Interferon-Driven Genes Signal Methotrexate Response in JIA
Higher baseline expression of interferon (IFN)-driven genes was tied to a better response to methotrexate in patients with juvenile idiopathic arthritis.
METHODOLOGY:
Analysis of the link between blood biomarkers and response to methotrexate in 97 children (median age at baseline, 8.5 years; 62.9% women) with nonsystemic juvenile idiopathic arthritis (JIA).
RNA sequencing was used to understand gene expression on CD4 + , CD8 + , CD14 + , and CD19 + cells and total peripheral blood mononuclear cells at baseline and at 6 months post-treatment with methotrexate.
, CD8 , CD14 , and CD19 cells and total peripheral blood mononuclear cells at baseline and at 6 months post-treatment with methotrexate. The link between response to methotrexate therapy and gene activity in specific cell types was tested using the limma-voom, gene set enrichment analysis, and a new 51-gene score.
Results were validated in 73 children with JIA, and pretreatment gene expression data were used to compare results with 240 adult patients with rheumatoid arthritis (RA).
TAKEAWAY:
Gene enrichment in the IFN-alpha (type I) and IFN-gamma (type II) response pathways was linked with treatment response in many cell types isolated from children with nonsystemic JIA.
Higher baseline expression of both type I and type II IFN-driven genes was associated with a better response to methotrexate at 6 months post-treatment in JIA patients but not in adult RA patients.
The 51-gene score, calculated from the expression levels of 51 specific IFN-response genes, was significantly higher in patients who responded to methotrexate than in those who did not (P = .00556).
IN PRACTICE:
'It is possible that MTX [methotrexate] treatment is more effective in a distinct immunophenotype present across many International League of Associations for Rheumatology subtypes, where IFN-driven processes are dominant early in the disease,' the authors wrote. 'Our study provides proof of principle that carefully designed analyses can yield hope for a more precision-based approach to treatment in the future for children and families living with arthritis,' they added.
SOURCE:
This study was led by Melissa Kartawinata of University College London Great Ormond Street Institute of Child Health in London and Wei-Yu Lin of the University of Cambridge in Cambridge, both in England. It was published online on May 20, 2025, in Annals of the Rheumatic Diseases.
LIMITATIONS:
This study may have been underpowered to identify pathways with small but biologically significant influence on treatment response. Whole-blood RNA samples were unavailable to test the association between 51-IFN gene score and treatment response. Additionally, treatment response can fluctuate over time, and this study only analyzed outcomes at 6 months.
DISCLOSURES:
This study received support from the Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, and Olivia's Vision. Additional support was provided by multiple organizations, including the Wellcome Trust and other sources. Several authors reported receiving funds and contributions in kind from various pharmaceutical companies.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
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