The plasma metabolome of systemic juvenile idiopathic arthritis is different to non-JIA controls and partially explained by chronic inflammation

Abstract

Abstract Background: Diagnosis of juvenile idiopathic arthritis (JIA) is challenging due to shared clinical features between subtypes and with other inflammatory conditions. A molecular signature may therefore be useful for subtype classification in JIA, and targeted plasma metabolomics profiling has the potential to provide such a signature. The study aimed to characterise the differences in the plasma metabolome between JIA patients and non-JIA controls, and to determine the extent to which these differences are due to chronic inflammation measured by glycoprotein acetyls (GlycA). Methods: Nuclear magnetic resonance (NMR) metabolomics of plasma of 73 children with JIA and 18 age- and sex- matched controls was assessed cross-sectionally. Associations between 71 metabolomic biomarkers and JIA, four JIA subtypes, and inflammation (measured by GlycA) were assessed using multivariable linear regression models. Results: Three biomarkers were different between the control and JIA group, with acetate reduced in JIA (mean difference -0.98 standard deviations, [95% confidence interval -1.49, -0.47], Padj =0.015), while docosahexaenoic acid (DHA) (1.01 [0.47, 1.55], Padj =0.015) and GlycA (0.91, [0.36, 1.46], Padj =0.041) were elevated in JIA. Subtype analysis revealed that systemic JIA (sJIA) samples accounted for these changes, with no significant metabolic differences identified in oligoarticular and polyarticular (rheumatoid factor positive and rheumatoid factor negative) JIA relative to controls. A total of 24 of 71 biomarkers were significantly different (Padj <0.05) in systemic JIA compared to controls, including acetate, DHA and GlycA. Of the 24 biomarkers, only 6 were significantly associated with levels of the inflammatory marker GlycA. Conclusion: The variation of plasma NMR metabolome of systemic JIA is the most pronounced relative to non-JIA controls and other JIA subtypes, which show limited evidence of metabolomic disruption. Only a small number of metabolomic profile differences in sJIA were associated with levels of GlycA, indicating a complex relationship between JIA, metabolic disruption, and chronic inflammation.