title: Mucosal improvement in patients with moderate to severe postoperative endoscopic recurrence of Crohn's disease and azathioprine metabolite levels.
abstract: BACKGROUND
  The value of azathioprine metabolites (6-thioguanine nucleotides [6-TGN]) in monitoring clinical treatment response is still controversially discussed. Data regarding thiopurine metabolite levels and endoscopic improvement are lacking.
  
  
  METHODS
  Data were analyzed post hoc from a 1-year, multicenter, double-blind, double-dummy, randomized trial comparing azathioprine 2.0 to 2.5 mg/kg per day versus mesalamine 4 g/d in a subset of 23 postoperative patients with Crohn's disease (CD) treated with azathioprine and having moderate-to-severe endoscopic recurrence according to a modified 6-grade score. Red blood cell (RBC) concentrations of 6-TGN, 6-methyl-mercaptopurine ribonucleotides (6-MMPR), and 6-methyl-thioguanine nucleotides (6-MTGN) were indicated as follows: area under the concentration-time curve, average concentration (C av), and concentration at the final study visit.
  
  
  RESULTS
  Overall, 74% of patients showed an improvement in the modified endoscopic score (P = 0.022). Median endoscopic score reduced from 4 at the baseline to 2 at the final visit. Patients with a high C av for 6-TGN (≥ 193 pmol/8 × 10(8) RBC; P = 0.017) or 6-MTGN (≥ 79.2 pmol/8 × 10(8) RBC; P = 0.035) significantly improved in endoscopic score, and the improvement in endoscopic score correlated with C av for 6-TGN (r = -0.51; P = 0.013). For concentration at the final visit, higher values for 6-TGN (≥ 142 pmol/8 × 10(8) RBC; P = 0.017) were associated with a better postoperative score. Sensitivity analysis revealed a significant correlation between 6-TGN (area under the concentration-time curve) and postoperative endoscopic improvement.
  
  
  CONCLUSIONS
  Our post hoc analysis from a double-blind, randomized trial suggests that higher RBC 6-TGN levels are associated with endoscopic improvement in patients with severe postoperative endoscopic recurrence of CD. Thus, our study provides first evidence on the utility of monitoring of thiopurine metabolites to achieve mucosal response in CD.
authors: Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors: Sieglinde
authors: S
authors: Angelberger
authors: Elke
authors: E
authors: Schaeffeler
authors: Alexander
authors: A
authors: Teml
authors: Wolfgang
authors: W
authors: Petritsch
authors: Olga
authors: O
authors: Shonova
authors: Milan
authors: M
authors: Lukas
authors: Simon
authors: S
authors: Bar-Meir
authors: Karin
authors: K
authors: Dilger
authors: Roland
authors: R
authors: Greinwald
authors: Ralph
authors: R
authors: Mueller
authors: Eduard F
authors: EF
authors: Stange
authors: Klaus R
authors: KR
authors: Herrlinger
authors: Matthias
authors: M
authors: Schwab
authors: Walter
authors: W
authors: Reinisch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D016099:Endoscopy, Gastrointestinal; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012372:ROC Curve; D012008:Recurrence; D012720:Severity of Illness Index; D013866:Thioguanine / Q000031:analogs & derivatives* / Q000097:blood; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000097:blood; D013873:Thionucleotides / Q000097:blood*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C035366:6-methylthioguanine; C003964:6-thioguanylic acid; D013868:Thioinosine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D013866:Thioguanine; D001379:Azathioprine