Juvenile idiopathic arthritis and HLA Class I and Class II interactions and age‐at‐onset effects

Objective

The aim of this study was to quantitate risk and to examine heterogeneity for HLA at high resolution in patients with the most common subtypes of juvenile idiopathic arthritis (JIA), IgM rheumatoid factor–negative polyarticular JIA and oligoarticular JIA. Use of 4‐digit comprehensive HLA typing enabled great precision, and a large cohort allowed for consideration of both age at disease onset and disease subtype.

Methods

Polymerase chain reaction–based high‐resolution HLA typing for class I and class II loci was accomplished for 820 patients with JIA and 273 control subjects. Specific HLA epitopes, potential interactions of alleles at specific loci and between loci (accounting for linkage disequilibrium and haplotypic associations), and an assessment of the current International League of Associations for Rheumatology classification criteria were considered.

Results

An HLA–DRB1/DQB1 effect was shown to be exclusively attributable to DRB1 and was similar between patients with oligoarticular JIA and a younger subgroup of patients with polyarticular JIA. Furthermore, patients with polyarticular JIA showed age‐specific related effects, with disease susceptibility in the group older than age 6 years limited to an effect of the HLA–DRB1*08 haplotype, which is markedly different from the additional susceptibility haplotypes, HLA–DRB1*1103/1104, found in the group with oligoarticular JIA and the group of younger patients with polyarticular JIA. Also in contrast to findings for oligoarticular JIA, patients with polyarticular arthritis had no evidence of an HLA class I effect. Markers associated with a reduced risk of disease included DRB1*1501, DRB1*0401, and DRB1*0701. DRB1*1501 was shown to reduce risk across the whole cohort, whereas DRB1*0401 and DRB1*0701 were protective for selected JIA subtypes. Surprisingly, the disease predisposition mediated by DPB1*0201 in individuals without any disease‐predisposing DRB1 alleles was great enough to overcome even the very strong protective effect observed for DRB1*1501.

Conclusion

Inherited HLA factors in JIA show similarities overall as well as differences between JIA subtypes.

     

Association of SLC11A1 (NRAMP1) with persistent oligoarticular and polyarticular rheumatoid factor-negative juvenile idiopathic arthritis in Finnish patients: haplotype analysis in Finnish families

OBJECTIVE: The SLC11A1 (formerly called NRAMP1) gene is important in natural resistance to a variety of intracellular infections mediated by macrophages and has been proposed as a candidate gene for autoimmune disease susceptibility. The aim of this study was to examine susceptibility in Finnish patients with persistent oligoarticular and polyarticular rheumatoid factor (RF)-negative juvenile idiopathic arthritis (JIA) due to the presence of the SLC11A1 locus on chromosome 2. METHODS: A total of 234 Finnish JIA nuclear families and 639 elderly Finnish controls without a history of JIA were evaluated for association with JIA at 3 intragenic single-nucleotide polymorphisms: an intragenic insertion/deletion, a promoter microsatellite (NRAMP1), and a 3' microsatellite (D2S1471). RESULTS: Analysis of marker haplotypes demonstrated a strong association of Finnish JIA with 6-marker, 4-marker, and 2-marker haplotypes. Most impressively, 1 of the 6-marker haplotypes showed an odds ratio (OR) of 4.0 (95% confidence interval [95% CI] 2.6-6.2) in all JIA patients, 3.5 (95% CI 1.9-6.5) in those with persistent oligoarticular JIA, and 4.1 (95% CI 2.5-6.7) in those with polyarticular RF-negative JIA. Stratification of the haplotype data suggested that susceptibility to JIA in the haplotype spanning the SLC11A1 locus is independent (P < 0.01) of an association with a DRB1 JIA shared epitope (DRB1*JIASE) that includes well-characterized strong susceptibility to DRB1*08 and *11 alleles. This SLC11A1 haplotype also had an additive effect with DRB1*JIASE in those with polyarticular, but not those with persistent oligoarticular, disease (P = 0.06, OR 2.9 [95% CI 0.9-9.2] versus P = 0.5, OR 1.6 [95% CI 0.4-6.0]). CONCLUSION: Taken together, these data provide support for the existence of a locus at or near SLC11A1 that is a strong susceptibility factor for JIA in Finnish patients.     

Wnt‐1–inducible signaling pathway protein 3 and susceptibility to juvenile idiopathic arthritis

Objective

To determine whether Wnt‐1–inducible signaling pathway protein 3 (WISP3) polymorphisms are associated with susceptibility to juvenile idiopathic arthritis (JIA).

Methods

The exons and the intron/exon boundaries of the WISP3 gene were mutation‐screened by denaturing high‐performance liquid chromatography in 86 patients with polyarticular‐course JIA (≥5 joints affected) and 15 controls. Seven single‐nucleotide polymorphisms (SNPs) were genotyped, using allelic discrimination, in a case–control study. Initially, 159 patients with polyarticular‐course JIA and 263 controls were studied, followed by study of a replication cohort of 181 patients with polyarticular‐course JIA and 355 controls. Available parents of patients with polyarticular‐course JIA were also genotyped. Finally, other JIA subgroups were studied (initial cohort, n = 218; replication cohort, n = 213). Single‐point and haplotype analysis was carried out.

Results

Positive association with SNP WISP3*G84A was observed and replicated in 2 cohorts of patients with polyarticular‐course JIA. Specifically, homozygosity of the mutant allele (WISP3*84AA) conferred a 2‐fold increased risk of disease susceptibility (for the initial cohort, odds ratio [OR] 2.1, 95% confidence interval [95% CI] 1.1–4.2, P = 0.03; for the replication cohort, OR 2.0, 95% CI 1.0–4.3, P = 0.05). Strong linkage disequilibrium was observed between SNPs; however, no haplotypic effect of an order of magnitude greater than the single‐point WISP3*G84A association was observed. Using the transmission disequilibrium test, a trend toward overtransmission of the WISP3*84A allele was observed in patients with polyarticular‐course JIA. No association of any WISP3 polymorphism was observed in the other JIA subgroups.

Conclusion

Association and replication of a polymorphism within the first intron of the WISP3 gene have been shown in patients with polyarticular‐course JIA. The functional significance of the WISP3*G84A SNP is being determined.

     

Positive association of SLC26A2 gene polymorphisms with susceptibility to systemic‐onset juvenile idiopathic arthritis

Objective

To investigate SLC26A2, the gene that causes diastrophic dysplasia, in juvenile idiopathic arthritis (JIA).

Methods

Nine polymorphisms across the SLC26A2 gene locus were investigated using MassArray genotyping in 826 UK Caucasian JIA cases and 617 ethnically matched healthy controls.

Results

Significant associations between multiple single‐nucleotide polymorphisms (SNPs) across SLC26A2 and systemic‐onset JIA were found. In each case, homozygosity for the minor allele conferred the increased risk of disease susceptibility: rs1541915 (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.4–3.7, P = 0.0003), rs245056 (OR 2.8, 95% CI 1.7–4.6, P = 0.00002), rs245055 (OR 2.5, 95% CI 1.2–5.0, P = 0.004), rs245051 (OR 2.3, 95% CI 1.4–3.7, P = 0.0005), rs245076 (OR 2.7, 95% CI 1.3–5.4, P = 0.0015), and rs8073 (OR 2.3, 95% CI 0.9–5.6, P = 0.04).

Conclusion

These findings show the value of using monogenic disease loci as candidates for investigation in JIA. We identified a subgroup‐specific association between SNPs within the SLC26A2 gene and systemic‐onset JIA. Our findings also highlight systemic‐onset JIA as being a distinctly different disease from that in the other JIA subgroups.

     

Proinflammatory responses to self HLA epitopes are triggered by molecular mimicry to Epstein‐Barr virus proteins in oligoarticular juvenile idiopathic arthritis

Objective

To evaluate whether abnormal T cell recognition may be generated by exposure to exogenous antigens presenting sequence homology with epitopes contained in self HLA alleles, and if such recognition may be part of the mechanisms that fuel inflammation in autoimmune diseases associated with certain HLA alleles.

Methods

Cytotoxic responses of peripheral blood mononuclear cells to 9‐mer peptides derived from HLA molecules (DRB1*1101, DRB1*0801, or DPB1*0201) associated with oligoarticular juvenile idiopathic arthritis (JIA) or homologous peptides derived from Epstein‐Barr virus (EBV) proteins (Bolf1 or Balf2) were analyzed in patients with oligoarticular JIA and in healthy controls matched for HLA–DRB1*1101, DRB1*0801, or DPB1*0201. Production of proinflammatory cytokines in culture supernatants was determined by enzyme‐linked immunosorbent assay.

Results

T cell cytotoxic responses and production of proinflammatory cytokines in response to stimulation with self HLA–derived peptides were found only in patients with oligoarticular JIA, and not in controls. Patients with oligoarticular JIA, but none of the healthy controls, had EBV–self HLA cross‐reactive T cells.

Conclusion

Our data suggest a disease‐ and allele‐specific mechanism of autoimmunity in oligoarticular JIA. This mechanism may be part of the pathogenesis of the disease, and could be the basis of one of the likely multiple candidates for antigen‐specific immunotherapy approaches in the future.

     

Biologic similarities based on age at onset in oligoarticular and polyarticular subtypes of juvenile idiopathic arthritis

Objective

To explore biologic correlates to age at onset in patients with juvenile idiopathic arthritis (JIA) using peripheral blood mononuclear cell (PBMC) gene expression analysis.

Methods

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.

Results

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.

Conclusion

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.

     

Variants in TNFAIP3, STAT4, and C12orf30 loci associated with multiple autoimmune diseases are also associated with juvenile idiopathic arthritis

Objective

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.

Methods

Cases were 445 children with JIA, and controls were 643 healthy adults. Using the TaqMan assay, subjects were genotyped for 8 single‐nucleotide polymorphisms in 7 loci including rs10499194 and rs6920220 in the TNFAIP3 locus, rs6679677 in the RSBN1 locus, rs17696736 in the C12orf30 locus, rs3761847 in the TRAF1/C5 locus, rs2104286 in the IL2RA locus, rs7574865 in the STAT4 locus, and rs2542151 in the PTPN2 locus. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results

The strongest associations with JIA risk or protection were observed for TNFAIP3 variants rs10499194 (OR 0.74 [95% CI 0.61–0.91], P < 0.004) and rs6920220 (OR 1.30 [95% CI 1.05–1.61], P = 0.015). We also observed associations between JIA and both STAT4 (OR 1.24 [95% CI 1.02–1.51], P = 0.029) and C12orf30 (OR 1.20 [95% CI 1.01–1.43], P = 0.041) variants. The PTPN2 variant rs2542151 deviated from Hardy‐Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1/C5, and RSBN1 were not associated with JIA. After stratification by JIA subtype, the TNFAIP3 and C12orf30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA.

Conclusion

We have demonstrated associations between JIA and variants in the 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.

     

The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat‐shock protein 60 capable of producing the regulatory cytokine interleukin‐10

Objective

To test the hypothesis that T cell reactivity to self heat‐shock protein 60 (Hsp60) in patients with remitting juvenile idiopathic arthritis (JIA) is part of an antiinflammatory, regulatory mechanism.

Methods

Using peripheral blood–derived mononuclear cells (PBMCs) and synovial fluid–derived mononuclear cells (SFMCs) obtained from patients with JIA, we analyzed the expression of CD30 and the induction of regulatory cytokines in response to human and mycobacterial Hsp60.

Results

In oligoarticular JIA patients, in vitro activation of PBMCs and SFMCs with Hsp60 induced a high expression of CD30 on CD4+, activated (HLA–DR–positive), memory (CD45RO+) T cells. The expression of CD30 induced by human Hsp60 was much higher than that induced by mycobacterial Hsp60. In oligoarticular JIA patients with active disease, the expression of CD30 in response to human Hsp60 was paralleled by a high interleukin‐10 (IL‐10):interferon‐γ (IFNγ) ratio. In addition, restimulated human Hsp60–specific T cell lines from oligoarticular JIA patients showed a high production of IL‐10 and a low production of IFNγ. In contrast, PBMCs and SFMCs from polyarticular JIA patients responded to human Hsp60 with virtually no expression of CD30 and a low IL‐10:IFNγ ratio.

Conclusion

The results show that T cells responding to human Hsp60 in oligoarticular JIA patients express CD30, and during active phases of the disease, these T cells have a cytokine profile with a high IL‐10:IFNγ ratio. These findings suggest that in oligoarticular JIA patients, human Hsp60–specific CD4+ cells have a regulatory function and contribute to disease remission.

     

Synovial fluid proteins differentiate between the subtypes of juvenile idiopathic arthritis

Objective

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory diseases, and no clinically useful prognostic markers to predict disease outcome in children with JIA are currently available. Synovial fluid likely reflects the proteins present in the inflamed synovium. The purpose of this study was to delineate the synovial fluid proteome and determine whether protein expression differs in the different subtypes of JIA.

Methods

Synovial fluid samples obtained from children with oligoarticular JIA, polyarticular JIA, or systemic JIA were compared. Two‐dimensional gel electrophoresis for protein separation and matrix‐assisted laser desorption ionization−time‐of‐flight mass spectrometry and quadripole time‐of‐flight mass spectrometry for protein identification were used for this study. Synovial fluid cells were analyzed by polymerase chain reaction (PCR) for the presence of haptoglobin messenger RNA (mRNA).

Results

The synovial fluid proteome of the samples was delineated. The majority of proteins showed overexpression in JIA synovial fluid as compared with noninflammatory control samples. There were 24 statistically significantly differentially expressed spots (>2‐fold change; P < 0.05) between the subtypes of JIA. PCR analysis revealed haptoglobin mRNA, suggesting that haptoglobin is locally produced in an inflamed joint in JIA.

Conclusion

Despite the similar histologic appearance of inflamed joints in patients with different subtypes of JIA, there are differences in protein expression according to the subtype 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.

     

Increased susceptibility to rheumatoid arthritis in Koreans heterozygous for HLA–DRB1*0405 and *0901

Objective

To investigate the association of susceptibility and protective HLA–DRB1 alleles with rheumatoid arthritis (RA) and its clinical markers in an Asian population.

Methods

All RA patients (n = 574) and control subjects (n = 392) were Korean. HLA–DRB1 typing and further subtyping of all alleles was performed by polymerase chain reaction, sequence‐specific oligonucleotide probe hybridization, and direct DNA sequencing analysis. We used a relative predispositional effects (RPEs) method and a false discovery rate correction method for multiple comparisons.

Results

The DRB1*0405 and *0901 alleles showed the most significant associations with RA (P = 7.83 × 10⁻²⁴, odds ratio [OR] 4.40 [95% confidence interval (95% CI) 3.24–5.99], and P = 3.76 × 10⁻⁹, OR 2.47 [95% CI 1.82–3.36], respectively). The RPEs test showed that the DRB1*0401 and *0410 alleles conferred susceptibility and that the DRB1*0701, *0802, *1301, *1302, *1403, and *1405 alleles showed significant protective effects. Susceptibility and protective alleles both showed a pattern consistent with additive genetic effects, and each influenced RA independently of the other. The compound heterozygote DRB1*0405/*0901 was associated with the highest risk of RA (corrected P = 1.81 × 10⁻¹¹, OR 58.2 [95% CI 7.95–425.70]). The mean age at disease onset was ∼4 years earlier or was 3 years earlier, respectively, in patients with at least 1 copy of the DRB1*0405 or the DRB1*0901 allele. Radiographic changes (stages II–IV) were more frequent in patients with at least 1 copy of DRB1*0405 (P = 0.032, 92.6% versus 84.3%, OR 2.33 [95% CI 1.24–4.39]).

Conclusion

The DRB1*0405/*0901 heterozygote has the strongest association with RA, suggesting that this heterozygote enhances the susceptibility to RA in Koreans.

     

Increased frequency of DRB1*11:01 in anti–hydroxymethylglutaryl‐coenzyme A reductase–associated autoimmune myopathy

Objective

To investigate the association of anti–hydroxymethylglutaryl‐coenzyme A reductase (anti‐HMGCR) myopathy with HLA class I and II antigens.

Methods

HLA antigens were determined in 1) 20 white and 8 African American anti‐HMGCR patients, 2) 487 white and 167 African American controls, and 3) 51 white subjects with mild self‐limited statin intolerance.

Results

White anti‐HMGCR patients had a higher frequency of the combination HLA–DR11, DQA5, and DQB7 than controls or statin‐intolerant subjects (70% versus 17%; odds ratio [OR] 11.7 [95% confidence interval (95% CI) 4.0–35.3], P = 4.1 × 10^?7 and 70% versus 21%; OR 8.3 [95% CI 2.2–33.9], P = 5.4 × 10^?4, respectively). This combination was not increased in African American anti‐HMGCR subjects compared to controls (13% versus 3%; OR 4.6 [95% CI 0.2–53.3], P = 0.2). However, DR11 was increased in African American anti‐HMGCR patients compared to controls (88% versus 21%; OR 26.4 [95% CI 3.1–590.3], P = 0.0002). High‐resolution mapping showed that 95% with DR11 had DRB1*11:01. DQA1 and DQB6 were less frequent in white anti‐HMGCR–positive patients compared to controls (25% versus 65%; OR 0.2 [95% CI 0.1–0.5], P = 5.5 × 10^?4 and 0% versus 45%; OR 0.0 [95% CI 0.0–0.3], P = 2.1 × 10^?5, respectively). DRB11 was not associated with particular disease features.

Conclusion

DRB1*11:01 is associated with an increased risk of anti‐HMGCR myopathy in whites and African Americans. These findings suggest a mechanistic link between statin exposure, increased HMGCR expression, and the possible presentation of HMGCR‐derived peptide(s) by DRB1*11:01.

     

Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets

Objective

To determine whether peripheral blood mononuclear cells (PBMCs) from children with recent‐onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures.

Methods

Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second‐line medications, such as methotrexate or biologic agents. RNA was extracted from isolated mononuclear cells, fluorescence labeled, and hybridized to commercial gene expression microarrays (Affymetrix HG‐U133 Plus 2.0). Data were analyzed using analysis of variance at a 5% false discovery rate threshold after robust multichip analysis preprocessing and distance‐weighted discrimination normalization.

Results

Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA patients and healthy controls. Hierarchical clustering of these probe sets distinguished 3 subgroups within the polyarticular JIA group. Prototypical patients within each subgroup were identified and used to define subgroup‐specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor β–inducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets.

Conclusion

Gene expression signatures in PBMCs from patients with recent‐onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease.

     

Evidence for linkage of HLA loci in juvenile idiopathic oligoarthritis: Independent effects of HLA–A and HLA–DRB1

Objective

Although multiple associations between HLA loci and juvenile oligoarthritis have previously been documented, evidence for linkage of HLA loci in oligoarthritis in UK Caucasians with juvenile idiopathic arthritis (JIA) has not been described. The aim of this study was to investigate linkage of HLA–A, B, and DRB1 in UK Caucasian JIA patients with oligoarthritis.

Methods

One hundred forty‐two families comprising affected offspring and their parents (45 with one parent available and 97 with both parents available) were typed for HLA–A, B, and DRB1 by polymerase chain reaction–sequence‐specific oligonucleotide probe. Single‐point and multipoint analyses were performed using various modifications of the extended transmission disequilibrium test. Linkage disequilibrium (LD) analysis was performed using the EH‐Plus system.

Results

Linkage to HLA–A and HLA–DRB1 was seen in oligoarthritis and in the International League of Associations for Rheumatology–defined subgroups of persistent oligoarthritis and extended oligoarthritis. Linkage to HLA–A, B, and DRB1 was also observed in female patients with oligoarthritis. Linkage of the HLA loci seemed to be attributable to maternal preferential transmission of alleles. Furthermore, LD patterns between the HLA–A, B, and DRB1 loci were investigated. HLA–A and HLA–DRB1 were confirmed as independent susceptibility loci for oligoarthritis.

Conclusion

This is the first study to establish linkage of HLA–A and HLA–DRB1 in oligoarthritis and to show that the 2 loci contribute independently to disease. Further studies are being performed to determine whether it is these loci or other genes in LD with them that are responsible for susceptibility to oligoarthritis in UK Caucasian patients with JIA.

     

Association of the IL2RA/CD25 gene with juvenile idiopathic arthritis

Objective

IL2RA/CD25, the gene for interleukin‐2 receptor α, is emerging as a general susceptibility gene for autoimmune diseases because of its role in the development and function of regulatory T cells and the association of single‐nucleotide polymorphisms (SNPs) within this gene with type 1 diabetes mellitus (DM), Graves' disease, rheumatoid arthritis (RA), and multiple sclerosis (MS). The aim of this study was to determine whether SNPs within the IL2RA/CD25 gene are associated with juvenile idiopathic arthritis (JIA).

Methods

Three SNPs within the IL2RA/CD25 gene, that previously showed evidence of an association with either RA, MS, or type 1 DM, were selected for genotyping in UK JIA cases (n = 654) and controls (n = 3,849). Data for 1 SNP (rs2104286) were also available from North American JIA cases (n = 747) and controls (n = 1,161). Association analyses were performed using Plink software. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results

SNP rs2104286 within the IL2RA/CD25 gene was significantly associated with UK JIA cases (OR for the allele 0.76 [95% CI 0.66–0.88], P for trend = 0.0002). A second SNP (rs41295061) also showed modest evidence for association with JIA (OR 0.80 [95% CI 0.63–1.0], P = 0.05). Association with rs2104286 was convincingly replicated in the North American JIA cohort (OR 0.84 [95% CI 0.65–0.99], P for trend = 0.05). Meta‐analysis of the 2 cohorts yielded highly significant evidence of association with JIA (OR 0.76 [95% CI 0.62–0.88], P = 4.9 × 10⁻⁵).

Conclusion

These results provide strong evidence that the IL2RA/CD25 gene represents a JIA susceptibility locus. Further investigation of the gene using both genetic and functional approaches is now required.

     

Higher frequency of allele 2 of the interleukin‐1 receptor antagonist gene in patients with juvenile idiopathic arthritis

Objective

An increased incidence of allele 2 of the interleukin‐1 receptor antagonist gene (IL1RN*2) in several inflammatory diseases has recently been reported. The aim of this study was to examine a variable number tandem repeat (VNTR) polymorphism of the IL1RN gene in patients with juvenile idiopathic arthritis (JIA).

Methods

Findings in 185 Czech patients with JIA were compared with those in 168 Czech controls, 50 JIA patients and 52 controls of Turkish origin, and 79 controls from central England. VNTR polymorphism analysis of IL1RN was performed by polymerase chain reaction using 2 flanking primers to amplify an 86‐bp tandem repeat region in intron 2.

Results

The frequency and carriage rate of IL1RN*2 were significantly increased in Czech JIA patients compared with the Czech controls (frequency 27.6% versus 15.8%; carriage rate 44.3% versus 26.2%). Increased frequency and carriage rate of IL1RN*2 were found in 23.3% and 40.0% of Turkish JIA patients and in 17.3% and 34.6% of ethnically matched controls. The high representation of IL1RN*2 in 52.3% of the 22 patients with extended oligoarthritis, 31.3% of the 56 patients with enthesitis‐related arthritis, and 42.9% of the 14 patients with other arthritis was particularly responsible for the increased frequency of IL1RN*2 in the Czech JIA patients. We found no association of IL1RN*2 with disease activity or severity parameters.

Conclusion

Inheritance of IL1RN*2 may contribute to genetic susceptibility in several forms of autoimmune diseases, including JIA. The IL1RN*2 allele may be useful as a prognostic indicator of the evolution of an extended oligoarticular course of JIA.

     

Association of the autoimmunity locus 4q27 with juvenile idiopathic arthritis

Objective

Juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis and an autoimmune etiology. In several autoimmune diseases, including rheumatoid arthritis (RA), an association with the 4q27 locus has been reported. We undertook this study to investigate the possible role of the 4q27 locus in JIA.

Methods

A case–control association study was conducted, with a total of 655 Caucasian JIA patients and 791 healthy controls divided into 2 independent sample sets. The rs6822844 marker in the 4q27 locus was genotyped.

Results

In the first and larger sample set, a 5% decrease in T allele frequency was observed in patients compared with controls (allelic odds ratio [OR] 0.72 [95% confidence interval 0.55–0.95], P = 0.019), and in the second set, a 3% decrease was observed (allelic OR 0.81 [95% confidence interval 0.61–1.09], P = 0.169). The combined data set generated an OR of 0.76 (95% confidence interval 0.62–0.93, P = 7.08 × 10⁻³). When the different JIA subtypes were analyzed individually, significant decreases were seen in the subtypes with a polyarticular course of disease (extended oligoarthritis [P = 0.019] and rheumatoid factor–negative polyarthritis [P = 0.038]).

Conclusion

Our findings suggest that the 4q27 locus, previously reported to be associated with RA, type 1 diabetes mellitus, celiac disease, and psoriatic arthritis, is also associated with susceptibility to JIA.

     

Disease control and health‐related quality of life in juvenile idiopathic arthritis

Objective

To examine variability in health‐related quality of life (HRQOL) in children with juvenile idiopathic arthritis (JIA) experiencing no or minimal clinical symptoms, and in a subgroup with polyarticular JIA treated with biologic agents for 12 months.

Methods

We defined 3 samples using a database of patients ages 2–18 years with JIA (n = 524; patient visits [PV] = 2,354): visits (PV = 2,155) with no or minimal clinical symptoms on at least 1 of 4 measures (active joint count, pain, physician global disease rating, Childhood Health Assessment Questionnaire); visits (PV = 941) with no or minimal symptoms on all 4 measures; and children (n = 31) with polyarticular JIA treated with biologic agents for 12 months. HRQOL was measured using the Pediatric Quality of Life Inventory (PedsQL) and the percentage of patients with suboptimal HRQOL was determined.

Results

In PV with a PedsQL score, suboptimal HRQOL by self‐report occurred in 362 (20.6%) PV with at least 1 indicator of minimal symptoms, and in 64 (7.9%) PV with all 4 measures indicating minimal symptoms (519 [25.7%] and 95 [10.7%], respectively, by parent report). For children with polyarticular JIA treated for 12 months with biologic agents, 7 (25.9%) patients by self‐report and 10 (35.7%) patients by parent report were in the suboptimal range of HRQOL.

Conclusion

A substantial percentage of patients with JIA who report no or mild clinical symptoms experience suboptimal HRQOL. This is also true for patients with polyarticular JIA treated with biologic agents for 12 months. Although disease activity and clinical symptoms are related to HRQOL, considerable unexplained variation in HRQOL exists. HRQOL needs to be assessed independently regardless of clinical status.

     

The effect of HLA–DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin α–tumor necrosis factor haplotype

Objective

HLA–DRB1, a major genetic determinant of susceptibility to rheumatoid arthritis (RA), is located within 1,000 kb of the gene encoding tumor necrosis factor (TNF). Because certain HLA–DRB1*04 subtypes increase susceptibility to RA, investigation of the role of the TNF gene is complicated by linkage disequilibrium (LD) between TNF and DRB1 alleles. By adequately controlling for this LD, we aimed to investigate the presence of additional major histocompatibility complex (MHC) susceptibility genes.

Methods

We identified 274 HLA–DRB1*04–positive cases of RA and 271 HLA–DRB1*04–positive population controls. Each subject was typed for 6 single‐nucleotide polymorphisms within a 4.5‐kb region encompassing TNF and lymphotoxin α (LTA). LTA–TNF haplotypes in these unrelated individuals were determined using a combination of family data and the PHASE software program.

Results

Significant differences in LTA–TNF haplotype frequencies were observed between different subtypes of HLA–DRB1*04. The LTA–TNF haplotypes observed were very restricted, with only 4 haplotypes constituting 81% of all haplotypes present. Among individuals carrying DRB1*0401, the LTA–TNF 2 haplotype was significantly underrepresented in cases compared with controls (odds ratio 0.5 [95% confidence interval 0.3–0.8], P = 0.007), while in those with DRB1*0404, the opposite effect was observed (P = 0.007).

Conclusion

These findings suggest that the MHC contains genetic elements outside the LTA–TNF region that modify the effect of HLA–DRB1 on susceptibility to RA.

     

Brief Report: Incidence of Selected Opportunistic Infections Among Children With Juvenile Idiopathic Arthritis

Objective

To compare incidence rates of selected opportunistic infections among children with and children without juvenile idiopathic arthritis (JIA).

Methods

Using US national Medicaid administrative claims data from 2000 through 2005, we identified a cohort of children with JIA based on physician diagnosis codes and dispensed medications. We also identified a non‐JIA comparator cohort of children diagnosed as having attention deficit hyperactivity disorder (ADHD). We defined 15 types of opportunistic infection using physician diagnosis or hospital discharge codes; criteria for 7 of these types also included evidence of treatment with specific antimicrobial agents. We calculated infection incidence rates. The rates in the ADHD comparator cohort were standardized to the age, sex, and race distribution of the JIA cohort. We calculated incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs) to compare infection rates.

Results

The JIA cohort included 8,503 children with 13,990 person‐years of followup. The ADHD comparator cohort included 360,362 children with 477,050 person‐years of followup. When all opportunistic infections were considered together as a single outcome, there were 42 infections in the JIA cohort (incidence rate 300 per 100,000 person‐years; IRR 2.4 [95% CI 1.7–3.3] versus ADHD). The most common opportunistic infections among children with JIA were 3 cases of Coccidioides (incidence rate 21 per 100,000 person‐years; IRR 101 [95% CI 8.1–5,319] versus ADHD), 5 cases of Salmonella (incidence rate 35 per 100,000 person‐years; IRR 3.8 [95% CI 1.2–9.5]), and 32 cases of herpes zoster (incidence rate 225 per 100,000 person‐years; IRR 2.1 [95% CI 1.4–3.0]).

Conclusion

Opportunistic infections are rare among children with JIA. Nevertheless, children with JIA had a higher rate of opportunistic infections, including an increased rate of Coccidioides, Salmonella, and herpes zoster compared to children with ADHD.