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

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.

Metabolomic analysis in spondyloarthritis: A systematic review

“…12 of 31 studies compared SpA cases with cases of other rheumatic diseases, such as rheumatoid arthritis (RA), osteoarthritis (OA) and gout. 7 studies analyzed the dynamic alterations in metabolic profiles in SpA patients before and after treatment (Gao et al, 2008;Kapoor et al, 2013;Nanus et al, 2015;Butbul et al, 2020;Bogunia-Kubik et al, 2021;Funk and Becker, 2021;Gupta et al, 2021;Ou et al, 2021). Regarding the metabolomic analysis in different subtypes of SpA, 13 studies included AS patients (Gao et al, 2008;Fischer et al, 2012;Jiang et al, 2013;Chen et al, 2015;Shao et al, 2016;Wang et al, 2016;He et al, 2019;Bogunia-Kubik et al, 2021;Eryavuz Onmaz et al, 2021;Lv et al, 2021;Onmaz et al, 2021;Ou et al, 2021).…”

“…7 studies included PsA patients (Madsen et al, 2010;Kapoor et al, 2013;Armstrong et al, 2014;Nanus et al, 2015;Souto-Carneiro et al, 2020;Bogunia-Kubik et al, 2021;Rocha et al, 2021). 5 studies included JIA patients (Zeft et al, 2014;Stoll et al, 2016;Butbul et al, 2020;Vernocchi et al, 2020;Funk and Becker, 2021). 5 studies included ReA patients (Ahmed et al, 2019;Guleria et al, 2019;Li et al, 2019;Muhammed et al, 2020;Dubey et al, 2021).…”

“…Dynamic alterations in the metabolic profile before and after treatment of spondyloarthritis TNF-alpha inhibitors (TNFi) have been widely used for SpA treatment. Five of 7 enrolled studies reported dynamic alterations in metabolites after TNFi therapy in SpA (Kapoor et al, 2013;Nanus et al, 2015;Manasson et al, 2017;Butbul et al, 2020;Bogunia-Kubik et al, 2021), while the other two studies focused on the influence of conventional therapy (Funk and Becker, 2021;Gupta et al, 2021). Kapoor et al (2013) and Bogunia-Kubik et al ( 2021) found elevated levels of isobutyrate and acetone in AS as well as elevated levels of acetate in PsA after TNFi therapy.…”

“…Reduced levels of glucose and elevated levels of LDL, PUFAs, isoleucine, glutamic acid and glycine were found by Gupta et al (2021) in the serum of SpA patients after conventional therapy, which partly corrected the aberrant metabolism observed in SpA patients. In addition, in the serum of JIA patients, MTX therapy increased the level of omega-3 unsaturated fatty acids (docosahexanoic acid and linoleic acid), which are antiinflammatory mediators (Funk and Becker, 2021).…”

“…By the use of high-throughput techniques, metabolomics can be used not only to identify promising novel biomarkers but also to provide insights into etiology, leading to the development of therapeutic targets (Johnson et al, 2016;Wishart, 2016). In recent years, an increasing number of studies have been conducted to investigate the broad network of metabolites in SpA using various human biological samples, including serum, plasma, tissue, urine and feces (Gao et al, 2008;Fischer et al, 2012;Jiang et al, 2013;Zeft et al, 2014;Chen et al, 2015;Shao et al, 2016;Stoll et al, 2016;Butbul et al, 2020;Vernocchi et al, 2020;Funk and Becker, 2021). However, some studies have inconsistent results or even the opposite results.…”