Advertisement

Current Gastroenterology Reports

, Volume 12, Issue 6, pp 471–478 | Cite as

Mucosal Healing in Inflammatory Bowel Disease: Where Do We Stand?

  • Christina HaEmail author
  • Asher Kornbluth
Article

Abstract

The definition of remission in Crohn’s disease and ulcerative colitis has evolved to include mucosal healing as a measure of treatment efficacy. Randomized, controlled trials have demonstrated mucosal healing is attainable with the current arsenal of therapies available to treat inflammatory bowel disease. Mucosal healing has been shown to reduce the likelihood of clinical relapse, reduce the risk of future surgeries, and reduce hospitalizations. This review focuses on the latest studies addressing clinical outcomes of mucosal healing in the clinical trial and practice setting.

Keywords

Crohn’s disease Ulcerative colitis Mucosal healing 

Notes

Disclosure

Conflicts of interest: Dr. Ha, none. Dr. Kornbluth has received grant or research support from Salix, Centocor, Abbott, UCB, and Osiris; served as consultant or scientific advisor to Salix, Shire, Centocor, Given Imaging, Prometheus, UCB, Abbott, Takeda, Alaven, Warner-Chilcott, and Axcan; and served on speakers’ bureaus for and received honoraria from Salix, Prometheus, Abbott, UCB, Axcan, Warner-Chilcott, and Centocor.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Kappelman MD, Rifas-Shiman SL, Kleinman K, et al.: The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol 2007, 5:1424–1429.CrossRefPubMedGoogle Scholar
  2. 2.
    Loftus EV Jr: Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 2004, 126:1504–1517.CrossRefPubMedGoogle Scholar
  3. 3.
    Cellier C, Sahmoud T, Froguel E, et al.: Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic Crohn’s disease. A prospective multicentre study of 121 cases. The Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives. Gut 1994, 35:231–235.CrossRefPubMedGoogle Scholar
  4. 4.
    Froslie KF, Jahnsen J, Moum BA, et al.: Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007, 133:412–422.CrossRefPubMedGoogle Scholar
  5. 5.
    Rutgeerts P, Vermeire S, Van Assche G: Mucosal healing in inflammatory bowel disease: impossible ideal or therapeutic target? Gut 2007, 56:453–455.CrossRefPubMedGoogle Scholar
  6. 6.
    Allez M, Lemann M, Bonnet J, et al.: Long term outcome of patients with active Crohn’s disease exhibiting extensive and deep ulcerations at colonoscopy. Am J Gastroenterol 2002, 97:947–953.PubMedGoogle Scholar
  7. 7.
    Carbonnel F, Lavergne A, Lemann M, et al.: Colonoscopy of acute colitis. A safe and reliable tool for assessment of severity. Dig Dis Sci 1994, 39:1550–1557.CrossRefPubMedGoogle Scholar
  8. 8.
    • Sandborn WJ, Feagan BG, Hanauer SB, et al.: A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn’s disease. Gastroenterology 2002, 122:512–530.CrossRefPubMedGoogle Scholar
  9. 9.
    • D’Haens G, Sandborn WJ, Feagan BG, et al.: A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 2007, 132:763–786. This article summarizes the disease activity indices in ulcerative colitis, highlighting the variable endoscopic features of the scoring systems used in the major ulcerative colitis clinical trials.Google Scholar
  10. 10.
    Mary JY, Modigliani R: Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut 1989, 30:983–989.CrossRefPubMedGoogle Scholar
  11. 11.
    Daperno M, D’Haens G, Van Assche G, et al.: Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc 2004, 60:505–512.CrossRefPubMedGoogle Scholar
  12. 12.
    Baron JH, Connell AM, Lennard-Jones JE: Variation between observers in describing mucosal appearances in proctocolitis. Br Med J 1964, 1:89–92.CrossRefPubMedGoogle Scholar
  13. 13.
    Feagan BG, Greenberg GR, Wild G, et al.: Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med 2005, 352:2499–2507.CrossRefPubMedGoogle Scholar
  14. 14.
    Schroeder KW, Tremaine WJ, Ilstrup DM: Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987, 317:1625–1629.CrossRefPubMedGoogle Scholar
  15. 15.
    Powell-Tuck J, Day DW, Buckell NA, et al.: Correlations between defined sigmoidoscopic appearances and other measures of disease activity in ulcerative colitis. Dig Dis Sci 1982, 27:533–537.CrossRefPubMedGoogle Scholar
  16. 16.
    Rachmilewitz D: Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ 1989, 298:82–86.CrossRefPubMedGoogle Scholar
  17. 17.
    Levine DS, Riff DS, Pruitt R, et al.: A randomized, double blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis. Am J Gastroenterol 2002, 97:1398–1407.PubMedGoogle Scholar
  18. 18.
    Hanauer S, Schwartz J, Robinson M, et al.: Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial. Pentasa Study Group. Am J Gastroenterol 1993, 88:1188–1197.PubMedGoogle Scholar
  19. 19.
    Hanauer SB, Robinson M, Pruitt R, et al.: Budesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose-ranging study. U.S. Budesonide enema study group. Gastroenterology 1998, 115:525–532.CrossRefPubMedGoogle Scholar
  20. 20.
    Sutherland LR, Martin F, Greer S, et al.: 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology 1987, 92:1894–1898.PubMedGoogle Scholar
  21. 21.
    Riley SA, Mani V, Goodman MJ, et al.: Microscopic activity in ulcerative colitis: what does it mean? Gut 1991, 32:174–178.CrossRefPubMedGoogle Scholar
  22. 22.
    Bitton A, Peppercorn MA, Antonioli DA, et al.: Clinical, biological, and histologic parameters as predictors of relapse in ulcerative colitis. Gastroenterology 2001, 120:13–20.CrossRefPubMedGoogle Scholar
  23. 23.
    Li CQ, Xie XJ, Yu T, et al.: Classification of inflammation activity in ulcerative colitis by confocal laser endomicroscopy. Am J Gastroenterol 2010, 105:1391–1396.CrossRefPubMedGoogle Scholar
  24. 24.
    •• Pineton de Chambrun G, Peyrin-Biroulet L, Lemann M, et al.: Clinical implications of mucosal healing for the management of IBD. Nat Rev Gastroenterol Hepatol 2010, 7:15–29. This article comprehensively reviews the definitions and scoring systems for mucosal healing and summarizes the evidence-based studies of the current arsenal of medications and their ability to achieve mucosal healing.Google Scholar
  25. 25.
    Lichtenstein GR, Rutgeerts P: Importance of mucosal healing in ulcerative colitis. Inflamm Bowel Dis 2010, 16:338–346.PubMedGoogle Scholar
  26. 26.
    Hanauer SB, Sandborn WJ, Kornbluth A, et al.: Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial. Am J Gastroenterol 2005, 100:2478–2485.CrossRefPubMedGoogle Scholar
  27. 27.
    Sandborn WJ, Regula J, Feagan BG, et al.: Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis. Gastroenterology 2009, 137:1934–1943 e1931–1933.Google Scholar
  28. 28.
    Kamm MA, Sandborn WJ, Gassull M, et al.: Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology 2007, 132:66–75.CrossRefPubMedGoogle Scholar
  29. 29.
    Lichtenstein GR, Kamm MA, Boddu P, et al.: Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol 2007, 5:95–102.CrossRefPubMedGoogle Scholar
  30. 30.
    Kamm MA, Lichtenstein GR, Sandborn WJ, et al.: Effect of extended MMX mesalamine therapy for acute, mild-to-moderate ulcerative colitis. Inflamm Bowel Dis 2009, 15:1–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Kamm MA, Lichtenstein GR, Sandborn WJ, et al.: Randomised trial of once- or twice-daily MMX mesalazine for maintenance of remission in ulcerative colitis. Gut 2008, 57:893–902.CrossRefPubMedGoogle Scholar
  32. 32.
    Kruis W, Kiudelis G, Racz I, et al.: Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial. Gut 2009, 58:233–240.CrossRefPubMedGoogle Scholar
  33. 33.
    Rutgeerts P, Sandborn WJ, Feagan BG, et al.: Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005, 353:2462–2476.CrossRefPubMedGoogle Scholar
  34. 34.
    Reinisch W, Sandborn WJ, Hommes DW, et al.: Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis. Gastroenterology 2010, 138:S114–S115.Google Scholar
  35. 35.
    Afif W, Leighton JA, Hanauer SB, et al.: Open-label study of adalimumab in patients with ulcerative colitis including those with prior loss of response or intolerance to infliximab. Inflamm Bowel Dis 2009, 15:1302–1307.CrossRefPubMedGoogle Scholar
  36. 36.
    D’Haens G, Van Deventer S, Van Hogezand R, et al.: Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 1999, 116:1029–1034.CrossRefPubMedGoogle Scholar
  37. 37.
    Rutgeerts P, Diamond RH, Bala M, et al.: Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc 2006, 63:433–442.CrossRefPubMedGoogle Scholar
  38. 38.
    Rutgeerts P, Feagan BG, Lichtenstein GR, et al.: Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology 2004, 126:402–413.CrossRefPubMedGoogle Scholar
  39. 39.
    • D’Haens G, Baert F, van Assche G, et al.: Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008, 371:660–667. This study demonstrated significantly greater rates of mucosal healing at week 104 in the early combined immunosuppresion group compared to the conventional therapy arm, even though clinical remission rates were similar.Google Scholar
  40. 40.
    Van Assche G, Magdelaine-Beuzelin C, D’Haens G, et al.: Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology 2008, 134:1861–1868.CrossRefPubMedGoogle Scholar
  41. 41.
    Van Moerkercke W, Ackaert C, Compernolle G, et al.: High infliximab trough levels are associated with mucosal healing in Crohn’s disease. Gastroenterology 2010, 138:S60.Google Scholar
  42. 42.
    •• Colombel JF, Sandborn WJ, Reinisch W, et al.: Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010, 362:1383–1395. This randomized, controlled trial of biologic- and immunomodulator-naïve Crohn’s disease patients with moderate to severe symptoms demonstrated greater clinical response and mucosal healing with combination infliximab and azathioprine compared to infliximab or azathioprine monotherapy.Google Scholar
  43. 43.
    Mantzaris GJ, Christidou A, Sfakianakis M, et al.: Azathioprine is superior to budesonide in achieving and maintaining mucosal healing and histologic remission in steroid-dependent Crohn’s disease. Inflamm Bowel Dis 2009, 15:375–382.CrossRefPubMedGoogle Scholar
  44. 44.
    Rutgeerts P, D’Haens GR, Van Assche G, et al.: Adalimumab induces and maintains mucosal healing in patients with moderate to severe ileocolonic Crohn’s disease—first results of the EXTEND trial. Gastroenterology 2009, 136:A116.CrossRefGoogle Scholar
  45. 45.
    Colombel J-F, Rutgeerts PJ, Sandborn WJ, et al.: Adalimumab treatment results in deep remission for patients with moderate to severe ileocolonic Crohn’s disease: results from EXTEND. Gastroenterology 2010, 138:S518.Google Scholar
  46. 46.
    Colombel J-F, Lemann M, Bouhnik Y, et al.: Endoscopic mucosal improvement in patients with active Crohn’s disease treated with certolizumab pegol: week 10 and 54 results of the MUSIC trial. Gastroenterology 2010, 138:S166.Google Scholar
  47. 47.
    •• Schnitzler F, Fidder H, Ferrante M, et al.: Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease. Inflamm Bowel Dis 2009, 15:1295–1301. This study assessed the long-term outcomes of mucosal healing with infliximab treatment. The authors found Crohn’s disease patients with mucosal healing had sustained clinical benefit of infliximab, fewer major abdominal surgeries and hospitalizations.Google Scholar
  48. 48.
    Rutgeerts PJ, Reinisch W, Thakkar R, et al.: Early mucosal healing status predicts long-term clinical benefits for adalimumab-treated patients with moderate to severe Crohn’s disease. Gastroenterology 2010, 138:S85.Google Scholar
  49. 49.
    Rutgeerts P, Geboes K, Camez A, et al.: Quality of life improvements in adalimumab-treated patients with mucosal healing: results from the EXTEND trial. Am J Gastroenterol 2009, 104:S461.Google Scholar
  50. 50.
    Gupta RB, Harpaz N, Itzkowitz S, et al.: Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology 2007, 133:1099–1105.CrossRefPubMedGoogle Scholar
  51. 51.
    Rutter M, Saunders B, Wilkinson K, et al.: Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 2004, 126:451–459.CrossRefPubMedGoogle Scholar
  52. 52.
    Rutter MD, Saunders BP, Wilkinson KH, et al.: Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 2004, 53:1813–1816.CrossRefPubMedGoogle Scholar
  53. 53.
    Kandiel A, Fraser AG, Korelitz BI, et al.: Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005, 54:1121–1125.CrossRefPubMedGoogle Scholar
  54. 54.
    Siegel CA, Marden SM, Persing SM, et al.: Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn’s disease: a meta-analysis. Clin Gastroenterol Hepatol 2009, 7:874–881.CrossRefPubMedGoogle Scholar
  55. 55.
    Beaugerie L, Brousse N, Bouvier AM, et al.: Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009, 374:1617–1625.CrossRefPubMedGoogle Scholar
  56. 56.
    Treton X, Bouhnik Y, Mary JY, et al.: Azathioprine withdrawal in patients with Crohn’s disease maintained on prolonged remission: a high risk of relapse. Clin Gastroenterol Hepatol 2009, 7:80–85.CrossRefPubMedGoogle Scholar
  57. 57.
    Cassinotti A, Actis GC, Duca P, et al.: Maintenance treatment with azathioprine in ulcerative colitis: outcome and predictive factors after drug withdrawal. Am J Gastroenterol 2009, 104:2760–2767.CrossRefPubMedGoogle Scholar
  58. 58.
    Lemann M, Mary JY, Colombel JF, et al.: A randomized, double-blind, controlled withdrawal trial in Crohn’s disease patients in long-term remission on azathioprine. Gastroenterology 2005, 128:1812–1818.CrossRefPubMedGoogle Scholar
  59. 59.
    •• Baert F, Moortgat L, Van Assche G, et al.: Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology 2010, 138:463–468. This study was the 2-year follow-up of the D’Haens study of early combined immunosuppression versus conventional therapy in the treatment of Crohn’s disease. The authors found complete mucosal healing predicted sustained steroid-free remission up to four years after steroid enrollment.Google Scholar
  60. 60.
    Louis E, Vernier-Massouille G, Grimaud J-C, et al.: Infliximab discontinuation in Crohn’s disease patients in stable remission on combination therapy with immunosuppressors: a propsective ongoing cohort study. Gastroenterology 2009, 136:A146.Google Scholar
  61. 61.
    Schoepfer AM, Beglinger C, Straumann A, et al.: Ulcerative colitis: correlation of the Rachmilewitz endoscopic activity index with fecal calprotectin, clinical activity, C-reactive protein, and blood leukocytes. Inflamm Bowel Dis 2009, 15:1851–1858.CrossRefPubMedGoogle Scholar
  62. 62.
    Sipponen T, Savilahti E, Kolho KL, et al.: Crohn’s disease activity assessed by fecal calprotectin and lactoferrin: correlation with Crohn’s disease activity index and endoscopic findings. Inflamm Bowel Dis 2008, 14:40–46.CrossRefPubMedGoogle Scholar
  63. 63.
    Schoepfer AM, Beglinger C, Straumann A, et al.: Fecal calprotectin correlates more closely with the Simple Endoscopic Score for Crohn’s disease (SES-CD) than CRP, blood leukocytes, and the CDAI. Am J Gastroenterol 2010, 105:162–169.CrossRefPubMedGoogle Scholar
  64. 64.
    Sorrentino D, Paviotti A, Terrosu G, et al.: Low-dose maintenance therapy with infliximab prevents postsurgical recurrence of Crohn’s disease. Clin Gastroenterol Hepatol 2010, 8:591–599 e591.Google Scholar
  65. 65.
    Rutgeerts P, Geboes K, Vantrappen G, et al.: Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990, 99:956–963.PubMedGoogle Scholar
  66. 66.
    Sipponen T, Karkkainen P, Savilahti E, et al.: Correlation of faecal calprotectin and lactoferrin with an endoscopic score for Crohn’s disease and histological findings. Aliment Pharmacol Ther 2008, 28:1221–1229.CrossRefPubMedGoogle Scholar
  67. 67.
    Rimola J, Rodriguez S, Garcia-Bosch O, et al.: Magnetic resonance for assessment of disease activity and severity in ileocolonic Crohn’s disease. Gut 2009, 58:1113–1120.CrossRefPubMedGoogle Scholar
  68. 68.
    Ordas I, Garcia-Bosch O, Rodriguez S, et al.: Validation of a magnetic resonance index of activity for ileocolonic Crohn’s disease. Gastroenterology 2010, 138:S75.Google Scholar
  69. 69.
    Horjus CS, Bruijnen R, de Jong D, et al.: Magnetic resonance enterography in the assessment of the disease activity in Crohn’s disease: a retrospective study. Gastroenterology 2010, 139:S527.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Division of Gastroenterology and HepatologyThe Johns Hopkins School of MedicineBaltimoreUSA
  2. 2.The Henry J. Danowitz Division of GastroenterologyThe Mount Sinai School of MedicineNew YorkUSA

Personalised recommendations