Correlation analyses of clinical and molecular findings identify candidate biological pathways in systemic juvenile idiopathic arthritis

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.

Comparison of biomarkers for systemic juvenile idiopathic arthritis

“…Expression array data overlapped with previous studies: 41 (including IL1B, NFATC3, STAT4 and other genes associated with the innate immune response), 2 (ATP2B1 and RNF14) and 64 genes were also identified by Ling et al, Allantaz et al, and the ANAJIS trial, respectively (8,29,30). Of the nine genes Articles in our group that met the more stringent false discovery rate, interestingly ZC3H12B encodes a protein with a role in proinflammatory actions of macrophages (31).…”

The Systemic Juvenile Idiopathic Arthritis Cohort of the Childhood Arthritis and Rheumatology Research Alliance Registry: 2010–2013

“…Molecular data from a study show a different gene expression pattern associated with arthritis in early sJIA compared with the expression pattern in children with persistent arthritis 41 . These children may be a distinct subgroup of sJIA, sometimes referred to as systemic onset, polyarticular course JIA.…”

Altered signaling in systemic juvenile idiopathic arthritis monocytes

“…At each visit, comprehensive clinical information was collected, as described previously [21]. The subject’s clinical status at sample collection was assessed, according to scoring systems that we previously devised and used to grade severity of systemic disease manifestations or of arthritis [4, 7, 21, 22]. Based on these scores, each sample was classified as “flare” or “quiescence”.…”

“…The presence of macrophage activation syndrome (MAS) in a subset of sJIA patients and the efficacy of anti-IL-1 and anti-IL-6 therapies highlight a key role for dysfunction of the innate immune system [1, 2]. Absence of typical characteristics of autoimmunity, such as autoantibodies, also implies a less prominent role for altered adaptive immunity, although it may contribute, especially to persistent disease with polyarticular arthritis [3, 4]. …”