Transcriptional profiling reveals monocyte signature associated with JIA patient poor response to methotrexate

The mechanisms that determine the efficacy or inefficacy of methotrexate in juvenile idiopathic arthritis (JIA) are ill-defined. The objective of this study was to identify a gene expression transcriptional signature associated with poor response to MTX in patients with JIA. RNA sequencing was used to measure gene expression in peripheral blood mononuclear cells (PBMC) collected from 47 patients with JIA prior to MTX treatment and 14 age-matched controls. Biological differences between all JIA patients and controls were explored by constructing a signature of differentially expressed genes. Unsupervised clustering and pathway analysis was performed. Transcriptional profiles were compared to a reference gene expression database representing sorted cell populations, including B and T lymphocytes, and monocytes. A signature of 99 differentially expressed genes (Bonferroni-corrected p<0.05) capturing the biological differences between all JIA patients and controls was identified. Unsupervised clustering of samples based on this list of 99 genes produced subgroups enriched for MTX response status. Comparing this gene signature to reference signatures from sorted cell populations revealed high concordance between the expression profiles of monocytes and of MTX non-responders. CXCL8 (IL-8) was the most significantly differentially expressed gene transcript comparing all JIA patients to controls (Bonferroni-corrected p=4.12E-10). Variability in clinical response to methotrexate in JIA patients is associated with differences in gene transcripts modulated in monocytes. These gene expression profiles may provide a basis for biomarkers predictive of treatment response. Overall design: Peripheral blood mononuclear cells (PBMC) collected from 47 patients with JIA prior to MTX treatment and 14 age-matched controls

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Moncrieffe H, Bennett MF, Tsoras M, Luyrink LK, Johnson AL, Xu H, Dare J, Becker ML, Prahalad S, Rosenkranz M, O'Neil KM, Nigrovic PA, Griffin TA, Lovell DJ, Grom AA, Medvedovic M, Thompson SD