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AB0189 Polymorphisms in genes involved in the metotrexate action mechanism. are they associated with response/toxicity of the drug?
  1. P. Moya1,
  2. J. Salazar2,3,
  3. A. Altés4,
  4. H. Corominas5,
  5. C. Diaz-Torne1,
  6. I. Castellví1,
  7. C. Geli1,
  8. M. E. Córica1,
  9. E. del Rio2,3,
  10. J. M. de Llobet1,
  11. M. Baiget2
  1. 1Rheumatology
  2. 2Genetics, Hospital de Sant Pau
  3. 35U705, CIBERER, Barcelona
  4. 4Hematology, Hospital Althaia, Manresa
  5. 5Rheumatology, Hospital Moisès Broggi, Barcelona, Spain

Abstract

Background Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease of unknown etiology. Methotrexate (MTX) is the first-line treatment option for newly diagnosed RA patients. However, only 50–70% of the patients will respond to MTX therapy and up to one third will discontinue treatment because of toxicity.

Objectives Studying SNPs (single nucleotide polymorphisms) described in the literature for its possible role as biomarkers of response and / or toxicity to MTX, in Spanish patients diagnosed with rheumatoid arthritis.

Methods We analyzed 27 TagSNPs in 5 candidate genes (DHFR, TYMS, MTHFR, ATIC and CCND1) involved in the action mechanism of MTX. We studied its association with the therapy-related efficacy and toxicity. One hundred and twenty-four adult patients with RA treated with MTX monotherapy were studied. TagSNPs within these genes were selected using bioinformatic tools and were genotyped using a 48.48 dynamic array on the BioMark system. Toxicity was measured as the time interval that MTX was administered. Efficacy was assessed using the DAS-28 EULAR response criteria.

Results Clinical data of the patients are shown in Table 1. The univariate analyses showed significant association with toxicity in the dominant model with two TagSNPs in the ATIC gene: rs10197559 (P=0.05) and rs16853826 (P=0.04). Two TagSNPs in the MTHFR gene showed significant association with response in the dominant model: rs11121832 (P=0.02) and rs17421511 (P=0.02).

Conclusions Polymorphisms in the ATIC and MTHFR genes may be considered as putative pharmacogenetic markers in RA patients treated with MTX on monotherapy.

  1. Kinder AJ, Hassell AB, Brand J, Brownfield A, Grove M, Shadforth MF. The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology 2005;44:61–6

  2. Wessels JA, van der Kooij SM, le Cessie S, Kievit W, Barerra P, Allaart CF, et al. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoidarthritis. Pharmacogenetics Collaborative Research Group. Arthritis Rheum 2007; 56: 1765–75

Acknowledgements Societat Catalana de Reumatologia.

Disclosure of Interest None Declared

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