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PHYSICIAN PERSPECTIVE - Viewpoint based on the following article: Gastroenterol Hepatol 2009;5(7):494-500

November 2009

Reviewed and edited by:

Remo Panaccione, MD, FRCPC, Director, Inflammatory Bowel Disease Clinic, Director of Research, GI Division

Associate Professor of Medicine, University of Calgary, Calgary, Alberta

A. Hillary Steinhart, MD, FRCPC, Head, Combined Division of Gastroenterology, Mount Sinai Hospital/University Health Network

Associate Professor of Medicine, University of Toronto, Toronto, Ontario

Defining the Benefits of Mucosal Healing in Ulcerative Colitis

By A. Hillary Steinhart, MD, FRCPC

The immediate goal of therapy in patients presenting with an acute episode of ulcerative colitis (UC) is relief of symptoms, but there is now good evidence that efficacy should also be judged by healing of the inflamed tissue. Endoscopic remission, a rigorous test of drug efficacy, correlates imperfectly with clinical remission but has been isolated as an important predictor of sustained remission. In a retrospective study with 740 inflammatory bowel disease (IBD) patients that included both those with UC and those with Crohn’s disease (CD), mucosal healing predicted fewer colectomies (P=0.02) and decreased use of steroids (P=0.02) over five years of follow-up.¹ In a phase III study with a biologic therapy in UC, mucosal healing at eight weeks was a strong predictor of sustained remission at 52 weeks, including fewer hospitalizations and fewer surgeries.² The correlation between acute mucosal healing and improved long-term outcomes suggests this should be the goal of induction therapies for both UC and CD.³

The importance of mucosal healing in UC is reflected in major clinical trials which have employed increasingly strict endoscopic definitions of inflammation control. While the focus of acute response to UC therapies in the past has been primarily on symptoms as defined by the UC Disease Activity Index (UCDAI) or the Mayo score, large efficacy trials now define efficacy as a UCDAI score of 1 or less but also specify absence of mucosal friability on sigmoidoscopy. This concept of disease resolution at the level of the tissue is driven by the evidence that early control of disease may alter its natural history by reducing the frequency of relapses and the potential for the most serious complications. Based on the importance of mucosal healing, reproducible, stringent and uniform definitions of this outcome are important for judging therapeutic options.

The advent of sustained-release formulations of 5-aminosalicylic acid (5-ASA) agents are permitting these traditional first-line therapies to be tested under the new definitions for acute disease and sustained disease resolution. The definition described above—a UCDAI score of 1 or less and absence of mucosal friability on sigmoidoscopy—was the end point for evaluating an oral mesalamine formulation with a controlled-release delivery designed to initiate release of active drug when the agent reaches the large bowel. This multi-matrix system (MMX) of delivery involves a pH-dependent coating resistant to the high acidity of the stomach with lipophilic and hydrophilic excipients that provide a relatively constant release as the product descends the large intestine.

Study Findings

Two phase III studies with this agent provided the evidence that 5-ASA remains a viable first-line agent even when the goal is complete mucosal healing.4 In one of the two studies, patients with mild to moderate UC were randomized to receive MMX mesalamine 1.2 g b.i.d., 4.8 g q.d. or placebo over eight weeks. In the other, patients were randomized to one of the four groups: MMX mesalamine 2.4 g q.d., 4.8 g q.d., delayed-release mesalamine 0.8 g t.i.d. or placebo. Of the 346 patients randomized to one of the MMX doses, 125 (36.1%) achieved a strict definition of endoscopic remission after eight weeks. Of those not in remission, 156 were treated for an additional eight weeks with 4.8 g per day and 95 (61%) achieved remission for a total of 220 (63.6%) in remission at the end of 16 weeks.

This follow-up study demonstrated that the high rate of mucosal healing achieved with an MMX 5-ASA therapy can be substantially increased with an additional eight weeks of treatment, permitting the majority of patients to reach the most stringent measure of response on this first-line agent. As predicted by studies associating mucosal healing with sustained benefit, all but two of the patients who healed on MMX mesalamine entered a maintenance study at 2.4 g with high relapse-free rates sustained whether eight or 16 weeks of therapy were required to achieve healing. Among those initially treated for eight weeks, the relapse-free rate at 12 months was 92.1%. In those who required an additional eight weeks of treatment at 4.8 g, 87.5% were relapse-free at 12 months.

On an intent-to-treat basis, 196 (56.6%) of the 346 mild-to-moderate UC patients who were initially randomized to an MMX therapy achieved clinical and endoscopic remission and were relapse-free for at least 12 months. This is a compelling demonstration of the efficacy of MMX 5-ASA and provides support for the important predictive value of mucosal healing for sustained disease control. It also establishes the importance of an adequate period of induction therapy.

Remission

These rates of remission and freedom from relapse may be credited to the progress made in sophisticated sustained-release delivery systems, even if relative efficacy in comparison with alternative treatment options is difficult to judge because of the variety of definitions of remission that have been employed previously. Even when healing is verified endoscopically, some studies have counted absence of ulcers rather than absence of mucosal friability as remission. The more rigorous definition of complete mucosal healing employed in the most recent 5-ASA trials not only reduces the opportunity for subjectivity in describing resolution but also incorporates the underlying premise that fully quiescent disease may provide a greater barrier to relapse than partial resolution.

Stepping up to immunomodulators may be required to achieve mucosal healing, particularly as the severity of UC increases, but the rationale for an adequate trial of 5-ASA is an opportunity for significant preservation of quality of life (QoL) using a therapy that has an excellent short- and long-term safety profile. In the randomized trials, the safety profile of MMX mesalamine has been similar to that observed in the placebo arms. In patients considered to be potential responders to 5-ASA, a second eight-week course of therapy is supported by the anticipated advantages of avoiding therapies that may be less well tolerated and any safety issues relevant to immunosuppression. In the case of biologics, disease control with a 5-ASA agent is associated with lower costs and less inconvenience. Although rapid control of symptoms cannot be ignored as a priority from the patient’s perspective, clinical symptoms were improved at eight weeks even among those who required 16 weeks to heal.

Rationale for High-dose Maintenance Therapy

By Remo Panaccione, MD, FRCPC

The potential advantages of maintaining remission with a 5-ASA agent are similar to those that support these agents as first-line therapy for induction for UC. Relative to immunomodulators, 5-ASA agents are well tolerated and avoid the risks inherent in immunosuppression. Relative to less well-tolerated therapies or more complicated dosing schedules, there is also a potential compliance advantage for patients who can be maintained on a single daily oral dose of 5-ASA. The potential for a reduced risk of colon cancer with prolonged maintenance 5-ASA is an additional consideration.^5,6

The data from the phase III studies with MMX mesalamine, which included both healing and maintenance phases, document the ability of 5-ASA therapy to provide prolonged freedom from relapse. In those who healed in the healing phase, whether over eight or 16 weeks, the rate of relapse-free remission at the end of 12 months was nearly 90% at all doses. However, the dose needed to achieve healing is likely to be relevant to the dose required to provide the maximum protection against relapse. In the initial healing phase, 58 (92.1%) of the 63 who had achieved clinical and endoscopic remission at the end of eight weeks on 2.4 g remained in remission at the end of 12 months on this dose. Similarly, 54 (90%) of the 60 patients who achieved clinical and endoscopic remission on an initial healing dose of 4.8 g at eight weeks and were then switched to a 2.4 g maintenance dose remained in remission at the end of 12 months.

In those who required longer periods to heal, higher doses were employed but led to similar rates of remission over 12 months. Specifically, of the 48 patients who initiated therapy on 2.4 g but required an additional eight weeks at 4.8 g for clinical and endoscopic healing, 42 (87.5%) remained in remission at the end of 12 months on the higher mesalamine dose. Of those who started on 4.8 g but required an additional eight weeks on this dose for clinical and endoscopic remission, 42 (89.4%) remained in remission at 12 months when maintained on 4.8 g. Of those who received 4.8 g, response rates appeared to be similar whether it was delivered in a single dose or two divided doses.

These data suggest that patients who require the higher dose of the active treatment to achieve endoscopic and clinical remission may do best on maintenance at the same dose. There are no randomized data comparing relapse rates in patients initiated on a low dose and stepped up to a higher dose or on the higher dose and stepped down to the lower dose; however, the persistent remissions achieved in individuals who required longer courses at higher doses for healing argues for the same dose to preserve the remission. In the maintenance arm of the phase III studies, the higher dose was not associated with a significantly greater burden in adverse events.

Relatively high doses of 5-ASA are also attractive when the alternative is stepping up to an immunotherapy such as azathioprine or methotrexate, which are associated with tolerability and safety issues. The recent evidence that 5-ASA can achieve rigorous definitions of mucosal healing has strengthened the role of these agents in first-line therapy even in patients with moderate disease, a group that represented 60% of the controlled trials with MMX mesalamine.

Mucosal Healing

The importance of acute mucosal healing to preserve remission intensifies the importance of recognizing treatment of UC, a chronic and sometimes progressive disease, in the context of preserving QoL over indefinite periods of follow-up. While the safety of 5-ASA has been stressed previously, the relative tolerability of this agent has important implications for the compliance essential to preventing relapse. When adherence was defined as filling 80% of prescriptions, relapse-free disease at 24 months was achieved in 89% of those who were adherent vs. 39% who were not (P<0.001). One of the concerns of stepping up to less well-tolerated therapies is that patients who feel better may be less likely to tolerate the adverse effects of the medication than those who are controlled on a less toxic agent.

An adequate or improved QoL is a global concept that is defined by multiple factors, including freedom from the symptoms of disease and a low burden from its treatments. In major guidelines, including those from Europe and the US,^7,8 5-ASA has been identified as the first-line therapy based on its efficacy and tolerability. Although symptom-related disease activity is the most important predictor of QoL,⁹ patients who respond to 5-ASA can also expect a low relative risk of adverse events and a relatively simple dosing regimen. Satisfaction with therapy that translates into sustained compliance has the potential to contribute independently to long-term disease control. This combination of attributes is an important basis on which to strive to heal and maintain UC with 5-ASA.

Summary

Despite the unpredictability of UC, there is now a substantial body of evidence that suggests that both remission and disease activity tend to be self-sustaining. Mucosal healing appears to create a barrier to relapse while persistent activity, even at low levels, is associated with a higher risk of flares when patients are followed for periods of 12 months or more. In turn, repeated disease relapses are associated with an increased risk of the complications of UC, including colectomy. These observations are the basis for seeking endoscopic resolution of UC during the initial acute course of therapy. Studies with an MMX formulation of 5-ASA, the first-line therapy for UC, have demonstrated that the majority of individuals with mild-to-moderate disease can achieve healing when given an adequate course of therapy at a sufficient dose. Patients who do heal on 5-ASA can anticipate a low risk of relapse while avoiding the risks of more aggressive treatments.

References:

1. Frøslie et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412-22.

2. Rutgeerts et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462-76.

3. Rutgeerts P. Mucosal healing in inflammatory bowel disease: impossible ideal or therapeutic target? Gut 2007;56:453-5.

4. Hanauer et al. MMX mesalamine for induction and maintenance therapy in mild-to-moderate ulcerative colitis. Gastroenterol Hepatol 2009;5:494-500.

5. Velayos et al. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 2005;100:1345-53.

6. Rubin et al. Will a 5-ASA a day keep the cancer (and dyspepsia) away? Am J Gastroenterol 2005;100:1354-6.

7. Travis et al. European evidence-based consensus on the management of ulcerative colitis: current management. J Crohns Colitis 2008;2:24-62.

8. Kornbluth et al. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2004;99:1371-85.

9. Han et al. Predictors of quality of life in ulcerative colitis: the importance of symptoms and illness representations. Inflamm Bowel Dis 2005;11:24-34.