Kartawinata, Melissa;
Lin, Wei-Yu;
Jebson, Beth;
O'Brien, Kathryn;
Ralph, Elizabeth;
Welsh, Emma;
Restuadi, Restuadi;
... Wallace, Chris; + view all
(2025)
Identification and validation of interferon-driven gene signature as a predictor of response to methotrexate in juvenile idiopathic arthritis.
Annals of the Rheumatic Diseases
10.1016/j.ard.2025.03.007.
(In press).
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Abstract
Objectives To identify and validate gene expression biomarkers of response to methotrexate (MTX) treatment in peripheral blood of children with juvenile idiopathic arthritis (JIA) measured before starting MTX treatment. Methods RNA sequencing was performed on sorted CD4+, CD8+, CD14+, and CD19+ cells, as well as peripheral blood mononuclear cells (PBMC) taken pre-treatment in a discovery cohort (n = 97) and 2 validation cohorts (n = 26 and n = 47, respectively) of patients with non-systemic JIA. Clinical data were recorded at baseline (timepoint 1) prior to treatment and 6 months (timepoint 2) of MTX treatment. Analysis tested the association of gene expression in specific cell types with treatment response using limma-voom, gene set enrichment analysis, and a novel 51-gene score against response to treatment. Parallel analysis, also using pre-treatment gene expression data, was performed in adult rheumatoid arthritis (RA) data (n = 240). Results In patients with JIA, the baseline expression of genes driven by interferon (IFN) alpha (type-I) or gamma (type-II) was associated with response to treatment at 6 months in 3 independent JIA cohorts. The direction of the association indicated that children with higher baseline expression of IFN-stimulated genes prior to MTX were more likely to be good responders. Comparison with adult RA indicated differences between PBMC and whole blood gene expression associations with response. Conclusions In children with JIA, a high IFN-driven gene signature is associated with a better response to MTX than those with a low IFN-driven gene signature. These data could pave the way to clinically validated tools to identify those most likely to require medications in addition to MTX to control inflammation.
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