title: Limitations of extensive TPMT genotyping in the management of azathioprine-induced myelosuppression in IBD patients.
abstract: OBJECTIVE
  TPMT deficiency is associated with azathioprine (AZA)-induced myelosuppression (MS). However, in one previous study, only about ¼ of MS episodes in Crohn's Disease patients under AZA can be attributed to TPMT deficiency. Recently, new TPMT mutations have been described and our aim is to investigate their clinical relevance before and after a first MS episode on thiopurine therapy.
  
  
  METHODS
  Clinical data from 61 IBD patients having developed MS during AZA therapy were collected. Sequencing analysis was carried out on TPMT cDNA for the presence of all currently known mutations.
  
  
  RESULTS
  Only TPMT *2, *3A and *3C mutations were found in this cohort. TPMT mutations were observed in 15 out of 61 patients (25%). Four out of 15 were homozygous for a TPMT mutation (low methylator, LM genotype) and 11 were heterozygous (intermediate methylator, IM genotype). Median delays of MS onset were 2, 2.75 and 6months in the LM, IM and HM (high methylator, wild type TPMT) groups, respectively. After the first MS episode, 36 patients resumed thiopurine treatment of which 13 experienced a second MS episode. This second episode was also rarely associated with TPMT mutations.
  
  
  CONCLUSIONS
  One quarter of MS episodes during AZA were associated with TPMT deficient genotype. After a first leucopenia episode, thiopurine therapy may be resumed in a majority of patients independently of their TPMT genotype.
authors: UCL Saint-Luc, Brussels, Belgium. Electronic address: Olivier.Dewit@uclouvain.be.
authors: O
authors: O
authors: Dewit
authors: UZA, Antwerp, Belgium.
authors: T
authors: T
authors: Moreels
authors: HHR, Roeselare, Belgium.
authors: F
authors: F
authors: Baert
authors: U Gent, Gent, Belgium.
authors: H
authors: H
authors: Peeters
authors: ULG, Liège, Belgium.
authors: C
authors: C
authors: Reenaers
authors: U Gent, Gent, Belgium.
authors: M
authors: M
authors: de Vos
authors: AZ St Lucas, Brugge, Belgium.
authors: Ph
authors: P
authors: Van Hootegem
authors: CHU St Pierre, Brussels, Belgium.
authors: V
authors: V
authors: Muls
authors: Queen Paola Children Hospital, Antwerp, Belgium.
authors: G
authors: G
authors: Veereman
authors: VUB, Brussels. Belgium.
authors: F
authors: F
authors: Mana
authors: UZA, Antwerp, Belgium.
authors: M
authors: M
authors: Van Outryve
authors: ZNA, Middelheim, Antwerp, Belgium.
authors: J
authors: J
authors: Holvoet
authors: ZNA, Middelheim, Antwerp, Belgium.
authors: S
authors: S
authors: Naegels
authors: UCL Saint-Luc, Brussels, Belgium.
authors: H
authors: H
authors: Piessevaux
authors: UCL Saint-Luc, Brussels, Belgium.
authors: Y
authors: Y
authors: Horsmans
authors: UCL Saint-Luc, Brussels, Belgium.
authors: J L
authors: JL
authors: Gala
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D004342:Drug Hypersensitivity / Q000150:complications* / Q000209:etiology / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases / Q000150:complications* / Q000188:drug therapy; D007970:Leukopenia; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010198:Pancytopenia / Q000139:chemically induced / Q000235:genetics; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000150:complications* / Q000209:etiology / Q000235:genetics; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine