Abstract
BackgroundClinicians have long appreciated the distinct phenotype of systemic juvenile idiopathic arthritis (SJIA) compared to polyarticular juvenile idiopathic arthritis (POLY). We hypothesized that gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with each disease would reveal distinct biological pathways when analyzed for significant associations with elevations in two markers of JIA activity, erythrocyte sedimentation rate (ESR) and number of affected joints (joint count, JC).MethodsPBMC RNA from SJIA and POLY patients was profiled by kinetic PCR to analyze expression of 181 genes, selected for relevance to immune response pathways. Pearson correlation and Student's t-test analyses were performed to identify transcripts significantly associated with clinical parameters (ESR and JC) in SJIA or POLY samples. These transcripts were used to find related biological pathways.ResultsCombining Pearson and t-test analyses, we found 91 ESR-related and 92 JC-related genes in SJIA. For POLY, 20 ESR-related and 0 JC-related genes were found. Using Ingenuity Systems Pathways Analysis, we identified SJIA ESR-related and JC-related pathways. The two sets of pathways are strongly correlated. In contrast, there is a weaker correlation between SJIA and POLY ESR-related pathways. Notably, distinct biological processes were found to correlate with JC in samples from the earlier systemic plus arthritic phase (SAF) of SJIA compared to samples from the later arthritis-predominant phase (AF). Within the SJIA SAF group, IL-10 expression was related to JC, whereas lack of IL-4 appeared to characterize the chronic arthritis (AF) subgroup.ConclusionsThe strong correlation between pathways implicated in elevations of both ESR and JC in SJIA argues that the systemic and arthritic components of the disease are related mechanistically. Inflammatory pathways in SJIA are distinct from those in POLY course JIA, consistent with differences in clinically appreciated target organs. The limited number of ESR-related SJIA genes that also are associated with elevations of ESR in POLY implies that the SJIA associations are specific for SJIA, at least to some degree. The distinct pathways associated with arthritis in early and late SJIA raise the possibility that different immunobiology underlies arthritis over the course of SJIA.
Highlights
Clinicians have long appreciated the distinct phenotype of systemic juvenile idiopathic arthritis (SJIA) compared to polyarticular juvenile idiopathic arthritis (POLY)
erythrocyte sedimentation rate (ESR) and joint count (JC)-associated gene expression in Juvenile idiopathic arthritis (JIA) ESR was chosen as a quantitative measure of systemic inflammation for our analysis, as it typically rises in association with flares of systemic symptoms and was assessed in the largest number of samples
We considered another measure of systemic inflammation, C-reactive protein (CRP), but few samples were assessed for CRP, precluding the use of this parameter in our analysis
Summary
Clinicians have long appreciated the distinct phenotype of systemic juvenile idiopathic arthritis (SJIA) compared to polyarticular juvenile idiopathic arthritis (POLY). There are unique immunophenotypic features in SJIA compared to other JIA subtypes, such as the lack of human leukocyte antigen (HLA) class II allele association, low or absent autoantibodies (antinuclear antibodies, rheumatoid factor or anti-CCP antibodies [8]), a tendency toward monocytosis [9,10], high levels of IL-18 [11,12] and natural killer cell abnormalities in at least a subset of patients [13] These immunologic features, together with the therapeutic efficacy of inhibitors of IL-1 or IL-6 in SJIA and AOSD, suggest that these diseases might be best classified as autoinflammatory rather than autoimmune [14,15,16,17]
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