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Oligoarticular and polyarticular JIA: epidemiology and pathogenesis.

ABSTRACT: Juvenile idiopathic arthritis (JIA) refers to a group of chronic childhood arthropathies of unknown etiology, 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 seems 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 are also 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 seem to drive joint damage.

SUBMITTER: Macaubas C

PROVIDER: S-EPMC4159935 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Oligoarticular and polyarticular JIA: epidemiology and pathogenesis.

Macaubas Claudia C Nguyen Khoa K Milojevic Diana D Park Jane L JL Mellins Elizabeth D ED

Nature reviews. Rheumatology 20091006 11

Juvenile idiopathic arthritis (JIA) refers to a group of chronic childhood arthropathies of unknown etiology, 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 diffe ...[more]

PMID: 19806151

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Project description:BackgroundAlthough 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.MethodsWe 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.ResultsWhile 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).ConclusionsWe 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.

Project description:Objective. To identify gene expression differences in peripheral blood from patients with early and late onset juvenile idiopathic arthritis (JIA). Methods. Peripheral blood mononuclear cells (PBMC) were isolated from 56 healthy controls and 104 patients with recent onset JIA (39 persistent oligoarticular, 45 RF-polyarticular, and 20 systemic). Poly(A) RNA was amplified and labeled using NuGEN Ovation, and gene expression 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 PBMC from children with oligoarticular JIA whose disease began before 6 years of age (age at onset [AaO] <6; early onset), compared to subjects whose disease began at 6 years of age or later (AaO ?6; late onset). In early onset patients there was greater expression of genes related to B-cells, and lesser expression of genes related to cells of the myeloid lineage. Support Vector Machine algorithms identified samples from early or late onset oligoarticular (97% accuracy) or polyarticular (89% accuracy) JIA patients, but not systemic JIA patients or healthy controls. Principal component analysis showed that the major classifier of samples was AaO regardless of whether they had oligoarticular or polyarticular JIA. Conclusion. PBMC gene expression analysis reveals biologic differences between early and late onset JIA patients independent of classification based on the number of joints involved. These data suggest AaO may be an important parameter to consider in JIA classification. Furthermore, different pathologic mechanisms may influence AaO, and understanding these processes may lead to improved treatment of JIA. Methods. Peripheral blood mononuclear cells (PBMC) were isolated from 56 healthy controls and 104 patients with recent onset JIA (39 persistent oligoarticular, 45 RF-polyarticular, and 20 systemic). Poly(A) RNA was amplified and labeled using NuGEN Ovation, and gene expression assessed with Affymetrix HG-U133 Plus 2.0 GeneChips®.

Dataset Information

Oligoarticular and polyarticular JIA: epidemiology and pathogenesis.

Publications

Oligoarticular and polyarticular JIA: epidemiology and pathogenesis.

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