title: 6-thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active crohn disease: results from a randomized, controlled, open trial.
abstract: BACKGROUND
  A prospective randomized trial in patients with Crohn disease studied whether 6-thioguanine nucleotide (6-TGN) concentration-adapted azathioprine (AZA) therapy is clinically superior to a standard dose of 2.5 mg/kg/day AZA.
  
  
  METHODS
  After 2 weeks of standard therapy, patients (n = 71) were randomized into standard (n = 32) or adapted-dose (n = 25) groups; 14 patients dropped out before randomization. In the adapted group, the AZA dose was adjusted to maintain 6-TGN concentrations between 250 and 400 pmol/8 x 10(8) erythrocytes (Ery). Response criteria were the number of patients in remission after 16 weeks without steroids (primary) and remission after 24 weeks, frequency of side effects, and quality of life (secondary).
  
  
  RESULTS
  After 16 weeks, 14 of 32 (43.8%) patients in the standard group vs 11 of 25 (44%) in the adapted group were in remission without steroids (intent-to-treat analysis). After 24 weeks, 43.8% vs 40% were in remission. No significant differences were found concerning quality of life, disease activity, 6-TGN concentrations, AZA dose, or dropouts due to side effects. Sixty-six patients had a wild-type thiopurine S-methyltransferase (TPMT) genotype, with TPMT activities of 8 to 20 nmol/(mL Ery x h). Five patients (dropouts after randomization) were heterozygous, with TPMT activities <8 nmol/(mL Ery x h). 6-Methyl mercaptopurine (6-MMP) concentrations >5700 pmol/8 x 10(8) Ery were not associated with hepatotoxicity.
  
  
  CONCLUSIONS
  Standard and adapted dosing with the provided dosing scheme led to identical 6-TGN concentrations and remission rates. Adapted dosing had no apparent clinical benefit for patients with TPMT activity between 8 and 20 nmol/(mL Ery x h). Additionally, 6-MMP monitoring had no predictive value for hepatotoxicity.
authors.affiliation: Department of Medicine I, Klinikum Braunschweig, Braunschweig, Germany. m.reinshagen@klinikum-braunschweig.de
authors.forename: Max
authors.initials: M
authors.lastname: Reinshagen
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Schütz
authors.forename: Victor W
authors.initials: VW
authors.lastname: Armstrong
authors.forename: Christoph
authors.initials: C
authors.lastname: Behrens
authors.forename: Christian
authors.initials: C
authors.lastname: von Tirpitz
authors.forename: Andreas
authors.initials: A
authors.lastname: Stallmach
authors.forename: Hans
authors.initials: H
authors.lastname: Herfarth
authors.forename: Jürgen
authors.initials: J
authors.lastname: Stein
authors.forename: Peter
authors.initials: P
authors.lastname: Bias
authors.forename: Guido
authors.initials: G
authors.lastname: Adler
authors.forename: Maria
authors.initials: M
authors.lastname: Shipkova
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kruis
authors.forename: Michael
authors.initials: M
authors.lastname: Oellerich
authors.forename: Nicolas
authors.initials: N
authors.lastname: von Ahsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003424:Crohn Disease / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004909:Erythrocyte Indices; D005260:Female; D005838:Genotype; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D008780:Methyltransferases / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D012074:Remission Induction; D013873:Thionucleotides / Q000097:blood*; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D006150:Guanine Nucleotides; D013873:Thionucleotides; C488629:azathiopurine; C003964:6-thioguanylic acid; C010240:6-methylthiopurine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase