title: A 6-thioguanine nucleotide threshold level of 400 pmol/8 x 10(8) erythrocytes predicts azathioprine refractoriness in patients with inflammatory bowel disease and normal TPMT activity.
abstract: OBJECTIVE
  A therapeutic level of 6-thioguanine nucleotides (6-TGN) has been reported in inflammatory bowel disease (IBD) patients under azathioprine (AZA). We investigated the threshold value of 6-TGN that may be predictive of AZA refractoriness and its impact on safety profile.
  
  
  METHODS
  Patients with normal thiopurine methyltransferase (TPMT) activity (7.5-14 U/mL erythrocytes), suffering from steroid-dependent or active IBD despite AZA use for at least 6 months, were prospectively included. Clinical efficacy, adverse events, and thiopurine metabolite levels were recorded at baseline, 1 month after each dose escalation, and thereafter every 3 months.
  
  
  RESULTS
  Fifty-five patients were included (43 with Crohn's disease, 12 with ulcerative colitis). After a mean follow-up of 12 months, 31 patients (56.3%) did not reach clinical remission despite a gradual increase in AZA dose and 6-TGN level of >400 pmol/8 x 10(8) erythrocytes, and were considered refractory to AZA (sensitivity 45%, specificity 100%). Adverse events occurred more frequently in these patients than in responders (42%vs 25%, respectively, P= 0.02). Among 55 patients, 15 cases of myelotoxicity associated with elevated levels of total methylated metabolites (14,500 pmol/8 x 10(8) erythrocytes vs 5,230 pmol/8 x 10(8) erythrocytes in patients without myelotoxicity, P= 0.03) were observed. Patients with total methylated metabolites of >11,100 pmol/8 x 10(8) erythrocytes had an increased risk of developing myelotoxicity (odds ratio [OR] 11.0, 95% confidence interval [CI] 1.1-250, P= 0.05).
  
  
  CONCLUSIONS
  A 6-TGN level of >400 pmol/8 x 10(8) erythrocytes in IBD patients with normal TPMT activity and steroid-dependent or active disease despite an optimal AZA regimen may predict refractoriness to this drug. Furthermore, high levels of methylated derivatives are associated with an increased risk of myelotoxicity.
authors.affiliation: Department of Gastroenterology, CHU Grenoble, Grenoble, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Roblin
authors.forename: Laurent
authors.initials: L
authors.lastname: Peyrin-Biroulet
authors.forename: Laurent P
authors.initials: LP
authors.lastname: Biroulet
authors.forename: Jean M
authors.initials: JM
authors.lastname: Phelip
authors.forename: Stéphane
authors.initials: S
authors.lastname: Nancey
authors.forename: Bernard
authors.initials: B
authors.lastname: Flourie
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000627:therapeutic use*; D004351:Drug Resistance; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008780:Methyltransferases / Q000378:metabolism*; D008875:Middle Aged; D011446:Prospective Studies; D013866:Thioguanine / Q000378:metabolism; D013873:Thionucleotides / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine