Identification of Metabolic Biomarkers in Relation to Methotrexate Response in Early Rheumatoid Arthritis

Abstract

This study aimed to identify baseline metabolic biomarkers for response to methotrexate (MTX) therapy in rheumatoid arthritis (RA) using an untargeted method. In total, 82 baseline plasma samples (41 insufficient responders and 41 sufficient responders to MTX) were selected from the Treatment in the Rotterdam Early Arthritis Cohort (tREACH, trial number: ISRCTN26791028) based on patients’ EULAR response at 3 months. Metabolites were assessed using high-performance liquid chromatography-quadrupole time of flight mass spectrometry. Differences in metabolite concentrations between insufficient and sufficient responders were assessed using partial least square regression discriminant analysis (PLS-DA) and Welch’s t-test. The predictive performance of the most significant findings was assessed in a receiver operating characteristic plot with area under the curve (AUC), sensitivity and specificity. Finally, overrepresentation analysis was performed to assess if the best discriminating metabolites were enriched in specific metabolic events. Baseline concentrations of homocystine, taurine, adenosine triphosphate, guanosine diphosphate and uric acid were significantly lower in plasma of insufficient responders versus sufficient responders, while glycolytic intermediates 1,3-/2,3-diphosphoglyceric acid, glycerol-3-phosphate and phosphoenolpyruvate were significantly higher in insufficient responders. Homocystine, glycerol-3-phosphate and 1,3-/2,3-diphosphoglyceric acid were independent predictors and together showed a high AUC of 0.81 (95% CI: 0.72–0.91) for the prediction of insufficient response, with corresponding sensitivity of 0.78 and specificity of 0.76. The Warburg effect, glycolysis and amino acid metabolism were identified as underlying metabolic events playing a role in clinical response to MTX in early RA. New metabolites and potential underlying metabolic events correlating with MTX response in early RA were identified, which warrant validation in external cohorts.

Protective Effect of Pycnogenol against Methotrexate-Induced Hepatic, Renal, and Cardiac Toxicity: An In Vivo Study

“…In our investigations, we observed a significant drop in the activity of the CAT and SOD enzymes, as well as a decrease in the levels of GSH and ATP in the MTX-treated groups. These results are in agreement with previous studies that reported that MTX treatment led to reduced GSH, SOD, and CAT activity, as well as elevated MDA [50][51][52]. Notably, the magnitude of GSH detected (pg/g tissue) in our experiments is lower than previously reported studies values.…”

Adenosine deaminase modulates metabolic remodeling and orchestrates joint destruction in rheumatoid arthritis

“…To further understand the mechanistic aspects of biologics and DMARDs, we re-analyzed the published metabolomic datasets. Comparative analysis showed that metabolomic pathways deregulated in our RA patient cohorts were modulated by biologics and DMARDs treatments as evident from the published literature 76,77 . Previous studies have also shown modulation of inflammatory cytokines after treatment with biologics and DMARDs in RA patients 78 .…”

Extracellular pyruvate kinase M2 promotes osteoclastogenesis and is associated with radiographic progression in early rheumatoid arthritis

“…Pyruvate can be present in the synovial fluid; pyruvate was detected at concentrations from 0.13 to 0.28 mM in four RA patients in the study of Treuhaft et al 1 . Additionally, a recent study showed that PEP can be detected in the circulation, and its levels are significantly higher in early RA patients with a therapeutic response to methotrexate 40 . Furthermore, extracellular pyruvate is reported to augment RANKL-induced osteoclastogenesis 32 .…”