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A SONIC Boom: Making Sense of Top Down Therapy for Crohn’s Disease
Thought some might find this of interest. Since you have to be a member on Medscape to read it (I believe, anyway) I thought I'd jut paste it here:
A SONIC Boom: Making Sense of Top Down Therapy for Crohn’s Disease
Jason Swoger, MD, Gastroenterology, 09:46PM Mar 3, 2010
One of the most discussed and debated topics in Crohn's disease therapy in the past 2 years has been how to best optimize the use of biologic therapies - either as scheduled monotherapy, or in combination with immunomodulators. Retrospective subgroup analysis of the CD registration trials did not show efficacy differences between these treatment approaches, though the studies were not designed or powered to answer this question. In terms of immunogenicity, scheduled therapy seemed to be essentially as effective as the use of concomitant immunomodulators.
The first trial to address this issue directly was the COMMITT trial, where a combination of methotrexate and infliximab was not significantly more effective than either medication alone. The SONIC trial, which up to now has only been reported in abstract form, found conflicting results. 508 patients with moderate to severe Crohn's, naïve to immunomodulators and biologics, were treated with either scheduled infliximab monotherapy, azathioprine monotherapy, or a combination of both drugs (using weight based azathioprine dosing). At 26 weeks, the primary endpoint of steroid-free remission was significantly greater in the group receiving combination therapy, compared to either of the other groups. The presence of mucosal healing was also significantly increased in the combination therapy group, though statistical significance was not achieved in comparison to infliximab alone. One year data was presented at this year's DDW, with 280 patients entering the extension phase. If patients not entering the extension study were assumed to be treatment failures (not in steroid-free remission), combination therapy was again found to significantly more effective than either monotherapy strategy. Among subjects in the extension arm (n=280), however, the only comparison that remained statistically significant was combination therapy vs. azathioprine monotherapy.
With the results of this study, has the pendulum swung back to combination therapy as an absolute rule, or standard of care? We don't know how this trial would affect patients with prior exposure to immunomodulators or biologics, or, more importantly, how to stratify patients who would most benefit from combination therapy. Disease duration may significantly affect response to this treatment strategy. What is desperately needed for the treatment of IBD is a predictive model, incorporating both clinical and genetic factors, that will help with the early identification of patients who will progress to a more severe CD course over time. Some patients with moderate to severe CD will be effectively treated with immunomodulator monotherapy, and the risks of long-term combination therapy may eventually outweigh the benefits in these patients.
While one year data is encouraging in terms of side effects, CD patients are often young, and we have no data on the risk of malignancy and infections after 10, 20, or 30 years of combination therapy. The durability of biologic therapy over this timeframe is also extremely questionable, and we do not know if patients will continue to respond to biologic therapy over a timeframe measured in decades. Debate continues about stopping either the immunomodulator or the biologic therapy after 6 or 12 months, and this has not been fully explored. If the biologic is stopped, is this ultimately an immunizing strategy, which will limit treatment options with future flares? SONIC used weight based dosing of azathioprine, but perhaps low doses of immunomodulators, or even methotrexate (which has not been associated with lymphomas) would be as effective, and mitigate any adverse effects. Though most gastroenterologists treating IBD feel that the 3 available anti-TNF agents are similar in efficacy, can we extrapolate the SONIC results to include adalimumab and certolizumab?
The treatment algorithm for CD initially switched from combination therapy to monotherapy, and is now again emphasizing the use of early combination therapy based on the SONIC results. While this data is compelling, patient selection remains a significant issue. Future blogs will incorporate the "top-down, step-up" results into the SONIC results, but we would be interested to hear how these results have changed clinical practice over the past year. Though SONIC answered a narrow question in a specific patient population, it leaves many complex questions unanswered.
Blog's authors:
About This Blog
This blog will focus primarily on treatment of the inflammatory bowel diseases, including ulcerative colitis, Crohn's disease, and pouchitis. Interesting and challenging cases will be discussed, as will new developments in the field for the diagnosis and treatment of IBD. We will also discuss some interesting cases pertaining to general gastroenterology, as well as important journal articles in the field that will affect the practice of our specialty.
* Jason Swoger
Jason Swoger, MD, MPH, is Assistant professor of Gastroenterology at University of Pittsburgh Medical Center (UPMC). Dr. Swoger completed his internal medicine residency at the Cleveland Clinic, and then went on to complete a fellowship in gastroenterology at Mayo Clinic, in Rochester, Minnesota. As a fellow, Dr. Swoger began to focus on inflammatory bowel disease and completed several clinical research projects aimed at the treatment of both ulcerative colitis and Crohn's disease. Dr. Swoger joined the faculty at UPMC in August 2009 and is seeing patients and conducting clinical research and clinical trials as part of the UPMC Inflammatory Bowel Disease Center.
* Miguel Regueiro
Dr. Miguel Regueiro is Associate Professor of Medicine in the Department of Medicine and Division of Gastroenterology, Hepatology, and Nutrition at UPMC. He completed his internal medicine internship, residency, and gastroenterology fellowship at Harvard Medical School's Beth Israel Hospital. Dr. Regueiro serves as Director of the Gastroenterology Fellowship, Co-Director and Clinical Head of the Inflammatory Bowel Disease Center, and is Associate Chief for Education in the Division of Gastroenterology, Hepatology, and Nutrition at UPMC. He cares for a large number of patients with Crohn's disease and ulcerative colitis. Dr. Regueiro's research focuses on defining the natural course of IBD, understanding the postoperative course of Crohn's disease, and exploring genotype-phenotype correlations.
Thought some might find this of interest. Since you have to be a member on Medscape to read it (I believe, anyway) I thought I'd jut paste it here:
A SONIC Boom: Making Sense of Top Down Therapy for Crohn’s Disease
Jason Swoger, MD, Gastroenterology, 09:46PM Mar 3, 2010
One of the most discussed and debated topics in Crohn's disease therapy in the past 2 years has been how to best optimize the use of biologic therapies - either as scheduled monotherapy, or in combination with immunomodulators. Retrospective subgroup analysis of the CD registration trials did not show efficacy differences between these treatment approaches, though the studies were not designed or powered to answer this question. In terms of immunogenicity, scheduled therapy seemed to be essentially as effective as the use of concomitant immunomodulators.
The first trial to address this issue directly was the COMMITT trial, where a combination of methotrexate and infliximab was not significantly more effective than either medication alone. The SONIC trial, which up to now has only been reported in abstract form, found conflicting results. 508 patients with moderate to severe Crohn's, naïve to immunomodulators and biologics, were treated with either scheduled infliximab monotherapy, azathioprine monotherapy, or a combination of both drugs (using weight based azathioprine dosing). At 26 weeks, the primary endpoint of steroid-free remission was significantly greater in the group receiving combination therapy, compared to either of the other groups. The presence of mucosal healing was also significantly increased in the combination therapy group, though statistical significance was not achieved in comparison to infliximab alone. One year data was presented at this year's DDW, with 280 patients entering the extension phase. If patients not entering the extension study were assumed to be treatment failures (not in steroid-free remission), combination therapy was again found to significantly more effective than either monotherapy strategy. Among subjects in the extension arm (n=280), however, the only comparison that remained statistically significant was combination therapy vs. azathioprine monotherapy.
With the results of this study, has the pendulum swung back to combination therapy as an absolute rule, or standard of care? We don't know how this trial would affect patients with prior exposure to immunomodulators or biologics, or, more importantly, how to stratify patients who would most benefit from combination therapy. Disease duration may significantly affect response to this treatment strategy. What is desperately needed for the treatment of IBD is a predictive model, incorporating both clinical and genetic factors, that will help with the early identification of patients who will progress to a more severe CD course over time. Some patients with moderate to severe CD will be effectively treated with immunomodulator monotherapy, and the risks of long-term combination therapy may eventually outweigh the benefits in these patients.
While one year data is encouraging in terms of side effects, CD patients are often young, and we have no data on the risk of malignancy and infections after 10, 20, or 30 years of combination therapy. The durability of biologic therapy over this timeframe is also extremely questionable, and we do not know if patients will continue to respond to biologic therapy over a timeframe measured in decades. Debate continues about stopping either the immunomodulator or the biologic therapy after 6 or 12 months, and this has not been fully explored. If the biologic is stopped, is this ultimately an immunizing strategy, which will limit treatment options with future flares? SONIC used weight based dosing of azathioprine, but perhaps low doses of immunomodulators, or even methotrexate (which has not been associated with lymphomas) would be as effective, and mitigate any adverse effects. Though most gastroenterologists treating IBD feel that the 3 available anti-TNF agents are similar in efficacy, can we extrapolate the SONIC results to include adalimumab and certolizumab?
The treatment algorithm for CD initially switched from combination therapy to monotherapy, and is now again emphasizing the use of early combination therapy based on the SONIC results. While this data is compelling, patient selection remains a significant issue. Future blogs will incorporate the "top-down, step-up" results into the SONIC results, but we would be interested to hear how these results have changed clinical practice over the past year. Though SONIC answered a narrow question in a specific patient population, it leaves many complex questions unanswered.
Blog's authors:
About This Blog
This blog will focus primarily on treatment of the inflammatory bowel diseases, including ulcerative colitis, Crohn's disease, and pouchitis. Interesting and challenging cases will be discussed, as will new developments in the field for the diagnosis and treatment of IBD. We will also discuss some interesting cases pertaining to general gastroenterology, as well as important journal articles in the field that will affect the practice of our specialty.
* Jason Swoger
Jason Swoger, MD, MPH, is Assistant professor of Gastroenterology at University of Pittsburgh Medical Center (UPMC). Dr. Swoger completed his internal medicine residency at the Cleveland Clinic, and then went on to complete a fellowship in gastroenterology at Mayo Clinic, in Rochester, Minnesota. As a fellow, Dr. Swoger began to focus on inflammatory bowel disease and completed several clinical research projects aimed at the treatment of both ulcerative colitis and Crohn's disease. Dr. Swoger joined the faculty at UPMC in August 2009 and is seeing patients and conducting clinical research and clinical trials as part of the UPMC Inflammatory Bowel Disease Center.
* Miguel Regueiro
Dr. Miguel Regueiro is Associate Professor of Medicine in the Department of Medicine and Division of Gastroenterology, Hepatology, and Nutrition at UPMC. He completed his internal medicine internship, residency, and gastroenterology fellowship at Harvard Medical School's Beth Israel Hospital. Dr. Regueiro serves as Director of the Gastroenterology Fellowship, Co-Director and Clinical Head of the Inflammatory Bowel Disease Center, and is Associate Chief for Education in the Division of Gastroenterology, Hepatology, and Nutrition at UPMC. He cares for a large number of patients with Crohn's disease and ulcerative colitis. Dr. Regueiro's research focuses on defining the natural course of IBD, understanding the postoperative course of Crohn's disease, and exploring genotype-phenotype correlations.
