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PReS-FINAL-2165: Pharmacogenetic determinants of response to methotrexate in juvenile idiopathic arthritis

ABSTRACT:

SUBMITTER: Pastore S

PROVIDER: S-EPMC4042611 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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PReS-FINAL-2155: Genetic variability of methotrexate transporters in patients with juvenile idiopathic arthritis

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Genetic determinants for methotrexate response in juvenile idiopathic arthritis.

Project description:Juvenile idiopathic arthritis (JIAs) is the most common chronic rheumatic disease of childhood and is an important cause of disability. The folic acid analog methotrexate is the first choice disease-modifying anti-rheumatic drug in this disease, however, 35-45% of patients fail to respond. Molecular elements, such as variants in genes of pharmacological relevance, influencing response to methotrexate in JIA, would be important to individualize treatment strategies. Several studies have evaluated the effects of candidate genetic variants in the complex pathway of genes involved in methotrexate pharmacodynamics and pharmacokinetics, however, results are still contrasting and no definitive genetic marker of methotrexate response useful for the clinician to tailor therapy of children with JIA has been identified. Recently, genome-wide approaches have been applied, identifying new potential biological processes involved in methotrexate response in JIA such as TGF-beta signaling and calcium channels. If these genomic results are properly validated and integrated with innovative analyses comprising deep sequencing, epigenetics, and pharmacokinetics, they will greatly contribute to personalize therapy with methotrexate in children with JIA.

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Nicotinamide Phosphoribosyltransferase Attenuates Methotrexate Response in Juvenile Idiopathic Arthritis and In Vitro.

Project description:Variability in response to methotrexate (MTX) in the treatment of juvenile idiopathic arthritis (JIA) remains unpredictable and poorly understood. Based on previous studies implicating an interaction between nicotinamide phosphoribosyltransferase (NAMPT) expression and MTX therapy in inflammatory arthritis, we hypothesized that increased NAMPT expression would be associated with reduced therapeutic response to MTX in patients with JIA. A significant association was found between increased plasma concentrations of NAMPT and reduced therapeutic response in patients with JIA treated with MTX. Inhibition of NAMPT in cell culture by either siRNA-based gene silencing or pharmacological inhibition with FK-866 was found to result in a fourfold increase in the pharmacological activity of MTX. Collectively, these findings provide evidence that NAMPT inhibits the pharmacological activity of MTX and may represent a predictive biomarker of response, as well as a therapeutic target, in the treatment of JIA with MTX.

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Predictors of lack of response to methotrexate in juvenile idiopathic arthritis associated uveitis.

Project description:ObjectivesTo investigate clinical features associated with lack of response to MTX in juvenile idiopathic arthritis associated uveitis (JIA-U).MethodsClinical records of JIA-U patients were retrospectively reviewed. Differences among variables were assessed by Mann-Whitney and χ2 or Fisher's exact tests as appropriate. Association between predictors and requirement of a biological disease-modifying antirheumatic drug (bDMARD) was evaluated by univariate Cox regression analysis and Kaplan-Meier curves. A multivariable logistic model was applied to estimate strength of association, adjusting for potential confounders.ResultsData from 99 JIA-U patients treated with MTX were analysed (82.8% female), with a mean follow up of 9.2 years and a mean age at uveitis onset of 5.7 years. In 65 patients (65.7%) at least one bDMARD to control uveitis was required. Children requiring a bDMARD for uveitis had lower age at JIA and uveitis onset, more frequent polyarticular course, higher frequency of bilateral uveitis at onset and higher prevalence of systemic steroids' use. Despite similar frequency of ocular damage at onset, MTX non-responders showed a higher percentage of ocular damage at last visit. Younger age at JIA onset, polyarticular course and a history of systemic steroids' use resulted independent factors associated to lack of response to MTX at Cox regression analysis. Kaplan-Meier curves and the multivariate model confirm the independent role of both polyarticular course and systemic steroids' use.ConclusionsYounger age at JIA onset, polyarticular course and a history of systemic steroids' use are predictors of a worse response to MTX in JIA-U.

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Metabolic Markers of Methotrexate Response in Juvenile Idiopathic Arthritis

Project description:Plasma from children with juvenile idiopathic arthritis collected pre-treatment and following 3 months of treatment with methotrexate were submitted for metabolomic profiling to the NIH West Coast Metabolomics Center.

2021-05-18 | ST001815 | MetabolomicsWorkbench

Methotrexate-induced nausea in the treatment of juvenile idiopathic arthritis.

Project description:Methotrexate is the most commonly used disease modifying antirheumatic drug in the treatment of juvenile idiopathic arthritis and can be effective in controlling disease in many patients.A significant proportion of patients experience nausea and vomiting induced by methotrexate therapy, which can lead to decreased quality of life and discontinuation of treatment with methotrexate. Many strategies have been employed in attempts to reduce methotrexate-induced nausea, including folate supplementation, switching from oral to subcutaneous methotrexate, anti-emetic therapy, behavioral therapy, and others. Anticipatory nausea can be difficult to treat, making primary prevention of nausea with anti-emetics an attractive approach.Understanding the prevalence and impact of methotrexate-induced nausea, as well as potentially effective interventions, may help maximize the therapeutic benefits of methotrexate.

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Single nucleotide polymorphisms associated with methotrexate-induced nausea in juvenile idiopathic arthritis.

Project description: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.PurposeTo 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).ResultEnrolled 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.ConclusionSummary: MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR).ImplicationsFurther analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.

| S-EPMC8017639 | biostudies-literature

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