title: Change in erythrocyte mean corpuscular volume during combination therapy with azathioprine and infliximab is associated with mucosal healing: a post hoc analysis from SONIC.
abstract: BACKGROUND
  The adequacy of exposure of purine analogs as measured by 6-thioguanine nucleotides concentrations in the setting of combination therapy remains poorly understood. The aim of this study was to investigate the relationship between the mean corpuscular volume (MCV) value (as a surrogate marker of 6-thioguanine nucleotides concentration) and Crohn's disease outcomes in the setting of combination therapy with infliximab.
  
  
  METHODS
  The SONIC trial was a randomized controlled trial comparing infliximab to azathioprine and to infliximab plus azathioprine in 508 Crohn's disease patients. An increase of at least 7 femtoliter (fL) of the MCV (ΔMCV) was used for statistical analysis.
  
  
  RESULTS
  At week 26, the mean increase of MCV was similar among patients treated with azathioprine alone (mean of 7.9 fL) or in combination with infliximab (mean of 8.5 fL). In the azathioprine group, 63.6% of patients with ΔMCV >7 were in steroid-free clinical remission at week 26 as compared with 33.3% of patients without ΔMCV >7 (P = 0.0046). In the combination therapy group, ΔMCV above 7 was associated with mucosal healing (75.0% for ΔMCV >7 versus 47.1% for ΔMCV <7, P = 0.0172) but not with steroid-free clinical remission. Patients with a ΔMCV above 7 were more likely to have infliximab trough level above 3 μg/mL at week 30 (68.4% versus 38.8% for ΔMCV <7, P = 0.0032).
  
  
  CONCLUSIONS
  These results suggest that ΔMCV above 7 (which is a surrogate for a higher 6-thioguanine nucleotides concentration) leads to improved Crohn's disease outcomes, even when combined with infliximab. It also suggests the possibility that a lower azathioprine exposure might be less effective in combination therapy.
authors.affiliation: *Division of Gastroenterology, University of California San Diego, La Jolla, California; †Service des Maladie de l'Appareil Digestif et INSERM U991, Centre Hospitalier Universitaire Pontchaillou et université de Rennes 1, Rennes, France; ‡Digestive Disease Associates, Gainesville, Florida; §Department of Medical Affairs, Janssen Biotech Inc., Horsham, Pennsylvania; ‖Department of Gastroenterology, Icahn Medical School at Mount Sinai, New York, New York; ¶Department of Gastroenterology, Academic Medical Center, Amsterdam, the Netherlands; **Imelda ziekenhuis, Bonheiden, Belgium; ††Department of Gastroenterology, Evangelismos Hospital, Athens, Greece; ‡‡Department of Medicine, ShaareZedek Medical Center, Jerusalem, Israel; §§Department of Internal Medicine III, University Vienna, Vienna, Austria; ‖‖Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium; and ¶¶Departments of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bouguen
authors.forename: Charles
authors.initials: C
authors.lastname: Sninsky
authors.forename: Kezhen L
authors.initials: KL
authors.lastname: Tang
authors.forename: Jean-Frederic
authors.initials: JF
authors.lastname: Colombel
authors.forename: Geert
authors.initials: G
authors.lastname: DʼHaens
authors.forename: Asher
authors.initials: A
authors.lastname: Kornbluth
authors.forename: Gerassimos J
authors.initials: GJ
authors.lastname: Mantzaris
authors.forename: Daniel
authors.initials: D
authors.lastname: Rachmilewitz
authors.forename: Walter
authors.initials: W
authors.lastname: Reinisch
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Mark
authors.initials: M
authors.lastname: Molenda
authors.forename: C
authors.initials: C
authors.lastname: Jannekevan der Woude
authors.forename: William J
authors.initials: WJ
authors.lastname: Sandborn
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D003424:Crohn Disease / Q000188:drug therapy* / Q000473:pathology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004909:Erythrocyte Indices / Q000187:drug effects*; D004912:Erythrocytes / Q000187:drug effects* / Q000473:pathology; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D000069285:Infliximab / Q000627:therapeutic use*; D008297:Male; D009092:Mucous Membrane / Q000187:drug effects* / Q000473:pathology; D011379:Prognosis; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; D000069285:Infliximab; D001379:Azathioprine