Controversies in mucosal healing in ulcerative colitis

Abstract

As clinicians we would all agree that the goal for our patients is to induce remission, which is usually defined as symptom resolution. Restoring continence and absence of rectal bleeding would be signs that the mucosa is at most minimally inflamed if not healed. However, there have not been any data to confirm that symptomatic improvement alters the natural history of the disease, nor decreases the lifetime risk for surgery. Because we understand the potential complications of this disease, it should not be enough that we “settle” for symptom resolution, but aim instead to decrease the risk of complications and alter the natural history of the disease. Until recently, mucosal healing endpoints have not been included in clinical trials. Clinical endpoints lead to high placebo responses, potentially diluting the effect of the therapy, even in large multinational trials. The hard endpoint of endoscopic mucosal healing reduces the number needed to power a study for treatment effect. The relevant questions during this discussion are: 1) What is endoscopic healing? 2) How often can we achieve this in ulcerative colitis (UC)? 3) Does mucosal healing change disease outcomes? and 4) Does mucosal healing lower the rate of complications? The history of mucosal healing starts in 2001 when Bitton et al1 reported on clinical, biological, and histologic parameters that would predict time to clinical relapse. One of the only factors that was statistically significant was basal plasmacytosis on rectal biopsy. The hazard ratio (HR) for predicting clinical relapse was 4.5 and the authors concluded that this factor may help identify patients with inactive UC who will require optimal maintenance therapy. An accepted definition of endoscopic healing has yet to be developed and validated. Everyone would agree that return to normal vascular pattern, the absence of friability, or ulcerations fits the bill, but what about some mild erythema or granularity? If there is no friability (however you want to measure it), should that suffice? Mucosal healing was defined as either completely normal (score of 0) or mild (score of 1) in the ASCEND and ACT trials but 1 in the MMX (mesalamine) trials. Using the ASCEND criteria, mucosal healing was achieved in up to 80% of those patients on 4.8 g/mesalamine/day at week 6.2,3 Using the stricter subscore of 0, then this percentage fell to 30%. In the MMX trials, 77.6% of patients had a score of 1 on 4.8 g/day at the end of the trial at 12 weeks.4,5 In the infliximab trial, healing was achieved by 62% of the 5 mg/kg dose at week 8, and was sustained in 45.5% of patients at week 54.6 If a score of 0 or 1 is acceptable, then certainly mucosal healing as an endpoint is an achievable and reasonable goal. Just because the majority of patients may achieve mucosal healing, does it make any difference? In the ACT trial, those patients with documented mucosal healing at week 8 and 30 were more likely to be in remission than those who did not (P 0.009).6 We do not have such data from the mesalamine trials, as endoscopy at the end of the trial was not part of the protocol. It would, however, make intuitive sense that those patients without any symptoms at the end of the trial would most likely have scores of 1 or 0. In a currently ongoing prospective study, preliminary results from patients with active UC were presented.7 Patients with mild to moderate UC were treated with 6 weeks of 4 g/day oral and 2 g enemas. In 78 patients, 59 achieved clinical remission. Endoscopic activity was still present in only 5. After a mean follow-up of 8.7 months, 15 (26%) relapsed. The cumulative rate of relapse at 1 year was 23% in patients with clinical and endoscopic remission and 80% in patients with only clinical remission. The conclusion of the authors was that persistence of endoscopic activity is a rare event, with active UC achieving clinical remission after 6 weeks, but a very strong predictor of early relapse. Data from the IBSEN study in Norway followed incident cases of UC over a period of 5 years.8 In all, 354 patients were endoscoped at 6 months to 2 years after their diagnosis, 328 Received for publication September 25, 2008; Accepted December 15, 2008. From the *Mayo Clinic, Rochester, Minnesota, Mount Sinai Hospital, New York, New York, University of Michigan Hospital, Ann Arbor, Michigan. Reprints: Dr. Peter Higgins, Box 0682, 1150 West Medical Center Dr., Ann Arbor, MI 48109 (e-mail: phiggins@umich.edu). Copyright © 2009 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20875 Published online 11 February 2009 in Wiley InterScience (www. interscience.wiley.com).