New Drugs, Diets, Diagnostics, and Therapeutic Techniques
Hello. I am Dr. David Johnson, Professor of Medicine and Chief of Gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia.
I have just returned from Chicago and Digestive Disease Week (DDW) 2014. Those of you who attended, I am sure, found a lot of new information. For those who didn't attend, I will try to highlight some things that might be coming down the pike and some of the potential game-changers for practice now and for the future.
The scientific session started with the Presidential Plenary Session from the American Gastroenterological Association and the American Society for Gastrointestinal Endoscopy, which was quite profound. The topic was a new oral drug in the alpha-4 integrin antagonist class.
The AJM300 study reported at DDW was conducted in Japan, and was a phase 2a, placebo-controlled, randomized trial with patients who were refractory to 5-aminosalicylic acid (ASA) or steroids. The primary endpoint of this 8-week trial was mucosal healing and clinical response. They found a 3:1 favorable effect for the active drug in terms of improvement and clinical mucosal healing as assessed by Mayo score.
With respect to clinical remission, there was about an 8-fold increase in the overall active therapy (24% vs 3%), so this is very exciting information. So far, we have had very limited exposure in terms of the number of patients and a fairly limited follow-up, but having an oral agent in that class of therapy would be quite exciting.
The next presentation in the Presidential Plenary Session was about a new biopsy technique that would be a game-changer for Barrett esophagus. This is called the WATS biopsy.
Seth Gross and his colleagues studied approximately 3500 biopsies from 35 gastroenterologists at several centers. Every patient with gastroesophageal reflux disease (GERD) underwent biopsy to look for Barrett esophagus, as did patients undergoing surveillance for Barrett esophagus. They did standard 4-quadrant biopsies and then superimposed the WATS biopsies.
The technique is a linear array that gives an up-and-down effect as you move down the field. Rather than the focality of the individual biopsies, you sample a much larger field, going down to the submucosa rather than the surface cells. There is also a computer scan that identifies abnormal cytology.
In this study, they found that the WATSbiopsy increased the diagnosis of Barrett esophagus by 64%. I found it amazing that Barrett esophagus could be missed that often, but nonetheless, that is what their data showed.
They also found more dysplasia, which was a game-changer for me. They found an extra 10 cases of dysplasia, and of note, a case of cancer that had been missed. Overall, they increased the identification of dysplasia and cancer by 58%.
This technique is simple and it doesn't increase the risk for harm from the biopsy itself. Several studies are ongoing, and we are using it in a clinical trial as well.
The next Presidential Plenary Session was about the FODMAP (fermentable oligo-di-monosaccharides and polyols) diet. These are carbohydrates that have been alleged to create a significant effect in patients with irritable bowel syndrome.
This study has raised the question of whether to give patients the FODMAP diet or to follow the growing trend of the gluten-free diet. Is that an added benefit? Gluten is a fructan, so it does fit into the FODMAP group. Is the FODMAP diet enough, or should we superimpose a gluten-free diet?
This study had more than 60 patients who were randomly assigned to a diet and were followed for 4 weeks with standardized and validated assessment tools. According to the clinical data, there was no difference between FODMAP, with or without the gluten-free diet, so restricting these patients to that degree doesn't seem to offer a benefit -- at least in this relatively small, although well-designed, study.
Therefore, compared with a standard diet or placebo, you don't necessarily have to start with FODMAP plus gluten-free. FODMAP by itself may be the way to go, and there are many education issues there for patients.
An interesting study by the Barrett's Consortium Group looked at the effect of proton pump inhibitors (PPIs) in patients with Barrett esophagus. They looked at approximately 2500 patients and found that use of PPIs was associated with a diminution of progression to high-grade dysplasia or cancer by 60%.
The effect of PPIs in dysplasia and progression to cancer has another resounding, emphatic "Yes, this makes a difference." A prospective, 10-year study is currently looking at this and will be out in the next few years.
In the current analysis, when the investigators adjusted for other risk factors for Barrett's-related cancers, statins didn't seem to make a difference -- which is discordant with previous studies in the last few years -- nor did aspirin by itself or obesity make a difference as a predictor. So, although somewhat discordant with what we have seen in previous studies, your patients with Barrett esophagus should probably stay on a PPI regardless of whether they have heartburn, at least until we have further information.
An abstract in the GERD category, by Ronnie Fass and colleagues, caught my eye. They looked at a database of patients to determine whether GERD was associated with myocardial infarction. What is the science behind that?
GERD is associated with the upregulation of a variety of host cytokines. A variety of interleukins (IL-6 and IL-10) and platelet-activating factor are upregulated, and the immune system is intrinsically tied to some of the atherosclerotic effects associated with coronary disease. Whether these 2 worlds of immunogenicity can be connected or stimulated by GERD was the question.
They looked at the database and culled out approximately 300,000 patients with GERD and compared them with 13.5 million patients who did not have GERD, using a matching assessment. They found that the GERD patients had a significant (5-6 times) increased risk for myocardial infarction after adjustment for other risks (eg, obesity, smoking, hypertension).
So GERD in and of itself seems to be a risk factor for myocardial disease and myocardial infarction. This may set the stage for the question of whether a therapeutic intervention for GERD can reduce that risk. That will warrant a great deal of analysis, and much interest is going to be generated by Dr. Fass's study.
The stomach was the next topic. A phase 2a study from Tony Lembo and colleagues involved more than 200 patients with gastroparesis to test a new ghrelin agonist: a subcutaneous injection that is given twice daily. The endpoints were symptom improvement and clinical efficacy of gastric emptying.
They found that the drug worked inordinately well -- but only in women, not in men. Among patients with gastroparesis, 80% are women anyway. The drug was particularly effective in the subgroup of patients with vomiting. This was a phase 2a randomized controlled trial, and the drug needs accelerated status by the US Food and Drug Administration (FDA) because of the dearth of drugs that we have in this area.
Henry Parkman and colleagues from Temple University reported a multicenter study that looked at the instillation of intranasal metoclopramide, which seemed to have some promise through its effect on gastric emptying. The drug didn't meet the primary endpoint of symptom improvement, but patients with vomiting seemed to be a particularly sensitive group for response to the drug. Intranasal metoclopramide removes much of the variability for absorption with the delay in gastric emptying, so its use makes sense. No neurologic effects were observed, but it was only a 4-week study.
We now have 2 studies of treatments for patients with gastroparesis that show promise.
Fecal microbiota transplant (FMT) for Clostridium difficile was a hot topic. The question is, if you are doing this, how do you screen the donors?
Garg and colleagues studied 27 patients and found that 18% developed irritable bowel symptoms -- and lo and behold, irritable bowel symptoms were present in the donor before the transplant. This raises the question: As you change the microbiota, do you change some of the disease proclivities? Irritable bowel syndrome seems to be transferable. These patients did not have irritable bowel syndrome, but they developed it within 4-6 weeks, and the effects lasted beyond 3 years in some patients.
This changes what I do in my practice, and I have done several FMTs. I screen donors for obesity, for example. In animal models, if you take a lean rat and transplant the microbiota from an obese rat, you can change the lean rat into an obese rat.
We use body mass index as a discriminator for donors, and I have added irritable bowel syndrome. Now, I use only healthy donors with no diseases or comorbid illnesses until we prove that these conditions aren't transferable in the microbiota and we fully understand the disease implications.
We need to be careful. Many things in the microbiota can influence disease. Some things are evolving, so we need to take a deep breath in and look closely at the donors.
Paul Moayyedi and colleagues looked at FMT as it relates to ulcerative colitis. They took 60 patients who were steroid- or 5-ASA-refractory and conducted a randomized, controlled study, administering a 50-mL fecal microbiota enema weekly for 6 weeks. They assessed mucosal healing, clinical improvement in symptoms, and clinical remission.
At 6 weeks, there was no significant effect of FMT. However, Dr. Moayyedi acknowledged that at only 6 weeks, the endpoint was probably assessed too quickly. Several patients had some clinical improvement, so when they assessed for symptoms in these patients at 12 weeks, they found that one third of them had clinical remission.
Whether this is a game-changer is still unknown. At least 13 studies listed on ClinicalTrials.gov are looking at FMT in patients with inflammatory bowel disease, Crohn disease, or ulcerative colitis. We can't throw this out yet just because it is a negative trial. It sets the stage for more answers.
I attended a presentation by a former FDA lawyer on the subject of FMT. At the present time, FMT is approved for relapsing C difficile only. For inflammatory bowel disease or irritable bowel syndrome, patients need to be in a clinical trial. So make sure you are only doing FMT for C difficile and not for any other condition outside of the context of a clinical trial.
I would also caution you to make sure when you get informed consent that you take the time to tell patients that we don't know all of the potential implications of FMT at the present time. Other things might develop, and this is why we screen for healthy donors.
We have heard many things that will change practice immediately, and some that are on the near horizon, at DDW 2014. Thanks for listening.
A New Oral Agent for Ulcerative Colitis
Hello. I am Dr. David Johnson, Professor of Medicine and Chief of Gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia.
I have just returned from Chicago and Digestive Disease Week (DDW) 2014. Those of you who attended, I am sure, found a lot of new information. For those who didn't attend, I will try to highlight some things that might be coming down the pike and some of the potential game-changers for practice now and for the future.
The scientific session started with the Presidential Plenary Session from the American Gastroenterological Association and the American Society for Gastrointestinal Endoscopy, which was quite profound. The topic was a new oral drug in the alpha-4 integrin antagonist class.
The AJM300 study reported at DDW was conducted in Japan, and was a phase 2a, placebo-controlled, randomized trial with patients who were refractory to 5-aminosalicylic acid (ASA) or steroids. The primary endpoint of this 8-week trial was mucosal healing and clinical response. They found a 3:1 favorable effect for the active drug in terms of improvement and clinical mucosal healing as assessed by Mayo score.
With respect to clinical remission, there was about an 8-fold increase in the overall active therapy (24% vs 3%), so this is very exciting information. So far, we have had very limited exposure in terms of the number of patients and a fairly limited follow-up, but having an oral agent in that class of therapy would be quite exciting.
Better Biopsies for Barrett Esophagus
The next presentation in the Presidential Plenary Session was about a new biopsy technique that would be a game-changer for Barrett esophagus. This is called the WATS biopsy.
Seth Gross and his colleagues studied approximately 3500 biopsies from 35 gastroenterologists at several centers. Every patient with gastroesophageal reflux disease (GERD) underwent biopsy to look for Barrett esophagus, as did patients undergoing surveillance for Barrett esophagus. They did standard 4-quadrant biopsies and then superimposed the WATS biopsies.
The technique is a linear array that gives an up-and-down effect as you move down the field. Rather than the focality of the individual biopsies, you sample a much larger field, going down to the submucosa rather than the surface cells. There is also a computer scan that identifies abnormal cytology.
In this study, they found that the WATSbiopsy increased the diagnosis of Barrett esophagus by 64%. I found it amazing that Barrett esophagus could be missed that often, but nonetheless, that is what their data showed.
They also found more dysplasia, which was a game-changer for me. They found an extra 10 cases of dysplasia, and of note, a case of cancer that had been missed. Overall, they increased the identification of dysplasia and cancer by 58%.
This technique is simple and it doesn't increase the risk for harm from the biopsy itself. Several studies are ongoing, and we are using it in a clinical trial as well.
Irritable Bowel Diet: FODMAP and Gluten-Free?
The next Presidential Plenary Session was about the FODMAP (fermentable oligo-di-monosaccharides and polyols) diet. These are carbohydrates that have been alleged to create a significant effect in patients with irritable bowel syndrome.
This study has raised the question of whether to give patients the FODMAP diet or to follow the growing trend of the gluten-free diet. Is that an added benefit? Gluten is a fructan, so it does fit into the FODMAP group. Is the FODMAP diet enough, or should we superimpose a gluten-free diet?
This study had more than 60 patients who were randomly assigned to a diet and were followed for 4 weeks with standardized and validated assessment tools. According to the clinical data, there was no difference between FODMAP, with or without the gluten-free diet, so restricting these patients to that degree doesn't seem to offer a benefit -- at least in this relatively small, although well-designed, study.
Therefore, compared with a standard diet or placebo, you don't necessarily have to start with FODMAP plus gluten-free. FODMAP by itself may be the way to go, and there are many education issues there for patients.
PPIs for Barrett Esophagus? Yes
An interesting study by the Barrett's Consortium Group looked at the effect of proton pump inhibitors (PPIs) in patients with Barrett esophagus. They looked at approximately 2500 patients and found that use of PPIs was associated with a diminution of progression to high-grade dysplasia or cancer by 60%.
The effect of PPIs in dysplasia and progression to cancer has another resounding, emphatic "Yes, this makes a difference." A prospective, 10-year study is currently looking at this and will be out in the next few years.
In the current analysis, when the investigators adjusted for other risk factors for Barrett's-related cancers, statins didn't seem to make a difference -- which is discordant with previous studies in the last few years -- nor did aspirin by itself or obesity make a difference as a predictor. So, although somewhat discordant with what we have seen in previous studies, your patients with Barrett esophagus should probably stay on a PPI regardless of whether they have heartburn, at least until we have further information.
GERD and Heart Disease
An abstract in the GERD category, by Ronnie Fass and colleagues, caught my eye. They looked at a database of patients to determine whether GERD was associated with myocardial infarction. What is the science behind that?
GERD is associated with the upregulation of a variety of host cytokines. A variety of interleukins (IL-6 and IL-10) and platelet-activating factor are upregulated, and the immune system is intrinsically tied to some of the atherosclerotic effects associated with coronary disease. Whether these 2 worlds of immunogenicity can be connected or stimulated by GERD was the question.
They looked at the database and culled out approximately 300,000 patients with GERD and compared them with 13.5 million patients who did not have GERD, using a matching assessment. They found that the GERD patients had a significant (5-6 times) increased risk for myocardial infarction after adjustment for other risks (eg, obesity, smoking, hypertension).
So GERD in and of itself seems to be a risk factor for myocardial disease and myocardial infarction. This may set the stage for the question of whether a therapeutic intervention for GERD can reduce that risk. That will warrant a great deal of analysis, and much interest is going to be generated by Dr. Fass's study.
New Hope for Gastroparesis
The stomach was the next topic. A phase 2a study from Tony Lembo and colleagues involved more than 200 patients with gastroparesis to test a new ghrelin agonist: a subcutaneous injection that is given twice daily. The endpoints were symptom improvement and clinical efficacy of gastric emptying.
They found that the drug worked inordinately well -- but only in women, not in men. Among patients with gastroparesis, 80% are women anyway. The drug was particularly effective in the subgroup of patients with vomiting. This was a phase 2a randomized controlled trial, and the drug needs accelerated status by the US Food and Drug Administration (FDA) because of the dearth of drugs that we have in this area.
Henry Parkman and colleagues from Temple University reported a multicenter study that looked at the instillation of intranasal metoclopramide, which seemed to have some promise through its effect on gastric emptying. The drug didn't meet the primary endpoint of symptom improvement, but patients with vomiting seemed to be a particularly sensitive group for response to the drug. Intranasal metoclopramide removes much of the variability for absorption with the delay in gastric emptying, so its use makes sense. No neurologic effects were observed, but it was only a 4-week study.
We now have 2 studies of treatments for patients with gastroparesis that show promise.
Fecal Microbiota: What Else Is Transplanted?
Fecal microbiota transplant (FMT) for Clostridium difficile was a hot topic. The question is, if you are doing this, how do you screen the donors?
Garg and colleagues studied 27 patients and found that 18% developed irritable bowel symptoms -- and lo and behold, irritable bowel symptoms were present in the donor before the transplant. This raises the question: As you change the microbiota, do you change some of the disease proclivities? Irritable bowel syndrome seems to be transferable. These patients did not have irritable bowel syndrome, but they developed it within 4-6 weeks, and the effects lasted beyond 3 years in some patients.
This changes what I do in my practice, and I have done several FMTs. I screen donors for obesity, for example. In animal models, if you take a lean rat and transplant the microbiota from an obese rat, you can change the lean rat into an obese rat.
We use body mass index as a discriminator for donors, and I have added irritable bowel syndrome. Now, I use only healthy donors with no diseases or comorbid illnesses until we prove that these conditions aren't transferable in the microbiota and we fully understand the disease implications.
We need to be careful. Many things in the microbiota can influence disease. Some things are evolving, so we need to take a deep breath in and look closely at the donors.
Paul Moayyedi and colleagues looked at FMT as it relates to ulcerative colitis. They took 60 patients who were steroid- or 5-ASA-refractory and conducted a randomized, controlled study, administering a 50-mL fecal microbiota enema weekly for 6 weeks. They assessed mucosal healing, clinical improvement in symptoms, and clinical remission.
At 6 weeks, there was no significant effect of FMT. However, Dr. Moayyedi acknowledged that at only 6 weeks, the endpoint was probably assessed too quickly. Several patients had some clinical improvement, so when they assessed for symptoms in these patients at 12 weeks, they found that one third of them had clinical remission.
Whether this is a game-changer is still unknown. At least 13 studies listed on ClinicalTrials.gov are looking at FMT in patients with inflammatory bowel disease, Crohn disease, or ulcerative colitis. We can't throw this out yet just because it is a negative trial. It sets the stage for more answers.
I attended a presentation by a former FDA lawyer on the subject of FMT. At the present time, FMT is approved for relapsing C difficile only. For inflammatory bowel disease or irritable bowel syndrome, patients need to be in a clinical trial. So make sure you are only doing FMT for C difficile and not for any other condition outside of the context of a clinical trial.
I would also caution you to make sure when you get informed consent that you take the time to tell patients that we don't know all of the potential implications of FMT at the present time. Other things might develop, and this is why we screen for healthy donors.
We have heard many things that will change practice immediately, and some that are on the near horizon, at DDW 2014. Thanks for listening.
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