Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Associations Between Ten Single-Nucleotide Polymorphisms of the Efficacy and Toxicity Rheumatoid Arthritis Patients Treated with Methotrexate

Swierkot,  J., Slezak,  R., Karpinski,  P.

Purpose:

We evaluated the relationship of ten single-nucleotide polymorphisms in genes encoding proteins in folate and transcobalamin pathways to toxicity and efficacy of MTX in patients with RA. MTX remains a cornerstone in the treatment of rheumatoid arthritis (RA). Approximately 10–30% of patients with RA discontinue MTX because of toxicity and 35–55% because of inefficacy. One possible cause of the differences in the efficacy and adverse drug reactions is genetic variation in how individuals metabolize drugs.

Method:

Ten polymorphisms in five cellular pathway genes (RFC 80G>A, GGH 401C>T, MTHFR 1298A>C and 677C>T, TSER*2/*3, TYMS 6 bp deletion, TCII 198M>T, 376L>S, 219I>L and 259P>R) were examined for their effects on MTX efficacy and toxicity in 274 RA caucasian patients who had been treated with MTX (up to 25 mg per week) and folic acid (5–10 mg per week) for at least 6 months or they stop MTX because of adverse events. Adverse events (AEs)(gastrointestinal effects, elevated liver enzymes, pneumonitis, alopecia, infections, hematological AEs and other AEs) were monitored during MTX treatment. Genomic DNA was obtained from the peripheral blood. We use a SNP typing methods based on the RFLP-PCR and ARMS-PCR

Results:

The effect of the ten SNPs on MTX-related efficacy and AEs was studied in 274 patients with RA. The SNPs genotypes had no effect on MTX response.

54% of patients described some toxicities during at least one study visit and 21% had AE leading to MTX withdrawal. Overall MTX-related AEs were more frequent in patients with the MTHFR 677T allele (CT and TT genotypes) than in those with the 677CC genotype (p = 0.03, OR:1.9) and GGH 401CC genotype than in those with GGH 401 CT and TT genotype (p=0.05, OR:3.4).

Furthermore, the 677T allele was associated with aminotransferases elevations among the subgroup of patients with MTX-related liver toxicity (p = 0.02; OR: 3.4). Other SNPs did not show significant associations with overall toxicity.

However MTX-related hepatotoxicity and alopecia was more frequent in patients with the RFC80 AA genotype than in those with the RFC 80 GG and RFC 80GA genotype (p=0.01, OR:3.57 and p=0.04, OR: 2.38). In patients with MTHFR 677CC genotype and RFC80GG or AG genotype the possibility of hepatotoxicity was only 1% and in the whole group 7,5%. A multivariate model that included the six SNPs showed that three risk genotypes, (GGH 401CC, MTHFR 677TT/CT, RFC80AA) were associated with MTX hepatotoxicity.

Conclusion:

There was no relationship between the ten SNPs and the efficacy of MTX treatment. MTHFR 677CC and GGH401 TT and CT polymorphisms were associated with a reduction in MTX related adverse effects.

Composite allele and haplotype analyses may help identify subsets of RA patients with adverse outcomes. Pharmacogenetic studies offer novel approaches to prospectively screen patients for genetic markers for optimal drug selection and minimum toxicity.

To cite this abstract, please use the following information:
Swierkot, J., Slezak, R., Karpinski, P.; Associations Between Ten Single-Nucleotide Polymorphisms of the Efficacy and Toxicity Rheumatoid Arthritis Patients Treated with Methotrexate [abstract]. Arthritis Rheum 2009;60 Suppl 10 :740
DOI: 10.1002/art.25820

Abstract Supplement

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