title: Normalization of mucosal tumor necrosis factor-α: A new criterion for discontinuing infliximab therapy in ulcerative colitis.
abstract: BACKGROUND
  Biological agents such as anti-tumor necrosis factor (TNF) induce remission in ulcerative colitis. There is however no consensus regarding the discontinuation of this treatment.
  
  
  OBJECTIVE
  The aim of this study is to assess whether clinical parameters and mucosal cytokine mRNAs in healed colonic mucosa can predict long-term remission in ulcerative colitis following discontinuation of infliximab (IFX) therapy.
  
  
  METHODS
  The prospective Tromsø Inflammatory Bowel Disease (IBD) Study is based on an intensified induction treatment algorithm with IFX to achieve disease remission. Following clinical and endoscopic remission, IFX treatment was discontinued, and follow-up until relapse was performed. Patients who achieved clinical and endoscopic remission following an induction course of IFX were included. Expression levels of TNF alpha (TNF), interferon gamma (IFNG), interleukin (IL) 6 (IL6), IL17A, IL23, and transforming growth factor beta (TGFB) were quantified by real-time PCR in mucosal biopsies obtained at colonoscopy. Remission was defined as Ulcerative Colitis Disease Activity Index (UCDAI) below 3, and an endoscopic sub-score of 0-1. Relapse was defined as UCDAI score >3 and endoscopic sub-score >1. Mucosal cytokine transcript levels from 20 non-IBD patients with a normal colonoscopy served as control group.
  
  
  RESULTS
  Of the 45 patients included, twenty patients (44%) had normalized levels of mucosal TNF expression at the time of mucosal healing, whereas 35 of 42 (83%) had normalized IL17A expression levels, and 31 of 36 (86%) had normalized IFNG expression levels. The median time to relapse was 8months (range 4-12). Normalization of TNF gene expression predicted 20months (1-39) relapse-free survival after withdrawal of IFX compared to 5months (3-7) in the group with elevated TNF expression. Mucosal expression levels of IL17A, IL23, IFNG, TGFB, IL6 did not predict long-term remission (>12months)
  
  
  CONCLUSIONS
  Normalization of mucosal TNF predicts long-term remission after discontinuation of IFX.
authors.affiliation: Research group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway. Electronic address: trine.olsen@unn.no.
authors.forename: Trine
authors.initials: T
authors.lastname: Olsen
authors.affiliation: Research group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway. Electronic address: renathe.rismo@unn.no.
authors.forename: Renathe
authors.initials: R
authors.lastname: Rismo
authors.affiliation: Research group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway. Electronic address: mona.dixon.gundersen@unn.no.
authors.forename: Mona Dixon
authors.initials: MD
authors.lastname: Gundersen
authors.affiliation: Research group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway. Electronic address: eyvind.j.paulssen@uit.no.
authors.forename: Eyvind J
authors.initials: EJ
authors.lastname: Paulssen
authors.affiliation: Research group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway. Electronic address: knut.johnsen@finnmarkssykehuset.no.
authors.forename: Knut
authors.initials: K
authors.lastname: Johnsen
authors.affiliation: Research group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway. Electronic address: jan.magnus.kvamme@unn.no.
authors.forename: Jan-Magnus
authors.initials: JM
authors.lastname: Kvamme
authors.affiliation: Research group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway. Electronic address: rasmus.goll@unn.no.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Goll
authors.affiliation: Research group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway. Electronic address: jon.florholmen@unn.no.
authors.forename: Jon
authors.initials: J
authors.lastname: Florholmen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D003106:Colon / Q000473:pathology; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D006801:Humans; D000069285:Infliximab / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012074:Remission Induction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D055815:Young Adult
chemical_list: D005765:Gastrointestinal Agents; C573415:IFNG protein, human; C508717:IL17A protein, human; C508840:IL23A protein, human; C508600:IL6 protein, human; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D015850:Interleukin-6; C508960:TGFB1 protein, human; C439524:TNF protein, human; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000069285:Infliximab
keywords: Biomarker; IBD; IL-17; Interferon-γ; Tumor necrosis factor-α