Background/Purpose: We have previously shown that neutrophils in children with polyarticular juvenile idiopathic arthritis (JIA) display abnormal transcriptional patterns linked to fundamental metabolic derangements. These transcriptional abnormalities include complex re-ordering of miRNA-RNA expression networks. In the current study, we sought to determine the effects of therapy of the reorganization of miRNA-RNA networks in polyarticular JIA.

Methods: In this cross-sectional analysis, we studied children with untreated, active JIA (ADU-n=35), 26 children with active disease on therapy with methotrexate + etanercept (ADT), and 14 children with inactive disease also on therapy (ID). We used Affymetrix exon and miRNA microarrays to identify expressed transcripts and compared results to findings from 35 healthy control (HC) children.

Results: Computational modeling demonstrated substantial re-ordering of miRNA-RNA networks after the initiation of therapy. Each of the 3 disease states, i.e., ADU, ADT, and ID, was associated with its own distinct transcriptional profile that showed only modest overlaps with the other 2. Gene ontology analysis corroborated this finding, as the genes showing differential expression between each of the disease states and HC were associated with different biological functions. Among the networks, the ADT state differed the most from HC while ID more strongly resembled HC. Computational modeling demonstrated complex interactions between transcription factors and miRNA that determine the gene expression signatures of each disease state.

Conclusion: Therapy for JIA induces substantial re-organization of neutrophil transcriptomes. It is interesting to note that each of the different treatment stages, which we derived from clinical observations (Wallace criteria), appear to be biologically distinct. These findings affirm the value of using the Wallace criteria for staging treatment response in JIA. Furthermore, these findings demonstrate that treatment response is not a linear process that results in gradual “normalization” of transcriptomes. Rather, treatment response occurs in distinct phases each with its own specific pattern of gene expression.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/modeling-transcriptional-rewiring-in-neutrophils-through-the-course-of-treated-juvenile-idiopathic-arthritis-2/