitoring TMJ inflammation and S100A12 may be a potential target of future anti-inflammatory therapy.
PMCID: PMC2883742  PMID: 20437698
Juvenile idiopathic arthritis; S100A12; contrast enhanced magnetic resonance imaging; temporomandibular joint; synovial inflammation
19.  Elevated IgG autoantibody production in oligoarticular juvenile idiopathic arthritis may predict a refractory course 
Although oligoarticular juvenile idiopathic arthritis (oJIA) is considered to carry the best prognosis among the JIA subtypes, many children evolve to a chronic course. A few studies have identified clinical risk factors for disease extension, and recent studies have evaluated synovial fluid markers. However, the only biological marker from the serum studied to date is the anti-nuclear antibody (ANA), regarding which there is mixed data regarding prognosis. No studies have evaluated whether additional autoantibodies may affect the articular prognosis of oJIA.
Microarrays containing candidate autoantigens were printed on slides, which were used to profile 36 children with oJIA and 18 controls. Unsupervised clustering analysis was used to identify distinct subgroups of JIA patients. Response to therapy after a mean interval of 4.9 months was evaluated.
Cluster analysis revealed two subgroups of oJIA patients, with identical clustering observed when children with onset over age six were excluded. Cluster 1 had higher levels of multiple autoantibodies compared to both cluster 2 as well as controls, including antibodies against several extracellular matrix (ECM) and nuclear antigens. Although the two patient clusters were similar with respect to clinical features and treatment decisions, children in cluster 1 were less likely to have attained remission by the follow-up visit.
Antibodies against ECM and possibly other antigens may identify a sub-group of children with oJIA who will require more aggressive therapy to attain control of the arthritis.
PMCID: PMC3171611  PMID: 21813070
oligoarticular; juvenile idiopathic arthritis; antibodies
20.  Variants in TNFAIP3, STAT4 and c12orf30 loci associated with multiple auto-immune diseases are also associated with Juvenile Idiopathic Arthritis 
Arthritis and rheumatism  2009;60(7):2124-2130.
Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA, to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors.
Cases were 445 children with JIA, and controls were 643 healthy adults. Eight single nucleotide polymorphisms (SNPs) in 7 loci [TNFAIP3 (rs10499194 and rs6920220), RSBN1 (rs6679677), C12ORF30 (rs17696736), TRAF1 (rs3761847), IL2RA (rs2104286), PTPN2 (rs2542151), and STAT4 (rs7574865)] were genotyped by the TaqMan assay. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated.
The strongest associations were observed for TNFAIP3 variants rs10499194 (OR: 0.74 (0.61-0.91); p <0.004), and TNFAIP3 rs6920220 (OR: 1.3 (1.05-1.61); p <0.02). We also observed associations between JIA and STAT4 (OR: 1.24 (1.02-1.51); p <0.03) and C12ORF30 (OR: 1.2 (1.01-1.43); p <0.04) variants. The PTPN2 variant rs2542151 deviated from Hardy-Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1, and RSBN1 were not associated with JIA. After stratification by JIA subtype, TNFAIP3 and C12ORF30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA.
We have demonstrated associations between JIA and variants in TNFAIP3, STAT4 and C12ORF30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus. Our results suggest that clinically distinct autoimmune phenotypes share common genetic susceptibility factors.
PMCID: PMC3104295  PMID: 19565500
JRA; genetics; autoimmune; association; juvenile idiopathic arthritis; rheumatoid arthritis
21.  Salivary Antioxidants and Metalloproteinases in Juvenile Idiopathic Arthritis 
Molecular Medicine  2009;16(3-4):122-128.
Juvenile idiopathic arthritis (JIA) is the most common autoimmune inflammatory disease in children; joint inflammation is the hallmark of the disease. Thirty-five children with JIA were studied, of whom 26 had active disease and 14 were receiving anti-TNF therapy (5 with Infliximab, 9 with Etanercept). Sixteen healthy controls also were studied. Saliva samples were obtained for analysis of anti-oxidant status, metalloproteinases (MMPs) and sialochemistry. The total antioxidant status was significantly higher in the saliva of all JIA patients, whether treated (P = 0.014) or not treated (P = 0.038) with anti-TNF agents. The increase in antioxidant status (TAS) in the saliva of the active patients was nearly two times higher than that of non-active patients (P = 0.01). MMP levels were significantly lower in JIA patients than in controls. MMP-9, MMP-3 and MMP-2 were lower in JIA patients without anti-TNF treatment by 36.7% (P = 0.01), 30.0% (P = 0.0001) and 10.7% (P = 0.0001), respectively. A greater reduction in MMP levels was observed in the group of patients treated with anti-TNF drugs: MMP-9, MMP-3 and MMP-2 were lower than in controls by 51.1% (P = 0.0001), 61.5% (P = 0.0001) and 55.4% (P = 0.0001), respectively. Children with JIA exhibited a significantly higher salivary antioxidant activity and significantly lower MMP levels. Anti-TNF treatment was associated with a further decrease in MMP levels in the saliva of JIA patients while an active state of JIA was associated with a further increase in the salivary antioxidant activity. Anti-TNF treatment may modulate the degradation process during the course of arthritis by inhibition of the activity of MMP.
PMCID: PMC2802555  PMID: 20062821
22.  Serum Amyloid A Circulating Levels and Disease Activity in Patients with Juvenile Idiopathic Arthritis 
Yonsei Medical Journal  2012;53(5):1045-1048.
The aim of our study was to evaluate the association between circulating levels of serum amyloid A protein (SAA) and disease activity in patients with juvenile idiopathic arthritis (JIA). Our study group included 41 JIA patients (9 male, 32 female), classified according to the International League of Associations for Rheumatology (ILAR) criteria (5); 16 had polyarticular onset disease and 25 had oligoarticular onset disease. Among 25 patients with oligoarticular disease, three had extended oligoarthritis. Serum amyloid A (SAA), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured in both patients and 26 healthy controls. SAA levels were higher in JIA patients versus healthy controls (p<0.001). Significant positive correlations were found between SAA and the presence of active joints (rho=0.363, p<0.05), the number of active joints (rho=0.418, p<0.05), ESR (R=0.702, p<0.05) and CRP (R=0.827, p<0.05). No significant correlations between ESR and the presence of active joints (rho=0.221, p=0.225) or between ESR and the number of active joints (rho=0.118, p=0.520) were demonstrated in JIA patients. No significant correlations were obtained between CRP and the presence of active joints (rho=0.034, p=0.855) or between CRP and the number of active joints (rho=0.033, p=0.859). We discovered a significant increase in SAA levels in JIA patients, compared to controls, and a strong positive correlation between SAA level and JIA disease activity. We also discerned SAA to be a more sensitive laboratory marker than ESR and CRP for evaluating the presence and number of active joints. We suggest that SAA can be used as an additional indicator of disease activity in JIA.
PMCID: PMC3423833  PMID: 22869491
Serum amyloid A; juvenile idiopathic arthritis; inflammatory markers; disease activity
23.  Association of the IL-10 Gene Family Locus on Chromosome 1 with Juvenile Idiopathic Arthritis (JIA) 
PLoS ONE  2012;7(10):e47673.
The cytokine IL-10 and its family members have been implicated in autoimmune diseases and we have previously reported that genetic variants in IL-10 were associated with a rare group of diseases called juvenile idiopathic arthritis (JIA). The aim of this study was to fine map genetic variants within the IL-10 cytokine family cluster on chromosome 1 using linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (tSNPs) approach with imputation and conditional analysis to test for disease associations.
Methodology/Principal Findings
Fifty-three tSNPs were tested for association between Caucasian paediatric cohorts [219 systemic JIA (sJIA), 187 persistent oligoarticular JIA (pOJIA), and 139 extended OJIA (eOJIA) patients], and controls (Wellcome Trust control cohort, WTCCC2). Significant association with sJIA was detected at rs1400986 in the promoter of IL-20 (odds ratio 1.53; 95% CI 1.21–1.93; p = 0.0004), but in no other subtypes. Imputation analysis identified additional associated SNPs for pOJIA at IL-20 and IL-24, including a rare, functional, missense variant at IL-24 with a p = 0.0002. Penalised logistic regression analysis with HyperLasso and conditional analysis identified several further associations with JIA subtypes. In particular, haplotype analysis refined the sJIA association, with a joint effect at rs1400986 and rs4129024 in intron 1 of MAPKAPK2 (p = 3.2E−5). For pOJIA, a 3-SNP haplotype including rs1878672 in intron 3 of IL-10 showed evidence for association (p = 0.0018). In eOJIA, rs10863962 (3′UTR of FCAMR) and rs12409577 (intron of IL-19) haplotype showed some evidence of association (p = 0.0003).
This study supports previous association of IL-20 with sJIA. Haplotype analyses provided stronger association signals than single point analyses, while a penalised logistic regression approach also suggested multiple independent association signals. Replication studies are required to confirm or refute these findings. The results indicate that combined effects with unknown/rare variants remain to be characterised in JIA, and represent a possible example of synthetic association in this region.
PMCID: PMC3475696  PMID: 23094074
24.  Differential expression patterns of recombination‐activating genes in individual mature B cells in juvenile idiopathic arthritis 
Annals of the Rheumatic Diseases  2006;65(10):1351-1356.
Re‐expression of the recombination‐activating genes (RAG) in peripheral B cells may be relevant in the development of autoreactive antibodies in autoimmune diseases. The presence of antinuclear antibodies (ANA) as a hallmark of oligoarticular juvenile idiopathic arthritis (o‐JIA, early‐onset type) indicates a breakdown in immunological tolerance.
To examine the expression of RAG genes in peripheral blood mature B lymphocytes in patients with o‐JIA.
777 memory B cells from peripheral blood, CD19+ CD27+ CD5+ or CD19+ CD27+ CD5−, isolated from three ANA+ children with o‐JIA and three healthy age‐matched children, were examined for the expression of RAG1 and RAG2 mRNA. mRNA transcripts of activation‐induced cytidine deaminase and immunoglobulin G were searched to further determine their developmental stage.
mRNA was present for any of the two RAG genes in the B cells of children with JIA and controls. However, the predominance of RAG1 or RAG2 was different. A significantly decreased frequency of RAG2‐expressing memory B cells in both CD5+ and CD5− populations was noted in children with JIA (p<0.001), whereas the number of RAG1‐expressing B cells was slightly increased. The coordinate expression of both the RAG genes was a rare event, similar in the CD5+ populations (1% in controls, 2% in children with JIA), but different among the CD5− compartments (5% v 0%; p<0.01).
These results argue for a reduced coordinate RAG expression in the peripheral CD5− memory B cells of patients with o‐JIA. Thus, it was hypothesised that impaired receptor revision contributes to autoimmune pathogenesis in JIA.
PMCID: PMC1798333  PMID: 16504994
25.  T Cell Expression of Granulocyte–Macrophage Colony-Stimulating Factor in Juvenile Arthritis Is Contingent Upon Th17 Plasticity 
Granulocyte–macrophage colony stimulating factor (GM-CSF) is a potent inflammatory mediator that is responsible for recruitment and activation of innate immune cells. Recent data from murine studies have identified Th17 cells as a key source of GM-CSF and suggest that T cell–derived GM-CSF is instrumental in the induction of autoimmune disease. The present study was undertaken to analyze the expression of T cell–derived GM-CSF in the joints of patients with juvenile idiopathic arthritis (JIA) and to investigate the differentiation of Th17 cells and how this relates to GM-CSF+ T helper cells.
Synovial fluid (SF) and peripheral blood (PB) samples from 24 patients with JIA were analyzed, by flow cytometry and reverse transcription–polymerase chain reaction, for expression of GM-CSF and the Th17 marker CD161. A cytokine capture assay was used to purify Th17 cells and test the plasticity of cytokine production in response to interleukin-12 (IL-12) and IL-23.
The frequency of GM-CSF–producing T helper cells was significantly enriched in SF mononuclear cells compared to PB mononuclear cells from the patients with JIA (24.1% of CD4+ T cells versus 2.9%) and closely correlated with the erythrocyte sedimentation rate (r2 = 0.91, P < 0.001). Synovial GM-CSF+ T cells were predominantly CD161+ and coexpressed interferon-γ (IFNγ), but not IL-17. Culture of Th17 cells in the presence of IL-12 led to rapid up-regulation of GM-CSF and IFNγ, recapitulating the phenotype of GM-CSF–expressing cells within the joint.
Our results identify a novel outcome of Th17 plasticity in humans that may account for the enrichment of GM-CSF–expressing T cells in the joints of patients with JIA. The association of GM-CSF expression with systemic inflammation highlights the potential role of Th17-related cytokines in the pathology of JIA.
PMCID: PMC4190686  PMID: 24692225

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