JIA Cases Research Articles

Revealing novel genomic insights and therapeutic targets for juvenile idiopathic arthritis through omics.

The genetic architecture of JIA remains only partially comprehended. There is a clear imperative for continued endeavours to uncover insights into the underlying causes of JIA. This study encompassed a comprehensive spectrum of endeavours, including conducting a JIA genome-wide association study (GWAS) meta-analysis that incorporated data from 4550 JIA cases and 18 446 controls. We employed in silico and genome-editing approaches to prioritizing target genes. To investigate pleiotropic effects, we conducted phenome-wide association studies. Cell-type enrichment analyses were performed by integrating bulk and single-cell sequencing data. Finally, we delved into potential druggable targets for JIA. Fourteen genome-wide significant non-HLA loci were identified, including four novel loci, each exhibiting pleiotropic associations with other autoimmune diseases or musculoskeletal traits. We uncovered strong genetic correlation between JIA and BMD traits at 52 genomic regions, including three GWAS loci for JIA. Candidate genes with immune functions were captured by in silico analyses at each novel locus, with additional findings identified through our experimental approach. Cell-type enrichment analysis revealed 21 specific immune cell types crucial for the affected organs in JIA, indicating their potential contribution to the disease. Finally, 24 known or candidate druggable target genes were prioritized. Our identification of four novel JIA-associated genes, CD247, RHOH, COLEC10 and IRF8, broadens the novel potential drug repositioning opportunities. We established a new genetic link between COLEC10, TNFRSF11B and JIA/BMD. Additionally, the identification of RHOH underscores its role in positive thymocyte selection, thereby illuminating a critical facet of JIA's underlying biological mechanisms.

Profiling the peripheral immune response to ex vivo TNF stimulation in untreated juvenile idiopathic arthritis using single cell RNA sequencing

BackgroundJuvenile Idiopathic Arthritis (JIA) is an autoimmune disease with a heterogenous clinical presentation and unpredictable response to available therapies. This personalized transcriptomics study sought proof-of-concept for single-cell RNA sequencing to characterize patient-specific immune profiles.MethodsWhole blood samples from six untreated children, newly diagnosed with JIA, and two healthy controls were cultured for 24 h with or without ex vivo TNF stimulation and subjected to scRNAseq to examine cellular populations and transcript expression in PBMCs. A novel analytical pipeline, scPool, was developed wherein cells are first pooled into pseudocells prior to expression analysis, facilitating variance partitioning of the effects of TNF stimulus, JIA disease status, and individual donor.ResultsSeventeen robust immune cell-types were identified, the abundance of which was significantly affected by TNF stimulus, which resulted in notable elevation of memory CD8 + T-cells and NK56 cells, but down-regulation of naïve B-cell proportions. Memory CD8 + and CD4 + T-cells were also both reduced in the JIA cases relative to two controls. Significant differential expression responses to TNF stimulus were also characterized, with monocytes showing more transcriptional shifts than T-lymphocyte subsets, while the B-cell response was more limited. We also show that donor variability exceeds the small degree of possible intrinsic differentiation between JIA and control profiles. An incidental finding of interest was association of HLA-DQA2 and HLA-DRB5 expression with JIA status.ConclusionsThese results support the development of personalized immune-profiling combined with ex-vivo immune stimulation for evaluation of patient-specific modes of immune cell activity in autoimmune rheumatic disease.

Juvenile Idiopathic Arthritis and Its HLA Association: A Study from Bangladesh

Background: HLA alleles may have association with overall JIA including specific sub-types. Determation of HLA DRB1, DPB1, DQA1, DQB1 and B27, may be helpful to diagnose JIA cases where diagnostic dilemma is present. The aim of the study was to find out the association of HLA alleles with JIA and its subtypes. Methods: This cross sectional study was conducted in the department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, from April 2020 to March 2021. A total of 50 cases and 25 controls attending pediatric rheumatology clinic and pediatric OPD were enrolled in the study. Data were collected by a pre-designed questionnaire containing socio-demographic, clinical and laboratory parameters. HLA DR-B1, DQ-A1, DQ-B1 and B27 typing were done for the cases and controls from blood samples by polymerase chain reaction sequence specific primer (PCR-SSP) method. Data were analyzed by SPSS version 26. Frequency, percentage, chi square test and Fisher exact tests were done for statistical analysis. Results: HLA DR-B1_10 had significant positive association whereas HLA DR-B1_03 and B1_16 had negative association with overall JIA cases. Poly-articular JIA, oligo-articular JIA and ERA had association with HLA DRB1_01, B1_08 and B1_12 respectively. HLA DQA1-01 and A1_02 had positive association. However, DQ-A1_06 was negatively associated with JIA cases. Oligo JIA was positively associated with HLA DQ-A1_01, whereas poly JIA and ERA had association with A1_02. Though, HLA DQ_B1 had no association with overall JIA cases, analysis showed association of poly JIA with DQ-B1_04. Frequency of HLA DQ-B1_02 and 03 were higher among ERA cases, though not significant, but they had strong association with HLA B27. Conclusion: HLA associations were present with overall JIA and each sub-groups had different patterns of HLA associations including some protective roles.

P61 SARS-CoV-2 vaccine safety in adolescents with inflammatory rheumatic and musculoskeletal diseases and adults with juvenile idiopathic arthritis: data from the EULAR COVAX physician-reported registry

Introduction/BackgroundThere is a lack of data on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccination safety in children and young people (CYP) with rheumatic and musculoskeletal diseases (RMDs) as they were excluded from initial vaccine trials. Vaccination guidance is based on data from adults with or CYP without RMDs.Description/MethodOur objective was to describe the safety of SARS-COV-2 vaccination in adolescents with inflammatory RMDs and adults with JIA. We described patient characteristics, flares, and adverse events in adolescent cases under 18 with inflammatory RMDs and adult cases aged 18 or above with JIA submitted to the European Alliance of Associations for Rheumatology (EULAR) COVAX registry.Discussion/ResultsThirty-six adolescent cases were reported from 4 countries, mostly female (58%) with JIA (42%: 28% non-systemic JIA, 14% systemic JIA) and a median age of 15 [IQR: 14.5, 17]. Most were in remission (64%) or had minimal (22%) disease activity at the time of vaccination. Over half of the adolescent group (56%) reported early reactogenic-like AEs. One mild polyarthralgia flare and one serious AE of special interest (malaise) were reported. No CYP reported SARS-CoV-2 infection post-vaccination. No cases of paediatric inflammatory multi-system syndrome or myocarditis adverse events were reported.Seventy-four adult JIA cases were reported from 11 countries; 73% were female with a median age of 26 [IQR: 23, 31]. Eight-five percent had ns-JIA and 15% had s-JIA. Almost two thirds (62%) reported early reactogenic-like AEs and two flares were reported (mild polyarthralgia and moderate uveitis). No serious AEs of special interest were reported among adults with JIA. Three 20-30 year old females were diagnosed with SARS-CoV-2 post-vaccination; all fully recovered.Key learning points/ConclusionIn this observational registry dataset, SARS-CoV-2 vaccines appeared safe in adolescents with RMDs and adults with JIA, with a low frequency of disease flares, serious AEs, and SARS-CoV-2 re-infection seen in both populations.

P162 Socio-economic status in patients with juvenile idiopathic arthritis in the United Kingdom

Abstract Background/Aims Juvenile idiopathic arthritis (JIA) is a chronic inflammatory condition affecting children and young people (CYP) with onset <16 years, and may be associated with long-term joint damage and disability if treatment is delayed. CYP with JIA from low socio-economic status (SES) have been shown to have poorer performance in school activities and self-reported functional assessments compared to those from higher SES groups, however SES association with incidence of JIA has rarely been explored. Therefore, this study aimed to investigate the association between socio-economic status and incident JIA in England. Methods CYP <16 years with a first JIA diagnostic code were identified in the Clinical Practice Research Datalink (CPRD) between the years 2000 and 2018, using a pre-defined codelist and were validated through linkage to Hospital Episode Statistics. Age- and gender-matched controls were identified at a ratio of 4:1. SES was defined using quintiles of indices of multiple deprivation (IMD). Descriptive analyses compared baseline characteristics (age, gender, age of first JIA code, IMD, region) in cases and controls. Logistic regression investigated the association between IMD quintiles in JIA cases compared to controls, adjusting for baseline characteristics, and linear regression analysed the association between age at first JIA code and IMD quintile. Results There were 1649 cases and 4748 controls included in this study. Most cases (1048, 64%) were female with median (interquartile range (IQR)) age at first JIA code 8.49 (4.20-12.05) years. Amongst cases, males were older at first JIA code, median (IQR) 9.80 (6.09-12.68) years, compared to females 7.55 (3.45-11.70) years. In both cases and controls, the proportion of CYP was highest in the most deprived quintile (IMD 1), 375/1649 (22.7%) and 1108/4738 (23.4%) respectively, and proportions remained similar in the remaining quintiles. There was no association identified between IMD quintile and occurrence of JIA, the multivariable odds ratio (95% CI) comparing most and least deprived groups was 0.98 (0.83-1.17). However, amongst cases there was an association between older age at diagnosis and higher SES [ß(95%CI) 0.15 years (0.01-0.29)] such that CYP in the IMD 5 quintile (highest SES) were on average 8 months older at their first JIA code compared to CYP in IMD 1. Conclusion This study found CYP from higher socio-economic groups appeared to be diagnosed at an older age than those from the least deprived backgrounds. Factors such as later presentation to healthcare after disease onset, delays in referrals to specialist care, delays in diagnosis by specialist care or differences in population demographics across IMD quantiles may all contribute to the older age of diagnosis in high SES group. Further research is required to explore these factors. Disclosure Y. Tan: None. R. Costello: None. K. Hyrich: None. J. Humphreys: None.

O006. Clinical features of paediatric HIV arthropathy

Abstract Background Advanced HIV infection is associated with an inflammatory arthritis, however few reports have described this disorder in children. This study aimed to describe the clinical features of HIV arthropathy in a case series of children in South Africa and compare these with features of JIA. Methods Retrospective data were collected from HIV-infected children with HIV arthropathy enrolled in a Paediatric Rheumatology clinic in Cape Town, South Africa. Data from a recently described, published cohort of children with JIA enrolled in the same clinic were included for comparison. Ethical approval was granted by the Human Research Ethics Committee of the University of Cape Town, with a waiver for consent. Results Eleven cases of HIV arthropathy were identified. Cases predominantly affected boys (8/11), and the median age of onset was 10.3 years (IQR 6.9–11.6). Most cases presented in the setting of advanced immunosuppression, with a median absolute CD4+ count of 389 cells/uL (IQR 322–449) and median CD4+ proportion of 19.5% (IQR 14.8–25.0) at presentation. The clinical presentation was variable, with both oligoarthritis (6/11) and polyarthritis (5/11) being prevalent. All cases exhibited large joint involvement, which was usually asymmetrical. In addition, four children had asymmetrical small joint involvement. Associated features included enthesitis (4/11) and dactylitis (1/11). The most consistent laboratory feature was elevated acute phase reactants, and typical ultrasonographic findings were joint effusions and synovial hypertrophy. JIA and HIV arthropathy presented at a similar age, with median age at HIV arthritis onset of 10.3 years (IQR 6.9–11.6) versus 9.25 years (IQR 4.5–12.3) at arthritis onset in the JIA subgroup. HIV arthropathy cases were predominantly male (M/F ratio 3.0), whereas JIA cases had an equal sex distribution (M/F ratio 0.9). Oligo-articular disease was more frequently described in children with HIV arthropathy (55%), compared to those with JIA (38%). Conclusion In this series, most cases of HIV arthropathy exhibited asymmetrical large joint oligoarthritis or polyarthritis, and presented in older boys with advanced immunosuppression. HIV arthropathy appears to present at a similar age to JIA, with a comparable pattern of joint involvement to oligo-articular and poly-articular JIA subtypes.

O01 Genetic risk factors associated with increased risk of uveitis in patients with juvenile idiopathic arthritis

Abstract Background/Aims Juvenile idiopathic arthritis (JIA) is a childhood-onset rheumatic disease, which is associated with increased risk of uveitis. Approximately 80% of childhood chronic anterior uveitis cases are JIA-associated (JIAU), where it is considered a serious complication with the potential to lead to permanent blindness. Studies have reported associations of increased risk of JIAU to genetic variation within human leukocyte antigen (HLA) genes, in particular amino acid positions of HLA-DRB1. Here we report the results of the largest fine-mapping study of HLA genes in JIAU to date. Methods Genotyping was performed using Illumina Infinium CoreExome and Infinium OnmiExpress arrays. Samples were excluded with a call rate <0.98, discrepancy between genetically inferred sex and database records, inferred relatedness (Identity-by-decent), or ancestral outlier based on principal component analysis (PCA). SNPs were excluded with a call rate <0.98 or a minor allele frequency (MAF) <0.01. HLA alleles, amino acids, and SNPs were imputed using SNP2HLA. Analysis was performed on markers with an information score >0.9 and MAF > 0.01 using logistic regression, or omnibus test for multi-allelic markers, including 3 PCs as covariates. Independent effects were identified using forward stepwise logistic regression by inclusion of previously identified variants as covariates. Results We analysed 7,425 markers across the HLA region in 450 JIAU cases and 2,024 JIA cases. We defined study-wide significance at a Bonferroni corrected threshold of 6.7x10-6. The most significant association was at amino acid position 13 of DRB1 (p-value = 3.0x10-30) where the presence of serine (OR 1.7, 95% CI 1.4-1.9) or glycine (OR 2.0, 95% CI 1.6-2.5) were associated with increased risk of uveitis. Conditioning on DRB1 position 13, found a further association to amino acid position 67 of DRB1 (p-value = 2.4x10-6, unconditioned p-value = 3.2x10-23). The presence of isoleucine (OR 1.5, 95% CI 1.2-1.9) and phenylalanine (OR 1.8 95%, CI 1.4-2.2) at position 67 were associated with increased risk. No further study-wide associations were found at DRB1. Conditioning on all HLA-DRB1 alleles identified an independent effect at amino acid position 69 in DPB1 (p-value = 5.3x10-7, unconditioned p-value = 1.1x10-10). The presence of glutamic acid was associated with increased risk (OR 1.7, 95% CI 1.4-2.0). Conclusion This is the largest genetic study of HLA regions in JIAU and further resolves the genetic risk factors in this key susceptibility region. The analysis in this study has independently validated the association signal at position 13 of HLA-DRB1 (highly correlated with position 11) that had been reported in a previous study. Conditional analysis of HLA-DRB1 revealed a novel secondary association signal at DRB1 to amino acid position 67. Conditional analysis on all DRB1 alleles confirmed association to position 69 of HLA-DPB1 where previous reports of this signal had been only modestly associated. Disclosure M. Tordoff: None. S.L. Smith: None. E. Lopez-Isac: None. A. Morris: None. S. Eyre: None. W. Thomson: None. J. Bowes: None.

P18 Investigating the role of rare genetic variants and susceptibility to juvenile idiopathic arthritis highlights the importance of monogenic disease genes

Abstract Background Juvenile idiopathic arthritis (JIA) is a rheumatic disease, onset before the age of sixteen. JIA is a common complex disease, with contributions from both genetic and environmental risk factors. However, given the young age of onset for JIA, it is possible that genetic risk factors influence susceptibility to a greater extent than environmental risk factors. While several susceptibility loci have been identified for JIA, they are mainly genetic variants that are common in the population. The role of rare genetic variants has not yet been fully explored in JIA. Therefore, the aims of this research were to use rare (<5%MAF) variant based analysis to further define the genetic architecture of JIA. Methods A total of 2,162 UK JIA cases were genotyped using the Illumina HumanCoreExome array and the Understanding Society’s UK household longitudinal study provided the genotype data for 9196 controls. Single variant analysis was used to calculate the association of variants to JIA susceptibility. Gene-based aggregation analysis, specifically the SKAT-O method, were used to calculate the association of whole gene regions to JIA cases. This gene-based aggregation method increases the statistical power of associations, which is valuable when attempting to identify rare variants. Study-wide significance for this research was calculated using a Bonferroni corrected threshold (P = 3.34x10-6). Results Several strongly associated candidate gene regions were identified using SKAT-O analysis. Firstly, the region mevalonate kinase (MVK) (P = 3.95x10-10) was found to be strongly associated. MVK has been reported in mevalonate kinase deficiency, a rare juvenile disease with a phenotype akin to systemic JIA. PYCR1 (P = 1.97x10-9) was an additional region of interest. Variants in this region have been reported in geroderma osteodysplasticum; a disease that results in dysplasia of the hips, hyperextensible joints and skeletal changes. The region WISP3 (P = 8.52x10-9) was also strongly associated. Variants from this region have previously been reported in progressive pseudorheumatoid dysplasia; a disease that can be clinically misdiagnosed with JIA due to similarities in phenotypes. Furthermore, LILRA2 (P = 2.89x10-7) presented as a strong candidate region, with the gene being upregulated in synovial tissue of rheumatoid arthritis patients. Conclusion This analysis has identified promising candidate genes that influence susceptibility to JIA and highlights two key points. Firstly, gene-burden tests of rare variants have the potential to identify novel susceptibility genes for juvenile-onset disease. While MVK and WISP3 have previously been reported to be associated with JIA, these associations were modest, and the current study provides compelling evidence to support their importance. Secondly, the results highlight the importance of investigating the contribution of monogenic genes in juvenile-onset common complex disease. Disclosures M.K. Tordoff None. T.A. Briggs None. S.L. Smith None. A. Yarwood None. W. Thomson None. J. Bowes None.

P20 The identification of novel genetic susceptibility loci for juvenile idiopathic arthritis by analysis across clinical subgroups

Abstract Background Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of childhood onset inflammatory joint diseases with strong evidence to support a genetic contribution to susceptibility. JIA is divided into seven clinical subgroups based on observed patterns of clinical symptoms using the International League of Associations for Rheumatology (ILAR) classification system. The genetic overlap between these groups is not completely understood and this lack of knowledge typically leads to the different ILAR groups being analysed as discrete entities potentially reducing the power of genetic association studies. The aim of this study was to conduct a large case-control association study on susceptibility to JIA to identify novel susceptibility loci and to investigate differences in these associations between the different ILAR groups for the purposes of maximising power. Methods JIA participants were genotyped on the Illumina Infinium CoreExome or OmniExpress arrays. UK population control genotype data was obtained from the Understanding Society Longitudinal Study. Quality control of data was performed conforming to conventional standards and imputation was performed using the Haplotype Reference Consortium panel on the Michigan Imputation Server. Association testing of all SNPs was performed with an additive model incorporating imputation uncertainty using SNPTEST. Testing for specificity and sharing across ILAR groups was performed using Bayesian multinomial regression in the Trinculo software package. Loci passing the suggestive significance threshold (5x10-6) were selected for meta-analysis with previously published JIA GWAS data assuming fixed effects and weighted by inverse-variance using the software package GWAMA. Results Following quality control the dataset consisted of > 7.4 million SNPs for 3305 JIA cases and 9196 controls. We found no strong evidence to support association of any SNP to a specific ILAR group with most of the SNPs showing evidence for sharing across multiple groups. Association testing in a combined dataset of all ILAR groups identified seven SNPs associated at genome-wide significance (5x10-8); six of these have previously been reported for JIA while one is a novel association. The novel association (rs497523, p-value = 7.12x10-9) maps to chromosome 16p11 and is located within intron one of the CCDC101 gene. Meta-analysis identified association to rs7647909 which is an intronic variant in the FOXP1 gene (p-value 2.0x10-9) and rs2614258 within the AHI1 gene (p-value 9.5x10-12). Conclusion We identified novel associations to SNPs in the CCDC101 and FOXP1 genes. In addition, we report a genome-wide significant association to AHI1, previously reported at suggestive significance levels. Fine mapping with the integration of genomic data will be required to identify the true causal gene at each of these loci. The results provide little evidence to support ILAR subgroup specificity for any of the associated variants and combined analysis of data across subgroups maximised power to identify novel associations. Disclosures J. Bowes None. M.C. Marion None. S. Smith None. A. Yarwood None. M. Sudman None. D. Tarasek None. C.D. Langefeld None. S.D. Thompson None. W. Thomson None.

P06 Genetics of juvenile idiopathic arthritis: the identification of a novel risk locus and clinical subgroup analysis

Poster presentation Tuesday 8 October Background Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of childhood onset inflammatory joint diseases with strong evidence to support a genetic contribution to susceptibility. JIA is divided into seven clinical subgroups based on observed patterns of clinical symptoms using the International League of Associations for Rheumatology (ILAR) classification system. The genetic overlap between these groups is not completely understood and this lack of knowledge typically leads to the different ILAR groups being analysed as discrete entities and reducing the overall power of genetic association studies. The aim of this study was to conduct a large case-control association study on susceptibility to JIA to identify novel susceptibility loci and to investigate differences in these associations between the different ILAR groups. Methods JIA participants were genotyped on the Illumina Infinium CoreExome or OmniExpress arrays at the University of Manchester. UK population control genotype data was obtained from the Understanding Society Longitudinal Study. Quality control of data was performed conforming to conventional standards based on call rate, cryptic relatedness and ancestry outliers. Imputation was performed using the Haplotype Reference Consortium panel on the Michigan Imputation Server followed by exclusion of SNPs with low imputation accuracy (r2 < 0.5) and low minor allele frequency (< 1%). Association testing of all SNPs was performed with an additive model incorporating imputation uncertainty using SNPTEST. A subset of SNPs independently associated with all JIA (p-value < 5x10-6) were tested to evaluate if they were specific to a particular ILAR group or shared across multiple ILAR groups using Bayesian multinomial regression and model selection methods implemented in the Trinculo software package. Results Following quality control, the dataset consisted of > 7.4 million SNPs for 3,305 JIA cases and 9,196 controls. Association testing in a combined dataset of all ILAR groups identified seven SNPs associated at genome-wide significance (5x10-8); six of these have previously been reported for JIA while one is a novel association. The novel association (rs497523, p-value = 7.12x10-9, OR 0.85, 95% CI 0.8:0.9) maps to chromosome 16p11 and is located within intron one of the CCDC101 gene. In a subset of 44 independently associated SNPs we found no strong evidence to support association of any SNP to a specific ILAR group with the majority of the SNPs showing evidence for sharing across multiple groups. Conclusion In a large case control association study for susceptibility to JIA, we identified a novel association to a SNP in the intron of CCDC101. This gene is involved in transcriptional regulation through histone acetyltransferase. The results support a general model of sharing of loci across multiple ILAR groups. The combined analysis of data across subgroups, informed by model sharing, will maximise power to identify novel associations. Conflicts of Interest The authors declare no conflicts of interest.

Pattern and Frequency of Anti-nuclear Antibody Positivity in Paediatric Rheumatic Diseases

Background: Anti-nuclear antibodies (ANAs) are specific antibodies directed against a variety of nuclear antigens detected in the serum of patients with many rheumatic and non-rheumatic diseases.These antibodies are not only involved in the pathogenesis, but also constitute the basis for diagnosis and treatment of paediatric rheumatic diseases. The objective of the study was to identify the patterns and frequency of ANA positivity in Paediatric Rheumatic Diseases.
 Methodology: It was a retrospective study. Fourteen hundred and sixty eight records of paediaric rheumatology patients were analyzed. Statistical analysis were done to observe the frequency and association of different patterns of ANA in Juvenile idiopathic arthritis and systemic lupus erythematosus patients.
 Results: Among the 1468 patients of PRDs, frequency of JIA cases was the highest (65 %) followed by SLE, Scleroderma, juvenile dermatomyositis, and others. Among the 261 PRD patients ANA positivity was 65%. ANA positivity was 100%, 92%, 40% and 31.5% in Mixed connective tissue disease, SLE, JDM and Scleroderma patients respectively. Homogenous staining pattern was found in 59% and speckled pattern in 22.9%. There was significant association between ANA positivity and uveitis in oligoarticular JIA patients. Significant association was also found between homogeneous patterns of ANA and renal involvement in SLE patients.
 Conclusion: ANA positivity was highest in MCTD cases followed by SLE cases. Majority of SLE cases had homogeneous pattern of ANA.Staining patterns of ANA had significant association with the clinical manifestations in SLE and JIA cases.
 Bangladesh J Child Health 2019; VOL 43 (1) :21-26

DNA methylation at IL32 in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common autoimmune rheumatic disease of childhood. We recently showed that DNA methylation at the gene encoding the pro-inflammatory cytokine interleukin-32 (IL32) is reduced in JIA CD4+ T cells. To extend this finding, we measured IL32 methylation in CD4+ T-cells from an additional sample of JIA cases and age- and sex-matched controls, and found a reduction in methylation associated with JIA consistent with the prior data (combined case-control dataset: 25.0% vs 37.7%, p = 0.0045). Further, JIA was associated with reduced IL32 methylation in CD8+ T cells (15.2% vs 25.5%, p = 0.034), suggesting disease-associated changes to a T cell precursor. Additionally, we measured regional SNPs, along with CD4+ T cell expression of total IL32, and the γ and β isoforms. Several SNPs were associated with methylation. Two SNPs were also associated with JIA, and we found evidence of interaction such that methylation was only associated with JIA in minor allele carriers (e.g. rs10431961 pinteraction = 0.011). Methylation at one measured CpG was inversely correlated with total IL32 expression (Spearman r = −0.73, p = 0.0009), but this was not a JIA-associated CpG. Overall, our data further confirms that reduced IL32 methylation is associated with JIA, and that SNPs play an interactive role.

THU0170 Efficacy and Safety of Infliximab in Juvenile Idiopathic Arthritis and Juvenile Ankylosing Spondylitis

ObjectivesThis study will provide evidence-based medical evidence in the application of infliximab for pediatric rheumatology.MethodsThe 45 cases of this study were allocated to treatment group and control group. The treatment...

SP0130 How to treat juvenile idiopathic arthritis and other paediatric rheumatic diseases

Diagnosis and management of pediatric rheumatic diseases has changed markedly in the past decade. Paediatric rheumatic diseases differ significant from their adult counterpart. For instance the ILAR classification of Juvenile...

AB0703 Temporomandibular joint involvement in children with juvenile idiopathic arthritis

BackgroundJuvenile idiopathic arthritis (JIA) is the most common autoimmune heterogenic diseases group of unknown etiology with7 subtypes. There are markedly high prevalence of temporomandibular joint (TMJ) involvement- 17 - 87%...

Independent replication analysis of genetic loci with previous evidence of association with juvenile idiopathic arthritis

BackgroundOver the last five years, there have been numerous reports of association of juvenile idiopathic arthritis with single nucleotide polymorphisms (SNPs) at various loci outside the major histocompatibility complex (MHC) region. However, the majority of these association findings have been generated using a limited number of international cohorts, and thus there is benefit in further independent replication. To address this, we examined a total of 56 SNPs in 42 non-MHC gene regions previously reported to be associated with JIA, in the ChiLdhood Arthritis Risk factor Identification sTudY (CLARITY), a new Australian collection of cases and healthy child controls.FindingsGenotyping was performed on a total of 324 JIA cases (mean age 9.7 years, 67.3% female) and 568 controls (mean age 7.8 years, 40.7% female). We demonstrated clear evidence for replication of association of JIA with SNPs in or around c12orf30, c3orf1, PTPN22, STAT4, and TRAF1-C5, confirming the involvement of these loci in disease risk. Further, we generated evidence supportive of replication of association of JIA with loci containing AFF3, CD226, MBL2, PSTPIP1, and RANTES (CCL5). These results were robust to sensitivity analyses for ethnicity.ConclusionWe have provided valuable independent data as to the underlying genetic architecture of this understudied pediatric autoimmune disease, further confirming five loci outside the MHC, and supporting a role for a further five loci in determining disease risk.

Clinical Aspects of Juvenile Idiopathic Arthritis: Extended Experience from Bangladesh

Objectives: To assess the different clinical aspects of JIA patients as well as the disease activity status during follow-up period. This study also compared its findings with the previous baseline study done in our country. Methodology: A prospective observational study carried out in the department of pediatrics, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh during the study period of January 2004 to December 2012. A total of 415 patients according to ILAR criteria were enrolled in the study. Patients who completed a 2 year follow-up period were assessed for disease activity status according to Wallace criteria. Data was collected in a predesigned questionnaire. Results: Among the 415 cases, M: F ratio was approximately 2:1. Age range of the patients was 14 months to 16 years. Highest number of patients were present in the age group 11-16 years (49%) followed by 6-10 years. The duration of illness was more than 12 months in the majority. Polyarticular RF negetive patients were most frequent (33%), followed by persistent oligo-arthritis (28 %). Among the patients who completed at least 2 years of follow-up, 68% achieved remission, of them 51% maintained remission and 16.3% had relapse. Conclusion: Late diagnosis with long duration of disease was still common. Clinical profile of this study was almost similar to our previous study but differed from western JIA cases mainly in term of sex, subtypes and duration of illness. Majority of the patients went into remission. Wrong diagnosis was gradually decreasing and it seems that awareness about JIA is gradually increasing among the medical professionals in our country.

Subtype specific genetic associations for juvenile idiopathic arthritis: ERAP1 with the enthesitis related arthritis subtype and IL23R with juvenile psoriatic arthritis.

IntroductionJuvenile idiopathic arthritis (JIA) is an umbrella term for all chronic childhood arthropathies and can be divided into seven subtypes. It includes the enthesitis related arthritis (ERA) subtype which displays symptoms similar to ankylosing spondylitis (AS) and juvenile-onset psoriatic arthritis which has similarities to psoriatic arthritis (PsA) and psoriasis (Ps). We, therefore, hypothesized that two well-established susceptibility loci for AS and Ps, ERAP1 and IL23R, could also confer susceptibility to these JIA subtypes.MethodsSingle nucleotide polymorphisms (SNPs) in ERAP1 (rs30187) and IL23R (rs11209026) were genotyped in JIA cases (n = 1,054) and healthy controls (n = 5,200). Genotype frequencies were compared between all JIA cases and controls using the Cochrane-Armitage trend test implemented in PLINK. Stratified analysis by ILAR subtype was performed.ResultsThe ERA subtype showed strong association with ERAP1 SNP (P trend = 0.005). The IL23R SNP showed significant association in the PsA subtype (P trend = 0.04). The SNPs were not associated with JIA overall or with any other subtype.ConclusionsWe present evidence for subtype specific association of the ERAP1 gene with ERA JIA and the IL23R gene with juvenile-onset PsA. The findings will require validation in independent JIA datasets. These results suggest distinct pathogenic pathways in these subtypes.

Molecular Epidemiology of Diarrheagenic Escherichia Coli Isolated from Young Children with Diarrhea

the cases. Immunoluminometric and immunonepholometric methods were used for PCT (Procalcitonin) and CRP (C reactive protein) detections, respectively. Eighteen (39.13%) among the 46 primary JIA and EC groups had infections in different regions of their body whereas only two indivudials from the HC showed infections (p < 0.05). M. pneumoniae infections were found much higher in the groups with primary and EC when compared with the HC. Furthermore, C. jejuni IgG seropositivity was detected significantly higher in JIA group than that of the HC. While, in JIA cases with regard to bacterial and viral factors, PCT levels were not found significantly higher (0.02 ng/ml), the mean value for CRP levels in patients with JIA were found 7.62mg/l. A statistically significant difference was detected between the primary JIA and EC groups and HC group for both PCT and CRP levels (p < 0.05). In conclusion, the results of our study which is the first in this field and including such a large group organisms in the same serial for JIA pathogenesis gave the idea that some microorganisms could trigger or worsen the clinical appearence in subject level. In particular, M. pneumoniae ve C. jejuni draw attention especially in primary JIA and EC. We suppose that it is possible to prevent antigenic stimulation and as a result to obtain recovery in clinical presentation with early detection of microorganisms which were thought to be primary or interfering factors causing infections in the aetiopathogenesis of JIA and also adding specific antimicrobial therapy to the standard regimen of JIA therapy to eradicate these microorganisms. The relationship between JIA aetiopathogenesis and microorganisms has to be clarified for the above reasons. To reach this goal, we suppose that conducting larger, serial, especially molecular based serial studies which include samples from synovial regions which are very difficult sampling will be helpfull.

Current perspectives of autologous stem cell transplantation for severe juvenile idiopathic arthritis

The majority of children with Juvenile Idiopathic Arthritis can nowadays be treated adequately. However despite the use of combinations of antirheumatic drugs, corticosteroids and the newer so called biologicals (blocking the TNF, Interleukin 1 or Interleukin 6 pathways) a proportion of children with arthritis remain resistant also to these therapies and suffer from a very severe, debilitating and potentially fatal disease. For such children autologous stem cell transplantation (ASCT) is successfully performed since 1997. Here we describe the long term outcome of the initial cohort of children with resistant Juvenile Idiopathic arthritis, treated with ASCT. The initial cohort of children was treated with a conditioning regimen containing Cyclophosphamide, anti thymocyte globulins and low dose Total Body irradiation. Overall favourable responses were seen, with a drug free remission rate of 50–55 %. In the more recent years late relapses were noted with lower percentages for drug free long term outcome. Special emphasis is given on 2 cases showing very late relapses, occurring after 7 and 9 years. The observed relapses are often less severe compared to the situation before SCT and can be treated successfully with conventional drugs in the majority of cases. More recently, ASCT was performed in 4 JIA children with a fludarabin containing regimen in stead of low dose TBI. With a 4 to 5 year follow up, these 4 patients are all in drug free full remission. Allogeneic transplant with an HLA matched family donor was reported in 2 JIA cases. Follow up of 1 and 3 year is sofar show clinical disease remission and tapering of medition. In conclusion, given the favourable long term outcome, SCT remains a valuable treatment option for children with drug resistant JIA.