Virchows Archiv

, Volume 472, Issue 1, pp 99–110 | Cite as

Disease activity and mucosal healing in inflammatory bowel disease: a new role for histopathology?

  • Rish K. Pai
  • Karel Geboes
Original Article


Histologic evaluation of disease activity in the setting of inflammatory bowel disease is gaining interest within the gastroenterology community. Recent data suggests that histologic measurements of inflammation in ulcerative colitis are more sensitive at detecting disease activity and perform better than endoscopic measurements in predicting clinical outcomes. Histologic measurements are also increasingly used in ulcerative colitis clinical trials to assess response to new therapies. Histologic measurements of disease activity are less well studied in Crohn’s disease, but are gaining attention. Current published treatment algorithms in inflammatory bowel disease do not take into consideration histologic activity; however, this may change in the near future. In order for histologic measurements to be included in clinical decision-making, validated, reliable, and responsive histologic scoring systems are needed. In this review, the recent literature on the significance of histologic activity in both ulcerative colitis and Crohn’s disease is summarized. Histologic scoring systems are also briefly discussed.


Inflammatory bowel disease Ulcerative colitis Crohn's disease Mucosal healing 


Compliance with ethical standards

The authors have complied with all ethical standards as outlined on the Virchows Archives website.

Conflict of interest

Rish K. Pai has received consulting income in the past 12 months from Robarts Clinical Trials (a non-commercial entity). Karel Geboes reports no conflicts of interest.


The authors have received no funding for this work.


  1. 1.
    Feagins LA, Melton SD, Iqbal R et al (2013) Clinical implications of histologic abnormalities in colonic biopsy specimens from patients with ulcerative colitis in clinical remission. Inflamm Bowel Dis 19:1477–1482. doi: 10.1097/MIB.0b013e318281f4ae CrossRefPubMedGoogle Scholar
  2. 2.
    Wolff S, Terheggen G, Mueller R et al (2013) Are endoscopic endpoints reliable in therapeutic trials of ulcerative colitis? Inflamm Bowel Dis 19:2611–2615. doi: 10.1097/01.MIB.0000437044.43961.00 CrossRefPubMedGoogle Scholar
  3. 3.
    Christensen B, Rubin DT (2016) Understanding endoscopic disease activity in IBD: how to incorporate it into practice. Curr Gastroenterol Rep 18:5. doi: 10.1007/s11894-015-0477-6 CrossRefPubMedGoogle Scholar
  4. 4.
    Peyrin-Biroulet L, Sandborn W, Sands BE et al (2015) Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol 110:1324–1338. doi: 10.1038/ajg.2015.233 CrossRefPubMedGoogle Scholar
  5. 5.
    Iacucci M, Ghosh S (2016) Mucosal healing—how deep is enough? Dig Dis Basel Switz 34:160–164. doi: 10.1159/000443133 CrossRefGoogle Scholar
  6. 6.
    Walsh AJ, Bryant RV, Travis SPL (2016) Current best practice for disease activity assessment in IBD. Nat Rev Gastroenterol Hepatol 13:567–579. doi: 10.1038/nrgastro.2016.128 CrossRefPubMedGoogle Scholar
  7. 7.
    Schroeder KW, Tremaine WJ, Ilstrup DM (1987) Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 317:1625–1629. doi: 10.1056/NEJM198712243172603 CrossRefPubMedGoogle Scholar
  8. 8.
    D’Haens G, Sandborn WJ, Feagan BG et al (2007) A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 132:763–786. doi: 10.1053/j.gastro.2006.12.038 CrossRefPubMedGoogle Scholar
  9. 9.
    Ulcerative colitis: clinical trial endpoints guidance for industry - UCM515143.pdf.Google Scholar
  10. 10.
    Geboes K, Riddell R, Ost A et al (2000) A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut 47:404–409CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Truelove SC, Richards WC (1956) Biopsy studies in ulcerative colitis. Br Med J 1:1315–1318CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bessissow T, Lemmens B, Ferrante M et al (2012) Prognostic value of serologic and histologic markers on clinical relapse in ulcerative colitis patients with mucosal healing. Am J Gastroenterol 107:1684–1692. doi: 10.1038/ajg.2012.301 CrossRefPubMedGoogle Scholar
  13. 13.
    Lemmens B, Arijs I, Van Assche G et al (2013) Correlation between the endoscopic and histologic score in assessing the activity of ulcerative colitis. Inflamm Bowel Dis 19:1194–1201. doi: 10.1097/MIB.0b013e318280e75f CrossRefPubMedGoogle Scholar
  14. 14.
    Zenlea T, Yee EU, Rosenberg L et al (2016) Histology grade is independently associated with relapse risk in patients with ulcerative colitis in clinical remission: a prospective study. Am J Gastroenterol 111:685–690. doi: 10.1038/ajg.2016.50 CrossRefPubMedGoogle Scholar
  15. 15.
    Bryant RV, Burger DC, Delo J et al (2016) Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up. Gut 65:408–414. doi: 10.1136/gutjnl-2015-309598 CrossRefPubMedGoogle Scholar
  16. 16.
    Kleer CG, Appelman HD (1998) Ulcerative colitis: patterns of involvement in colorectal biopsies and changes with time. Am J Surg Pathol 22:983–989CrossRefPubMedGoogle Scholar
  17. 17.
    Wright R, Truelove SR (1966) Serial rectal biopsy in ulcerative colitis during the course of a controlled therapeutic trial of various diets. Am J Dig Dis 11:847–857CrossRefPubMedGoogle Scholar
  18. 18.
    Bitton A, Peppercorn MA, Antonioli DA et al (2001) Clinical, biological, and histologic parameters as predictors of relapse in ulcerative colitis. Gastroenterology 120:13–20CrossRefPubMedGoogle Scholar
  19. 19.
    Christensen B, Hanauer SB, Erlich J et al (2017) Histologic normalization occurs in ulcerative colitis and is associated with improved clinical outcomes. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. doi: 10.1016/j.cgh.2017.02.016
  20. 20.
    Park S, Abdi T, Gentry M, Laine L (2016) Histological disease activity as a predictor of clinical relapse among patients with ulcerative colitis: systematic review and meta-analysis. Am J Gastroenterol 111:1692–1701. doi: 10.1038/ajg.2016.418 CrossRefPubMedGoogle Scholar
  21. 21.
    Rutter M, Saunders B, Wilkinson K et al (2004) Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126:451–459CrossRefPubMedGoogle Scholar
  22. 22.
    Gupta RB, Harpaz N, Itzkowitz S et al (2007) Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology 133:1099–1105; quiz 1340-1341. doi: 10.1053/j.gastro.2007.08.001 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Korelitz BI, Sultan K, Kothari M et al (2014) Histological healing favors lower risk of colon carcinoma in extensive ulcerative colitis. World J Gastroenterol 20:4980–4986. doi: 10.3748/wjg.v20.i17.4980 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Mosli MH, Feagan BG, Sandborn WJ et al (2014) Histologic evaluation of ulcerative Colitis: a systematic review of disease activity indices. Inflamm Bowel Dis. doi: 10.1097/01.MIB.0000437986.00190.71
  25. 25.
    Bryant RV, Winer S, Travis SPL, Riddell RH (2014) Systematic review: histological remission in inflammatory bowel disease. Is “complete” remission the new treatment paradigm? An IOIBD initiative. J Crohns Colitis 8:1582–1597. doi: 10.1016/j.crohns.2014.08.011 CrossRefPubMedGoogle Scholar
  26. 26.
    Jauregui-Amezaga A, Geerits A, Das Y et al (2016) A simplified Geboes score for ulcerative colitis. J Crohns Colitis. doi: 10.1093/ecco-jcc/jjw154
  27. 27.
    Mosli MH, Feagan BG, Zou G et al (2017) Development and validation of a histological index for UC. Gut 66:50–58. doi: 10.1136/gutjnl-2015-310393 CrossRefPubMedGoogle Scholar
  28. 28.
    Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C et al (2017) Development and validation of the Nancy histological index for UC. Gut 66:43–49. doi: 10.1136/gutjnl-2015-310187 CrossRefPubMedGoogle Scholar
  29. 29.
    Marchal-Bressenot A, Scherl A, Salleron J, Peyrin-Biroulet L (2016) A practical guide to assess the Nancy histological index for UC. Gut. doi: 10.1136/gutjnl-2016-312722
  30. 30.
    Truelove SC, Hambling MH (1958) Treatment of ulcerative colitis with local hydrocortisone hemisuccinate sodium; a report on a controlled therapeutic trial. Br Med J 2:1072–1077CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Gross V, Bar-Meir S, Lavy A et al (2006) Budesonide foam versus budesonide enema in active ulcerative proctitis and proctosigmoiditis. Aliment Pharmacol Ther 23:303–312. doi: 10.1111/j.1365-2036.2006.02743.x CrossRefPubMedGoogle Scholar
  32. 32.
    Sherlock ME, MacDonald JK, Griffiths AM et al (2015) Oral budesonide for induction of remission in ulcerative colitis Cochrane Database Syst Rev:CD007698. doi: 10.1002/14651858.CD007698.pub3
  33. 33.
    Gross V, Bunganic I, Belousova EA et al (2011) 3g mesalazine granules are superior to 9mg budesonide for achieving remission in active ulcerative colitis: a double-blind, double-dummy, randomised trial. J Crohns Colitis 5:129–138. doi: 10.1016/j.crohns.2010.11.006 CrossRefPubMedGoogle Scholar
  34. 34.
    Kruis W, Kiudelis G, Rácz I et al (2009) Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial. Gut 58:233–240. doi: 10.1136/gut.2008.154302 CrossRefPubMedGoogle Scholar
  35. 35.
    Magro F, Lopes SI, Lopes J et al (2016) Histological outcomes and predictive value of faecal markers in moderately to severely active ulcerative colitis patients receiving infliximab. J Crohns Colitis 10:1407–1416. doi: 10.1093/ecco-jcc/jjw112 CrossRefPubMedGoogle Scholar
  36. 36.
    Sandborn WJ, Feagan BG, Wolf DC et al (2016) Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med 374:1754–1762. doi: 10.1056/NEJMoa1513248 CrossRefPubMedGoogle Scholar
  37. 37.
    Molander P, Sipponen T, Kemppainen H et al (2013) Achievement of deep remission during scheduled maintenance therapy with TNFα-blocking agents in IBD. J Crohns Colitis 7:730–735. doi: 10.1016/j.crohns.2012.10.018 CrossRefPubMedGoogle Scholar
  38. 38.
    Baars JE, Nuij VJAA, Oldenburg B et al (2012) Majority of patients with inflammatory bowel disease in clinical remission have mucosal inflammation. Inflamm Bowel Dis 18:1634–1640. doi: 10.1002/ibd.21925 CrossRefPubMedGoogle Scholar
  39. 39.
    Brennan GT, Melton SD, Spechler SJ, Feagins LA (2017) Clinical implications of histologic abnormalities in ileocolonic biopsies of patients with Crohn’s disease in remission. J Clin Gastroenterol 51:43–48. doi: 10.1097/MCG.0000000000000507 CrossRefPubMedGoogle Scholar
  40. 40.
    Bressenot A, Peyrin-Biroulet L (2015) Histologic features predicting postoperative Crohn’s disease recurrence. Inflamm Bowel Dis 21:468–475. doi: 10.1097/MIB.0000000000000224 CrossRefPubMedGoogle Scholar
  41. 41.
    Kotanagi H, Kramer K, Fazio VW, Petras RE (1991) Do microscopic abnormalities at resection margins correlate with increased anastomotic recurrence in Crohn’s disease? Retrospective analysis of 100 cases. Dis Colon rectum 34:909–916Google Scholar
  42. 42.
    Fazio VW, Marchetti F, Church M et al (1996) Effect of resection margins on the recurrence of Crohn’s disease in the small bowel. A randomized controlled trial. Ann Surg 224:563–573CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Wolff BG, Beart RW, Frydenberg HB et al (1983) The importance of disease-free margins in resections for Crohn’s disease. Dis Colon rectum 26:239–243Google Scholar
  44. 44.
    Decousus S, Boucher A-L, Joubert J et al (2016) Myenteric plexitis is a risk factor for endoscopic and clinical postoperative recurrence after ileocolonic resection in Crohn’s disease. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver 48:753–758. doi: 10.1016/j.dld.2016.02.023 Google Scholar
  45. 45.
    Lemmens B, de Buck van Overstraeten A, Arijs I et al (2017) Submucosal plexitis as a predictive factor for postoperative endoscopic recurrence in patients with Crohn’s disease undergoing a resection with ileocolonic anastomosis: results from a prospective single-centre study. J Crohns Colitis 11:212–220. doi: 10.1093/ecco-jcc/jjw135 CrossRefPubMedGoogle Scholar
  46. 46.
    Sokol H, Polin V, Lavergne-Slove A et al (2009) Plexitis as a predictive factor of early postoperative clinical recurrence in Crohn’s disease. Gut 58:1218–1225. doi: 10.1136/gut.2009.177782 CrossRefPubMedGoogle Scholar
  47. 47.
    Rahier J-F, Dubuquoy L, Colombel J-F et al (2013) Decreased lymphatic vessel density is associated with postoperative endoscopic recurrence in Crohn’s disease. Inflamm Bowel Dis 19:2084–2090. doi: 10.1097/MIB.0b013e3182971cec CrossRefPubMedGoogle Scholar
  48. 48.
    Anseline PF, Wlodarczyk J, Murugasu R (1997) Presence of granulomas is associated with recurrence after surgery for Crohn’s disease: experience of a surgical unit. Br J Surg 84:78–82CrossRefPubMedGoogle Scholar
  49. 49.
    Denoya P, Canedo J, Berho M et al (2011) Granulomas in Crohn’s disease: does progression through the bowel layers affect presentation or predict recurrence? Colorectal Dis Off J Assoc Coloproctology G B Irel 13:1142–1147. doi: 10.1111/j.1463-1318.2010.02421.x Google Scholar
  50. 50.
    Wolfson DM, Sachar DB, Cohen A et al (1982) Granulomas do not affect postoperative recurrence rates in Crohn’s disease. Gastroenterology 83:405–409PubMedGoogle Scholar
  51. 51.
    Mojtahed A, Khanna R, Sandborn WJ et al (2014) Assessment of histologic disease activity in Crohn’s disease: a systematic review. Inflamm Bowel Dis 20:2092–2103. doi: 10.1097/MIB.0000000000000155 CrossRefPubMedGoogle Scholar
  52. 52.
    D’Haens GR, Geboes K, Peeters M et al (1998) Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 114:262–267CrossRefPubMedGoogle Scholar
  53. 53.
    Agnholt J, Dahlerup JF, Buntzen S et al (2003) Response, relapse and mucosal immune regulation after infliximab treatment in fistulating Crohn’s disease. Aliment Pharmacol Ther 17:703–710CrossRefPubMedGoogle Scholar
  54. 54.
    Sipponen T, Kärkkäinen P, Savilahti E et al (2008) Correlation of faecal calprotectin and lactoferrin with an endoscopic score for Crohn’s disease and histological findings. Aliment Pharmacol Ther 28:1221–1229. doi: 10.1111/j.1365-2036.2008.03835.x CrossRefPubMedGoogle Scholar
  55. 55.
    Mantzaris GJ, Christidou A, Sfakianakis M et al (2009) Azathioprine is superior to budesonide in achieving and maintaining mucosal healing and histologic remission in steroid-dependent Crohn’s disease. Inflamm Bowel Dis 15:375–382. doi: 10.1002/ibd.20777 CrossRefPubMedGoogle Scholar
  56. 56.
    Geboes K, Rutgeerts P, Opdenakker G et al (2005) Endoscopic and histologic evidence of persistent mucosal healing and correlation with clinical improvement following sustained infliximab treatment for Crohn’s disease. Curr Med Res Opin 21:1741–1754. doi: 10.1185/030079905X65457 CrossRefPubMedGoogle Scholar
  57. 57.
    Naini BV, Cortina G (2012) A histopathologic scoring system as a tool for standardized reporting of chronic (ileo) colitis and independent risk assessment for inflammatory bowel disease. Hum Pathol 43:2187–2196. doi: 10.1016/j.humpath.2012.03.008 CrossRefPubMedGoogle Scholar
  58. 58.
    Reinisch W, Colombel J-F, D’Haens G et al (2016) Characterisation of mucosal healing with adalimumab treatment in patients with moderately to severely active Crohn’s disease: results from the EXTEND Trial. J Crohns Colitis. doi: 10.1093/ecco-jcc/jjw178
  59. 59.
    Saverymuttu SH, Camilleri M, Rees H, et al (1986) Indium 111-granulocyte scanning in the assessment of disease extent and disease activity in inflammatory bowel disease. A comparison with colonoscopy, histology, and fecal indium 111-granulocyte excretion. Gastroenterology 90:1121–1128Google Scholar
  60. 60.
    Riley SA, Mani V, Goodman MJ, et al (1991) Microscopic activity in ulcerative colitis: what does it mean? Gut 32:174–178Google Scholar
  61. 61.
    Feagan BG, Greenberg GR, Wild G, et al (2005) Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med 352:2499–2507. doi: 10.1056/NEJMoa042982
  62. 62.
    Rubin DT, Huo D, Hetzel JT, et al (2007) Increased degree of histological inflammation predicts colectomy and hospitalization in patients with ulcerative colitis. Gatroenterology 132:A19Google Scholar
  63. 63.
    Silva MA, Menezes J, Wizman S, et al (2003) Cytokine tissue levels as markers of disease activity in pediatric Crohn disease. Pediatr Res 54:456–461. doi: 10.1203/01.PDR.0000083002.91602.40
  64. 64.
    Colombel JF, Solem CA, Sandborn WJ, et al (2006) Quantitative measurement and visual assessment of ileal Crohn’s disease activity by computed tomography enterography: correlation with endoscopic severity and C reactive protein. Gut 55:1561–1567. doi: 10.1136/gut.2005.084301

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© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Mayo Clinic ArizonaScottsdaleUSA
  2. 2.University of LeuvenLeuvenBelgium

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