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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

15th United European Gastroenterology Week (UEGW)

Paris, France / October 27-31, 2007

Until recent years, clinical remission in inflammatory bowel disease (IBD) was a significant treatment goal, particularly in patients with moderate-to-severe involvement. The data demonstrating the importance of controlling lesions as well as symptoms have become available only recently, partially as a consequence of clinical trials with tumour necrosis factor alpha (TNF-a) inhibitors, which have typically included baseline and follow-up colonoscopies to evaluate the effect of treatment on disease progression. The controlled evidence that mucosal healing is associated with a reduced risk of hospitalizations and colectomy has altered the paradigm for defining effective therapy.

“Our therapeutic goals and strategies are changing,” reported Dr. Jean-Frédéric Colombel, Centre hospitalier régional universitaire, Lille, France. “We can look beyond symptom remission to assess mucosal healing as a treatment goal.”

The introduction of infliximab and the subsequent biologics adaluminab and, most recently, certolizumab, was life-altering for many patients with moderate-to-severe IBD who respond poorly to other options. The rapid control of IBD symptoms is attributed to the targeted control of TNF-a, an important pro-inflammatory mediator, but the reduction in long-term complications, such as hospitalization and colectomy, now appears to be at least partially due to an increased likelihood of mucosal healing with these agents. Recently, a published study offered evidence for mucosal healing as a clinical indicator and a treatment goal in IBD (Froslie et al. Gastroenterology 2007;133:412-22).

Dr. Julián Panés, Head, Inflammatory Bowel Disease Unit, Hospital Clínic Barcelona, Spain, cited an infliximab study presented two years ago that found that those who achieved mucosal healing at eight weeks had a more than fourfold increased likelihood of being in clinical remission at week 30 (48.3% vs. patients without mucosal healing at week 8, 9.5%) (Sandborn et al. ACG 2005, Abstract 841). New data are continuing to build on the story that mucosal healing during the induction phase explains the lower risk of relapse during maintenance.

“Infliximab is a good drug with which to achieve remission at a histological level,” Dr. Panés reported. Calling mucosal healing “an achievable goal,” he cited an increasing body of evidence leading to better outcomes in ulcerative colitis (UC) with mucosal healing, among them, data from ACT (Acute Ulcerative Colitis Trials).

In new data from the placebo-controlled ACT 1 and 2 trials, the biological was associated with a 43% reduction (OR 0.57, 95% CI: 0.37-0.91; P=0.012) in the risk of colectomy relative to placebo through one year after the first infusion. In addition, the number of UC-related hospitalizations was significantly lower (P=0.003) with the TNF-a inhibitor. Previously reported data from the ACT trials had already established that mucosal healing rates were significantly lower on placebo than infliximab when evaluated at weeks 8 and 30 (P<0.009) in both ACT trials.

As reported by Dr. William J. Sandborn, Mayo Clinic, Rochester, Minnesota, “Infliximab induction followed by maintenance significantly reduced the incidence of colectomy, and decreased the proportions of patients with UC-related hospitalizations and UC-related surgeries.” Presenting the new data on behalf of the multinational team of ACT investigators, Dr. Sandborn indicated that reductions in colectomy are an important goal because it is one of the most important sources of IBD morbidity and one of the complications that patients fear the most.

Similar data associating TNF-a inhibitors with a reduced need for surgery were reported for Crohn’s disease by Dr. Fabian Schnitzler, University Hospital Gasthuisberg, Leuven, Belgium, and co-investigators. In their recently completed single institution study, 611 Crohn’s disease patients treated since 1995 were evaluated. Prior to the introduction of biologicals, 39% of patients had required surgery. After the introduction of infliximab, only 23% have undergone colectomy. Among patients who initiated scheduled TNF-a inhibitor treatment, the colectomy rate has been 9% vs. 26% of patients who have received an episodic regimen. In the minority of patients whose TNF-a inhibitor was stopped due to lack of benefit, the colectomy rate was 57%. Other types of morbidity, such as hospitalization rates, have also been reduced since the introduction of biologicals. Again, the relative benefit was greatest in those who received scheduled vs. episodic treatment from the start.

“In those who started on scheduled therapy, the hospitalization rate after a median 48 months of follow-up has been 26% vs. 48% for those on episodic therapy,” reported Dr. Schnitzler. “These data demonstrate that the initiation of infliximab in Crohn’s is associated with a reduced morbidity with the best results achieved with scheduled rather than episodic therapy.”

Another analysis from the same 611 patients has demonstrated that biologicals also reduce steroid dependence. In data presented by Dr. Schnitzler’s colleague, Dr. Paul Rutgeerts, senior author of the Belgium study, steroids were completely withdrawn in 70% to 88% of Crohn’s patients who were on steroids at the time that their TNF-a inhibitor was initiated. The reduction depended on whether patients were initiated and maintained on scheduled therapy, initiated on episodic therapy and then switched to scheduled therapy, or initiated and maintained on episodic therapy.

“Patients do not like corticosteroids, which have many side effects and are not effective for maintaining remission, but it is often difficult to wean patients from these drugs,” Dr. Rutgeerts remarked. Prior to the introduction of biologicals, only 20% to 30% of patients on long-term corticosteroids at his institution could be successfully weaned. “These data, drawn from our own experience and not from a trial, clearly demonstrate the ability of infliximab to permit us to reduce steroid dependence in the majority of patients.”

The experience with targeted therapies, which have played an important role in demonstrating the link with mucosal healing, has permitted a new orientation in Canada in the management of IBD. The concept that mucosal healing is important has now been embraced by many clinicians. In a survey of more than 250 gastroenterologists from five European countries, mucosal healing was identified as an important objective in Crohn’s disease by 79% of respondents and for UC by 87%. The respondents further confirmed that biologicals are an integral part of their management strategies.

“In patients not experiencing improvement from steroid and immunosuppressive therapy, 93% of respondents reported that they are likely to prescribe biologic therapy in Crohn’s disease and 80% reported that they are likely to prescribe it in UC. Seventy-nine per cent reported that they would not recommend surgery for their patients if biologics have not yet been tried,” reported Dr. Gert Van Assche, also from University Hospital Gasthuisberg.

The growing amount of data to define the benefit:risk ratio of biologics in very specific groups of patients is providing the confidence to consider more aggressive treatment regimens earlier in an effort to achieve mucosal healing. According to Dr. Remo Panaccione, Director, Inflammatory Bowel Disease Clinic, University of Calgary, Alberta, such studies as SONIC, which is randomizing Crohn’s disease patients who have failed 5-aminosalicyclic acid drugs to infliximab alone or azathioprine plus infliximab, will further define how biologics are best employed to improve outcome. Again, if mucosal healing has a critical role to play in reducing the long-term morbidity of IBD, therapies most likely to provide healing may be best employed earlier in the disease course.

Summary

The introduction of infliximab and other TNF-a inhibitors controls symptoms in a large proportion of IBD patients unresponsive to other options, but new data suggest that the relative advantage of these agents for mucosal healing may be far more important for long-term outcome than their ability to achieve clinical remission. If healing is achieved, the risk of relapse appears to be dramatically reduced, thereby reducing the subsequent risk of hospitalization and colectomy. Scheduled induction and maintenance appears to be more effective than episodic regimens for achieving mucosal healing and reducing morbidity, but the most important emerging question is whether early introduction of biologics to heal lesions may also be an important predictor of improved long-term control.

Note: At the time of printing, certolizumab is not available in Canada.