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.
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.
Project description: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.
Project description:AimsWe investigated whether several polymorphisms within the methotrexate (MTX) pathway genes were related to the toxicity and efficacy of MTX in 92 Japanese patients with articular-type juvenile idiopathic arthritis (JIA).MethodsEight gene polymorphisms within the MTX pathway genes, namely, RFC, BCRP, MTHFR (two), FPGS, γ-glutamyl hydrolase (GGH; two) and ATIC, were genotyped using TaqMan assays. Liver dysfunction was defined as an increase in alanine transaminase to five times the normal upper limit. Non-responders to MTX were defined as patients refractory to MTX and were therefore treated with biologics.ResultsThe non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction (P=0.028, odds ratio=6.90, 95% confidence interval 1.38-34.5), even after adjustment for the duration of MTX treatment. A longer interval from disease onset to treatment (8.5 and 21.3 months, P=0.029) and rheumatoid factor positivity (P=0.026, odds ratio=2.87, 95% confidence interval 1.11-7.39) were associated with lower efficacy of MTX.ConclusionsThe non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction, presumably because the C allele of GGH C16T may reduce the activity of GGH. The time interval before MTX treatment and rheumatoid factor positivity were associated with the efficacy of MTX treatment. The pharmacogenetics of the MTX pathway genes affects the toxicity and efficacy of MTX in Japanese JIA patients.
Project description:This analysis aims to calculate MTX monotherapy persistence and describe the occurrence of and factors associated with the occurrence of adverse drug reactions (ADRs) with MTX. Patients with JIA starting MTX monotherapy from two UK studies were included. Patient characteristics, treatment details and ADR occurrence were collected at treatment start, 6 months, 1 year and annually. The following groups of ADRs were included: gastrointestinal, elevated liver enzymes, leukopenia, drug hypersensitivity, rash, needle phobia and any events leading to permanent MTX discontinuation. Treatment exposure was calculated from MTX start until MTX monotherapy cessation, last follow-up or 31 December 2017 (cut-off), whichever came first. Survival analysis assessed the time on MTX monotherapy and the time to the first ADR on MTX monotherapy within 2 years. Multivariable logistic regression assessed characteristics associated with any ADR and gastrointestinal ADRs. A total of 577 patients started MTX. At 2 years, 310 (54%) were no longer on MTX monotherapy. Reasons included ineffectiveness (60%; 161/185 started a biologic), adverse event (25%), remission (8%) and patient/family decision (3%). Over this time, 212 (37%) patients experienced one or more ADR; commonly gastrointestinal (68%) or elevated liver enzymes (26%). Lower physician global assessment and older age predicted any ADR and gastrointestinal ADR, respectively. Patients with polyarticular RF and JIA had reduced odds of both any ADR and a gastrointestinal ADR. After 2 years, more than half the patients were no longer on MTX monotherapy, while more than one-third experienced one or more ADR, most commonly gastrointestinal. Research focusing on identifying which children will respond and/or experience ADRs is crucial to inform treatment decisions and management planning.
Project description:Folates exist as a fluctuating pool of polyglutamated metabolites that may serve as a clinical marker of methotrexate (MTX) activity. This study was undertaken to evaluate circulating folate content and folate polyglutamate distribution in juvenile idiopathic arthritis (JIA) patients and in a cell culture model based on MTX exposure and folate supply.Blood, plasma, and red blood cell (RBC) measurements of MTX and folates were obtained from previously published data sets and an additional analysis of JIA patients receiving MTX (n = 98) and those not receiving MTX (n = 78). Erythroblastoid cells maintained in culture were exposed to MTX and grown under varying levels of folic acid supplementation. Samples were analyzed for cellular folate and MTX content.Circulating folate levels were lower in JIA patients receiving MTX, with reduced levels of blood, plasma, and RBC 5-methyl-tetrahydrofolate (5mTHF) (P < 0.0001). Average polyglutamate chain length (Gluavg ) of RBC 5mTHF was elevated in JIA patients receiving MTX (median ± interquartile range 5.63 ± 0.15 versus 5.54 ± 0.11 in those not receiving MTX; P < 0.001) and correlated with both RBC MTX accumulation (P = 0.02) and reduced plasma 5mTHF levels (P = 0.008). MTX exposure and folate deprivation in erythroblastoid cells resulted in a depletion of bioactive folate species that was associated with a shift to higher Gluavg values for several species, most notably tetrahydrofolate (THF) and 5,10-methylene-tetrahydrofolate (CH2 THF). Increased Gluavg resulted from the depletion of short-chain and the accumulation of long-chain glutamate species.Our findings indicate that folate content and polyglutamate distribution are responsive markers of MTX activity and folate supply in vivo and in vitro, and may provide novel clinical markers of pharmacologic activity of MTX.
Project description:ObjectivesMethotrexate (MTX) is one of the most frequently used, highly effective disease-modifying drugs in juvenile idiopathic arthritis (JIA) therapy. The drug can be administered orally or subcutaneously, but the efficacy and tolerance of these two routes of administration raise doubts in JIA patients. The aim of the study was to evaluate MTX efficacy and tolerability after switching from the oral to the subcutaneous route of administration in children with JIA.Material and methodsA single-centre, questionnaire-based assessment of MTX efficacy and tolerance in 126 unselected JIA patients with longer than 6 months of follow-up was performed. In all patients, MTX was initially administered orally. The response to MTX treatment was analysed according to American College of Rheumatology (ACR) paediatric criteria.ResultsSix-month MTX therapy was effective (ACR score ≥ 30) in 83 children (65.9%). The oral route of MTX administration was changed to subcutaneous in 32 patients after a mean period of 14 months due to intolerance (n = 20) or reluctance to take the oral formulation (n = 12). This group of children was significantly younger (p = 0.02) but did not differ from the group of children that continued oral treatment in other aspects, including MTX dose. Six months after switching from oral to subcutaneous MTX the ACR score remained unchanged. Three children (9.4%) still reported symptoms of drug intolerance.ConclusionsThe switch from oral to subcutaneous MTX may increase the response rate in JIA patients with intolerance of its oral formulation. The reluctance to take oral MTX can be anticipated in early childhood, and should be considered in the individualization of therapy, having also in mind the lower risk of severe gastrointestinal adverse drug reactions.
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.