title: Histologic Normalization Occurs in Ulcerative Colitis and Is Associated With Improved Clinical Outcomes.
abstract: OBJECTIVE
  Mucosal healing, determined by histologic analysis, is a potential therapeutic target for patients with ulcerative colitis (UC). However, the histologic features of tissue normalization, as an outcome of treatment, have not been well described. We examined the prevalence and predictive values of normalization of the colonic mucosa, based on histologic analysis (histologic normalization) in patients with UC, and determined its association with risk of clinical relapse, compared with histologic disease quiescence and endoscopic mucosal healing.
  
  
  METHODS
  We performed a retrospective study of 646 patients with confirmed UC who underwent colonoscopy at a tertiary medical center from August 2005 through October 2013. We reviewed reports from pathology analyses of random mucosal biopsies from each colon segment, and categorized them into 3 groups based on histology findings: (1) normalization (completely normal mucosa with no features of chronicity present), (2) quiescence (crypt atrophy or branching without signs of active inflammation including erosions, abscesses, or focal neutrophil infiltration), or (3) active disease (epithelial infiltration by neutrophils, crypt abscesses, erosions, or ulceration). Histology findings were compared with clinical and endoscopic findings. We assessed variables associated with histology findings and, in patients in clinical remission (Simple Clinical Colitis Activity Index score ≤2 and subscore of ≤1 for stool frequency or rectal bleeding), predictive values for clinical relapse at follow-up evaluations 6 months later or more were calculated.
  
  
  RESULTS
  Of the 646 patients included in the study, 60% had endoscopic mucosal healing, 40% had histologic quiescence, and 10% had histologic normalization. The level of agreement between mucosal and histologic activity was moderate (agreement for 68% of samples; κ = 0.50; P < .001). On multivariate analysis, only proctitis associated with histologic normalization (P = .002). Of 310 patients in clinical remission at initial review, 25% had a clinical relapse, after a median time of 16 months (interquartile range, 10-23 months). Histologic normalization was independently associated with increased odds of relapse-free survival compared with histologic quiescence (hazard ratio, 4.31; 95% confidence interval, 1.48-12.46; P = .007) and histologic activity (hazard ratio, 6.69; 95% confidence interval, 2.16-20.62; P = .001); mucosal healing was not associated with increased odds of relapse-free survival compared with no mucosal healing (hazard ratio, 1.02; 95% confidence interval, 0.56-1.85; P = .954).
  
  
  CONCLUSIONS
  Histologic normalization of colonic mucosa can be used as a clinical endpoint for patients with UC. We associated histologic normalization with increased odds of relapse-free survival compared with endoscopic healing or histologic quiescence. Further studies are needed to determine whether histologic normalization should be a goal of treatment for patients with UC.
authors.affiliation: Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois; Department of Gastroenterology, Alfred Hospital and Monash University, Melbourne, Australia; Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Britt
authors.initials: B
authors.lastname: Christensen
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Hanauer
authors.affiliation: Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Erlich
authors.affiliation: Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois.
authors.forename: Olufemi
authors.initials: O
authors.lastname: Kassim
authors.affiliation: Department of Gastroenterology, Alfred Hospital and Monash University, Melbourne, Australia.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Gibson
authors.affiliation: Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois; Department of Pathology, University of Chicago Medicine, Chicago, Illinois.
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
authors.affiliation: Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois; Department of Pathology, University of Chicago Medicine, Chicago, Illinois.
authors.forename: John
authors.initials: J
authors.lastname: Hart
authors.affiliation: Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, Illinois. Electronic address: drubin@medicine.bsd.uchicago.
authors.forename: David T
authors.initials: DT
authors.lastname: Rubin
mesh_terms: D000328:Adult; D001706:Biopsy; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000473:pathology*; D003106:Colon / Q000473:pathology*; D003113:Colonoscopy; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000473:pathology*; D008297:Male; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents
keywords: Histopathology; Inflammatory Bowel Disease; Mucosal Healing; Normalization