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FRI0015 Azathioprine withdrawal in rheumatoid arthritis patients. role of tpmt genetic polymorphisms
  1. H Corominas1,
  2. M Domènech2,
  3. A Laiz1,
  4. M Moreno1,
  5. C Geli1,
  6. C Diaz1,
  7. G Vázquez1,
  8. M Baiget2
  1. 1Unitat de Reumatolgia. Servei de Medicina Interna
  2. 2Servei de Genètica, Hospital de La Santa Creu I Sant Pau, Barcelona, Catalonia-Spain

Abstract

Background Dose-dependent Azathioprine´s bone marrow toxicity is widely accepted, although identification of the genetic polimorphysm of the Thiopurine methyltransferase (TPMT) is being recently recognised.

Objectives The aim of the study was to investigate, if the appearance of drug related side effects, such as haematologic toxicity was due to the presence of allelic variants of the TPMT gene.

Methods 111 RA patients DNA´s from WBC were amplified by PCR. Digestion with enzymes (MwoI and Acc) were performed, to identify the different allelic variants of the TPMT gene. MwoI digestion of the 284 bp PCR product resulted in fragments that either remained intact (mutant allele A460) or were cut in two segments of 267 bp and 17 bp (wild type allele G460A). AccI restriction site was present when the G719 mutation existed, the PCR products containing this mutation were cleaved (207 bp and 86 bp fragments) when digested with AccI, while the wild type fragments (A719) were not digested. Results were compared with 105 DNA samples from healthy donors. X2 tests on genotype frequencies and p < 0.05 was statistically significant.

Results 9.5% of healthy controls and 7.2% RA patients were heterozygous for a mutant allele of the TPMT gene. The most frequent variant in both groups was the TPMT 3A (G460A, A719G). Within the 111 RA, 40 of them had followed Aza therapy. 8 of them were still following this therapy, and 32 had to withdrawal Azathioprine therapy due to non response (n = 27) or adverse side effects (n = 5): These last 5 patients were homozygous for the Wild type TPMT allele.

Conclusion TPMT genotype is to identify patients at risk of severe bone marrow toxicity if treated with Aza, Our study reveals that, severe side effects due to Azathioprine cannot be explained by the presence of these two mutant alleles.

References

  1. Kerstens PJ, Stolk JN, De Abreu RA, Lambooy LHJ, van de Putte LBA, Boeermooms A. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Arthritis Rheum. 1995;38:142–5

  2. Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, Relling MV Evans WE. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997;126:608–14

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