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 - Inflammatory Bowel Diseases 2011: 6th Congress of the European Crohn’s and Colitis Organisation (ECCO)

Dublin, Ireland / February 24-26, 2011

In patients with moderate-to-severe Crohn’s disease (CD) who had failed conventional therapy, the landmark SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease) trial showed that patients treated with the TNF-a inhibitor infliximab (IFX), either as monotherapy or in combination with azathioprine (AZA), were significantly more likely to have a corticosteroid-free clinical remission and mucosal healing than those receiving AZA monotherapy (Colombel et al. N Engl J Med 2010;362:1383-95). The greatest efficacy was seen with combination therapy, exposing the limitations of AZA in CD. Dr. Remo Panaccione, University of Calgary, Alberta, stated, “We needed to show that a similar approach would be possible in ulcerative colitis (UC).”

Combination Therapy in UC: Building on SUCCESS

To that end, a similar study was initiated in patients with moderate to severe UC. The UC SUCCESS trial compared the same IFX-based strategies with AZA in anti-TNF-naive adults with moderate-severe UC (Mayo score 6 to 12) who were failing corticosteroids and either naive to AZA/6-mercaptopurine (6-MP) or AZA-free for =3 months before entry. Principal investigator Dr. Panaccione presented results of the trial here at ECCO-IBD. As in SONIC, UC SUCCESS patients treated with a combination strategy were more likely to achieve response, steroid-free remission and mucosal healing than those treated with AZA monotherapy. “The results of this study will guide our way forward in treating UC,” he told delegates.

UC SUCCESS randomized 239 patients to AZA 2.5 mg/kg plus placebo or IFX 5 mg/kg plus placebo or in combination at their respective doses. A significantly greater proportion of patients in the AZA/IFX arm achieved the primary efficacy end point of steroid-free remission (Mayo score =2) at week 16 compared with the AZA arm (40% vs. 24%, P=0.032). The proportion of steroid-free remission achieved was similar in both monotherapy arms. As Dr. Panaccione pointed out, these rates were consistent with those seen in ACT (Active Ulcerative Colitis Trials) 1 and 2 (Rutgeerts et al. N Engl J Med 2005;353:2462-76).

At week 16, significantly greater proportions of patients achieved secondary end points of clinical response (decrease in total Mayo score =3 points and 30% lower than baseline Mayo score) with either combination therapy (77%, P=0.001) or IFX alone (69%, P=0.018) vs. AZA alone (50%) and mucosal healing (Mayo endoscopy subscore of 0 or 1) (63%, P=0.001; 55%, P=0.028; and 37%, respectively) (Figure 1). “Again, we are not only seeing results with significant P values, but significant therapeutic gains,” Dr. Panaccione noted.

Figure 1.

“We learned from the ACT trials that introducing IFX in patients with moderate to severe UC led to decreases in colectomy rates,” Dr. Panaccione noted. “Patients in these trials were treated later than in UC SUCCESS and we know that in CD, the earlier the patients are treated, the better the expected outcome should be. Perhaps now it is time to consider this approach in UC,” he suggested. “We need to start changing our thinking based not only on UC SUCCESS, but also from what we have learned in CD. In steroid-dependent UC patients in the first or second flare-up, consider IFX alone or in combination with AZA as the next step,” he proposed.

Emerging Options

Among TNF-a inhibitors, adalimumab’s efficacy in inducing and maintaining clinical remission in UC patients with an inadequate response to conventional therapy was demonstrated in M06-827, a phase III randomized, double-blind study in patients with moderate to severe UC. Presented here by Dr. Gert Van Assche, University Hospital of Gasthuisberg, Leuven, Belgium, the study enrolled 494 intent-to-treat adults with UC (Mayo score 6 to 12 and endoscopic subscore 2 or 3 despite treatment with corticosteroids and/or immunosuppressants). Patients who had discontinued a TNF-a inhibitor due to intolerance or loss of response were included and randomized to placebo or adalimumab 160 mg at week 0, 80 mg at week 2 and 40 mg at week 4. Dose escalation to 40 mg weekly was permitted for patients with inadequate response on open-label administration. A greater proportion of patients treated with active therapy achieved clinical remission at week 8 and at week 52. Significantly more actively-treated patients also achieved clinical response and mucosal healing at week 8 and sustained clinical remission and mucosal healing at week 52, compared with placebo. Active therapy demonstrated a greater effect in anti-TNF-naive patients. Real-world long-term clinical experience will determine its role as another option in UC and particularly in anti-TNF-naive patients.

Acute Severe UC

Acute severe UC (ASUC) occurs in 15% of UC patients. Although intravenous (i.v.) corticosteroids are the mainstay of treatment, 40% of ASUC patients are refractory to steroids, and cyclosporine (CsA) and IFX are effective rescue options. Dr. David Laharie, Hôpital du Haut-Lévêque, Pessac, France, presented the results of the first randomized trial comparing CsA and IFX in 116 adults with ASUC.

All patients with ASUC fulfilled criteria for steroid failure (Lichtiger score >10) and were randomized to i.v. CsA (2 mg/kg/day for 1 week, then switched to oral formulation during 98 days) or IFX (5 mg/kg at weeks 0, 2 and 6). Treatment failure, the primary end point of the study, was seen in 60% of patients on CsA compared with 54% on IFX. The short-term response rate (at day 7) was similar in the 2 groups (85.4% vs. 85.7%, respectively). Three-month colectomy rates were also similar at 18% with CsA and 21% with IFX.

Although equally effective as IFX, CsA is harder to manage and requires frequent monitoring and Dr. Paul Rutgeerts, University of Leuven, commented that IFX might be a safer choice for the treatment of ASUC.

Considerations for an Optimal Treatment Algorithm

A retrospective analysis showed that maintenance IFX therapy is efficacious in severe i.v. steroid-refractory UC but optimal rescue therapy is still being debated, according to Dr. Marc Ferrante, University Hospital of Gasthuisberg. He noted that short-term clinical response, short-term mucosal healing (P=0.032) and normalization of C-reactive protein (CRP) were predictors of relapse-free and colectomy-free survival.

“The optimal treatment algorithm for UC still needs to be defined,” Dr. Rutgeerts cautioned. The way forward is to optimize patient selection and take predictors of colectomy into account. “Mucosal healing is the key therapeutic target and should be achieved early and maintained over time,” he told delegates. “Goals of treatment are better defined and we are able to reduce steroid use for our patients and heal their mucosa with IFX therapy, and this impacts on the long-term outcome of the disease.”

Other Findings Presented at ECCO-IBD

In a retrospective case-control study, Lutgens et al. determined that disease extent (>50% of the colon), pseudopolyps and colonic stenosis were independent risk factors for colorectal cancer (CRC). Primary sclerosing cholangitis was also associated with a non-significant increased risk of CRC. Investigators reported that 5-ASA medication was found to be protective.

From an analysis of the Spanish ENEIDA Registry, Gordillo et al. showed that independent predictive factors for developing high-grade dysplasia and CRC in UC were male gender and primary sclerosing cholangitis. Independent protective factors were the use of immunomodulators and inclusion in a colonoscopy surveillance program (both P=0.005).

Summary

The main objectives in UC management remain similar to those in CD: achieve corticosteroid-free clinical remission, induce complete mucosal healing and decrease colectomy rates. Predictors of decreased colectomy rates are short-term clinical response, short-term mucosal healing and normalization of CRP. Studies have shown that patients treated with anti-TNF-based therapy are more likely to achieve response and mucosal healing than those on monotherapy. The 5-year experience with IFX in UC shows reduced steroid use and increased rate of complete mucosal healing, which could affect the long-term outcome of the disease. Use of anti-TNF therapy and participation in a colonoscopy surveillance program may help reduce the incidence of CRC.