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Objective: Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)-negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes., Methods: Three cohorts comprising 2,751 patients with oligoarticular or RF-negative polyarticular JIA were genotyped using the Affymetrix Genome-Wide SNP Array 6.0 or the Illumina HumanCoreExome-12+ Array. Overall, 15,886 local and out-of-study controls, typed on these platforms or the Illumina HumanOmni2.5, were used for association analyses. High-quality single-nucleotide polymorphisms (SNPs) were used for imputation to 1000 Genomes prior to SNP association analysis., Results: Meta-analysis showed evidence of association (P < 1 × 10 -6 ) at 9 regions: PRR9&#95;LOR (P = 5.12 × 10 -8 ), ILDR1&#95;CD86 (P = 6.73 × 10 -8 ), WDFY4 (P = 1.79 × 10 -7 ), PTH1R (P = 1.87 × 10 -7 ), RNF215 (P = 3.09 × 10 -7 ), AHI1&#95;LINC00271 (P = 3.48 × 10 -7 ), JAK1 (P = 4.18 × 10 -7 ), LINC00951 (P = 5.80 × 10 -7 ), and HBP1 (P = 7.29 × 10 -7 ). Of these, PRR9&#95;LOR, ILDR1&#95;CD86, RNF215, LINC00951, and HBP1 were shown, for the first time, to be autoimmune disease susceptibility loci. Furthermore, associated SNPs included cis expression quantitative trait loci for WDFY4, CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22., Conclusion: This study provides evidence of both unique JIA risk loci and risk loci overlapping between JIA and other autoimmune diseases. These newly associated SNPs are shown to influence gene expression, and their bounding regions tie into molecular pathways of immunologic relevance. Thus, they likely represent regions that contribute to the pathology of oligoarticular JIA and RF-negative polyarticular JIA., (© 2017, American College of Rheumatology.)

We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor-negative polyarticular JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 × 10(-8)) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 × 10(-6)). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 × 10(-6)) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.

Objective: In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. The present study was undertaken to identify novel JIA-predisposing loci using genome-wide approaches., Methods: The discovery cohort consisted of Caucasian JIA cases (n = 814) and local controls (n = 658) genotyped on the Affymetrix Genome-Wide SNP 6.0 Array, along with 2,400 out-of-study controls. In a replication study, we genotyped 10 single-nucleotide polymorphisms (SNPs) in 1,744 cases and 7,010 controls from the US and Europe., Results: Analysis within the discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011) (odds ratio [OR] 1.37, P = 1.88 × 10(-6) ) and at 10q21 near JMJD1C (rs647989 [OR 1.59, P = 6.1 × 10(-8) ], rs12411988 [OR 1.57, P = 1.16 × 10(-7) ], and rs10995450 [OR 1.31, P = 6.74 × 10(-5) ]). Meta-analysis provided further evidence of association for these 4 SNPs (P = 3.6 × 10(-7) for rs4688011, P = 4.33 × 10(-5) for rs6479891, P = 2.71 × 10(-5) for rs12411988, and P = 5.39 × 10(-5) for rs10995450). Gene expression data on 68 JIA cases and 23 local controls showed cis expression quantitative trait locus associations for C3orf1 SNP rs4688011 (P = 0.024 or P = 0.034, depending on the probe set) and JMJD1C SNPs rs6479891 and rs12411988 (P = 0.01 or P = 0.04, depending on the probe set and P = 0.008, respectively). Using a variance component liability model, it was estimated that common SNP variation accounts for approximately one-third of JIA susceptibility., Conclusion: Genetic association results and correlated gene expression findings provide evidence of JIA association at 3q13 and suggest novel genes as plausible candidates in disease pathology., (Copyright © 2012 by the American College of Rheumatology.)

Objective: To test for associations between non-major histocompatibility complex susceptibility loci previously reported in autoimmune diseases and juvenile idiopathic arthritis (JIA)., Methods: Published autoimmune disease genome-wide association studies were reviewed, and 519 single-nucleotide polymorphisms (SNPs) were selected for association testing. The initial cohort included 809 JIA cases and 3,535 controls of non-Hispanic, European ancestry. Of the SNPs, 257 were successfully genotyped, while 168 were imputed with quality. Based on findings in the initial cohort, replication was sought for 21 SNPs in a second cohort of 1,015 JIA cases and 1,569 controls collected in the US and Germany. For the initial cohort, tests for association were adjusted for potential confounding effects of population structure by including principal components derived from a genome-wide association study as covariates in logistic regression models. Odds ratios (ORs) and 95% confidence intervals were calculated., Results: Testing for association of previously reported autoimmune disease genetic associations in the initial cohort suggested associations with JIA in 13 distinct loci. Of these, 7 were validated in the replication cohort. Meta-analysis results for the replicating loci included PTPN22 (rs6679677 [OR 1.58, P = 1.98 × 10(-12) ], rs2476601 [OR 1.64, P = 1.90 × 10(-13) ], and rs2488457 [OR 1.32, P = 6.74 × 10(-8) ]), PTPN2 (rs1893217 [OR = 1.33, P = 1.60 × 10(-9) ] and rs7234029 [OR 1.35, P = 1.86 × 10(-10) ]), ADAD1-IL2-IL21 (rs17388568 [OR 1.24, P = 1.13 × 10(-6) ] and rs13143866 [OR 0.83, P = 1.95 × 10(-4) ]), STAT4 (rs3821236 [OR = 1.27, P = 2.36 × 10(-6) ] and rs7574865 [OR = 1.31, P = 2.21 × 10(-6) ]), C12orf30 (rs17696736 [OR = 1.19, P = 2.59 × 10(-5) ]), COG6 (rs7993214 [OR = 0.76, P = 1.10 × 10(-5) ]), and ANGPT1 (rs1010824 [OR = 0.79, P = 2.91 × 10(-4) ]). These polymorphisms have been reported in diseases such as rheumatoid arthritis, type 1 diabetes mellitus, Crohn's disease, and multiple sclerosis., Conclusion: General susceptibility loci for autoimmunity are shared across diseases, including JIA, suggesting the potential for common therapeutic targets and mechanisms., (Copyright © 2010 by the American College of Rheumatology.)

Objective: To compare the incidence of liver toxicity and clinical response between 2 initial dosing regimens of methotrexate (MTX) for treatment of juvenile idiopathic arthritis (JIA)., Methods: Clinical and laboratory data were abstracted from the medical records of 220 children newly prescribed MTX from the same geographic region. One cohort received initial doses of MTX > 0.5 mg/kg/week ("high-dose") and one cohort received initial doses of MTX

Objectives: Intra-articular corticosteroids injection (IAC) is a mainstay for the treatment of children with chronic arthritis; nonetheless its efficacy showed variability among published studies and it is still not possible to predict the outcome in a single patient. Our objective was to study the profile of biomarkers in the synovial fluid (SF) obtained at the time of injection and establish if such profile predicts duration of effect., Methods: SF obtained from patients who underwent knee arthrocentesis and injection was procured and stored for cytokine analysis. Records of those patients who had at least 6 months of follow-up from the injection were reviewed. Time to flare was recorded. Levels of IL-6, IL-1alpha, TNF-alpha, IL-2sR, MMP-3, IL-10 and TGF-Beta1 were measured by ELISA. For primary analysis each patient was utilized once. For secondary analysis each injected knee was considered a single event., Results: 60 samples from 33 patients were obtained. In the primary analysis we found a correlation between MMP-3 synovial fluid levels and outcome at 6 months (p=0,02; p=0,03 for different quartiles). In the secondary analysis we found that IL-6 and IL-10 levels predicted outcome at six and at 12 months (IL-6: p=0.01; p=0.02 respectively) (IL-10: p=0.017; p=0.01 respectively), with higher levels of IL-6 predicting shorter time to relapse and higher levels of IL-10 longer duration of corticosteroids effect., Conclusions: Our study identified MMP-3 and possibly IL-6 and IL-10 as candidates for the development of a set of biomarkers to predict response to IAC among children with chronic arthritis at the time of injection.

This is the first report of a CARD15 mutation-positive patient with Blau syndrome who exhibited interstitial lung disease, a feature historically considered absent from Blau syndrome, while typical of the adult form of sarcoidosis. This case illustrates the continued evolution of the phenotype of a disease initially conceived as a familial inflammatory granulomatous disease limited to the triad of synovitis, dermatitis, and uveitis.