Risk factors for abnormal hepatic enzyme elevation by methotrexate treatment in patients with rheumatoid arthritis: A hospital based-cohort study

Hakamata, Jun; Hashiguchi, Masayuki; Kaneko, Yuko; Yamaoka, Kunihiro; Shimizu, Mikiko; Maruyama, Junya; Takeuchi, Tsutomu; Mochizuki, Mayumi

doi:10.1080/14397595.2017.1414765

Cited by 14 publications

(9 citation statements)

References 37 publications

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“…A total of 862 citations were collected from electronic databases, and, after excluding duplicates, screening titles and abstracts, and reading full articles, a total of 39 articles were included. 8,9,26-62 The study selection process is presented in Figure 1. The main characteristics of studies are summarized in Additional file 1: Table S1.…”

Section: Resultsmentioning

confidence: 99%

“…8 Interindividual differences in susceptibility to adverse events are suggested to be due to genetic polymorphisms related to the capacity of transporters and enzymes that mediate the biotransformation and accumulation/elimination of MTX in the body. 9 Therefore, identifying predictors of MTX toxicity is important for the management of RA to achieve individualized treatment. Accumulating evidence suggests associations between gene polymorphisms and MTX toxicity in RA patients.…”

Section: Introductionmentioning

confidence: 99%

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Are gene polymorphisms related to adverse events of methotrexate in patients with rheumatoid arthritis? A retrospective cohort study based on an updated meta-analysis

Huang

Fan

Qiu

et al. 2020

Therapeutic Advances in Chronic Disease

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Aims: We performed an updated meta-analysis to verify correlations between gene polymorphisms and adverse events in methotrexate (MTX)-treated rheumatoid arthritis (RA) patients. Then, we conducted a retrospective cohort study of Han Chinese in China. Methods: Relevant studies were collected from the PubMed database and the EMBASE database until December 2017. Pre-allele, dominant, recessive, codominant, and homozygotic models were applied. In addition, a retrospective cohort study enrolling 162 RA patients treated with MTX was conducted. Single nucleotide polymorphism (SNP) genotyping was analyzed by PCR and product sequencing. Results: A total of 39 studies were included in 20 meta-analyses; meta-analysis showed a significant association between MTX-related toxicity and 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T(rs1801133) polymorphism in East Asian RA patients, and significant associations were observed between MTX-related toxicity and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) 347C>G (rs2372536), reduced folate carrier 1 (RFC-1) 80G>A (rs1051266), and adenosine triphosphate-binding cassette B1 (ABCB1) 3435C>T(rs1045642) polymorphisms in European RA patients but not in East Asian RA patients. Moreover, in our retrospective cohort study, ATIC 347C>G(rs2372536) and ABCB1 3435C>T(rs1045642) polymorphisms were not associated with MTX-related toxicity. However, a significant association was observed between MTX-related toxicity and RFC-1 80G>A (rs1051266) polymorphism in Chinese Han RA patients. Conclusion: Evidence-based results suggest that the MTHFR 677C>T(rs1801133), ATIC 347C>G(rs2372536), RFC-1 80G>A (rs1051266), ABCB1 3435C>T(rs1045642) polymorphisms are associated with MTX-related toxicity. Larger and more stringent study designs may provide more accurate findings for the effects of these SNPs on MTX-related toxicity, and larger sample-size studies of the Chinese Han population should be conducted for further validation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Are gene polymorphisms related to adverse events of methotrexate in patients with rheumatoid arthritis? A retrospective cohort study based on an updated meta-analysis

Huang

Fan

Qiu

et al. 2020

Therapeutic Advances in Chronic Disease

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“…It has been reported that TYMS 28bp VNTR ( Baggott et al, 1986 ), MTHFR 677C>T ( Berkun et al, 2004 ; Caliz et al, 2012 ; Berkani et al, 2017 ), MTHFR 1298A>C ( Berkun et al, 2004 ; Davis et al, 2014 ; Berkani et al, 2017 ), ATIC 347C>G ( Muralidharan et al, 2016 ; Hakamata et al, 2018 ), MTR A2756G ( Nikbakht et al, 2012 ) and MTRR 66A>G ( Dervieux et al, 2006 ) may be associated with MTX toxicity. A study of 273 Caucasian patients with RA treated with MTX for at least 6 months showed that there were no associations between TYMS gene polymorphisms and the toxicity of MTX treatment ( Swierkot et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms of TYMS, MTHFR, ATIC, MTR, and MTRR Are Related to the Outcome of Methotrexate Therapy for Rheumatoid Arthritis in a Chinese Population

Liu

Fan²,

et al. 2018

Front. Pharmacol.

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Objective: Analysis of the relationship between single nucleotide polymorphisms (SNPs) and outcomes of methotrexate (MTX) therapy for rheumatoid arthritis (RA) in China.Materials and Methods: TYMS 28 bp VNTR (rs34743033), MTHFR [677C>T (rs1801133) and 1298A>C (rs1801131)], ATIC 347C>G (rs2372536), MTR A2756G (rs1805087), and MTRR 66A>G (rs1801394) enzyme proteins may be related to the outcomes of MTX therapy, according to our previous meta-analysis. A total of 162 patients with RA were included in our study. SNPs were evaluated using polymerase chain reaction (PCR). Disease Activity Score 28 (DAS28) was used to evaluate the clinical response, and adverse drug reactions (ADRs) were collected after physical examinations of the patients.Results: The MTHFR 677C>T gene showed a relationship with the ADRs of MTX in the Recessive model [TT vs. (CC+CT)] (p = 0.04, OR = 2.20, 95% CI: 1.01, 4.77). In the Codominant model [CT vs. (CC+TT)], the MTHFR 677C>T gene also showed a trend of association with ADRs (p = 0.08, OR = 0.52, 95% CI: 0.25, 1.08). No significant difference was found between TYMS, MTHFR, ATIC, MTR, and MTRR gene polymorphisms and the RA response or ADRs related to MTX in our study.Conclusion: Our results showed that the MTHFR [677C>T (rs1801133)] TT genotype is associated with ADRs to MTX in Chinese RA patients. Other SNPs, including TYMS 28bp VNTR (rs34743033), MTHFR [677C>T (rs1801133) and 1298A>C (rs1801131)], ATIC 347C>G (rs2372536), MTR A2756G (rs1805087), and MTRR 66A>G (rs1801394) gene polymorphisms, were not associated with MTX treatment outcomes. Further studies are required to validate these findings.

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“…Polymorphisms in genes encoding transporters and enzymes mediating the biotransformation and elimination of MTX have been suggested as one cause of adverse events [ 7 ]. In fact, several studies have shown that two single-nucleotide polymorphisms (SNPs) (rs1891133 and rs1801131) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, which is involved in the intracellular MTX pathway, are associated with MTX toxicity [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis

Contreras

López-Medina

Estévez

et al. 2021

JCM

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Objective: to identify new single-nucleotide polymorphisms (SNPs) in genes encoding proteins involved in methotrexate (MTX) metabolism and to evaluate the associations of these SNPs with MTX toxicity or intolerance in a southern Spanish cohort of patients with rheumatoid arthritis (RA). Methods: An observational, retrospective, and multicenter study was conducted at three participating hospitals in southern Spain. The main variable was intolerance to MTX (i.e., bDMARD monotherapy), defined as an interruption of treatment due to adverse events or toxicity. Patients being treated with MTX and bDMARDs (combined treatment) at the time of the study visit were considered “tolerant” of MTX. Ten polymorphisms were selected for sequencing in our patients according to a literature review. Each polymorphism was classified according to three possible genotypes (e.g., two homozygous (AA or GG) and one heterozygous (AG)), and the association of these combinations with MTX intolerance was evaluated. Results: A total of 227 patients were included in the final analysis (107 intolerant of MTX and 120 tolerant). A significant association was observed between MTX intolerance and the GGH-T401C AA/AG genotype (OR 2.13, 95% CI 1.06–4.29) in comparison with the GG genotype. On the other hand, an inverse association was observed between the ABCC2-C24T TT/TC genotype and intolerance to MTX (OR 0.59, 95% CI 0.35–1.00) in comparison with the CC genotype. Conclusion: This study provides new data on the association between genetic polymorphisms and MTX intolerance, which may contribute to the development of new biomarkers and personalized medicine in patients with RA.

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Risk factors for abnormal hepatic enzyme elevation by methotrexate treatment in patients with rheumatoid arthritis: A hospital based-cohort study

Abstract: MTX-induced abnormal hepatic enzyme elevation in Japanese RA patients was associated with dosage and eGFR as nongenetic factors, and with ABCB1 3435C>T and ATIC 347C>G as genetic factors in this hospital-based cohort study.

Cited by 14 publications

References 37 publications

Are gene polymorphisms related to adverse events of methotrexate in patients with rheumatoid arthritis? A retrospective cohort study based on an updated meta-analysis

Are gene polymorphisms related to adverse events of methotrexate in patients with rheumatoid arthritis? A retrospective cohort study based on an updated meta-analysis

Genetic Polymorphisms of TYMS, MTHFR, ATIC, MTR, and MTRR Are Related to the Outcome of Methotrexate Therapy for Rheumatoid Arthritis in a Chinese Population

Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis

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