1H NMR-based metabolomic analysis for identifying serum biomarkers to evaluate methotrexate treatment in patients with early rheumatoid arthritis

Abstract

Abstract. To identify the major serum biomarkers predicting the response to methotrexate (MTX) treatment in patients with early rheumatoid arthritis (RA), we evaluated the relationships between the individual response to MTX and various associated factors utilizing the 1 H nuclear magnetic resonance ( 1 H NMR)-based metabolomic method. Thirty-eight early RA patients were enrolled in this cohort study, and they received MTX (10 mg/week) orally as monotherapy for 24 weeks. According to the American College of Rheumatology criteria for improvement, clinical evaluation following MTX treatment was carried out at baseline and at the end of 24 weeks. Furthermore, collected serum samples were analyzed using 600 M 1 H NMR for spectral binning. The obtained data were processed by both the unsupervised principal component analysis (PCA) and the supervised partial least squares discriminant analysis (PLS-DA). Lastly, multivariate analyses were performed to recognize the spectral pattern of endogenous metabolites related to MTX treatment. Differential clustering of 1 H NMR spectra identified by PCA was found between the effective (n=25) and non-effective (n=13) group of RA patients receiving MTX treatment. Multivariate statistical analysis showed a difference in metabolic profiles between the two groups using PLS-DA (R 2 =0.802, Q 2 =0.643). In targeted profiling, 11 endogenous metabolites of the effective group showed a significant difference when compared with those of the non-effective group (p<0.05). Serum metabolites correlated with MTX treatment in patients with early RA were identified, which may be the major predictive factors for evaluating the response to MTX treatment in patients with early RA. Furthermore, our results highlight the usefulness of 1 H NMR-based metabolomics as a feasible and efficient prognostic tool for predicting therapeutic efficacy to MTX treatment. IntroductionRheumatoid arthritis (RA) is a systemic chronic inflammatory joint disease, which is characterized by persistent synovitis, systemic inflammation and autoantibodies (1). Methotrexate (MTX) is the most widely used and is regarded as the anchor drug in the treatment of RA. Despite the advent of newer biologic therapies, MTX retains its central role since it is relatively inexpensive, broad experience with its use exists, and it is widely used in combination regimens with other disease-modifying antirheumatic drugs (DMARDs) (2). In the US and European countries, the recommended general dose of MTX is 15-20 mg/week, but individual optimal dose is in the range of 5-25 mg/week. In China, the conventional dose of MTX is 10 mg/week, but in practice 5-20 mg/week is prescribed based on individual sensitivity to and tolerance of MTX (3,4). Although well proven, it is recognized that there are large individual differences in the optimal dose of MTX for RA patients (5). The reasons for those individual differences are thought to be different concentrations of intracellular MTX-polyglutamates (MTX-PGs) and different enzyme activities at MTX-active sit...

Lipid and Metabolic Changes in Rheumatoid Arthritis

“…Of note, recent metabolic phenotyping of atherosclerotic plaques showed perturbations in acylcarnitine metabolism which the authors suggest is related to dysregulation of fatty acid metabolism and mitochondrial dysfunction [93••]. Wang et al reported serum NMR-based metabolomics analysis on patients with early RA treated with methotrexate (the goldstandard DMARD) and showed that the patients could be grouped into those that benefitted from the drug and those that did not [94]. Our group has also shown that baseline 1 H NMR urine metabolic profiles discriminated between RA patients who did or did not have a good response to TNF therapy with a sensitivity of 88.9 % and a specificity of 85.7 % [95].…”

Metabolomics in rheumatic diseases: desperately seeking biomarkers

“…In one study 103 , a 1 H-NMR metabolomic approach was applied to 38 patients with active RA. After 24 weeks, patients who responded to methotrexate treatment showed significant elevations in serum levels of uric acid, taurine, methionine, glycine, histidine and hypoxanthine, and reductions in levels of uracil, TMAO, α-oxoglutarate, aspartate, and tryptophan, compared with patients in whom methotrexate was not effective 103 .…”

“…In one study 103 , a 1 H-NMR metabolomic approach was applied to 38 patients with active RA. After 24 weeks, patients who responded to methotrexate treatment showed significant elevations in serum levels of uric acid, taurine, methionine, glycine, histidine and hypoxanthine, and reductions in levels of uracil, TMAO, α-oxoglutarate, aspartate, and tryptophan, compared with patients in whom methotrexate was not effective 103 . NMR analysis of urine from 16 patients with RA and 20 with psoriasis (before anti-TNF therapy) 104 identified upregulation of histamine, glutamine, phenylacetic acid, xanthine, xanthurenic acid and creatinine, and downregulation of ethanolamine, p-hydroxyphenylpyruvic acid and phosphocreatine in samples from patients who had a good response to therapy.…”

Protective effect of higenamine ameliorates collagen-induced arthritis through heme oxygenase-1 and PI3K/Akt/Nrf-2 signaling pathways

“…RA is a type of chronic and systemic autoimmune disease that is characterized by erosive joint synovitis, which harms body systems and organs, such as joints, the heart and the kidney (11). RA attacks facet joints symmetrically, for instance, articulationes digitorum manus, articulationes digitorum pedis and wrist joints (12).…”