title: Normalization of mucosal cytokine gene expression levels predicts long-term remission after discontinuation of anti-TNF therapy in Crohn's disease.
abstract: OBJECTIVE
  To investigate mucosal cytokine gene expression levels in healed mucosa after anti-tumor necrosis factor (TNF) therapy in patients with Crohn's disease (CD) as possible risk factors for relapse after discontinuation of therapy.
  
  
  METHODS
  Thirty-seven CD patients treated with anti-TNF agents until complete mucosal healing, documented by endoscopy, discontinued anti-TNF treatment and entered a follow-up study. Levels of mRNA expression of interleukin (IL)17A (IL17A), IL23, interferon-gamma (IFNG), TNF-alpha (TNF), IL10 and Forkhead Box P3 (FOXP3) were measured in biopsies from healed mucosa and analyzed as possible risk factors of relapse. Mucosal cytokine transcript levels from patients without CD served as controls.
  
  
  RESULTS
  Patients were followed after therapy withdrawal until relapse. Median time to relapse was 20 and 68 weeks for patients with elevated and normalized IL17A and TNF expression levels, respectively (p = 0.02 for IL17A and p = 0.003 for TNF, log-rank). Expression levels of TNF, IL17A and FOXP3 were significantly higher in patients who relapsed before 26 weeks than in those who did not relapse, and also higher in patients with relapse before week 52 versus non-relapsers. Elevated expression levels of TNF and IL17A in healed mucosa significantly increased the risk of relapse (HR = 3.4, p = 0.03, sensitivity 80%, specificity 38% and HR = 4.1, p = 0.008, sensitivity 81%, specificity 61%, respectively).
  
  
  CONCLUSIONS
  Normalization of mucosal gene expression of cytokines after anti-TNF therapy does not occur in all patients with healed mucosa as judged by endoscopy. Normalization of TNF and/or IL17A expression predicts long-term remission.
authors.affiliation: Institute of Clinical Medicine, University of Tromsø, Research Group of Gastroenterology and Nutrition, Tromsø, Norway. renathe.rismo@unn.no
authors.forename: Renathe
authors.initials: R
authors.lastname: Rismo
authors.forename: Trine
authors.initials: T
authors.lastname: Olsen
authors.forename: Guanglin
authors.initials: G
authors.lastname: Cui
authors.forename: Eyvind J
authors.initials: EJ
authors.lastname: Paulssen
authors.forename: Ingrid
authors.initials: I
authors.lastname: Christiansen
authors.forename: Knut
authors.initials: K
authors.lastname: Johnsen
authors.forename: Jon
authors.initials: J
authors.lastname: Florholmen
authors.forename: Rasmus
authors.initials: R
authors.lastname: Goll
mesh_terms: D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics*; D016207:Cytokines / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012008:Recurrence; D012074:Remission Induction; D012680:Sensitivity and Specificity; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics; D028761:Withholding Treatment; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab