BackgroundMethotrexate (MTX) is currently the anchor drug widely used worldwide in the treatment of rheumatoid arthritis (RA). However, the therapeutic response to MTX has been shown to vary widely among individuals, genders and ethnic groups. The reason for this has been not clarified but it is considered to be partially due to several mechanisms in the cellular pathway of MTX including single-nucleotide polymorphisms (SNPs). The purpose of this study was to investigate the allelic frequencies in different ethnic and/or population groups in the 10 polymorphisms of enzyme proteins and transporters related to the MTX response and pharmacokinetics including MTHFR, TYMS, RFC1, FPGS, GGH, ABCB1, ABCC2 and ABCG2 in unrelated healthy Japanese adults and patients with RA.MethodsTen polymorphisms, methylenetetrahydrofolate reductase (MTHFR) 1298, thymidylate synthase (TYMS) 3'-UTR, reduced folate carrier 1 (RFC1) 80 and−43, folypolyglutamyl synthase (FPGS) 1994, γ-glutamyl hydrolase (GGH) 452 and−401, the ABC transporters (ABCB1 3435, ABCC2 IVS23 + 56, ABCG2 914) of enzyme proteins and transporters related to MTX response and pharmacokinetics in 299 unrelated healthy Japanese adults and 159 Japanese patients with RA were investigated to clarify their contributions to individual variations in response and safety to MTX and establish personalized MTX therapy. SNPs were evaluated using real-time polymerase chain reaction (PCR).ResultsComparison of allelic frequencies in our study with other ethnic/population groups of healthy adults and RA patients showed significant differences in 10 polymorphisms among healthy adults and 7 among RA patients. Allelic frequencies of MTHFR 1298 C, FPGS 1994A and ABCB1 3435 T were lower in Japanese than in Caucasian populations and those of ABCC2 IVS23 + 56 C and ABCG2 914A were higher in Japanese than in Caucasian/European populations in both healthy adults and RA patients. Allelic frequencies of MTHFR 1298 C, GGH−401 T, ABCB1 3435 T, and ABCG2 914A were higher in healthy Japanese adults than in an African population, and those of RFC1 80A, RFC1−43C and ABCC2 IVS23 + 56 C in healthy Japanese adults were lower than in Africans. However, no significant differences were seen in the distribution of allelic frequencies between healthy Japanese adults and RA patients.ConclusionThe variations in allelic frequencies in different ethnic and/or population groups in healthy adults and RA patients may contribute to individual variations in MTX response and toxicity.

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammatory status, joint destruction, disability, and pain. Methotrexate (MTX) has been confirmed to reduce disease activity and delay or stabilize the development of bone erosions. However, major drawbacks are that patients show great interindividual variability in response to MTX and the unpredictable occurrence of side effects. A strategy for personalized MTX treatment to predict its efficacy and toxicity has not yet been determined.To establish personalized MTX therapy in Japanese patients with rheumatoid arthritis, we performed a preliminary study for predicting better methotrexate efficacy including single-nucleotide polymorphisms (SNPs) for MTX-related transporters/enzymes.MethodsDisease control status (good or poor) was judged by the number of Disease Activity Scores (DAS28) of <2 for 6–12 months. The response index R was calculated by the improved area under the curve (AUC) of the DAS28 score for 0–3 or 0–6 months by dividing the cumulative dose of MTX during 0–3 or 0–6 months, respectively. Genotyping of alleles of RFC1 80G > A, RFC1 –43 T > C, FPGS 1994G > A, GGH 401C > T, MTHFR 1298A > C, and TYMS 3'-UTR (−6/+6) was performed using the real-time PCR system.ResultsSeven of 21 patients were judged as good responders in terms of disease control, and the remainder as poor responders. For 0–3 months after starting MTX administration, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 96.0 mg and 25.4 and 118.0 mg and 23.4, respectively. For 0–6 months, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 192.0 mg and 51.0 and 214.0 mg and 47.6, respectively. Statistically significant differences between the 2 groups in the 0–6-month period were observed in DAS28 AUC improvement and index R. A slight tendency for a correlation between G/G genotypes and A allele genotypes in RFC1 80 genotypes was observed, although it did not reach statistical significance.ConclusionThis study suggested that aggressive RA treatment with MTX from the early period of administration is necessary to obtain a good response after 6 months, although no SNPs predicting a better treatment response to MTX were identified.

BackgroundVinorelbine is known to be effective in the treatment of non-small cell lung cancer and breast cancer. However, venous irritation is a common side effect. Although there have been some reports on risk factors for venous irritation in patients receiving vinorelbine, the factors evaluated have been limited and the results inconclusive. The aim of this study was to identify risk factors for venous irritation in patients receiving vinorelbine, and factors likely associated with venous irritation, including new factors such as hot compress with a hot towel  for prevention of venous irritation.MethodsWe retrospectively reviewed patients treated with vinorelbine at Kyorin University Hospital, Japan, between March 2013 and December 2016 and divided them into the two groups according to whether or not they had venous irritation. Clinical characteristics were compared between the two groups.ResultsVenous irritation occurred in 24 (38.1%) of 63 patients who received vinorelbine. The median number of times vinorelbine was administered before onset of venous irritation was 3 (range 1–14). The group with venous irritation had a significantly lower body surface area than the group without venous irritation (p = 0.035). Low body surface area was also the only significant risk factor for vinorelbine-associated venous irritation in multivariate analysis (adjusted odds ratio 70.42 per 1 m2decrement, 95% confidence interval 1.54–3236.25, p = 0.029). There was no association between the occurrence of venous irritation and the other covariates, such as use of a hot compress, history of diabetes mellitus, or use of a generic formulation of vinorelbine.ConclusionLow body surface area may be a risk factor for venous irritation in patients receiving vinorelbine. Use of hot compress with a hot towel did not prevent venous irritation.

Sex differences in the prevalence of autoimmune diseases such as rheumatoid arthritis (RA) are well known, but little is known about those differences in relation to therapeutic response. Reduced folate carrier-1 (RFC-1), folypolyformyl glutamate synthase (FPGS), and γ-glutamyl hydrolase (GGH) are important transporters and enzymes that convert methotrexate (MTX) in the body. This study investigated the sex differences in mRNA expression of RFC-1, FPGS, and GGH in 190 unrelated healthy Japanese people. The genotypes and mRNA expression were determined using the real-time PCR method. Significant differences between men and women were observed in RFC-1, FPGS, and GGH mRNA expression. The mRNA expression of FPGS and GGH was greater in women than that in men, but the expression of RFC-1 was less in the former than the latter. In stratified analysis by genotype, significant differences in sex-specific mRNA expression were observed in G/G of FPGS, C/C of GGH 452, and C/C of GGH -401. All showed greater mRNA expression in women than in men. In the 5 single-nucleotide polymorphisms RFC-1 80G>A, RFC-1 -43T>C, FPGS 1994G>A, GGH 452C>T, and GGH -401C>T examined, the FPGS 1994 G/G (1.46-fold), GGH 452 C/C (2.16-fold), and GGH -401 C/C (2.68-fold) genotypes showed significantly higher mRNA expression in women than in men. Healthy Japanese adults in this study showed sex-specific differences in mRNA expression that differed among RFC-1, FPGS, and GGH. Therefore, the relationship between genetic polymorphisms and mRNA expression including sex differences might contribute to the variation in the efficacy/toxicity of MTX in patients with RA.