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PRIORITY PRESS - 2011 Advances in Inflammatory Bowel Diseases - Crohn’s and Colitis Foundation (CCF) Clinical & Research Conference

Hollywood, Florida / December 1-3, 2011

Hollywood, Florida. Outcome is superior in patients with an inflammatory bowel disease (IBD), whether ulcerative colitis or Crohn’s disease, when remission includes mucosal healing. The data are so persuasive that there is now an exploration of the concept of mucosal healing, which applies to normal or near normal histologic recovery. The principle of mucosal healing, like mucosal healing, is that greater degrees of disease quiescence provide a greater barrier to relapse. Relative to partial resolution of inflammatory activity in IBD, which appears to be more readily triggered into periodic clinical flares, profound levels of disease control appear to render less likely both the initiation of the cascade of inflammatory signals and a resurgence of disease activity. IBD therapies were once guided by symptom control, but symptom relief and healing have a limited correlation. Healing is therefore an important goal for a chronic disease in which long-term outcomes must be considered in any treatment scheme.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The premise of mucosal healing in inflammatory bowel disease (IBD), which is now being considered by the U.S. Food and Drug Administration as a therapeutic target when demonstrating efficacy in IBD, is that risk of relapse declines in parallel with resolution of inflammatory activity. Currently, the best evidence of inflammatory control is mucosal healing, although other markers, including serum assays of circulating inflammatory mediators or a return to normal or near normal histology, may be useful. The common goal in all strategies is achieving a degree of disease quiescence that will provide a higher barrier to relapse.

“Over the long term, we need to ask ourselves how we are going to keep patients from progressing to hospitalization and colectomy,” suggested Dr. David T. Rubin, University of Chicago, Illinois. “One way will be to substitute objective goals for symptom-based control. Another is to focus on long-term outcomes rather than short-term management.”

Corroborative Evidence

Speaking specifically about the control of ulcerative colitis (UC), Dr. Rubin emphasized that the treatment goal for an acute flare should now be mucosal healing. This is based on evidence that less rigorous end points increase the risk for relapse and serious adverse complications from progressive disease, such as hospitalization and surgery. Importantly, symptom control may be achieved without healing, but healing may also be achieved without complete symptom control.

“We now have a great deal of data to tell us that healing on endoscopy is our treatment goal in the acute management of UC. The trials have demonstrated the benefits of mucosal and histologic healing in UC with reductions in hospitalization, reductions in surgery and reductions in neoplasia, so ultimately, that is indeed our goal,” agreed Dr. Stephen B. Hanauer, University of Chicago. He cited a study in which the relapse rate at 1 year was 80% in those with a clinical remission defined by symptoms but 23% (P<0.0001) in those with a clinical and endoscopic remission. In another, the rates of colectomy during lifetime follow-up was 19% vs. 81% (P<0.02) in those who did or did not have mucosal healing 1 year after initial therapy.

Mucosal Healing, Lower Relapse Risk

The improved outcomes in patients who achieve healing are not specific to treatment, even though the likelihood of healing in patients with severe disease is clearly related to use of the most effective therapies. In mild to moderate UC, mucosal healing—which is achieved in up to 32% of patients at 8 weeks with controlled-release mesalamine—predicts a lower relapse at 1 year than partial healing. According to Dr. Hanauer, the same relationship between healing and improved outcome is observed with each UC treatment. He cited a study with corticosteroids in which 49% of those with complete healing were relapse-free at 1 year. In contrast, prolonged responses in those with a partial remission were uncommon and at 22% were steroid-dependent after 1 year. In those without a response to corticosteroids at 1 month, 29% had gone on to surgery by 1 year.

Findings from SUCCESS

In patients with moderate to severe UC, mesalamine is not an appropriate first-line therapy. The question of whether to start with an immunosuppressant such as azathioprine (AZA), a biologic or both was addressed in an important study called SUCCESS, which was presented at the 2011 European Crohn's and Colitis Organization (ECCO) meeting (Panaccione et al.
J Crohn's Colitis 2011;5:S-80, Abs. 13). The 16-week, double-blind trial recruited 231 biologic-naïve patients with a Mayo score of at least 6. For eligibility, patients had to be failing corticosteroids and either naïve to AZA or had stopped AZA at least 3 months before entry. Subjects were randomized to AZA 2.5 mg/kg plus placebo, infliximab 5 mg/kg plus placebo or to infliximab 5 mg/kg plus AZA 2.5 mg/kg. Non-responders (Mayo score reduction <1 point) on the AZA arm at week 8 were eligible to receive infliximab subsequently.

The healing rates at 16 weeks climbed steeply in those receiving infliximab relative to those receiving AZA (55% vs. 37%; P=0.028). There was a further climb in those receiving both active therapies relative to infliximab alone (63% vs. 55%; P=0.295). Although this difference did not reach statistical significance, Dr. Hanauer indicated that the stepwise improvement would support the advantage of moving quickly to more aggressive therapy in patients with moderate to severe UC.

Indeed, there is some evidence that the speed at which inflammation is suppressed is also a prognostic indicator. In a placebo-controlled study with adalimumab, 71% of UC patients on the TNF inhibitor vs. 38% of those in the placebo group that had healing at 8 weeks were in remission at 1 year. Although this did not have another active treatment arm to prove that relative ability to achieve faster healing predicts increased long-term remission, it is consistent with the concept that the ability to efficiently turn off inflammatory activity is an important prognostic indicator.

“The data from this study and others suggests that therapies able to produce mucosal healing in the short term have a high likelihood of preserving remission in the long-term,” confirmed Dr. Edward V. Loftus, Mayo Clinic, Rochester, Minnesota.

ACT Studies

In UC, the ACT trials have been perhaps the most influential in encouraging earlier use of the most effective therapies. In these trials published 6 years ago (Rutgeerts et al N Engl J Med 2005;353:2462-76), patients with moderate-to-severe active UC despite treatment with concurrent medications were randomized to placebo, infliximab 5 mg/kg, or infliximab 10 mg/kg administered at weeks 0, 2 and 6 and then every 8 weeks. After 46 weeks, patients in ACT 1 were followed for a year. After 54 weeks, patients in ACT 2 were followed for
30 weeks. In both studies, mucosal healing was achieved at week 8 in approximately 60% of patients randomized to either dose of infliximab. This was approximately double the rate of healing in the placebo group and the highest rate of healing ever observed in a UC study.

“Perhaps the most important result was the difference in cumulative colectomy rates at the end of 54 weeks, which were almost twice as high in the placebo group [17% vs. 10%; P=0.02],” Dr. Hanauer told delegates.

Step Up Therapy

In UC, there has been a relative reluctance to step up therapy at the same pace in refractory patients as there has been in CD. However, the nature of the inflammatory cascade is similar, and the principles of management in regard to suppressing the underlying mediators of disease to improve long-term outcome are the same. A substantial proportion of patients with mild to moderate UC will respond to mesalamine, which is well tolerated and has been associated with a reduced risk of colon cancer in epidemiologic studies, but stepping up therapy should be based on the objective end point of mucosal healing.  

Summary

In UC as in CD, the criteria for effective treatment of acute flares are becoming more stringent because of the evidence that control of inflammatory activity predicts a lower long-term risk of complications, including hospitalization and colectomy. The importance of mucosal healing for predicting outcome appears to be independent of treatment used. This is consistent with the concept that the inflammatory cascade is less likely to reignite at greater degrees of relative quiescence. This concept is fundamental to the algorithms required to prevent long-term complications.  

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