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

Abstract

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.

Figure 1

Heat maps of samples using age at onset–related probe sets. Eight hundred thirty-two probe sets reflecting differentially expressed genes were identified between samples from patients with early-onset persistent oligoarticular disease and from patients with late-onset persistent oligoarticular disease (false discovery rate 5%). Hierarchical clustering of the probe sets was used to identify patterns in the data from patients with persistent oligoarticular disease (A) or from control subjects (B). Vertical bars indicate clusters of probe sets with similar expression patterns related to cells of the myeloid lineage (a), immunoglobulins (b1), or B cells (b2). In the clustering diagram, red indicates increased expression relative to the median of all samples, blue indicates decreased expression relative to the median of all samples, and yellow indicates the median of all samples. Bottom in A and B, Bars indicate samples from patients with early-onset disease (younger patients) (red) or samples from patients with late-onset disease (older patients) (yellow). Bottom in A only, Bars indicate antinuclear antibody status (blue indicates positive, magenta indicates negative, cyan indicates not tested).

Figure 2

Evaluation of 832 age at onset–related probe sets in additional subtypes of juvenile idiopathic arthritis (JIA). Eight hundred thirty-two probe sets reflecting differentially expressed genes between samples from patients with early-onset persistent oligoarticular disease and from patients with late-onset persistent oligoarticular disease were used to cluster samples from patients with rheumatoid factor–negative polyarticular JIA (A) or from patients with systemic JIA (B). Vertical bars indicate clusters of probe sets with similar expression patterns related to cells of the myeloid lineage (a), immunoglobulins (b1), or B cells (b2). In the clustering diagram, red indicates increased expression relative to the median of all samples, blue indicates decreased expression relative to the median of all samples, and yellow indicates the median of all samples. Bottom, Bars indicate samples from patients with early-onset disease (younger patients) (red) or samples from patients with late-onset disease (older patients) (yellow).

Figure 3

Principal components analysis (PCA) for 832 age at onset–related probe sets. Samples from patients with persistent oligoarticular juvenile idiopathic arthritis (JIA) and patients with rheumatoid factor (RF)–negative polyarticular JIA were arranged according to PCA using the 832 age at onset–related probe sets. The first 3 principal components are shown, comprising 41% (x-axis), 11% (y-axis), and 6% (z-axis) of the total variation observed. Each point represents 1 sample. A, Red indicates early-onset disease, and yellow indicates late-onset disease. B, Red indicates persistent oligoarticular disease, and blue indicates RF-negative polyarticular disease.