Methotrexate pharmacogenetics: The first step toward individualized therapy in rheumatoid arthritis

Ranganathan, Prabha; McLeod, Howard L.

doi:10.1002/art.21762

Cited by 127 publications

(75 citation statements)

References 66 publications

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“…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 sites (6 cytokines and other mediators of inflammation, such as tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10), may also correlate with the efficacy of MTX (7,8).…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Chen

Yang

et al. 2012

Experimental and Therapeutic Medicine

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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...

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Section: Introductionmentioning

confidence: 99%

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

Wang

Chen

Yang

et al. 2012

Experimental and Therapeutic Medicine

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“…3 These polymorphisms affect receptors related with the transport of MTX into the cell, such as the reduced folate receptor and membrane-associated folate receptors, as well as enzymes involved in folate metabolism such as 5,10-methylenetetrahydrofolate reductase and thymidylate synthase. 4 Genetic polymorphisms affecting the folate metabolic pathway and MTX transporters modify the toxicity of the drug, but do not seem to influence the efficacy of the drug. 5 To circumvent the systemic toxicity of MTX, the use of the intra-articular route of drug administration was tested, but the results were not satisfactory because MTX is rapidly cleared from the joint cavity.…”

Section: Introductionmentioning

confidence: 99%

Intra-articular methotrexate associated to lipid nanoemulsions: anti-inflammatory effect upon antigen-induced arthritis

Mello¹,

Tavares²,

Bulgarelli³

et al. 2013

IJN

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“…The A-C substitution (A1298C) of MTHFR has a similar effect with C677T during pregnancy [21]. Moreover, MTRR 66GG also has the risk of elevating blood homocysteine [22] and is associated with fetal intrauterine growth restriction [23]. Since C677T and A1298C of MTHFR and A66G of MTRR are all common polymorphisms and play important roles in folate metabolism.…”

Section: Discussionmentioning

confidence: 99%

Individualized Supplementation of Folic Acid According to Polymorphisms of Methylenetetrahydrofolate Reductase (MTHFR), Methionine Synthase Reductase (MTRR) Reduced Pregnant Complications

Li¹,

Jiang²,

Xu³

et al. 2015

Gynecol Obstet Invest

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Objective: This study aimed to detect the genotype distributions and allele frequencies of methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms of pregnant women in Jiaodong region in China, and to investigate whether folic acid supplementation affect the pregnancy complications. Setting: A total of 7,812 pregnant women from the Jiaodong region in Shandong province in China. Methods: By using Taqman-MGB, 2,928 pregnant women (case group) were tested for the genotype distributions and allele frequencies of MTHFR C677T, A1298C and MTRR A66G polymorphisms. Folic acid metabolism ability was ranked at four levels and then pregnant women in different rank group were supplemented with different doses of folic acid. Their pregnancy complications were followed up and compared with 4,884 pregnant women without folic acid supplementation (control group) in the same hospital. Results: The allele frequencies of MTHFR C677T were 49.1 and 50.9%; those of MTHFR A1298C were 80.2 and 19.8%, and those of MTRR A66G were 74.1 and 25.9%. After supplemented with folic acid, the complication rates in different age groups were significantly reduced, especially for gestational diabetes mellitus and hypertension. Conclusion: Periconceptional folic acid supplementation and healthcare following gene polymorphism testing may be a powerful measure to decrease congenital malformations.

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Methotrexate pharmacogenetics: The first step toward individualized therapy in rheumatoid arthritis

Cited by 127 publications

References 66 publications

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

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

Intra-articular methotrexate associated to lipid nanoemulsions: anti-inflammatory effect upon antigen-induced arthritis

Individualized Supplementation of Folic Acid According to Polymorphisms of Methylenetetrahydrofolate Reductase (MTHFR), Methionine Synthase Reductase (MTRR) Reduced Pregnant Complications

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