Reports

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.

PRIORITY PRESS - 18th United European Gastroenterology Week

Barcelona, Spain / October 23-27, 2010

Mucosal healing after an acute episode of ulcerative colitis (UC) provides a greater barrier to relapse and its potential complications, including hospitalizations and colectomy bowel resections, according to several epidemiologic and clinical trials. However, mucosal healing is a high standard of efficacy. This has created a tension for clinicians unsure of how quickly to step up therapy when mucosal healing, which promises a reduced risk of complications, is not immediately achieved. In an evolving reorientation, it is not the premise of step-up strategy that is being questioned. Rather, it is the duration of time spent at each step on the way to the treatment goal.

Mucosal Healing Through Step-up Therapy

There is “a disconnect in clinical practice [between current treatment goals and the speed at which] patients should be moved through the treatment algorithm,” according to Dr. Manuel Barreiro De Acosta, University Hospital of Santiago de Compostela, Spain. In a special symposium at the UEGW devoted to the importance of producing mucosal healing and how to step up patients to achieve this goal. Dr. De Acosta reported, “Moving faster through the treatment algorithm will allow patients to receive appropriate therapy” critical for reducing the risk of complications.”

The tumour necrosis factor alpha (TNF-a) inhibitors, which are the cornerstone biologics, have demonstrated that mucosal healing can be achieved even in severe forms of UC. Guidelines generally recommend TNF-a inhibitors when other therapies have failed, but Dr. De Acosta argued that failure is poorly defined. While experts participating in the UEGW symposium, including Dr. De Acosta, did not disagree with this classic stepped-therapy approach which begins with 5-aminosalicylates (5-ASA) and moves to immunomodulators such as azathioprine (AZA) and 6-mercaptopurine (6-MP) with corticosteroids for short courses to regain disease control—they suggested failure is not defined by hospitalization.

“The perception is that infliximab should only be used in patients with severe UC,” observed Dr. Paul Rutgeerts, University of Leuven, Belgium. Referring to the first and most widely used TNF-a inhibitor, he objected strongly to this premise, noting that reserving this treatment for salvage in hospitalized patients exposes them to a far higher rate of potential complications, including colectomy, and is inconsistent with the evidence-based trials, the majority of which evaluated biologics in patients with moderate-to-severe rather than severe UC.

Indeed, the proportion of patients treated with infliximab who remained in clinical remission at 54 weeks was actually higher in those with moderate disease started on therapy in the outpatient setting than those with severe disease started in the hospital (45% vs. 19%; P=0.009), according to recent data (Seow et al. Gut 2010;59:49-54) cited by Dr. De Acosta. He contended that optimal benefits might be provided when TNF-a inhibitors are delivered at an early stage of failure than to be withheld until uncontrolled disease produces a hospitalization.

The same point was made by Dr. Geert D’Haens, Imelda General Hospital Bonheiden, Belgium. In outlining key goals of UC management, he indicated that producing and maintaining mucosal healing might be the most important because all the others, such as a reduction in hospitalizations and other disease-related morbidity as well as improvements in quality of life (QoL), follow. He agreed with others that there is now compelling evidence that mucosal healing leads to a reduction in morbidity and mortality and, as a result, an improvement in QoL.

Corroborative Study Findings

The key phase III placebo-controlled study demonstrating efficacy with TNF-a inhibitors in UC was called ACT I (Acute ulcerative Colitis Trial) and enrolled patients with moderate-to-severe UC (Rutgeerts et al. N Engl J Med 2005;353:2462-73). Infliximab, the study drug, achieved mucosal healing in about 60% of patients on either of the 2 active doses studies at 8 weeks (vs. 33% on placebo) but provided sustained mucosal healing at week 54 in about 46% (vs. 18% on placebo). A new post-hoc analysis has demonstrated that those who achieved mucosal healing had a reduced risk for colectomy.

In fact, all long-term outcomes have so far correlated with mucosal healing at the completion of induction therapy, according to Dr. Jean-Frédéric Colombel, Centre Hospitalier Universitaire (CHU), Lille, France. He noted that endoscopic score after 8 weeks of treatment predicted likelihood of symptoms at both 30 and 54 weeks so that those with a score of 0 were less likely to have symptoms at follow-up than those with a score of 1, while those with a score of 1 were less likely to have symptoms than those with a score of 2. The differences were substantial. For example, 73.7% of patients with an endoscopic score of 0 vs. 47.3% in those with an endoscopic score of 1 were symptom-free at 54 weeks. The proportion symptom-free with an endoscopic score of 3 after induction was 10% (Figure 1).

Figure 1.

“Mucosal healing is an important treatment goal,” Dr. Colombel concurred. He suggested these findings provide strong support for the conclusions drawn by Drs. De Acosta, Rutgeerts and D’Haens about the value of moving more quickly to agents capable of mucosal healing when endoscopic disease persists in patients on an immunomodulator or who require steroids.

Data from the Leuven cohort, which now includes 217 consecutive UC patients followed on infliximab for 6 months to almost 10 years, also reinforce the key importance of early mucosal healing in regard to long-term disease control. Again, the majority of patients in this cohort have moderate rather than severe disease. On induction therapy, 49% achieved complete mucosal healing. Providing data on up to 7 years of follow-up, Dr. Rutgeerts reported that colectomy was performed in about 50% of those who did not achieve complete mucosal healing vs. less than 10% of those who did.

Conversely, while failure to achieve mucosal healing on infliximab predicted an increased risk of colectomy, studies of the Leuven cohort also demonstrated that C-reactive protein (CRP) serum level of 5 mg/L or above was an independent predictor of colectomy. The ability of CRP, which is a sensitive marker of a pro-inflammatory state, to predict future colectomy rates is consistent with the importance of therapies that produce a sustained downregulation of inflammatory activity.

“Infliximab saves colons,” Dr. Rutgeerts stated. He called the Leuven cohort a “real-life experience that shows sustained efficacy with infliximab for up to 4 years,” but he referred to both the ACT I data and the Leuven cohort to confirm that “treatment with infliximab is as effective in UC as it is in Crohn’s disease.” He maintained that “scheduled maintenance treatment is indicated in patients who achieve clinical and endoscopic response at week 8.”

However, clinicians remain faced with the dilemma of when to declare failure in order to step up therapy. According to Dr. De Acosta, who attempted to tackle this issue, it is reasonable to start AZA in patients who require steroids to control a flare, but an evaluation should be conducted after 12 weeks. For those who are steroid-refractory after flaring on AZA, Dr. De Costa recommended moving directly to the TNF-a inhibitor.

He suggested that allowing patients to cycle on multiple rounds of steroids or waiting until patients are severe and hospitalized before starting infliximab is a “big gap” in current care that could be remedied by a willingness to step patients up to an effective therapy at a more rapid pace.

Summary

Guidelines suggest that TNF-a inhibitors should be reserved for patients who fail therapy without defining failure. While many clinicians currently reserve biologics for patients with severe disease, many experts disagree. Treatment outcome appears to be strongly influenced by the degree to which the initial flare is controlled. In those who achieve complete mucosal healing, there is a reduced risk of steroid dependency, hospitalization and colectomy.