Methotrexate-induced nausea and vomiting in adolescent and young adult patients

Patil, Pravin; Parker, Richard; Rawcliffe, Christine; Olaleye, Abigail; Moore, Samantha; Daly, Nicola; Sen, Debajit; Ioannou, Yiannis

doi:10.1007/s10067-013-2389-x

Cited by 40 publications

(40 citation statements)

References 7 publications

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“…MTX intolerance is much more frequent in younger patients than in adults [ 14 ]. It mostly occurs within the first year of treatment and worsens over time [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Mutations in the MTHFR gene are not associated with Methotrexate intolerance in patients with juvenile idiopathic arthritis

et al. 2016

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BackgroundMethotrexate (MTX) intolerance is a frequent problem of long-term treatment in juvenile idiopathic arthritis (JIA). Mutations in the methylentetrahydrofolate reductase (MTHFR) gene may increase toxicity of MTX, potentially constituting an initial stimulus for this conditioned response. The objective of this study was to investigate the relationship of common MTHFR gene mutations and occurrence of MTX intolerance in pediatric patients with JIA treated with MTX.MethodsConsecutive JIA patients on at least 3 months of MTX treatment were included in this study. Intolerance to MTX was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire, and MTX intolerance was defined as MISS values of ≥ 6. Presence of the two most common mutations in the MTHFR gene (C677T and A1298C) was tested using a PCR assay. Results were analyzed using descriptive and non-parametric statistics.Results196 patients were included (73 % female). Of those, 93 (46 %) showed MTX intolerance. 168 patients were genotyped for C677T and A1298C. MTX intolerance was not found to be significantly more frequent among patients with hetero- and homozygous or homozygous mutations C677T or A1298C compared to wild type or heterozygous mutations. Analysis of the correlation between numbers of mutations in these two loci to the MISS score did not yield a statistically significant correlation.ConclusionMutations in the MTHFR gene were not found to be significantly more frequent in JIA patients intolerant to MTX. Toxicity associated with the MTHFR gene seems to result from mechanisms different to those involved in clinical MTX intolerance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12969-016-0071-y) contains supplementary material, which is available to authorized users.

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“…MTX intolerance is much more frequent in younger patients than in adults [ 14 ]. It mostly occurs within the first year of treatment and worsens over time [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Mutations in the MTHFR gene are not associated with Methotrexate intolerance in patients with juvenile idiopathic arthritis

et al. 2016

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“… ? + Outcome: MTX adverse effects [ 34 ] Prospective + + +/− + + + + + [ 18 ] Prospective + + +/− + + + ? ?…”

Section: Methodsmentioning

confidence: 99%

Prediction of methotrexate efficacy and adverse events in patients with juvenile idiopathic arthritis: a systematic literature review

Dijkhuizen

Wulffraat

2014

Pediatr Rheumatol

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BackgroundMethotrexate (MTX) is the cornerstone disease-modifying anti-rheumatic drug in juvenile idiopathic arthritis (JIA). In JIA, it is important to start effective treatment early to avoid long-term sequelae, such as joint damage. To accomplish this goal, it is crucial to know beforehand who is going to respond well to MTX. In addition, MTX adverse effects such as MTX intolerance occur frequently, potentially hindering its efficacy. To avoid inefficacy of an otherwise effective drug, the physician should be timely aware of these adverse events. Consequently, to optimise treatment of JIA patients with MTX, predictors for efficacy and adverse events should be used in daily clinical practice. The aim of this study was to summarise the existing knowledge about such predictors.MethodsA systematic literature search was performed in PubMed, Embase and The Cochrane Library, and 1,331 articles were identified. These were selected based on their relevance to the topic and critically appraised according to pre-defined criteria. Predictors for MTX efficacy and adverse events were extracted from the literature and tabulated.ResultsTwenty articles were selected. The overall quality of the studies was good. For MTX efficacy, candidate predictors were antinuclear antibody positivity, the childhood health assessment questionnaire score, the myeloid-related protein 8/14 level, long-chain MTX polyglutamates, bilateral wrist involvement and some single nucleotide polymorphisms (SNPs) in the adenosine triphosphate binding cassette and solute carrier transporter gene families. For MTX adverse events, potential predictors were alanine aminotransferase and thrombocyte level and two SNPs in the γ-glutamyl hydrolase and methylenetetrahydrofolate reductase genes. However, validation of most predictors in independent cohorts was still lacking.ConclusionsInteresting candidate predictors were found, especially for MTX efficacy. However, most of these were not validated. This should be the goal of future efforts. A clinically relevant way to validate the predictors is by means of creating a clinical prediction model.Electronic supplementary materialThe online version of this article (doi:10.1186/1546-0096-12-51) contains supplementary material, which is available to authorized users.

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“…Large inter-individual variation exists in the level of MTX-induced nausea among children with JIA. From mild discomfort to a level of MTX-induced nausea that affects health-related quality of life to such an extent that premature termination is necessary (4)(5)(6). Genetic factors are thought to in uence the inter-individual variation in MTX-induced nausea.…”

Section: Background and Hypothesismentioning

confidence: 99%

Single Nucleotide Polymorphisms Associated with Methotrexate-induced Nausea in Juvenile Idiopathic Arthritis

Kyvsgaard

Mikkelsen

Als

et al. 2020

Preprint

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BackgroundContext: Methotrexate (MTX) is a cornerstone in the treatment of juvenile idiopathic arthritis (JIA). MTX treatment is commonly associated with nausea. Large inter-individual variation exists in the level of MTX-induced nausea, possibly due to genetic factors. Purpose: To investigate whether MTX-induced nausea was associated with single nucleotide polymorphisms (SNPs) in genes encoding MTX-transporter proteins, a MTX metabolizing enzyme and a nausea receptor.FindingsMethods: Children aged ≥9 years treated with MTX for JIA were eligible. MTX-induced nausea was registered by the children’s completion of a nausea diary (min. 7 days) and the parents’ completion of the MTX intolerance severity score (MISS). The selected SNPs were: SLCO1B1 (rs4149056; rs4149081), SLCO1B3 (rs2117032), SLC19A1 (rs1051266), ABCC2 (rs2273697; rs3740066; rs717620), ABCB1 (rs2032582; rs1045642), MTHFR (rs1801131, rs1801133), HTR3A (rs1062613; rs1985242; rs1176713) and HTR3B (rs1176744). Results: Enrolled were 121 JIA patients (82 girls: 39 boys) with a median age of 13.3 years (IQR: 11.3-15.1). The median MTX dose was 9.7 mg/m2/week (IQR: 9.0-10.9). The median MTX treatment duration prior to enrolment was 340 days (IQR: 142-766). The SNP analysis was available for 119 patients. MTX intolerance was associated with the genotype distribution of rs1801133 (MTHFR) (p= 0.02). There was no additive effect of the minor alleles for any of the selected SNPs, nor any significant haplotype associations. Conclusion Summary: MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR). Implications: Further analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.

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Methotrexate-induced nausea and vomiting in adolescent and young adult patients

Cited by 40 publications

References 7 publications

Mutations in the MTHFR gene are not associated with Methotrexate intolerance in patients with juvenile idiopathic arthritis

Mutations in the MTHFR gene are not associated with Methotrexate intolerance in patients with juvenile idiopathic arthritis

Prediction of methotrexate efficacy and adverse events in patients with juvenile idiopathic arthritis: a systematic literature review

Single Nucleotide Polymorphisms Associated with Methotrexate-induced Nausea in Juvenile Idiopathic Arthritis

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