Optimizing Biologic and Conventional Therapies for Inflammatory Bowel Disease
Stephen B. Hanauer, MD, a world-renowned expert in IBD, discusses the latest advances in IBD treatment, including the evolving role of conventional therapy and expanding the role of biologic therapy. Hanauer also shares his research on the efficacy of adalimumab and study of higher versus standard adalimumab dosing regimens in patients with moderate to severely active ulcerative colitis.
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Learn more about Stephen Hanauer, MD
Stephen Hanauer, MD
Dr. Hanauer is the Clifford Joseph Barborka Professor of Medicine in the Division of Gastroenterology and Hepatology; and the medical director of the Digestive Health Center at Northwestern Medicine.Learn more about Stephen Hanauer, MD
Transcription:
Optimizing Biologic and Conventional Therapies for Inflammatory Bowel Disease
Melanie Cole (Host): Welcome. This is Better Edge, a Northwestern Medicine podcast for physicians. I’m Melanie Cole and today we’re giving an update on inflammatory bowel disease. Joining me is Dr. Stephen Hanauer. He’s the Clifford Joseph Barborka Professor of Medicine in the Division of Gastroenterology and Hepatology and he’s the Medical Director of the Digestive Health Center at Northwestern Medicine. Dr. Hanauer, it’s a pleasure to have you join us today. Let’s start by telling us the current state of Crohn’s and colitis today. what are we seeing in the trends?
Stephen Hanauer, MD (Guest): What we’re seeing in our current trends of inflammatory bowel disease are a number of new agents both conventional agents as well as biologics that are being introduced into the marketplace primarily for what we consider to be moderate to severe disease, either ulcerative colitis or Crohn’s disease. One of the problems we have with these new therapies is that we have limited ability to predict which drug is going to be most effective for which patient type. But I’d like to talk a little bit more about the field as to where we are going as far as therapeutic outcomes. Because we used to treat patients with ulcerative colitis and Crohn’s disease according to symptoms but now, we are identifying more biologic targets that have actually improved the outcome of patients when they are treated to these targets rather than just symptomatic improvement.
And we continue to move deeper into these targets with over the past several years the treatment to what was called mucosal healing or endoscopic improvement. And what we’ve learned is that when we treat patients to endoscopic improvement; the outcomes as far as surgery and hospitalizations are actually reduced. But we can now go further and treat patients not only to endoscopic improvement but also to histologic improvement. And when we achieve those targets of improving the histology; we can actually go further and reduce medical relapses as well as reducing the risk of cancer in ulcerative colitis.
Host: That’s so interesting. What a great topic we’re discussing today Dr. Hanauer. You mentioned biologic therapies for the treatment of inflammatory bowel disease. Which are most effective? If you were telling other providers what they should be looking at; what do you want them to know?
Dr. Hanauer: That’s an excellent question. And until the past several months, we really did not have a good way to answer that because there has been an absence of head to head clinical trials with one biologic versus another. To date, all of the clinical trials have compared a biologic to placebo. And what we’ve identified is that most of the biologic categories including TNF inhibitors, including leukocyte trafficking agents, including IL-1223 inhibitors and even the new conventional JAK inhibitor, the conventional therapy that is not a biologic; we see about 35 to 40% remission rates. But we can’t distinguish between these.
Most recently, there has been a large clinical trial that compared adalimumab, a TNF inhibitor to natalizumab a leukocyte trafficking agent in moderate to severe ulcerative colitis with both agents administered in their approved doses. In this first head to head study, we actually found that natalizumab had better outcomes as far as clinical remissions and endoscopic improvement compared to the TNF inhibitor although to be honest, there were no differences in steroid-free remissions between the two groups.
But in this first head to head trial, a number of misconceptions were actually disproved. And that first misconception is that the adhesion molecules or the biologics targeting leukocyte trafficking had a slower onset of action. That was not the case in the head to head trial.
Host: That is so interesting. And thank you so much Dr. Hanauer for telling us about the study on patients with moderate to severe ulcerative colitis and those TNF inhibitors and as you are currently leading ten clinical trials, one of which is evaluating higher doses of the TNF inhibitors versus the standard dosing regimen; is this more effective? What are you seeing?
Dr. Hanauer: Well we’ve actually completed a multicenter study that was mandated by the Food and Drug Administration to look at adalimumab, which is known as Humira, marketed as Humira in the approved doses versus adalimumab in essentially a doubled dose induction therapy. So, patients who received standard doses received 160 milligrams initially followed by 80 milligrams followed by 40 milligrams every other week. In the high dose group, patients received 320 milligrams initially, followed by 160 milligrams after two weeks and then followed by 80 milligrams. The conception was that the higher dose would be more effective. But it turns out in both ulcerative colitis and in Crohn’s disease, the standard dose was equally effective to the high dose induction therapy.
We are currently waiting on results regarding maintenance treatment with the higher versus the lower doses but as far as induction is concerned; the misconception that higher doses would be better was disproven by this multicenter study.
Host: Well then Dr. Hanauer, what about the standard therapies such as thiopurines? How has that role evolved in inflammatory bowel diseases?
Dr. Hanauer: There has actually been a pendulum regarding immunosuppressive agents and we’re focusing on the thiopurines that being azathioprine and mercaptopurine. These are oral conventional agents that have been used for well more than 40 years for the treatment of ulcerative colitis and Crohn’s disease. But their role in the treatment has gradually evolved. We have subsequently learned that these agents are effective at maintaining steroid induced remissions for both ulcerative colitis or Crohn’s disease. So, it is possible in patients treated with steroids to move directly to a thiopurine. We’ve also learned that thiopurines can be effective at reducing postoperative recurrence of Crohn’s disease when they are administered shortly after surgery.
But the most common use now of thiopurines has been in combination with biologic therapies in particular, with infliximab because another head to head study in Crohn’s disease known as the SONIC study compared infliximab alone to azathioprine alone compared to the combination. And all of the outcomes were improved in the patients who received combination therapy. So, the three roles of thiopurines in inflammatory bowel disease are number one: as steroid sparing agents, number two: as potential agents to reduce postoperative recurrence of Crohn’s disease and number three: in combinations with biologics in particular, infliximab for patients on long-term therapy with either Crohn’s or ulcerative colitis.
Host: What about then mild or moderate IBD? Are there treatments that exist that can delay or prevent disease progression? What do you want other providers to know about management of the mild or moderate IBDs, preventing bowel obstructions, just general information.
Dr. Hanauer: That’s a really great question. And Melanie, we used to talk about treatment according to the severity of symptoms. And what we’ve learned is that the severity of disease really goes beyond symptoms and it goes towards predicting the prognosis. The patients who are going to proceed with ulcerative colitis to need colectomies, to have their colons out or for patients with Crohn’s disease to require surgical resections. What we have learned is that there are factors in both ulcerative colitis and Crohn’s disease that predict the prognosis which include the extent of disease, the depth of ulcers, whether patients present with complications, how extensive the disease actually is and in those individuals, we use more of a top down approach with more aggressive therapies rather than treating just to their symptoms as I suggested earlier in the discussion.
So, first and foremost, early intervention can change the course of the disease. But to be honest, we do not really have effective therapies that have been approved for mild to moderate Crohn’s disease. In the setting of ulcerative colitis, the amino salicylates the five amino salicylic acid or mesalamine compounds are very effective in mild to moderate ulcerative colitis. But not so in the setting of Crohn’s disease. So, we really need more direction from pharmaceutical companies to target these earlier patients as you alluded to, to prevent their progression towards complications.
Host: Before we wrap up, Dr. Hanauer, what’s next when it comes to this area of study? What about IBD and prostate cancer? Is this important to note? Tell us where the research is going. Give us a little blueprint.
Dr. Hanauer: Well our research is beginning to demonstrate how inflammation may actually increase the risk of cancer. And in studies with our pathology colleagues, we’ve identified that neutrophils a form of white blood cells actually release local microRNA which can inhibit DNA repair and lead to mutations and cancers. So, in the setting of inflammation, we now have a potential reason why individuals are at increased risk of cancer in ulcerative colitis, but other cancers related to inflammation as well, such as lung cancer in smokers, such as skin cancer with ultraviolet light exposure, such as cancer in chronic inflammatory diseases such as hepatitis. So, our current approaches are to reduce inflammation to actually reduce the risk of cancer.
Now we have identified an association between prostate cancer and men with inflammatory bowel disease. And this may be related to either the local inflammation in the rectum or more generalized inflammation and we are continuing to try to elucidate the mechanisms of the increased risk of prostate cancer in the setting of ulcerative colitis and Crohn’s disease.
Host: What an exciting time to be in your field. Dr. Hanauer, what would you like other providers to know and to take away from this segment?
Dr. Hanauer: What I’d like them to know is that the holy grail of a biomarker to predict response still eludes us. We are currently moving to treating towards more biologic targets than symptoms to improve long-term outcomes. We clearly need more head to head trials between therapeutic agents to identify which is going to be more effective than another and finally, we need to continue to look at therapeutic drug monitoring of levels of both conventional agents as well as biologics to optimize treatment paradigms.
Host: Thank you so much Dr. Hanauer for such great information today and for joining us. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. To refer your patient or for more information on the latest advances in medicine please visit our website at www.nm.org to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. For more health tips, and updates, follow us on your social channels. I’m Melanie Cole
Optimizing Biologic and Conventional Therapies for Inflammatory Bowel Disease
Melanie Cole (Host): Welcome. This is Better Edge, a Northwestern Medicine podcast for physicians. I’m Melanie Cole and today we’re giving an update on inflammatory bowel disease. Joining me is Dr. Stephen Hanauer. He’s the Clifford Joseph Barborka Professor of Medicine in the Division of Gastroenterology and Hepatology and he’s the Medical Director of the Digestive Health Center at Northwestern Medicine. Dr. Hanauer, it’s a pleasure to have you join us today. Let’s start by telling us the current state of Crohn’s and colitis today. what are we seeing in the trends?
Stephen Hanauer, MD (Guest): What we’re seeing in our current trends of inflammatory bowel disease are a number of new agents both conventional agents as well as biologics that are being introduced into the marketplace primarily for what we consider to be moderate to severe disease, either ulcerative colitis or Crohn’s disease. One of the problems we have with these new therapies is that we have limited ability to predict which drug is going to be most effective for which patient type. But I’d like to talk a little bit more about the field as to where we are going as far as therapeutic outcomes. Because we used to treat patients with ulcerative colitis and Crohn’s disease according to symptoms but now, we are identifying more biologic targets that have actually improved the outcome of patients when they are treated to these targets rather than just symptomatic improvement.
And we continue to move deeper into these targets with over the past several years the treatment to what was called mucosal healing or endoscopic improvement. And what we’ve learned is that when we treat patients to endoscopic improvement; the outcomes as far as surgery and hospitalizations are actually reduced. But we can now go further and treat patients not only to endoscopic improvement but also to histologic improvement. And when we achieve those targets of improving the histology; we can actually go further and reduce medical relapses as well as reducing the risk of cancer in ulcerative colitis.
Host: That’s so interesting. What a great topic we’re discussing today Dr. Hanauer. You mentioned biologic therapies for the treatment of inflammatory bowel disease. Which are most effective? If you were telling other providers what they should be looking at; what do you want them to know?
Dr. Hanauer: That’s an excellent question. And until the past several months, we really did not have a good way to answer that because there has been an absence of head to head clinical trials with one biologic versus another. To date, all of the clinical trials have compared a biologic to placebo. And what we’ve identified is that most of the biologic categories including TNF inhibitors, including leukocyte trafficking agents, including IL-1223 inhibitors and even the new conventional JAK inhibitor, the conventional therapy that is not a biologic; we see about 35 to 40% remission rates. But we can’t distinguish between these.
Most recently, there has been a large clinical trial that compared adalimumab, a TNF inhibitor to natalizumab a leukocyte trafficking agent in moderate to severe ulcerative colitis with both agents administered in their approved doses. In this first head to head study, we actually found that natalizumab had better outcomes as far as clinical remissions and endoscopic improvement compared to the TNF inhibitor although to be honest, there were no differences in steroid-free remissions between the two groups.
But in this first head to head trial, a number of misconceptions were actually disproved. And that first misconception is that the adhesion molecules or the biologics targeting leukocyte trafficking had a slower onset of action. That was not the case in the head to head trial.
Host: That is so interesting. And thank you so much Dr. Hanauer for telling us about the study on patients with moderate to severe ulcerative colitis and those TNF inhibitors and as you are currently leading ten clinical trials, one of which is evaluating higher doses of the TNF inhibitors versus the standard dosing regimen; is this more effective? What are you seeing?
Dr. Hanauer: Well we’ve actually completed a multicenter study that was mandated by the Food and Drug Administration to look at adalimumab, which is known as Humira, marketed as Humira in the approved doses versus adalimumab in essentially a doubled dose induction therapy. So, patients who received standard doses received 160 milligrams initially followed by 80 milligrams followed by 40 milligrams every other week. In the high dose group, patients received 320 milligrams initially, followed by 160 milligrams after two weeks and then followed by 80 milligrams. The conception was that the higher dose would be more effective. But it turns out in both ulcerative colitis and in Crohn’s disease, the standard dose was equally effective to the high dose induction therapy.
We are currently waiting on results regarding maintenance treatment with the higher versus the lower doses but as far as induction is concerned; the misconception that higher doses would be better was disproven by this multicenter study.
Host: Well then Dr. Hanauer, what about the standard therapies such as thiopurines? How has that role evolved in inflammatory bowel diseases?
Dr. Hanauer: There has actually been a pendulum regarding immunosuppressive agents and we’re focusing on the thiopurines that being azathioprine and mercaptopurine. These are oral conventional agents that have been used for well more than 40 years for the treatment of ulcerative colitis and Crohn’s disease. But their role in the treatment has gradually evolved. We have subsequently learned that these agents are effective at maintaining steroid induced remissions for both ulcerative colitis or Crohn’s disease. So, it is possible in patients treated with steroids to move directly to a thiopurine. We’ve also learned that thiopurines can be effective at reducing postoperative recurrence of Crohn’s disease when they are administered shortly after surgery.
But the most common use now of thiopurines has been in combination with biologic therapies in particular, with infliximab because another head to head study in Crohn’s disease known as the SONIC study compared infliximab alone to azathioprine alone compared to the combination. And all of the outcomes were improved in the patients who received combination therapy. So, the three roles of thiopurines in inflammatory bowel disease are number one: as steroid sparing agents, number two: as potential agents to reduce postoperative recurrence of Crohn’s disease and number three: in combinations with biologics in particular, infliximab for patients on long-term therapy with either Crohn’s or ulcerative colitis.
Host: What about then mild or moderate IBD? Are there treatments that exist that can delay or prevent disease progression? What do you want other providers to know about management of the mild or moderate IBDs, preventing bowel obstructions, just general information.
Dr. Hanauer: That’s a really great question. And Melanie, we used to talk about treatment according to the severity of symptoms. And what we’ve learned is that the severity of disease really goes beyond symptoms and it goes towards predicting the prognosis. The patients who are going to proceed with ulcerative colitis to need colectomies, to have their colons out or for patients with Crohn’s disease to require surgical resections. What we have learned is that there are factors in both ulcerative colitis and Crohn’s disease that predict the prognosis which include the extent of disease, the depth of ulcers, whether patients present with complications, how extensive the disease actually is and in those individuals, we use more of a top down approach with more aggressive therapies rather than treating just to their symptoms as I suggested earlier in the discussion.
So, first and foremost, early intervention can change the course of the disease. But to be honest, we do not really have effective therapies that have been approved for mild to moderate Crohn’s disease. In the setting of ulcerative colitis, the amino salicylates the five amino salicylic acid or mesalamine compounds are very effective in mild to moderate ulcerative colitis. But not so in the setting of Crohn’s disease. So, we really need more direction from pharmaceutical companies to target these earlier patients as you alluded to, to prevent their progression towards complications.
Host: Before we wrap up, Dr. Hanauer, what’s next when it comes to this area of study? What about IBD and prostate cancer? Is this important to note? Tell us where the research is going. Give us a little blueprint.
Dr. Hanauer: Well our research is beginning to demonstrate how inflammation may actually increase the risk of cancer. And in studies with our pathology colleagues, we’ve identified that neutrophils a form of white blood cells actually release local microRNA which can inhibit DNA repair and lead to mutations and cancers. So, in the setting of inflammation, we now have a potential reason why individuals are at increased risk of cancer in ulcerative colitis, but other cancers related to inflammation as well, such as lung cancer in smokers, such as skin cancer with ultraviolet light exposure, such as cancer in chronic inflammatory diseases such as hepatitis. So, our current approaches are to reduce inflammation to actually reduce the risk of cancer.
Now we have identified an association between prostate cancer and men with inflammatory bowel disease. And this may be related to either the local inflammation in the rectum or more generalized inflammation and we are continuing to try to elucidate the mechanisms of the increased risk of prostate cancer in the setting of ulcerative colitis and Crohn’s disease.
Host: What an exciting time to be in your field. Dr. Hanauer, what would you like other providers to know and to take away from this segment?
Dr. Hanauer: What I’d like them to know is that the holy grail of a biomarker to predict response still eludes us. We are currently moving to treating towards more biologic targets than symptoms to improve long-term outcomes. We clearly need more head to head trials between therapeutic agents to identify which is going to be more effective than another and finally, we need to continue to look at therapeutic drug monitoring of levels of both conventional agents as well as biologics to optimize treatment paradigms.
Host: Thank you so much Dr. Hanauer for such great information today and for joining us. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. To refer your patient or for more information on the latest advances in medicine please visit our website at www.nm.org to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. For more health tips, and updates, follow us on your social channels. I’m Melanie Cole