Functional polymorphisms and methotrexate treatment outcome in recent-onset rheumatoid arthritis

Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, PO Box 9600, NL 2300 RC Leiden, The Netherlands.
Pharmacogenomics (Impact Factor: 3.22). 02/2010; 11(2):163-75. DOI: 10.2217/pgs.09.139
Source: PubMed


Clinical response to methotrexate (MTX) treatment differs among rheumatoid arthritis patients. Genetic variation can partly account for this phenomenon. In this study, functional polymorphisms in genes related to the mechanism of action of MTX or immunopathogenesis of rheumatoid arthritis were studied for association with treatment outcome in a Dutch cohort of patients with early rheumatoid arthritis. Furthermore, tests for replication of previous research on these genetic variants were performed according to reported end points.
Seven polymorphisms in seven genes were analyzed in 205 genotyped patients with active rheumatoid arthritis. All patients received standardized MTX treatment (< or =25 mg per week orally) combined with folic acid. MTX treatment outcome was evaluated by disease activity score criteria and adverse drug events. The following genetic variants were analyzed and correlated: ABCB1 3435C>T, ITPA IVS2 +21A>C, HLA-G (-14 bp >+14 bp), TGFB1 +869T>C and TLR4 +896A>G. In case of significant differences, regression analyses were applied. Since carriers of the minor alleles of the SNPs DHFR 829C>T and IMPDH2 +787C>T were not observed, no statistical analyses could be performed.
No significant associations or replications of these genetic variants with MTX efficacy were demonstrated. Regarding toxicity, patients carrying the ABCB1 3435T-allele and TLR4 +896G-allele were 2.5-times more likely to develop adverse drug events at 6 months (odds ratio: 2.6; 95% CI: 1.1-6.2, and odds ratio: 2.5; 95% CI: 1.1-6.1, respectively). Additionally, this chance increased almost fourfold in patients with the two unfavorable genotypes (odds ratio: 3.9; 95% CI: 1.5-10.3). However, none of these associations remained significant after correction for multiple testing (p < 0.004).
Our data indicate that MTX toxicity was potentially associated with ABCB1 3435C>T and TLR4 +896A>G. However, after correction, none of these associations remained significant. Furthermore, no significant associations or replications of these functional variants with efficacy were found.

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Available from: Tahar van der Straaten, Jan 08, 2015
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    • "The analysis of the HLA-G 14bp INS/DEL polymorphism in 156 MTX-treated RA patients has shown an increase of the 14bp DEL/DEL genotype in the responder group, characterized by a reduction in disease activity score (DAS)28 measured before and after six months of treatment with MTX [101]. In contrast to this study, there are two researches with negative results: i) 130 RA patients have presented no significant difference in 14bp DEL/INS allelic and genotypic distribution in patients responsive to MTX (DAS28 < 3.2) [102]; ii) 186 RA patients, who have never been treated with MTX, have prospectively been followed and have been considered as responders with a DAS28 of up to 2.4 after six months of treatment [103]. No significant association between HLA-G 14bp INS/DEL and MTX efficacy has been observed. "
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