Optimizing Therapy for IBD

Digestive Disease Week 2011

Stephen B. Hanauer, MD


May 17, 2011

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Hello, I'm Dr. Stephen Hanauer from the University of Chicago, and I'm here in my hometown of Chicago at Digestive Disease Week. I'd like to give you some updates on therapies for inflammatory bowel disease (IBD) from this year's meeting for Medscape.

This year's meeting has really brought forth a consensus on therapies for both ulcerative colitis and Crohn disease, particularly with respect to biologic therapy.

Biologics for Pediatric IBD

Several trials have now been completed in children with either ulcerative colitis or Crohn disease treated with anti-tumor necrosis factor (TNF) biologics. Jeff Hyams is presenting 2 abstracts[1,2] at this year's meeting on the role of adalimumab in children with Crohn disease, and infliximab as an effective therapy in pediatric ulcerative colitis. We now see data in children that are similar to what we have seen in adults with different anti-TNF biologic strategies. The results in children are somewhat better than adults. We have seen that biologic therapy in the earlier disease population tends to do better than in patients with late disease, and the data from the pediatric population really reflect the same finding that we've seen in adults.

In addition to the pediatric studies, a large trial of adalimumab for treatment of ulcerative colitis was presented.[3] Reinisch[4] had previously published a trial of adalimumab in ulcerative colitis that demonstrated efficacy in the short term, and at this year's meeting we see a presentation of adalimumab both at 8 weeks and at 52 weeks demonstrating both short- and long-term effectiveness of this anti-TNF strategy in ulcerative colitis. Now we have 2 anti-TNF agents with demonstrated effectiveness in ulcerative colitis: infliximab and adalimumab.

Monotherapy or Combination Therapy?

You may recall that SONIC [Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease], which tested infliximab alone vs infliximab plus azathioprine or azathioprine alone, demonstrated that the combination therapy was most effective in the treatment of Crohn disease.

At this year's meeting, Panccione and colleagues[5] are presenting what's known as the SUCCESS trial in ulcerative colitis. They used a similar design, randomly assigning patients with steroid-dependent ulcerative colitis to receive infliximab alone, infliximab plus azathioprine, or azathioprine alone. Once again, combination therapy was most effective and better than either monotherapies for the treatment of refractory ulcerative colitis. We see a great consilience now about combination therapy not only in Crohn disease but also in ulcerative colitis.

Trough Serum Levels and CRP

Furthering our evidence of how we can optimize treatment with biologic strategies in IBD, our Belgian colleagues[6] have actually led the way. At this year's meeting they have demonstrated the importance of trough serum concentrations as well as normalization of C-reactive protein (CRP) to optimize long-term treatment strategies with infliximab. Individuals who maintained trough serum concentrations and had lower normalized CRPs did far better than patients who had absent infliximab at the end of their treatment cycle, or patients who failed to have a complete response in terms of CRP.

Head-to-Head: Cyclosporine vs Infliximab

As far as biologic strategies are concerned, over the past several years we have been having debates as to whether cyclosporine or infliximab would be superior for patients with severe ulcerative colitis in the setting of the hospital. We know that infliximab can be effective in moderate to severe outpatients, on the basis of the ACT [Active Ulcerative Colitis] studies, and there have been some preliminary trials of anti-TNF biologics in ulcerative colitis.

Our French colleagues[7] have performed a controlled trial evaluating cyclosporine vs infliximab in the hospitalized setting of patients with severe ulcerative colitis. Patients were treated with either 2 mg/kg of cyclosporine or 5-mg/kg dosing of infliximab. Happily, it's a win-win situation. The mean time to response for both groups was 7 days, and 85% of the patients treated with either cyclosporine or infliximab improved. We're continuing to observe the long-term outcomes from these patients, but at least in the short-term it appears that cyclosporine and infliximab have equal efficacy. We need to understand some of the subtleties of this as far as the real severity of these hospitalized patients, but this is confirming the benefits that we have seen from both agents in independent clinical trials.

Continuing Controversy: Biologics in the Setting of Surgery

The last word on biologics retains some controversy as far as their safety in the setting of surgery. Reports are conflicting about whether biologic therapy is associated with increasing postoperative complications. The key factor is to control for the severity of the disease and the status of the patient independent of treatment, but we continue to see conflicting reports, in which some observers have identified a modest risk for anti-TNF therapy as far as infections are concerned[8]; whereas other groups have identified no difference in the safety of surgery in the setting of biologic therapy.[9]

Future IBD Therapies

Three therapies are highlighted for future use in either ulcerative colitis or Crohn disease. The drug that is closest to coming to market is probably an MMX [once-daily, multi-matrix] formulation of budesonide that has been reported in 2 clinical trials[10,11] at this year's meeting, demonstrating effectiveness in patients with mild-to-moderate ulcerative colitis.

In addition, 2 novel treatments have also been explored. Janus kinase (JAK) inhibitors that block many of the downstream cytokine and inflammatory mediators are being tested in rheumatoid arthritis and have also been tested in Crohn disease[12] and ulcerative colitis.[13] Early results of the phase 2 studies look very promising for this novel therapy that is not a biologic agent and will actually be taken orally.

As far as novel biologics are concerned, phase 2 data were presented at this year's meeting on the potential use of ustekinumab, an IL-12/23 inhibitor that has been very successful in psoriasis with promising clinical results.[14]

There are great opportunities for us to optimize both our biologic and conventional medical therapies, and this year's meeting has helped us to identify some of these factors, such as combination therapy and the potential of using trough levels to monitor patients. I hope this has been useful for you. I thank you for listening. This is Steve Hanauer from the University of Chicago for Medscape.


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