ACG 2014

PHILADELPHIA – In long-term follow-up for the treatment of inflammatory bowel disease, the novel monoclonal antibody vedolizumab continues to remain free of serious infections or other signs of major complications from altered immune function, according to pooled data presented at the annual meeting of the American College of Gastroenterology.

Over the course of follow-up, which now extends to 104 weeks in these trials, called GEMINI 1 and GEMINI 2, overall infection rates have been about the same in the vedolizumab and placebo arms even when corticosteroids or immunosuppressive agents are used concurrently, according to Dr. Edward V. Loftus Jr., professor of medicine at the Mayo Clinic, Rochester, Minn.

There is particular focus on the safety of vedolizumab, because of the theoretical risks of biologics overall and vedolizumab specifically. Vedolizumab has been shown to provide sustained remissions relative to placebo in both Crohn’s disease and ulcerative colitis in the previously presented and updated GEMINI trials, but this agent, like other biologics, alters mediators of immune function.

The follow-up summarized at the ACG meeting, which evaluated risk of adverse events of vedolizumab alone or in combination with other inflammatory bowel disease (IBD) agents that affect immune function, suggests that the risk of adverse events is low, but the conclusion is not definitive.

“There was not a signal of more side effects with combination therapy, which is reassuring. However, the study is limited by the number of adverse events available to analyze,” said Dr. David T. Rubin, section chief of gastroenterology, hepatology, and nutrition at the University of Chicago. The likelihood of a high risk of adverse events is diminishing as follow-up and patient sample size increase, but Dr. Rubin suggested that clinicians should monitor any IBD patient taking an immunosuppressive agent for infectious complications.

“At the University of Chicago IBD Center, we have now treated more than 100 patients and are studying this therapy to better understand its performance in postmarket,” Dr. Rubin said in an interview. “So far, we have made similar observations to the clinical trials and to those made by Dr. Loftus here at the ACG.”

Unlike tumor necrosis factor (TNF) inhibitors, which were the first biologics to be licensed for use in IBD, vedolizumab inhibits the migration of leukocytes in the GI tract by preventing the alpha₄beta₇ subunit from binding to the adhesion molecule MAdCAM-1. It has been unclear whether or to what degree vedolizumab shares the known risk, albeit small, of inducing opportunistic infections observed with TNF inhibitors.

The most recent data continue to suggest that there is no greater risk of infection or other complications of immune function for vedolizumab than other biologics, and the risk may be lower. In the pooled GEMINI data with 1,434 patients followed during induction and maintenance phases with data in some groups out to 104 weeks, the overall percentages of infection and the individual infections rates have been “similar,” Dr. Loftus reported.

“The exception has been nasopharyngitis, which was less common in the placebo group,” said Dr. Loftus, providing relative rates of approximately 13% and 9% for vedolizumab and placebo, respectively. He noted, however, that the length of follow-up has been longer in the vedolizumab relative to the placebo groups. Rates of tuberculosis, Clostridium difficile colitis, and other serious infections have not differed significantly.

In addition, there has been no association between vedolizumab and progressive multifocal leukoencephalopathy (PML) so far. Concern about a risk for PML was raised by the relationship of vedolizumab to natalizumab, which blocks the same adhesion compounds and has been associated with PML. The absence of PML in follow-up so far is consistent with evidence that the activity of vedolizumab, unlike the activity of natalizumab, is largely or entirely confined to the GI tract.

No multicenter, randomized trials have yet to be conducted comparing either the efficacy or safety of vedolizumab, which was approved in May 2014 for the treatment of moderate to severe Crohn’s disease and ulcerative colitis, to other biologics used in IBD.

PHILADELPHIA – In long-term follow-up for the treatment of inflammatory bowel disease, the novel monoclonal antibody vedolizumab continues to remain free of serious infections or other signs of major complications from altered immune function, according to pooled data presented at the annual meeting of the American College of Gastroenterology.

Over the course of follow-up, which now extends to 104 weeks in these trials, called GEMINI 1 and GEMINI 2, overall infection rates have been about the same in the vedolizumab and placebo arms even when corticosteroids or immunosuppressive agents are used concurrently, according to Dr. Edward V. Loftus Jr., professor of medicine at the Mayo Clinic, Rochester, Minn.

There is particular focus on the safety of vedolizumab, because of the theoretical risks of biologics overall and vedolizumab specifically. Vedolizumab has been shown to provide sustained remissions relative to placebo in both Crohn’s disease and ulcerative colitis in the previously presented and updated GEMINI trials, but this agent, like other biologics, alters mediators of immune function.

The follow-up summarized at the ACG meeting, which evaluated risk of adverse events of vedolizumab alone or in combination with other inflammatory bowel disease (IBD) agents that affect immune function, suggests that the risk of adverse events is low, but the conclusion is not definitive.

“There was not a signal of more side effects with combination therapy, which is reassuring. However, the study is limited by the number of adverse events available to analyze,” said Dr. David T. Rubin, section chief of gastroenterology, hepatology, and nutrition at the University of Chicago. The likelihood of a high risk of adverse events is diminishing as follow-up and patient sample size increase, but Dr. Rubin suggested that clinicians should monitor any IBD patient taking an immunosuppressive agent for infectious complications.

“At the University of Chicago IBD Center, we have now treated more than 100 patients and are studying this therapy to better understand its performance in postmarket,” Dr. Rubin said in an interview. “So far, we have made similar observations to the clinical trials and to those made by Dr. Loftus here at the ACG.”

Unlike tumor necrosis factor (TNF) inhibitors, which were the first biologics to be licensed for use in IBD, vedolizumab inhibits the migration of leukocytes in the GI tract by preventing the alpha₄beta₇ subunit from binding to the adhesion molecule MAdCAM-1. It has been unclear whether or to what degree vedolizumab shares the known risk, albeit small, of inducing opportunistic infections observed with TNF inhibitors.

The most recent data continue to suggest that there is no greater risk of infection or other complications of immune function for vedolizumab than other biologics, and the risk may be lower. In the pooled GEMINI data with 1,434 patients followed during induction and maintenance phases with data in some groups out to 104 weeks, the overall percentages of infection and the individual infections rates have been “similar,” Dr. Loftus reported.

“The exception has been nasopharyngitis, which was less common in the placebo group,” said Dr. Loftus, providing relative rates of approximately 13% and 9% for vedolizumab and placebo, respectively. He noted, however, that the length of follow-up has been longer in the vedolizumab relative to the placebo groups. Rates of tuberculosis, Clostridium difficile colitis, and other serious infections have not differed significantly.

In addition, there has been no association between vedolizumab and progressive multifocal leukoencephalopathy (PML) so far. Concern about a risk for PML was raised by the relationship of vedolizumab to natalizumab, which blocks the same adhesion compounds and has been associated with PML. The absence of PML in follow-up so far is consistent with evidence that the activity of vedolizumab, unlike the activity of natalizumab, is largely or entirely confined to the GI tract.

No multicenter, randomized trials have yet to be conducted comparing either the efficacy or safety of vedolizumab, which was approved in May 2014 for the treatment of moderate to severe Crohn’s disease and ulcerative colitis, to other biologics used in IBD.

PHILADELPHIA – In long-term follow-up for the treatment of inflammatory bowel disease, the novel monoclonal antibody vedolizumab continues to remain free of serious infections or other signs of major complications from altered immune function, according to pooled data presented at the annual meeting of the American College of Gastroenterology.

Over the course of follow-up, which now extends to 104 weeks in these trials, called GEMINI 1 and GEMINI 2, overall infection rates have been about the same in the vedolizumab and placebo arms even when corticosteroids or immunosuppressive agents are used concurrently, according to Dr. Edward V. Loftus Jr., professor of medicine at the Mayo Clinic, Rochester, Minn.

There is particular focus on the safety of vedolizumab, because of the theoretical risks of biologics overall and vedolizumab specifically. Vedolizumab has been shown to provide sustained remissions relative to placebo in both Crohn’s disease and ulcerative colitis in the previously presented and updated GEMINI trials, but this agent, like other biologics, alters mediators of immune function.

The follow-up summarized at the ACG meeting, which evaluated risk of adverse events of vedolizumab alone or in combination with other inflammatory bowel disease (IBD) agents that affect immune function, suggests that the risk of adverse events is low, but the conclusion is not definitive.

“There was not a signal of more side effects with combination therapy, which is reassuring. However, the study is limited by the number of adverse events available to analyze,” said Dr. David T. Rubin, section chief of gastroenterology, hepatology, and nutrition at the University of Chicago. The likelihood of a high risk of adverse events is diminishing as follow-up and patient sample size increase, but Dr. Rubin suggested that clinicians should monitor any IBD patient taking an immunosuppressive agent for infectious complications.

“At the University of Chicago IBD Center, we have now treated more than 100 patients and are studying this therapy to better understand its performance in postmarket,” Dr. Rubin said in an interview. “So far, we have made similar observations to the clinical trials and to those made by Dr. Loftus here at the ACG.”

Unlike tumor necrosis factor (TNF) inhibitors, which were the first biologics to be licensed for use in IBD, vedolizumab inhibits the migration of leukocytes in the GI tract by preventing the alpha₄beta₇ subunit from binding to the adhesion molecule MAdCAM-1. It has been unclear whether or to what degree vedolizumab shares the known risk, albeit small, of inducing opportunistic infections observed with TNF inhibitors.

The most recent data continue to suggest that there is no greater risk of infection or other complications of immune function for vedolizumab than other biologics, and the risk may be lower. In the pooled GEMINI data with 1,434 patients followed during induction and maintenance phases with data in some groups out to 104 weeks, the overall percentages of infection and the individual infections rates have been “similar,” Dr. Loftus reported.

“The exception has been nasopharyngitis, which was less common in the placebo group,” said Dr. Loftus, providing relative rates of approximately 13% and 9% for vedolizumab and placebo, respectively. He noted, however, that the length of follow-up has been longer in the vedolizumab relative to the placebo groups. Rates of tuberculosis, Clostridium difficile colitis, and other serious infections have not differed significantly.

In addition, there has been no association between vedolizumab and progressive multifocal leukoencephalopathy (PML) so far. Concern about a risk for PML was raised by the relationship of vedolizumab to natalizumab, which blocks the same adhesion compounds and has been associated with PML. The absence of PML in follow-up so far is consistent with evidence that the activity of vedolizumab, unlike the activity of natalizumab, is largely or entirely confined to the GI tract.

No multicenter, randomized trials have yet to be conducted comparing either the efficacy or safety of vedolizumab, which was approved in May 2014 for the treatment of moderate to severe Crohn’s disease and ulcerative colitis, to other biologics used in IBD.

PHILADELPHIA – The first trial conducted in gastroesophageal reflux diseases that employed control of regurgitation as a primary endpoint found a significant advantage for transoral fundoplication over a sham procedure, according to the results presented at the American College of Gastroenterology (ACG).

On the basis of these results “TF [transoral fundoplication] should be considered in GERD [gastroesophageal reflux disease] patients with small or absent hiatal hernia who suffer from troublesome regurgitation despite PPI therapy,” reported Dr. Peter J. Kahrilas, the Gilbert H. Marquardt Professor of Medicine, a professor of medicine, gastroenterology, and hepatology, at Northwestern University, Chicago*.

The focus on regurgitation in this trial was partially driven by the lack of previous evidence for an effective therapy. In those trials that have included change in regurgitation among secondary endpoints, Dr. Kahrilas said control on this symptom has typically been “significantly less” than that observed with heartburn.

In this study, called RESPECT, 129 patients were randomized in a 2:1 ratio to TF performed with the Esophyx device or to a sham procedure. Both groups were initiated on a standard dose of proton pump inhibitors (PPIs), but PPIs were discontinued in the TF arm 2 weeks after the procedure. In the sham group, an increase in PPI dose was permitted at the 2-week and 12-week assessments in those not already at the maximum double the standard dose limit.

The primary endpoint was elimination of troublesome regurgitation based on the regurgitation-related fields from the Reflux Disease Questionnaire (RDQ), which is a validated tool for GERD assessment. On this basis, symptoms at the final 26-week assessment had resolved in 67% of patients randomized to TF and 25% (P = .023) randomized to the sham procedure. Early failure rates were also significantly lower in the TF group (11% vs. 36%; P = .002).

Intraesophageal acid levels assessed with 48-hour pH monitoring at the end of the study “were improved but not normalized in the TF group and unchanged in the sham group,” Dr. Kahrilas reported.

Adverse events, although more common in the TF group, were infrequent in both arms, and none were serious. Summarizing risk of adverse events, Dr. Kahrilas said, “TF appears safe without typical fundoplication side effects.”

The specific mechanism of benefit for controlling regurgitation has not been defined, but Dr. Kahrilas suggested, “We think we are restricting the volume of reflux.”

Regurgitation is “the ignored symptom of GERD,” according to Dr. Kahrilas. Although this symptom can be significant to patients, clinicians have had limited treatment options.

This point was emphasized by Dr. Nicholas Shaheen, director, Center for Esophageal Diseases and Swallowing, University of North Carolina, Chapel Hill. In an interview, Dr. Shaheen said effective therapy for regurgitation is an unmet need.

“Patients with predominant regurgitation are not uncommon and PPIs do appear to be less effective for this symptom,” Dr. Shaheen reported. “Having a treatment option with efficacy specific for this symptom could be helpful.”

Dr. Peter Kahrilas has numerous financial relationships with pharmaceutical companies including EndoGastric, the sponsor of this trial.

*Correction, 10/27/2014: An earlier version of this article misstated Dr. Kahrilas' position.

PHILADELPHIA – The first trial conducted in gastroesophageal reflux diseases that employed control of regurgitation as a primary endpoint found a significant advantage for transoral fundoplication over a sham procedure, according to the results presented at the American College of Gastroenterology (ACG).

On the basis of these results “TF [transoral fundoplication] should be considered in GERD [gastroesophageal reflux disease] patients with small or absent hiatal hernia who suffer from troublesome regurgitation despite PPI therapy,” reported Dr. Peter J. Kahrilas, the Gilbert H. Marquardt Professor of Medicine, a professor of medicine, gastroenterology, and hepatology, at Northwestern University, Chicago*.

The focus on regurgitation in this trial was partially driven by the lack of previous evidence for an effective therapy. In those trials that have included change in regurgitation among secondary endpoints, Dr. Kahrilas said control on this symptom has typically been “significantly less” than that observed with heartburn.

In this study, called RESPECT, 129 patients were randomized in a 2:1 ratio to TF performed with the Esophyx device or to a sham procedure. Both groups were initiated on a standard dose of proton pump inhibitors (PPIs), but PPIs were discontinued in the TF arm 2 weeks after the procedure. In the sham group, an increase in PPI dose was permitted at the 2-week and 12-week assessments in those not already at the maximum double the standard dose limit.

The primary endpoint was elimination of troublesome regurgitation based on the regurgitation-related fields from the Reflux Disease Questionnaire (RDQ), which is a validated tool for GERD assessment. On this basis, symptoms at the final 26-week assessment had resolved in 67% of patients randomized to TF and 25% (P = .023) randomized to the sham procedure. Early failure rates were also significantly lower in the TF group (11% vs. 36%; P = .002).

Intraesophageal acid levels assessed with 48-hour pH monitoring at the end of the study “were improved but not normalized in the TF group and unchanged in the sham group,” Dr. Kahrilas reported.

Adverse events, although more common in the TF group, were infrequent in both arms, and none were serious. Summarizing risk of adverse events, Dr. Kahrilas said, “TF appears safe without typical fundoplication side effects.”

The specific mechanism of benefit for controlling regurgitation has not been defined, but Dr. Kahrilas suggested, “We think we are restricting the volume of reflux.”

Regurgitation is “the ignored symptom of GERD,” according to Dr. Kahrilas. Although this symptom can be significant to patients, clinicians have had limited treatment options.

This point was emphasized by Dr. Nicholas Shaheen, director, Center for Esophageal Diseases and Swallowing, University of North Carolina, Chapel Hill. In an interview, Dr. Shaheen said effective therapy for regurgitation is an unmet need.

“Patients with predominant regurgitation are not uncommon and PPIs do appear to be less effective for this symptom,” Dr. Shaheen reported. “Having a treatment option with efficacy specific for this symptom could be helpful.”

Dr. Peter Kahrilas has numerous financial relationships with pharmaceutical companies including EndoGastric, the sponsor of this trial.

*Correction, 10/27/2014: An earlier version of this article misstated Dr. Kahrilas' position.

PHILADELPHIA – The first trial conducted in gastroesophageal reflux diseases that employed control of regurgitation as a primary endpoint found a significant advantage for transoral fundoplication over a sham procedure, according to the results presented at the American College of Gastroenterology (ACG).

On the basis of these results “TF [transoral fundoplication] should be considered in GERD [gastroesophageal reflux disease] patients with small or absent hiatal hernia who suffer from troublesome regurgitation despite PPI therapy,” reported Dr. Peter J. Kahrilas, the Gilbert H. Marquardt Professor of Medicine, a professor of medicine, gastroenterology, and hepatology, at Northwestern University, Chicago*.

The focus on regurgitation in this trial was partially driven by the lack of previous evidence for an effective therapy. In those trials that have included change in regurgitation among secondary endpoints, Dr. Kahrilas said control on this symptom has typically been “significantly less” than that observed with heartburn.

In this study, called RESPECT, 129 patients were randomized in a 2:1 ratio to TF performed with the Esophyx device or to a sham procedure. Both groups were initiated on a standard dose of proton pump inhibitors (PPIs), but PPIs were discontinued in the TF arm 2 weeks after the procedure. In the sham group, an increase in PPI dose was permitted at the 2-week and 12-week assessments in those not already at the maximum double the standard dose limit.

The primary endpoint was elimination of troublesome regurgitation based on the regurgitation-related fields from the Reflux Disease Questionnaire (RDQ), which is a validated tool for GERD assessment. On this basis, symptoms at the final 26-week assessment had resolved in 67% of patients randomized to TF and 25% (P = .023) randomized to the sham procedure. Early failure rates were also significantly lower in the TF group (11% vs. 36%; P = .002).

Intraesophageal acid levels assessed with 48-hour pH monitoring at the end of the study “were improved but not normalized in the TF group and unchanged in the sham group,” Dr. Kahrilas reported.

Adverse events, although more common in the TF group, were infrequent in both arms, and none were serious. Summarizing risk of adverse events, Dr. Kahrilas said, “TF appears safe without typical fundoplication side effects.”

The specific mechanism of benefit for controlling regurgitation has not been defined, but Dr. Kahrilas suggested, “We think we are restricting the volume of reflux.”

Regurgitation is “the ignored symptom of GERD,” according to Dr. Kahrilas. Although this symptom can be significant to patients, clinicians have had limited treatment options.

This point was emphasized by Dr. Nicholas Shaheen, director, Center for Esophageal Diseases and Swallowing, University of North Carolina, Chapel Hill. In an interview, Dr. Shaheen said effective therapy for regurgitation is an unmet need.

“Patients with predominant regurgitation are not uncommon and PPIs do appear to be less effective for this symptom,” Dr. Shaheen reported. “Having a treatment option with efficacy specific for this symptom could be helpful.”

Dr. Peter Kahrilas has numerous financial relationships with pharmaceutical companies including EndoGastric, the sponsor of this trial.

*Correction, 10/27/2014: An earlier version of this article misstated Dr. Kahrilas' position.

PHILADELPHIA – A registry created by the National Institutes of Health (NIH) to track idiosyncratic drug-induced liver injury (DILI) largely confirms the significant risks suggested by small studies and textbook summaries, according to newly summarized data presented at the American College of Gastroenterology (ACG).

According to the registry, antimicrobials dominate cases of DILI, a substantial minority of DILI patients die of this complication or require liver transplant, and the risks of adverse outcomes from DILI are far greater in the presence of hepatitis or another preexisting liver disease, reported Dr. Naga P. Chalasani, chief of the division of gastroenterology and hepatology, Indiana University school of medicine, Indianapolis.

Since 2004, when the Drug Induced Liver Injury Network was established by the NIH, 1,257 patients have been enrolled of which 899 were found to have probable, highly likely, or definite DILI by an adjudication committee charged with determining causality. The mortality rate overall was 6.2% with an additional 4% undergoing liver transplant.

The most commonly implicated causal agents by class were antimicrobials (45.4%), herbal and dietary supplements (16.1%), cardiovascular agents (9.7%), and CNS agents (9.1%) with a wide variety of other classes falling in at much lower representation. Nine of the top 10 individual agents implicated in DILI (amoxicillin-clavulanate led the list) were antimicrobials. The exception — and in the 10^th spot — was diclofenac.

“What may be of interest to the clinician is how long it takes on average to recover,” Dr. Chalasani observed. For those who present with jaundice, which represented about 70% of patients in the registry, the average was about 70 days. This information may be useful “if a patient asks you how long I am going to be yellow.”

Characterizing DILI as hepatocellular, cholestatic, or mixed may have value in assessing risk. According to Dr. Chalasani, the rates of DILI-related death were higher in cholestatic than hepatocellular presentations, but the risk of liver transplant was lower. In the mixed group, liver-related death was uncommon, and there were no liver transplants even though these patients more often developed chronic DILI.

The average time from exposure to DILI in drugs with a short latency was 36 days. Drugs with a long latency, defined as more than 1 year, included nitrofurantoin, statins, amiodarone, and mercaptopurine.

“The pattern of long latency is very interesting. Patients are often on a stable dose of a given drug for a length of time and doing well and then the dose is escalated and, boom, they present with DILI,” Dr. Chalasani reported.

Despite the hypothesis that there might be differences in characteristics and outcomes from long versus short latencies, none were seen.

Stevens-Johnson Syndrome (SJS) was observed in about 1% of the DILI patients in the registry. Antimicrobials were again implicated in patients who developed SJS, but the list of most common drugs in this subset also included lamotrigine and carbamazepine.

Patients with preexisting liver disease, such as a form of hepatitis or nonalcoholic fatty liver disease, represented 10% of the registry population. The causative agents were similar with the exception of azathioprine, which appeared to impose an even greater risk in those with liver disease than in those without.

“Although it has been written in the textbooks, this is the first set of data to show DILI in patients with preexisting liver disease imposes a three times higher likelihood of death than in those without liver disease,” Dr. Chalasani reported.

DILI is a rare disease, occurring in only about 20/100,000 patients. As a result, the NIH registry is considered an essential tool for gathering data on this complication in order to assess its causes and prognosis.

Dr. Chalasani reports that he and his coauthors have multiple financial relationships with industry but none that are relevant to this study.

PHILADELPHIA – A registry created by the National Institutes of Health (NIH) to track idiosyncratic drug-induced liver injury (DILI) largely confirms the significant risks suggested by small studies and textbook summaries, according to newly summarized data presented at the American College of Gastroenterology (ACG).

According to the registry, antimicrobials dominate cases of DILI, a substantial minority of DILI patients die of this complication or require liver transplant, and the risks of adverse outcomes from DILI are far greater in the presence of hepatitis or another preexisting liver disease, reported Dr. Naga P. Chalasani, chief of the division of gastroenterology and hepatology, Indiana University school of medicine, Indianapolis.

Since 2004, when the Drug Induced Liver Injury Network was established by the NIH, 1,257 patients have been enrolled of which 899 were found to have probable, highly likely, or definite DILI by an adjudication committee charged with determining causality. The mortality rate overall was 6.2% with an additional 4% undergoing liver transplant.

The most commonly implicated causal agents by class were antimicrobials (45.4%), herbal and dietary supplements (16.1%), cardiovascular agents (9.7%), and CNS agents (9.1%) with a wide variety of other classes falling in at much lower representation. Nine of the top 10 individual agents implicated in DILI (amoxicillin-clavulanate led the list) were antimicrobials. The exception — and in the 10^th spot — was diclofenac.

“What may be of interest to the clinician is how long it takes on average to recover,” Dr. Chalasani observed. For those who present with jaundice, which represented about 70% of patients in the registry, the average was about 70 days. This information may be useful “if a patient asks you how long I am going to be yellow.”

Characterizing DILI as hepatocellular, cholestatic, or mixed may have value in assessing risk. According to Dr. Chalasani, the rates of DILI-related death were higher in cholestatic than hepatocellular presentations, but the risk of liver transplant was lower. In the mixed group, liver-related death was uncommon, and there were no liver transplants even though these patients more often developed chronic DILI.

The average time from exposure to DILI in drugs with a short latency was 36 days. Drugs with a long latency, defined as more than 1 year, included nitrofurantoin, statins, amiodarone, and mercaptopurine.

“The pattern of long latency is very interesting. Patients are often on a stable dose of a given drug for a length of time and doing well and then the dose is escalated and, boom, they present with DILI,” Dr. Chalasani reported.

Despite the hypothesis that there might be differences in characteristics and outcomes from long versus short latencies, none were seen.

Stevens-Johnson Syndrome (SJS) was observed in about 1% of the DILI patients in the registry. Antimicrobials were again implicated in patients who developed SJS, but the list of most common drugs in this subset also included lamotrigine and carbamazepine.

Patients with preexisting liver disease, such as a form of hepatitis or nonalcoholic fatty liver disease, represented 10% of the registry population. The causative agents were similar with the exception of azathioprine, which appeared to impose an even greater risk in those with liver disease than in those without.

“Although it has been written in the textbooks, this is the first set of data to show DILI in patients with preexisting liver disease imposes a three times higher likelihood of death than in those without liver disease,” Dr. Chalasani reported.

DILI is a rare disease, occurring in only about 20/100,000 patients. As a result, the NIH registry is considered an essential tool for gathering data on this complication in order to assess its causes and prognosis.

Dr. Chalasani reports that he and his coauthors have multiple financial relationships with industry but none that are relevant to this study.

PHILADELPHIA – A registry created by the National Institutes of Health (NIH) to track idiosyncratic drug-induced liver injury (DILI) largely confirms the significant risks suggested by small studies and textbook summaries, according to newly summarized data presented at the American College of Gastroenterology (ACG).

According to the registry, antimicrobials dominate cases of DILI, a substantial minority of DILI patients die of this complication or require liver transplant, and the risks of adverse outcomes from DILI are far greater in the presence of hepatitis or another preexisting liver disease, reported Dr. Naga P. Chalasani, chief of the division of gastroenterology and hepatology, Indiana University school of medicine, Indianapolis.

Since 2004, when the Drug Induced Liver Injury Network was established by the NIH, 1,257 patients have been enrolled of which 899 were found to have probable, highly likely, or definite DILI by an adjudication committee charged with determining causality. The mortality rate overall was 6.2% with an additional 4% undergoing liver transplant.

The most commonly implicated causal agents by class were antimicrobials (45.4%), herbal and dietary supplements (16.1%), cardiovascular agents (9.7%), and CNS agents (9.1%) with a wide variety of other classes falling in at much lower representation. Nine of the top 10 individual agents implicated in DILI (amoxicillin-clavulanate led the list) were antimicrobials. The exception — and in the 10^th spot — was diclofenac.

“What may be of interest to the clinician is how long it takes on average to recover,” Dr. Chalasani observed. For those who present with jaundice, which represented about 70% of patients in the registry, the average was about 70 days. This information may be useful “if a patient asks you how long I am going to be yellow.”

Characterizing DILI as hepatocellular, cholestatic, or mixed may have value in assessing risk. According to Dr. Chalasani, the rates of DILI-related death were higher in cholestatic than hepatocellular presentations, but the risk of liver transplant was lower. In the mixed group, liver-related death was uncommon, and there were no liver transplants even though these patients more often developed chronic DILI.

The average time from exposure to DILI in drugs with a short latency was 36 days. Drugs with a long latency, defined as more than 1 year, included nitrofurantoin, statins, amiodarone, and mercaptopurine.

“The pattern of long latency is very interesting. Patients are often on a stable dose of a given drug for a length of time and doing well and then the dose is escalated and, boom, they present with DILI,” Dr. Chalasani reported.

Despite the hypothesis that there might be differences in characteristics and outcomes from long versus short latencies, none were seen.

Stevens-Johnson Syndrome (SJS) was observed in about 1% of the DILI patients in the registry. Antimicrobials were again implicated in patients who developed SJS, but the list of most common drugs in this subset also included lamotrigine and carbamazepine.

Patients with preexisting liver disease, such as a form of hepatitis or nonalcoholic fatty liver disease, represented 10% of the registry population. The causative agents were similar with the exception of azathioprine, which appeared to impose an even greater risk in those with liver disease than in those without.

“Although it has been written in the textbooks, this is the first set of data to show DILI in patients with preexisting liver disease imposes a three times higher likelihood of death than in those without liver disease,” Dr. Chalasani reported.

DILI is a rare disease, occurring in only about 20/100,000 patients. As a result, the NIH registry is considered an essential tool for gathering data on this complication in order to assess its causes and prognosis.

Dr. Chalasani reports that he and his coauthors have multiple financial relationships with industry but none that are relevant to this study.

PHILADELPHIA - The risk of both colorectal cancer and CRC-related mortality can be reduced in patients with inflammatory bowel disease by adhering to guideline-directed colonoscopy surveillance recommendations, according to a large retrospective cohort study presented at the annual meeting of the American College of Gastroenterology.

After adjustment for age, sex, duration of disease, type of IBD, and coexisting primary cholangitis, the odds ratio (OR) for CRC was reduced by 35% (OR, 0.65; 95% confidence interval, 0.45-0.93), according to Dr. Ashwin Ananthakrishnan, a gastroenterologist at Massachusetts General Hospital, Boston.

Many professional societies, including the ACG, recommend colonoscopy surveillance in IBD patients within 8-10 years of diagnosis, and subsequently at 2- to 3-year intervals, but these recommendations were created without direct evidence of benefit. The aim of the study was to evaluate the effect of colonoscopy surveillance on CRC incidence.

The 6,823 patients who formed the cohort were gathered through electronic medical records from multiple participating institutions. The incidence of CRC was compared in the 2,764 patients who underwent colonoscopy within 3 years prior to a diagnosis of CRC or the end of the follow-up period and the 4,059 without colonoscopy in this period.

Of the 154 cases of CRC observed during follow-up, 43 occurred in the group that had undergone colonoscopy and 111 occurred in the group that had not, producing an incidence of 1.6% and 2.7%, respectively. Although there were potentially relevant differences between the two patient groups – the colonoscopy group had a lower incidence of ulcerative colitis (49% vs. 54%) and a younger age (47 vs. 49 years) – the advantage persisted after adjustment.

In addition, death due to CRC was lower in the group that underwent colonoscopy in the past 3 years (14% vs. 34%; P = .012), producing an odds ratio of 0.34 (95% CI, 0.12-0.95) for this endpoint.

Dr. Ananthakrishnan acknowledged that the limitations of the study included recruitment from a largely tertiary-center population and lack of information on the extent of IBD or the stage of cancer, but he called the overall findings “robust.” He concluded that these data may provide the best support yet for the current guidelines.

“I do not think this suggests we should be doing anything any differently,” Dr. Ananthakrishnan said in an interview, “but it does reinforce the value of the guidelines for those who may not be applying them now.”

Asked for his perspective on these data, Dr. Stephen Hanauer, professor of gastroenterology and hepatology, Northwestern University, Chicago, was more circumspect.

“There is evidence that the incidence of CRC is going down in patients with IBD, and it may be due to better surveillance, but this study has some limitations,” Dr. Hanauer commented. “It could have been just that those who received colonoscopy had less advanced IBD and a lower cancer risk.”

The definitive answer is dependent on a prospective and randomized trial, but there is limited demand for such a study when the increased risk of CRC in patients with IBD is well accepted, making surveillance attractive. Dr. Hanauer did not dispute the logic behind current screening recommendations.

Dr. Ananthakrishnan reported having no relevant financial relationships to disclose.

AGA Resources

The AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease is available online here.

PHILADELPHIA - The risk of both colorectal cancer and CRC-related mortality can be reduced in patients with inflammatory bowel disease by adhering to guideline-directed colonoscopy surveillance recommendations, according to a large retrospective cohort study presented at the annual meeting of the American College of Gastroenterology.

After adjustment for age, sex, duration of disease, type of IBD, and coexisting primary cholangitis, the odds ratio (OR) for CRC was reduced by 35% (OR, 0.65; 95% confidence interval, 0.45-0.93), according to Dr. Ashwin Ananthakrishnan, a gastroenterologist at Massachusetts General Hospital, Boston.

Many professional societies, including the ACG, recommend colonoscopy surveillance in IBD patients within 8-10 years of diagnosis, and subsequently at 2- to 3-year intervals, but these recommendations were created without direct evidence of benefit. The aim of the study was to evaluate the effect of colonoscopy surveillance on CRC incidence.

The 6,823 patients who formed the cohort were gathered through electronic medical records from multiple participating institutions. The incidence of CRC was compared in the 2,764 patients who underwent colonoscopy within 3 years prior to a diagnosis of CRC or the end of the follow-up period and the 4,059 without colonoscopy in this period.

Of the 154 cases of CRC observed during follow-up, 43 occurred in the group that had undergone colonoscopy and 111 occurred in the group that had not, producing an incidence of 1.6% and 2.7%, respectively. Although there were potentially relevant differences between the two patient groups – the colonoscopy group had a lower incidence of ulcerative colitis (49% vs. 54%) and a younger age (47 vs. 49 years) – the advantage persisted after adjustment.

In addition, death due to CRC was lower in the group that underwent colonoscopy in the past 3 years (14% vs. 34%; P = .012), producing an odds ratio of 0.34 (95% CI, 0.12-0.95) for this endpoint.

Dr. Ananthakrishnan acknowledged that the limitations of the study included recruitment from a largely tertiary-center population and lack of information on the extent of IBD or the stage of cancer, but he called the overall findings “robust.” He concluded that these data may provide the best support yet for the current guidelines.

“I do not think this suggests we should be doing anything any differently,” Dr. Ananthakrishnan said in an interview, “but it does reinforce the value of the guidelines for those who may not be applying them now.”

Asked for his perspective on these data, Dr. Stephen Hanauer, professor of gastroenterology and hepatology, Northwestern University, Chicago, was more circumspect.

“There is evidence that the incidence of CRC is going down in patients with IBD, and it may be due to better surveillance, but this study has some limitations,” Dr. Hanauer commented. “It could have been just that those who received colonoscopy had less advanced IBD and a lower cancer risk.”

The definitive answer is dependent on a prospective and randomized trial, but there is limited demand for such a study when the increased risk of CRC in patients with IBD is well accepted, making surveillance attractive. Dr. Hanauer did not dispute the logic behind current screening recommendations.

Dr. Ananthakrishnan reported having no relevant financial relationships to disclose.

AGA Resources

The AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease is available online here.

PHILADELPHIA - The risk of both colorectal cancer and CRC-related mortality can be reduced in patients with inflammatory bowel disease by adhering to guideline-directed colonoscopy surveillance recommendations, according to a large retrospective cohort study presented at the annual meeting of the American College of Gastroenterology.

After adjustment for age, sex, duration of disease, type of IBD, and coexisting primary cholangitis, the odds ratio (OR) for CRC was reduced by 35% (OR, 0.65; 95% confidence interval, 0.45-0.93), according to Dr. Ashwin Ananthakrishnan, a gastroenterologist at Massachusetts General Hospital, Boston.

Many professional societies, including the ACG, recommend colonoscopy surveillance in IBD patients within 8-10 years of diagnosis, and subsequently at 2- to 3-year intervals, but these recommendations were created without direct evidence of benefit. The aim of the study was to evaluate the effect of colonoscopy surveillance on CRC incidence.

The 6,823 patients who formed the cohort were gathered through electronic medical records from multiple participating institutions. The incidence of CRC was compared in the 2,764 patients who underwent colonoscopy within 3 years prior to a diagnosis of CRC or the end of the follow-up period and the 4,059 without colonoscopy in this period.

Of the 154 cases of CRC observed during follow-up, 43 occurred in the group that had undergone colonoscopy and 111 occurred in the group that had not, producing an incidence of 1.6% and 2.7%, respectively. Although there were potentially relevant differences between the two patient groups – the colonoscopy group had a lower incidence of ulcerative colitis (49% vs. 54%) and a younger age (47 vs. 49 years) – the advantage persisted after adjustment.

In addition, death due to CRC was lower in the group that underwent colonoscopy in the past 3 years (14% vs. 34%; P = .012), producing an odds ratio of 0.34 (95% CI, 0.12-0.95) for this endpoint.

Dr. Ananthakrishnan acknowledged that the limitations of the study included recruitment from a largely tertiary-center population and lack of information on the extent of IBD or the stage of cancer, but he called the overall findings “robust.” He concluded that these data may provide the best support yet for the current guidelines.

“I do not think this suggests we should be doing anything any differently,” Dr. Ananthakrishnan said in an interview, “but it does reinforce the value of the guidelines for those who may not be applying them now.”

Asked for his perspective on these data, Dr. Stephen Hanauer, professor of gastroenterology and hepatology, Northwestern University, Chicago, was more circumspect.

“There is evidence that the incidence of CRC is going down in patients with IBD, and it may be due to better surveillance, but this study has some limitations,” Dr. Hanauer commented. “It could have been just that those who received colonoscopy had less advanced IBD and a lower cancer risk.”

The definitive answer is dependent on a prospective and randomized trial, but there is limited demand for such a study when the increased risk of CRC in patients with IBD is well accepted, making surveillance attractive. Dr. Hanauer did not dispute the logic behind current screening recommendations.

Dr. Ananthakrishnan reported having no relevant financial relationships to disclose.

AGA Resources

The AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease is available online here.

PHILADELPHIA - The risk of both colorectal cancer and CRC-related mortality can be reduced in patients with inflammatory bowel disease by adhering to guideline-directed colonoscopy surveillance recommendations, according to a large retrospective cohort study presented at the annual meeting of the American College of Gastroenterology.

After adjustment for age, sex, duration of disease, type of IBD, and coexisting primary cholangitis, the odds ratio (OR) for CRC was reduced by 35% (OR, 0.65; 95% confidence interval, 0.45-0.93), according to Dr. Ashwin Ananthakrishnan, a gastroenterologist at Massachusetts General Hospital, Boston.

Many professional societies, including the ACG, recommend colonoscopy surveillance in IBD patients within 8-10 years of diagnosis, and subsequently at 2- to 3-year intervals, but these recommendations were created without direct evidence of benefit. The aim of the study was to evaluate the effect of colonoscopy surveillance on CRC incidence.

The 6,823 patients who formed the cohort were gathered through electronic medical records from multiple participating institutions. The incidence of CRC was compared in the 2,764 patients who underwent colonoscopy within 3 years prior to a diagnosis of CRC or the end of the follow-up period and the 4,059 without colonoscopy in this period.

Of the 154 cases of CRC observed during follow-up, 43 occurred in the group that had undergone colonoscopy and 111 occurred in the group that had not, producing an incidence of 1.6% and 2.7%, respectively. Although there were potentially relevant differences between the two patient groups – the colonoscopy group had a lower incidence of ulcerative colitis (49% vs. 54%) and a younger age (47 vs. 49 years) – the advantage persisted after adjustment.

In addition, death due to CRC was lower in the group that underwent colonoscopy in the past 3 years (14% vs. 34%; P = .012), producing an odds ratio of 0.34 (95% CI, 0.12-0.95) for this endpoint.

Dr. Ananthakrishnan acknowledged that the limitations of the study included recruitment from a largely tertiary-center population and lack of information on the extent of IBD or the stage of cancer, but he called the overall findings “robust.” He concluded that these data may provide the best support yet for the current guidelines.

“I do not think this suggests we should be doing anything any differently,” Dr. Ananthakrishnan said in an interview, “but it does reinforce the value of the guidelines for those who may not be applying them now.”

Asked for his perspective on these data, Dr. Stephen Hanauer, professor of gastroenterology and hepatology, Northwestern University, Chicago, was more circumspect.

“There is evidence that the incidence of CRC is going down in patients with IBD, and it may be due to better surveillance, but this study has some limitations,” Dr. Hanauer commented. “It could have been just that those who received colonoscopy had less advanced IBD and a lower cancer risk.”

The definitive answer is dependent on a prospective and randomized trial, but there is limited demand for such a study when the increased risk of CRC in patients with IBD is well accepted, making surveillance attractive. Dr. Hanauer did not dispute the logic behind current screening recommendations.

Dr. Ananthakrishnan reported having no relevant financial relationships to disclose.

PHILADELPHIA - The risk of both colorectal cancer and CRC-related mortality can be reduced in patients with inflammatory bowel disease by adhering to guideline-directed colonoscopy surveillance recommendations, according to a large retrospective cohort study presented at the annual meeting of the American College of Gastroenterology.

After adjustment for age, sex, duration of disease, type of IBD, and coexisting primary cholangitis, the odds ratio (OR) for CRC was reduced by 35% (OR, 0.65; 95% confidence interval, 0.45-0.93), according to Dr. Ashwin Ananthakrishnan, a gastroenterologist at Massachusetts General Hospital, Boston.

Many professional societies, including the ACG, recommend colonoscopy surveillance in IBD patients within 8-10 years of diagnosis, and subsequently at 2- to 3-year intervals, but these recommendations were created without direct evidence of benefit. The aim of the study was to evaluate the effect of colonoscopy surveillance on CRC incidence.

The 6,823 patients who formed the cohort were gathered through electronic medical records from multiple participating institutions. The incidence of CRC was compared in the 2,764 patients who underwent colonoscopy within 3 years prior to a diagnosis of CRC or the end of the follow-up period and the 4,059 without colonoscopy in this period.

Of the 154 cases of CRC observed during follow-up, 43 occurred in the group that had undergone colonoscopy and 111 occurred in the group that had not, producing an incidence of 1.6% and 2.7%, respectively. Although there were potentially relevant differences between the two patient groups – the colonoscopy group had a lower incidence of ulcerative colitis (49% vs. 54%) and a younger age (47 vs. 49 years) – the advantage persisted after adjustment.

In addition, death due to CRC was lower in the group that underwent colonoscopy in the past 3 years (14% vs. 34%; P = .012), producing an odds ratio of 0.34 (95% CI, 0.12-0.95) for this endpoint.

Dr. Ananthakrishnan acknowledged that the limitations of the study included recruitment from a largely tertiary-center population and lack of information on the extent of IBD or the stage of cancer, but he called the overall findings “robust.” He concluded that these data may provide the best support yet for the current guidelines.

“I do not think this suggests we should be doing anything any differently,” Dr. Ananthakrishnan said in an interview, “but it does reinforce the value of the guidelines for those who may not be applying them now.”

Asked for his perspective on these data, Dr. Stephen Hanauer, professor of gastroenterology and hepatology, Northwestern University, Chicago, was more circumspect.

“There is evidence that the incidence of CRC is going down in patients with IBD, and it may be due to better surveillance, but this study has some limitations,” Dr. Hanauer commented. “It could have been just that those who received colonoscopy had less advanced IBD and a lower cancer risk.”

The definitive answer is dependent on a prospective and randomized trial, but there is limited demand for such a study when the increased risk of CRC in patients with IBD is well accepted, making surveillance attractive. Dr. Hanauer did not dispute the logic behind current screening recommendations.

Dr. Ananthakrishnan reported having no relevant financial relationships to disclose.

PHILADELPHIA - The risk of both colorectal cancer and CRC-related mortality can be reduced in patients with inflammatory bowel disease by adhering to guideline-directed colonoscopy surveillance recommendations, according to a large retrospective cohort study presented at the annual meeting of the American College of Gastroenterology.

After adjustment for age, sex, duration of disease, type of IBD, and coexisting primary cholangitis, the odds ratio (OR) for CRC was reduced by 35% (OR, 0.65; 95% confidence interval, 0.45-0.93), according to Dr. Ashwin Ananthakrishnan, a gastroenterologist at Massachusetts General Hospital, Boston.

Many professional societies, including the ACG, recommend colonoscopy surveillance in IBD patients within 8-10 years of diagnosis, and subsequently at 2- to 3-year intervals, but these recommendations were created without direct evidence of benefit. The aim of the study was to evaluate the effect of colonoscopy surveillance on CRC incidence.

The 6,823 patients who formed the cohort were gathered through electronic medical records from multiple participating institutions. The incidence of CRC was compared in the 2,764 patients who underwent colonoscopy within 3 years prior to a diagnosis of CRC or the end of the follow-up period and the 4,059 without colonoscopy in this period.

Of the 154 cases of CRC observed during follow-up, 43 occurred in the group that had undergone colonoscopy and 111 occurred in the group that had not, producing an incidence of 1.6% and 2.7%, respectively. Although there were potentially relevant differences between the two patient groups – the colonoscopy group had a lower incidence of ulcerative colitis (49% vs. 54%) and a younger age (47 vs. 49 years) – the advantage persisted after adjustment.

In addition, death due to CRC was lower in the group that underwent colonoscopy in the past 3 years (14% vs. 34%; P = .012), producing an odds ratio of 0.34 (95% CI, 0.12-0.95) for this endpoint.

Dr. Ananthakrishnan acknowledged that the limitations of the study included recruitment from a largely tertiary-center population and lack of information on the extent of IBD or the stage of cancer, but he called the overall findings “robust.” He concluded that these data may provide the best support yet for the current guidelines.

“I do not think this suggests we should be doing anything any differently,” Dr. Ananthakrishnan said in an interview, “but it does reinforce the value of the guidelines for those who may not be applying them now.”

Asked for his perspective on these data, Dr. Stephen Hanauer, professor of gastroenterology and hepatology, Northwestern University, Chicago, was more circumspect.

“There is evidence that the incidence of CRC is going down in patients with IBD, and it may be due to better surveillance, but this study has some limitations,” Dr. Hanauer commented. “It could have been just that those who received colonoscopy had less advanced IBD and a lower cancer risk.”

The definitive answer is dependent on a prospective and randomized trial, but there is limited demand for such a study when the increased risk of CRC in patients with IBD is well accepted, making surveillance attractive. Dr. Hanauer did not dispute the logic behind current screening recommendations.

Dr. Ananthakrishnan reported having no relevant financial relationships to disclose.