Factors Predicting the Therapeutic Response to Methotrexate in Japanese Patients with Rheumatoid Arthritis: A Hospital-Based Cohort Study

Abstract

Methotrexate (MTX) is used widely as a first-line drug for the treatment of rheumatoid arthritis (RA) worldwide. There are large interindividual differences in the therapeutic response to MTX, but it is not known which factors influence them. We therefore investigated predictive factors associated with the therapeutic response to MTX in a hospital-based cohort study. Japanese adult RA outpatients prescribed MTX were enrolled and their characteristics were collected from the electronic medical records. The European League Against Rheumatism (EULAR) response criteria were used as the response to MTX therapy. The observation period was 1 year after beginning MTX administration. Sixteen types of single-nucleotide polymorphisms were investigated using the real-time PCR method. Associations between the MTX response and patient characteristics were evaluated using the multivariate logistic regression model. Among 70 Japanese adult RA outpatients, 52 were classified as MTX responders. In multivariate analysis, patients with the solute carrier family 19 member 1 (SLC19A1) 80G>A A/A genotype had a better response than those with the A/G or G/G genotype, and patients with the C allele of γ-glutamyl hydrolase (GGH) 16T>C had a better response than those with the T/T genotype.This study showed that the therapeutic response to MTX in Japanese RA patients was associated with the genetic polymorphisms of SLC19A1 80G>A and GGH 16T>C in actual clinical practice.

Influence of RFC1 c.80A>G Polymorphism on Methotrexate-Mediated Toxicity and Therapeutic Efficacy in Rheumatoid Arthritis: A Meta-analysis

“…MTX-mediated efficacy was elucidated in 9 studies representing 1517 RA patients, out of which 797 responded to MTX therapy (52.5%; Table 4). 9,14-16,21, [28][29][30][31] The distribution of genotypes is in accordance with HWE in all the studies. Allele contrast, recessive, and dominant models showed positive association between RFC1 c.80 A>G and MTX therapeutic efficacy (Table 5).…”

Toward Overcoming Treatment Failure in Rheumatoid Arthritis

“…BCRP transported both methotrexate and polyglutamylated methotrexate and participated in methotrexate resistance ( 44 ). Good response to methotrexate was associated with a decrease in expression of BCRP in RA patients ( 45 ), while the association of BCRP polymorphisms with the effectiveness of methotrexate was not observed ( 46 ), suggesting that BCRP expression was not genetically determined, but might be associated with environmental factors ( 45 ). BCRP inhibition could be a strategy for overcoming nonresponse to methotrexate.…”

Comparative analysis of the treatment-naïve microbiome across rheumatic diseases to predict MTX treatment response

“…In RA patients, the factors of sex, age, symptom duration, and smoking status [20], as well as specific genetic polymorphisms [21], have been identified to influence the inter-individual variability in MTX response. In addition, the gut microbiota influences the metabolism and biotransformation of orally administered MTX, as specific groups of bacteria have been associated with detecting the MTX conversion products in the feces of rats [22].…”