Metabolomic Profiling Identifies Exogenous and Microbiota-Derived Metabolites as Markers of Methotrexate Efficacy in Juvenile Idiopathic Arthritis.

Ryan Sol Funk,Mara L Becker

doi:10.3389/fphar.2021.768599

Ryan Sol Funk, Mara L Becker

Open Access

https://doi.org/10.3389/fphar.2021.768599

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Abstract

Variability in methotrexate (MTX) efficacy represents a barrier to early and effective disease control in the treatment of juvenile idiopathic arthritis (JIA). This work seeks to understand the impact of MTX on the plasma metabolome and to identify metabolic biomarkers of MTX efficacy in a prospective cohort of children with JIA. Plasma samples from a cohort of children with JIA (n = 30) collected prior to the initiation of MTX and after 3 months of therapy were analyzed using a semi-targeted global metabolomic platform detecting 673 metabolites across a diversity of biochemical classes. Disease activity was measured using the 71-joint count juvenile arthritis disease activity score (JADAS-71) and clinical response to MTX was based on achievement of ACR Pedi 70 response. Metabolomic analysis identified 50 metabolites from diverse biochemical classes that were altered following the initiation of MTX (p < 0.05) with 15 metabolites reaching a false-discovery rate adjusted p-value (q-value) of less than 0.05. Enrichment analysis identified a class-wide reduction in unsaturated triglycerides following initiation of MTX (q = 0.0009). Twelve of the identified metabolites were significantly associated with disease activity by JADAS-71. Reductions in three metabolites were found to be associated with clinical response by ACR Pedi 70 response criteria and represented several microbiota and exogenously derived metabolites including: dehydrocholic acid, biotin, and 4-picoline. These findings support diverse metabolic changes following initiation of MTX in children with JIA and identify metabolites associated with microbial metabolism and exogenous sources associated with MTX efficacy.

Highlights

Rapid control of disease activity to prevent irreversible joint damage and improve long-term outcomes continues to be a major therapeutic goal in the treatment of juvenile idiopathic arthritis (JIA) (Consolaro et al, 2012)
No significant differences in baseline demographic characteristics nor baseline measures of disease activity were found between the groups
There were no significant differences in baseline clinical characteristics with the remaining portion of the cohort excluded from this work (n 38) including JIA subtype, age, gender, MTX route of administration, MD-VAS, PT-VAS, CHAQ, baseline active joint count, baseline JADAS-71, ESR or CRP

Summary

Introduction

Rapid control of disease activity to prevent irreversible joint damage and improve long-term outcomes continues to be a major therapeutic goal in the treatment of juvenile idiopathic arthritis (JIA) (Consolaro et al, 2012). MTX is characterized by a delayed onset of action with approximately one in three patients failing to adequately respond to initial treatment (Ruperto et al, 2004). At this time, no reliable biomarkers exist to guide drug selection and optimization and the current approach wastes precious time and jeopardizes the overarching goal of early disease control (Funk and Becker, 2016). There exists a need to apply novel analytical approaches to further understand the pharmacology of MTX and to identify biomarkers to guide clinicians in the selection and optimization of drug therapy

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