Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis

Dervieux, Thierry; Greenstein, Neal S.; Kremer, Joel M.

doi:10.1002/art.22129

Cited by 175 publications

(151 citation statements)

References 34 publications

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“…In the present study, 93.75% of the patients with relapse were carriers of the T allele (Table III); this agrees with previous experimental studies, which identified the T allele as a risk for relapse to ALL (28). This suggests that the presence of the -A317G and C829T polymorphisms, and the strong association with the risk of relapse (p<0.05) (Table IV) may be a factor that led to more than 50% of deaths in the patients with ALL included in this study.…”

Section: Discussionsupporting

confidence: 93%

Survival and risk of relapse of acute lymphoblastic leukemia in a Mexican population is affected by dihydrofolate reductase gene polymorphisms

Gómez‐Gómez

Organista‐Nava

Saavedra‐Herrera

et al. 2012

Experimental and Therapeutic Medicine

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Abstract. Dihydrofolate reductase (DHFR) is the major target of methotrexate, a key component in childhood acute lymphoblastic leukemia (ALL) treatment. Polymorphisms in the gene coding for DHFR have been associated with adverse event treatment. This study evaluated the effect of the -A317G and C829T polymorphisms in the DHFR gene on survival and risk of relapse of ALL. Seventy patients with ALL and 100 healthy individuals were genotyped by the polymerase chain reactionrestriction fragment length polymorphism method. An association between the polymorphisms and the risk of relapse was found (p<0.05); patients with the -317G/G genotype were found to have an 8.55 (95% CI 1.84-39.70) higher chance of relapse and carriers of the 829T/T genotype had a 14.0 (95% CI 1.13-172.63) higher chance of relapse. Other variables, such as age and leukocyte count, were associated (p<0.05) with the risk of relapse of the disease. Individuals with the G/G and T/T genotype of the -A317G and C829T polymorphisms had poorer survival compared to other genotype groups (log-rank test; p<0.05). Although preliminary, these data seem to suggest a role for the DHFR polymorphisms in the risk of relapse of ALL and the mortality risk in these patients. IntroductionIn Mexico, acute leukemia is considered a public health issue; it represents the fourth leading cause of mortality of all neoplastic malignancies in children under 15 years of age (1). The mortality rate from 1996 to 2000 was 63.7 per 1 million children, one of the highest rates reported in the world (2). In 2005, leukemia was the second cause of mortality in the State of Guerrero in children less than 15 years of age, according to the National Institute of Statistics, Geography and Computing (INEGI) (3).Methotrexate (MTX) is an antineoplastic agent used in the treatment of patients with acute lymphoblastic leukemia (ALL) and was introduced five decades ago to clinical oncology. It is presently used in the treatment of other neoplastic diseases, including osteosarcoma, breast cancer, head and neck cancer, and non-Hodgkin's lymphoma (4,5). MTX is a folic acid antagonist, and its efficacy as an antineoplastic treatment is largely attributed to its high affinity for dihydrofolate reductase (DHFR) (EC 1.5.1.3), the enzyme which is responsible to catalyze the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) (6). The major mechanism of MTX action involves competitive inhibition of DHFR, leading to the impaired regeneration of THF from DHF; essential for the biosynthesis of purines and thymidylate, thus it also blocks the novo synthesis of DNA (7,8). A subset of patients develop adverse events of resistance to MTX; however, approximately 80% of ALL children experience good clinical response (5,9,10).The mechanisms that lead to clinical failure to MTX are DHFR overexpression, impaired intracellular transport and decreased levels of reduced folate carrier at the cell membrane (11,12). Changes in the levels of DHFR expression and consequently in the sensitivity to MTX can also be due t...

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Section: Discussionsupporting

confidence: 93%

Survival and risk of relapse of acute lymphoblastic leukemia in a Mexican population is affected by dihydrofolate reductase gene polymorphisms

Gómez‐Gómez

Organista‐Nava

Saavedra‐Herrera

et al. 2012

Experimental and Therapeutic Medicine

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“…To address this question, we determined the frequency of Tregs and CD39 + Tregs, as well as the density of CD39 expression on Tregs in RA patients before and after MTX treatment (at least 3 mo of MTX administration at doses ≥15 mg/wk). First, we demonstrated that the MTX resistance is not a consequence of a low availability of intracellular active MTX (22,23). We measured total MTX polyglutamate metabolites levels in erythrocytes from RA patients treated at least 3 mo with MTX.…”

Section: Resultsmentioning

confidence: 98%

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

Peres¹,

Liew

Talbot³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

116

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Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4 + CD25 + FoxP3 + ) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39 + CD4 + CD25 + FoxP3 + Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control (P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients.methotrexate | rheumatoid arthritis | adenosine | biomarker | ectonucleotidases

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“…It must be realized that other studies have shown an association between SHMT 1420CϾT, MTHFR 677CϾT, and MTHFR 1298AϾC with MTX efficacy (19,22). Due to our multiple stepwise backward statistical approach, only those factors contributing most to MTX efficacy at 6 months of treatment were selected.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, the influences of demographic, clinical, immunologic, and genetic factors on the state of disease in patients with RA have been studied (10)(11)(12)(13)(14)(15)(16)(17)(18). Specifically, polymorphisms in genes coding for methylenetetrahydrofolate reductase (MTHFR), adenosine monophosphate deaminase (AMPD1), aminoimidazole carboxamide ribonucleotide transformylase (ATIC), serine hydroxymethyltransferase 1 (SHMT1), and inosine triphosphate pyrophosphatase (ITPA) demonstrate association with the MTX response (19)(20)(21)(22). Nongenetic factors such as low disease activity at baseline, male sex, treatment with nonsteroidal antiinflammatory drugs (NSAIDs), and lower levels of creatinine clearance are also related to the efficacy of MTX (23).…”

mentioning

confidence: 99%

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

Wessels

Kooij

Cessie

et al. 2007

Arthritis & Rheumatism

221

152

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Objective. To develop a clinical pharmacogenetic model to predict the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA).Methods. Two hundred five patients with newly diagnosed RA and active disease were treated with MTX (initiated at a dosage of 7.5 mg/week and increased to 15 mg/week after 4 weeks) and folic acid (1 mg/day). If the Disease Activity Score (DAS) was >2.4 at 3 months, the dosage of MTX was increased up to 25 mg/week. Twenty-four baseline variables possibly influencing disease state and drug response were selected. In addition, 17 polymorphisms in 13 genes related to the MTX mechanism of action, purine and pyrimidine synthesis, were determined. Factors were compared between responders (defined as patients with a DAS <2.4 at 6 months) and nonresponders. In case of differences, a stepwise selection procedure identified the predictors for response. A clinical score was designed by simplifying regression coefficients of the independent variables. Cutoff levels were chosen based on the clinical score, and positive and negative response rates were calculated. An evaluation of the model was performed in a second group of patients.Results. The model for MTX efficacy consisted of sex, rheumatoid factor and smoking status, the DAS, and 4 polymorphisms in the AMPD1, ATIC, ITPA, and MTHFD1 genes. This prediction model was transformed into a scoring system ranging from 0 to 11.5. Scores of <3.5 had a true positive response rate of 95%. Scores of >6 had a true negative response rate of 86%. Sixty percent of the patients were categorized as either responders or nonresponders, whereas 32% of the patients were categorized using a nongenetic model. Evaluation of the model in 38 additional patients with RA supported the results.Conclusion. This study established a model for predicting the efficacy of MTX in patients with RA. This pharmacogenetic model may lead to better-tailored initial treatment decisions in patients with RA.

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Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis

Cited by 175 publications

References 34 publications

Survival and risk of relapse of acute lymphoblastic leukemia in a Mexican population is affected by dihydrofolate reductase gene polymorphisms

Survival and risk of relapse of acute lymphoblastic leukemia in a Mexican population is affected by dihydrofolate reductase gene polymorphisms

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

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