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.

Download full-text


Available from: Tahar van der Straaten, Jan 08, 2015
31 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human leucocyte antigen-G (HLA-G) is a non-classical HLA class I molecule with an important role at the fetus-maternal interface, preventing fetus recognition and abortion. The role of HLA-G as an immune-modulatory and anti-inflammatory molecule has led to investigate its role in pathological conditions. In these years, HLA-G has been shown to have an important implication in inflammatory pathologies. The focus of this review is to up-date the scientific knowledge on the expression of HLA-G molecules in inflammatory conditions.
    08/2012; 11(6). DOI:10.2174/187152812803590037
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Antirheumatic agents are among commonly used drugs associated with adverse hepatic reactions. Sulfasalazine and azathioprine are among the most important causes of acute hepatotoxicity. Because such a large number of people take NSAIDs, even the rare occurrence of hepatotoxicity from these agents might contribute substantially to the total burden of drug-induced liver disease. A wide spectrum of hepatotoxic effects is described with antirheumatic drugs. Studies investigating genetic susceptibility to diclofenac hepatotoxicity have expanded our understanding of the potential drug-specific, class-specific and general factors involved in its pathogenesis, and methotrexate-associated liver disease demonstrates the interaction between drug, host and environmental factors that determines the likelihood and magnitude of liver disease. Infliximab therapy is associated with typical drug-induced autoimmune hepatitis. Although validated causality assessment methods have been used to objectively assess the strength of the association between a drug and a clinical event, in practice the diagnosis of drug-induced liver injury (DILI) involves a clinical index of suspicion, pattern recognition, the establishment of a temporal relationship between drug exposure and the adverse event, and the exclusion of alternative explanations for the clinical presentation. Detailed understanding of genetic and environmental factors underlying an individual's susceptibility would enable risk reduction and potentially primary prevention of hepatotoxicity.
    Nature Reviews Rheumatology 01/2011; 7(3):139-50. DOI:10.1038/nrrheum.2010.214 · 9.85 Impact Factor
  • Source
    Pharmacogenetics and Genomics 02/2011; 21(10):679-86. DOI:10.1097/FPC.0b013e328343dd93 · 3.48 Impact Factor
Show more