Pharmacogenetics Of Methotrexate Research Articles

Pharmacogenetic Sex-Specific Effects of Methotrexate Response in Patients with Rheumatoid Arthritis.

Methotrexate (MTX) is a commonly used drug for the treatment of rheumatoid arthritis (RA), but its effectiveness can vary greatly among patients. Pharmacogenetics, the study of how genetic variations can affect drug response, has the potential to improve the personalized treatment of RA by identifying genetic markers that can predict a patient's response to MTX. However, the field of MTX pharmacogenetics is still in its early stages and there is a lack of consistency among studies. This study aimed to identify genetic markers associated with MTX efficacy and toxicity in a large sample of RA patients, and to investigate the role of clinical covariates and sex-specific effects. Our results have identified an association of ITPA rs1127354 and ABCB1 rs1045642 with response to MTX, polymorphisms of FPGS rs1544105, GGH rs1800909, and MTHFR genes with disease remission, GGH rs1800909 and MTHFR rs1801131 polymorphisms with all adverse events, and ADA rs244076 and MTHFR rs1801131 and rs1801133, However, clinical covariates were more important factors to consider when building predictive models. These findings highlight the potential of pharmacogenetics to improve personalized treatment of RA, but also emphasize the need for further research to fully understand the complex mechanisms involved.

Pharmacogenomics of Methotrexate: Current Status and Future Outlook.

Methotrexate (MTX) is a folate analogue with high therapeutic efficiency in the treatment of cancers and autoimmune diseases. The efficacy and toxicity of MTX may be altered by genetic polymorphisms in genes involved in MTX metabolic pathway. Personalized pharmacotherapy based on gene polymorphisms enables a more efficient, compatible and cost-effective treatment of patients. The present article aims to review genetic polymorphisms associated with MTX pharmacokinetics, toxicity, and outcome, and points out future development directions of individualized MTX therapy. Details regarding the pharmacogenetics and pharmacogenomics of MTX are obtained from PubMed literatures. The influences of single nucleotide polymorphisms (SNPs) in genes involved in MTX pathway are controversial. Many pharmacogenetic associations are disease specific and race specific. Present studies have almost limited to some certain ethnic groups and diseases. The data from these studies are not convincing enough to draw far-reaching conclusions about the applicability of MTX pharmacogenetics in clinical practice. Studies with large scale and multiple centers are needed in the future. MTX-PG inhibits folic metabolism through three mechanisms. TS, MTHFR and ATIC are the rate-limiting enzymes separately. The function of SNPs in these genes is often onesided. Works focusing on the analysis of polymorphism in MTX transporters should be more efficient and meaningful.

Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies.

Pharmacogenetics of methotrexate (MTX) contributes to interindividual differences in toxicity. We aimed to evaluate the impact of SNPs within the MTX pathway genes on MTX-induced toxicity and MTX plasma levels at 48 h following treatment in Asian adults with acute lymphoblastic leukemia or non-Hodgkin lymphoma. Patients (n = 71) were genotyped for MTHFR C677T, MTHFR A1298C, SLC19A1 G80A, ABCG2 C421A and ABCB1 C3435T using the Sequenom MassARRAY platform. Plasma MTX concentrations at 48 h were measured by fluorescence polarization immunoassay. Forty-eight patients had hematopoietic toxicity, 51 had hepatic toxicity and 36 had mucositis. Patients homozygous for MTHFR 677TT were associated with increased risk of both hematopoietic (odds ratio [OR]: 9.03; 95% CI: 2.28-36.16; p = 0.002) and hepatic (OR: 3.92; 95% CI: 1.01-15.11; p = 0.036) toxicities. Hepatic toxicity was associated with SLC19A1 G80A (OR: 5.27, 95% CI: 1.21-22.72; p = 0.032) and ABCB1 C3435T (OR: 8.62; 95% CI: 1.96-37.57; p = 0.004). However, polymorphisms in MTHFR A1298C and ABCG2 C421A were not associated with any of the toxicities, and mucositis was not associated with any polymorphisms of the MTX pathway genes. Patients with MTHFR C677T and ABCB1 C3435T polymorphisms appear to have significantly higher MTX plasma concentrations (p < 0.05). Our results in Asian adults provides evidence for the contribution pharmacogenetics to the toxicity of high-dose MTX and plasma MTX concentrations at 48 h following treatment in patients with acute lymphoblastic leukemia or non-Hodgkin lymphoma. These results will contribute towards the effort of MTX therapy individualization.

P0177 Impact of genetic polymorphisms of MTHFR, SLC, and ABC on high-dose methotrexate toxicity and plasma levels in adults with haematological malignancies

<h3>Background</h3> High-dose methotrexate has been shown to be useful in acute lymphoblastic leukaemia (ALL) or non-Hodgkin lymphoma (NHL). However, it causes toxicity in the bone marrow, liver, and gastrointestinal tract. Pharmacogenetics of methotrexate and its relationship with plasma concentrations are conflicting. We aimed to evaluate the impact of single nucleotide polymorphisms (SNPs) within the <i>MTHFR</i>, <i>SLC</i>, and <i>ABC</i> genes on methotrexate-induced toxicity and methotrexate plasma levels at 48h in Asian adults with ALL or non-Hodgkin lymphoma. <h3>Methods</h3> Seventy-one patients were genotyped for <i>MTHFR</i> C667T, <i>MTHFR</i> A1298C, <i>SLC19A1</i> G80A, <i>ABCG2</i> C421A, and <i>ABCB1</i> C3435T using the Sequenom MassARRAY platform. Plasma methotrexate concentrations at 48h were measured by fluorescence polarization immunoassay. <h3>Findings</h3> Forty-eight patients had haematopoietic toxicity, 51 had hepatic toxicity, and 36 had mucositis. Homozygous 677TT of <i>MTHFR</i> was associated with increased risk of both hematopoietic (odds ratio [OR] 9.00, 95% confidence interval [CI] 2.24–36.17, <i>p</i>=0.002) and hepatic (OR 3.94, 95% CI 1.03–15.13, <i>p</i>=0.036) toxicities. Hepatic toxicity was associated with <i>SLC19A1</i> G80A (OR 5.25, 95% CI 1.21–22.74, <i>p</i>=0.032) and <i>ABCB1</i> C3435T (OR 8.64, 95% CI 1.99–37.55, <i>p</i>=0.004). However, polymorphisms in <i>MTHFR</i> A1298C and <i>ABCG2</i> C421A were not associated with any of the toxicities, and mucositis was not associated with any polymorphisms of the methotrexate pathway genes. Patients with <i>MTHFR</i> C677T and <i>ABCB1</i> C3435T polymorphisms seemed to have significantly higher methotrexate plasma concentrations (<i>p</i><0.05). <h3>Interpretation</h3> Our findings support evidence for the pharmacogenetic contribution to the toxicity of high-dose methotrexate and plasma methotrexate concentrations at 48h in patients with ALL or NHL. These results will contribute to individualisation of high-dose methotrexate therapy.

Pharmacogenetics of methotrexate in acute lymphoblastic leukaemia: why still at the bench level?

The antifolate drug methotrexate (MTX) was introduced into clinical practice about 60 years ago and remains an important component of different acute lymphoblastic leukemia (ALL) treatment protocols. It acts by inhibiting several enzymes in the folate pathway, thereby resulting in the disruption of folate homeostasis. To date, treatment regimens have not been personalized despite there being experimental evidence that gene polymorphisms of folate metabolizing enzymes affect MTX response. The aim of this review was to evaluate the influence of genetic polymorphisms of the enzymes involved in the MTX pathway on ALL treatment outcomes and identify factors underlining the failure to personalize MTX therapy. We conducted a literature search in PUBMED and Google Scholar using the following key words: methotrexate, polymorphism, acute lymphoblastic leukemia, pharmacogenetics, pharmacogenomics and personalized medicine. The reasons for the failure to personalize MTX therapy may be due to (1) most studies involving single-center, small-sized cohorts, (2) differences in MTX dose across different protocols, (3) failure to consider minimal residual disease as a risk factor for post-induction treatment, (4) differences in outcome criteria between studies and (5) failure to consider the folate levels of a patient before initiation of MTX therapy. Although high-throughput techniques allow the mapping of thousands of genetic polymorphisms in a single run, it remains a major challenge to dissect out folate-metabolizing enzymes which have a high impact on the efficacy and toxicity of MTX and which, therefore, could be the targets for intervention. Prospective pharmacogenetic studies which consider all of the above-mentioned factors should be undertaken to facilitate the design of personalized MTX treatment for ALL patients.

Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia

AbstractThe pharmacogenetics of methotrexate (MTX) was investigated in a large cohort of pediatric patients with acute lymphoblastic leukemia (ALL). Four hundred ninety-nine children with ALL from the ALL-BFM (Berlin–Frankfurt–Münster) 2000 trial who received 1996 courses of MTX at 5 g/m2 were genotyped for 8 single nucleotide polymorphisms in 5 candidate genes of the MTX/folate pathway. Patients' MTX pharmacokinetics, MTX toxicities, and outcomes were correlated with the genotypes. The interindividual variability in MTX kinetics had a substantial genetic component between 68% and 75%. The SLCO1B1 rs4149056 variant was significantly associated with MTX kinetics. In a multiple regression model, MTX area under the concentration time curve (AUC)0-48h increased by 26% (P < .001) per SLCO1B1 rs4149056 C allele. MTX AUC0-48h was a significant predictor of overall toxic adverse events during MTX courses (R2 = 0.043; P < .001), whereas the thymidylate synthase rs34743033 tandem repeat polymorphism was predictive of stomatitis (R2 = 0.018; P = .009), a frequent side effect of high-dose MTX. Multiple Cox regression analyses revealed an association of minimal residual disease (hazard ratio 7.3; P < .001) and methylenetetrahydrofolate reductase rs1801131 (hazard ratio 3.1; P = .015) with event-free survival in the ALL-BFM 2000 study population. Genetic variations substantially influence the kinetics and response to high-dose MTX therapy in childhood ALL.

THU0126 The Influence of Clinical and Genetic Variables on Methotrexate-Related Toxicity in Portuguese Rheumatoid Arthritis Patients

BackgroundMethotrexate is the cornerstone of treatment of RA1. However, major drawbacks of MTX therapy are the large interpatient variability in clinical response and unpredictable appearance of a large spectrum of...

AB0163 The influence of clinical and genetic variables on methotrexate effectiveness in portuguese rheumatoid arthritis patients

BackgroundMethotrexate is the mainstay DMARD in RA treatment1. Despite its effectiveness, additional DMARDs are often required to achieve the recommended goals of low disease activity/remission1. Given the clinical implications of...

THU0220 Establishment of a Prediction Model for Hepatotoxicity of Methotrexate by Using Dmet Microarray Profiling in Japanese Patients with Rheumatoid Arthritis

BackgroundEfficacy and toxicity of methotrexate (MTX) differs among individual patients, suggesting the influence of genetic variations in enzymes associated with MTX metabolism and folate metabolic pathway. Recent advances in pharmacogenetics...

Methotrexate Pharmacogenetics in Rheumatoid Arthritis: a Status Report

Methotrexate (MTX), an antifolate drug, is the first-line disease-modifying agent for the treatment of rheumatoid arthritis (RA) worldwide. MTX has excellent long-term efficacy, tolerability and safety. Early initiation of MTX in patients with RA controls joint destruction and slows progression of disease. However, the clinical response to MTX and frequency of adverse effects from the drug exhibit marked interpatient variability. Over the past decade, there has been a quest to identify genetic markers that reliably predict MTX efficacy and toxicity and help optimize MTX therapy in RA; that is, the field of MTX pharmacogenetics. This review will summarize key pharmacogenetic studies examining SNPs in the genes encoding enzymes in the MTX cellular pathway and their association with MTX response in RA. As evident from this review, MTX pharmacogenetics in RA remains a muddled field, mostly due to inconsistent results from several small underpowered studies.

Clinical Pharmacogenetics of Methotrexate

It is well known that interindividual variability can affect the response to many drugs in relation to age, gender, diet, and organ function. Pharmacogenomic studies have also documented that genetic polymorphisms can exert clinically significant effects in terms of drug resistance, efficacy and toxicity by modifying the expression of critical gene products (drug-metabolizing enzymes, transporters, and target molecules) as well as pharmacokinetic and pharmacodynamic parameters. A growing body of in vitro and clinical evidence suggests that common polymorphisms in the folate gene pathway are associated with an altered response to methotrexate (MTX) in patients with malignancy and autoimmune disease. Such polymorphisms may also induce significant MTX toxicity requiring expensive monitoring and treatment. Although the available data are not conclusive, they suggest that in the future MTX pharmacogenetics could play a key role in clinical practice by improving and tailoring treatment. This review describes the genetic polymorphisms that significantly influence MTX resistance, efficacy, and toxicity.

Race and Methotrexate Pharmacogenetics in Rheumatoid Arthritis

To the Editor: Fisher and Cronstein are to be commended for their recent metaanalysis on methylenetetrahydrofolate reductase (MTHFR) polymorphisms and methotrexate (MTX) toxicity in rheumatoid arthritis (RA)1. Their work exposes the lack of sound pharmacogenetic data on MTX in RA and underscores that there is a long way to go before MTX pharmacogenetics is ready to guide clinical decision-making in RA. In the discussion, the authors note the paucity of data in the literature to determine whether the presence or absence of a single-nucleotide … Address correspondence to Dr. Ranganathan. E-mail: prangana{at}dom.wustl.edu

Polymorphisms in Methotrexate Pathways: What Is Clinically Relevant, What Is Not, and What Is Promising

Methotrexate (MTX) is a folate inhibitor that is used successfully in treating a great variety of malignancies and autoimmune diseases. However, there are certain drawbacks to its use, as a significant percentage of patients do not respond to the therapy or develop serious adverse effects. In the last ten years there has been a growing body of evidence pointing to the clinical significance of polymorphisms in genes that are involved in the metabolism, transport, and function of folates and MTX. Indeed, many studies have shown that both the toxicity and the efficacy of this drug can be modified by the presence of these genetic alterations. However, there is also a great deal of contradictory evidence that has as yet prevented the acceptance of any definitive conclusions. This review aims to summarize current knowledge on the pharmacogenetics of MTX, dealing with the reasons for numerous reported discrepancies. The particular focus will be on studies analyzing interactions between single nucleotide polymorphisms (SNPs) along a certain pathway rather than following a single-SNP design. New approaches and future directions in the study of MTX pharmacogenetics will also be discussed.

An update on methotrexate

Methotrexate (MTX) has been used for the treatment of rheumatoid arthritis (RA) for about three decades now. MTX is one of the most effective and commonly used medicines to treat various forms of arthritis and other rheumatic conditions. MTX was shown to improve signs and symptoms of RA, disease activity and function, to a similar degree as the tumor necrosis factor blockers, and it inhibits radiographic progression to a smaller degree than the antitumor necrosis factor agents. MTX is considered as the anchor drug among the disease-modifying antirheumatic agents, and it is internationally accepted as the first choice in the management of RA. This review was performed on the basis of a PubMed literature search looking at all publications on MTX and arthritis in 2008. MTX seems to even prolong the life span of patients who tolerate the drug and have clinical benefit from this therapy; this may partly be explained by beneficial effects on cardiovascular mortality. The reason for this may well be the suppression of inflammation, but direct atheroprotective effects of MTX may also play a role. MTX is used as monotherapy and in combination with other disease-modifying antirheumatic agents or biologic agents such as the antitumor necrosis factor agents. The 'early' use of MTX within 5 years after disease onset is clearly associated with improved outcomes. The management of RA should include an early strong suppression of inflammation and continuously a tight control strategy. The pharmacodynamics and kinetics of MTX are still incompletely understood. In this review, we especially cover the following themes: new clinical studies on the use of MTX in RA, the use of MTX in other rheumatic conditions, prediction of response to MTX, optimal dosage, MTX use in the elderly, the mechanism of action, the pharmacokinetics and the pharmacogenetics of MTX, the prevention of side effects, and the overall long-term safety.

An Update on Methotrexate Pharmacogenetics in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the joints. When left untreated, the disease can result in irreversible joint damage with high morbidity and mortality. Disease-modifying antirheumatic drugs are the cornerstones of treatment in RA. Disease-modifying antirheumatic drugs not only ameliorate the clinical signs and symptoms of disease, but also prevent the radiographic progression of joint damage. Methotrexate is one such disease-modifying antirheumatic drug that has been used in the treatment of RA for over two decades with excellent long-term efficacy and safety. However, there is significant variability in patients' response to methotrexate, both in terms of efficacy and toxicity. At the present time, there are no reliable means of predicting, a priori, an individual patient's response to methotrexate. In this review, recent published literature on the pharmacogenetics of methotrexate in RA is highlighted. Pharmacogenetics may be a powerful tool for optimizing methotrexate therapy in patients with RA.

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Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the joints. Despite the availability of the new biological agents such as TNF-blocking agents, methotrexate (MTX) remains as the primary agent for the treatment of RA due to the low and broad experience with its use. The efficacy and adverse drug reactions of MTX are variable among patients, and this is partially contributed in genetic difference of drug-metabolizing enzymes, transporters, and receptors In this review, we described MTX pharmacogenetics that was related to a large interindividual variation on efficacy and adverse drug reactions in RA patients, including MTX transporter pharmacogenetics, MTX glutamation pharmacogenetics, folate pathway pharmacogenetics, and adenosine pathway pharmacogenetics. We also described the clinical implications between their pharmacogenetics and clinical outcomes (efficacy and/or adverse drug reactions of MTX)

The pharmacogenetics of methotrexate

Methotrexate (MTX) is a cornerstone of therapy for rheumatoid arthritis. However, it is not universally effective and up to one-third of patients fail to respond to treatment, either because of inefficacy or adverse events, although at present it is not possible to predict therapy response accurately. Pharmacogenetics is the study of variability in drug response due to heredity. MTX has a complex intracellular metabolism and acts via a number of key enzymes. This review critically appraises the studies of MTX pharmacogenetics and highlights the need for further work in this area.