Transcriptional profiles of JIA patient blood with subsequent poor response to methotrexate

• Published in: Rheumatology (Oxford, England) England), 2017-09, Vol.56 (9), p.1542-1551
• Main Authors: Moncrieffe, Halima, Bennett, Mark F, Tsoras, Monica, Luyrink, Lorie K, Johnson, Anne L, Xu, Huan, Dare, Jason, Becker, Mara L, Prahalad, Sampath, Rosenkranz, Margalit, O'Neil, Kathleen M, Nigrovic, Peter A, Griffin, Thomas A, Lovell, Daniel J, Grom, Alexei A, Medvedovic, Mario, Thompson, Susan D
• Format: Article
• Language: English
• Subjects: Adolescent; Antirheumatic Agents - therapeutic use; Arthritis, Juvenile - drug therapy; Arthritis, Juvenile - genetics; Case-Control Studies; Child; Clinical Science; Cluster Analysis; Female; Gene Expression Profiling - methods; Humans; Male; Methotrexate - therapeutic use; Monocytes - metabolism; Sequence Analysis, RNA - methods; Severity of Illness Index; Transcription, Genetic; Transcriptome; Treatment Failure
• ISSN: 1462-0324; 1462-0332
• DOI: 10.1093/rheumatology/kex206

The mechanisms that determine the efficacy or inefficacy of MTX in 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 collected from 47 patients with JIA prior to MTX treatment and 14 age-matched controls. Differentially expressed baseline genes between responders and non-responders were evaluated. 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. 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 with reference signatures from sorted cell populations revealed high concordance between the expression signatures of monocytes and of MTX non-responders. CXCL8 (IL-8) was the most significantly differentially expressed gene transcript comparing all JIA patients with controls (Bonferroni-corrected P = 4.12 × 10-10). Variability in clinical response to MTX 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.