From the AGA Journals

Increasing dosages of mesalamine by 2.4 g/d for patients with quiescent ulcerative colitis can dramatically reduce concentrations of fecal calprotectin and ultimately decrease the likelihood of relapse, according to the results of a new Dose Escalation and Remission (DEAR) study published in the November issue of Clinical Gastroenterology and Hepatology (2014;12:1887-93.e3).

In an open-label, randomized controlled trial, 119 patients with quiescent ulcerative colitis (UC) in remission were screened for Simple Clinical Colitis Activity Index scores, fecal calprotectin (FC) of 50 mcg/gram, and intake of no more than 3 g of mesalamine per day between October 2008 and March 2012. These subjects were divided into four groups based on FC levels, with Group 1 comprising 58 representing a baseline of FC < 50 mcg/gram, and groups 2-4 having 61 individuals with elevated baseline FC levels. Group 1 patients were retained for an observational follow-up study but were not included in the randomized controlled trial.

© selvanegra / thinkstockphotos.com

Participants were either told to maintain their current medication regimen or were prescribed a multimatrix mesalamine of either 2.4 or 4.8 g/d for 6 weeks, depending on their initial FC levels, after which point FC levels were taken. Participants in Group 2 with FC < 50 mcg/g were kept in an observational follow-up study group, while the rest of the participants were randomly assigned to continue their 2.4 g/d regimen, or increase their intake to 4.8 g/d.

Individuals in Group 3 with FC levels greater than 50 mcg/g were randomly assigned to either the 2.4- or 4.8-g/d regimen for 6 weeks; after that point, those whose FC levels had decreased below 50 continued with their regimen while those whose FC levels remained high were upped to 4.8 g/d. Subjects in Group 4 who were not already on a multimatrix mesalamine regimen and whose FC levels were above 50 mcg/g were randomized to continue their medication or add 2.4 g/d of mesalamine; after 6 weeks, if FC levels remained above 50, the dosage was increased to 4.8 g/d.

The primary outcome of continued remission with FC no greater than 50 mcg/g was observed in 3.8% of controls and 26.9% of participants in the dose escalation group (P = .0496). Others within the same group experienced secondary outcomes of FC levels below 100 mcg/gram (P = .04) and below 200 mcg/g (P = .005). Furthermore, among patients who were in remission during the randomization phase of the study, relapse occurred far sooner in those whose FC was above 200 mcg/g than those whose FC levels were below that mark.

“Our study adds to the evidence supporting FC concentration as a valid biomarker for UC,” said lead authors Dr. Mark T. Osterman and Dr. Faten N. Aberra of the University of Pennsylvania’s department of medicine, Philadelphia. “Perhaps more importantly, our results offer a novel way to use FC testing to positively impact outcomes in UC. We demonstrated efficacy of intervention to reduce FC (a surrogate for mucosal inflammation) before symptoms develop in patients at potentially increased risk of relapse.”

Dr. Osterman is a consultant for AbbVie, Elan, Janssen, and UCB and receives research funding from UCB. Dr. Aberra is a consultant for Janssen and research investigator for Amgen, Janssen, and UCB. Other coauthors disclosed ties to numerous pharmaceutical companies.

[email protected]

Increasing dosages of mesalamine by 2.4 g/d for patients with quiescent ulcerative colitis can dramatically reduce concentrations of fecal calprotectin and ultimately decrease the likelihood of relapse, according to the results of a new Dose Escalation and Remission (DEAR) study published in the November issue of Clinical Gastroenterology and Hepatology (2014;12:1887-93.e3).

In an open-label, randomized controlled trial, 119 patients with quiescent ulcerative colitis (UC) in remission were screened for Simple Clinical Colitis Activity Index scores, fecal calprotectin (FC) of 50 mcg/gram, and intake of no more than 3 g of mesalamine per day between October 2008 and March 2012. These subjects were divided into four groups based on FC levels, with Group 1 comprising 58 representing a baseline of FC < 50 mcg/gram, and groups 2-4 having 61 individuals with elevated baseline FC levels. Group 1 patients were retained for an observational follow-up study but were not included in the randomized controlled trial.

© selvanegra / thinkstockphotos.com

Participants were either told to maintain their current medication regimen or were prescribed a multimatrix mesalamine of either 2.4 or 4.8 g/d for 6 weeks, depending on their initial FC levels, after which point FC levels were taken. Participants in Group 2 with FC < 50 mcg/g were kept in an observational follow-up study group, while the rest of the participants were randomly assigned to continue their 2.4 g/d regimen, or increase their intake to 4.8 g/d.

Individuals in Group 3 with FC levels greater than 50 mcg/g were randomly assigned to either the 2.4- or 4.8-g/d regimen for 6 weeks; after that point, those whose FC levels had decreased below 50 continued with their regimen while those whose FC levels remained high were upped to 4.8 g/d. Subjects in Group 4 who were not already on a multimatrix mesalamine regimen and whose FC levels were above 50 mcg/g were randomized to continue their medication or add 2.4 g/d of mesalamine; after 6 weeks, if FC levels remained above 50, the dosage was increased to 4.8 g/d.

The primary outcome of continued remission with FC no greater than 50 mcg/g was observed in 3.8% of controls and 26.9% of participants in the dose escalation group (P = .0496). Others within the same group experienced secondary outcomes of FC levels below 100 mcg/gram (P = .04) and below 200 mcg/g (P = .005). Furthermore, among patients who were in remission during the randomization phase of the study, relapse occurred far sooner in those whose FC was above 200 mcg/g than those whose FC levels were below that mark.

“Our study adds to the evidence supporting FC concentration as a valid biomarker for UC,” said lead authors Dr. Mark T. Osterman and Dr. Faten N. Aberra of the University of Pennsylvania’s department of medicine, Philadelphia. “Perhaps more importantly, our results offer a novel way to use FC testing to positively impact outcomes in UC. We demonstrated efficacy of intervention to reduce FC (a surrogate for mucosal inflammation) before symptoms develop in patients at potentially increased risk of relapse.”

Dr. Osterman is a consultant for AbbVie, Elan, Janssen, and UCB and receives research funding from UCB. Dr. Aberra is a consultant for Janssen and research investigator for Amgen, Janssen, and UCB. Other coauthors disclosed ties to numerous pharmaceutical companies.

[email protected]

Increasing dosages of mesalamine by 2.4 g/d for patients with quiescent ulcerative colitis can dramatically reduce concentrations of fecal calprotectin and ultimately decrease the likelihood of relapse, according to the results of a new Dose Escalation and Remission (DEAR) study published in the November issue of Clinical Gastroenterology and Hepatology (2014;12:1887-93.e3).

In an open-label, randomized controlled trial, 119 patients with quiescent ulcerative colitis (UC) in remission were screened for Simple Clinical Colitis Activity Index scores, fecal calprotectin (FC) of 50 mcg/gram, and intake of no more than 3 g of mesalamine per day between October 2008 and March 2012. These subjects were divided into four groups based on FC levels, with Group 1 comprising 58 representing a baseline of FC < 50 mcg/gram, and groups 2-4 having 61 individuals with elevated baseline FC levels. Group 1 patients were retained for an observational follow-up study but were not included in the randomized controlled trial.

© selvanegra / thinkstockphotos.com

Participants were either told to maintain their current medication regimen or were prescribed a multimatrix mesalamine of either 2.4 or 4.8 g/d for 6 weeks, depending on their initial FC levels, after which point FC levels were taken. Participants in Group 2 with FC < 50 mcg/g were kept in an observational follow-up study group, while the rest of the participants were randomly assigned to continue their 2.4 g/d regimen, or increase their intake to 4.8 g/d.

Individuals in Group 3 with FC levels greater than 50 mcg/g were randomly assigned to either the 2.4- or 4.8-g/d regimen for 6 weeks; after that point, those whose FC levels had decreased below 50 continued with their regimen while those whose FC levels remained high were upped to 4.8 g/d. Subjects in Group 4 who were not already on a multimatrix mesalamine regimen and whose FC levels were above 50 mcg/g were randomized to continue their medication or add 2.4 g/d of mesalamine; after 6 weeks, if FC levels remained above 50, the dosage was increased to 4.8 g/d.

The primary outcome of continued remission with FC no greater than 50 mcg/g was observed in 3.8% of controls and 26.9% of participants in the dose escalation group (P = .0496). Others within the same group experienced secondary outcomes of FC levels below 100 mcg/gram (P = .04) and below 200 mcg/g (P = .005). Furthermore, among patients who were in remission during the randomization phase of the study, relapse occurred far sooner in those whose FC was above 200 mcg/g than those whose FC levels were below that mark.

“Our study adds to the evidence supporting FC concentration as a valid biomarker for UC,” said lead authors Dr. Mark T. Osterman and Dr. Faten N. Aberra of the University of Pennsylvania’s department of medicine, Philadelphia. “Perhaps more importantly, our results offer a novel way to use FC testing to positively impact outcomes in UC. We demonstrated efficacy of intervention to reduce FC (a surrogate for mucosal inflammation) before symptoms develop in patients at potentially increased risk of relapse.”

Dr. Osterman is a consultant for AbbVie, Elan, Janssen, and UCB and receives research funding from UCB. Dr. Aberra is a consultant for Janssen and research investigator for Amgen, Janssen, and UCB. Other coauthors disclosed ties to numerous pharmaceutical companies.

[email protected]

A mutation in the hepatitis E virus might contribute to ribavirin treatment failure in transplant recipients with chronic HEV infection, according to a small study published in the November issue of Gastroenterology.

The study is the first to find in vitro evidence for a virulence mutation in HEV, said Dr. Yannick Debing at the University of Leuven in Belgium, Dr. Annett Gisa at the Hanover Medical School in Germany, and their associates.

Courtesy: American Gastroenterological Association

The researchers studied 15 solid-organ transplant recipients who received ribavirin monotherapy for chronic HEV infection. Thirteen patients were successfully treated, but two with genotype 3c infections failed therapy. Viral RNA levels in both of these patients initially dropped and then rose, suggesting emerging resistance to ribavirin therapy, the investigators said (Gastroenterology 2014 Aug. 30 [doi: 10.1053/j.gastro.2014.08.040]).

When the researchers sequenced HEV genomes from the nonresponders, they found a G1634R mutation in HEV viral polymerase that conferred greater replication capacity compared with wild-type HEV, even after in vitro ribavirin treatment, they reported. “It may be interesting to assess the possible use of position 1634 as a prognostic marker, and accordingly to adjust the dose and duration of ribavirin therapy based on the presence of the G1634R variant,” Dr. Debing and his associates said.

The mutation consisted of a G-to-A nucleotide substitution in the C-terminal region of viral polymerase, the investigators said. By comparing HEV sequences in GenBank (an open-access collection of publicly available nucleotide sequences and their proteins), they found that G1634 was the most common amino acid sequence in genotype 3 HEV, while the K1634 sequence predominated in genotypes 1 and 4.

A subgenomic replicon of genotype 3 HEV with the 1634R mutation showed no increase in ribavirin sensitivity, compared with the wild-type replicon (50% effective concentration [EC50] values, 5.1 ± 4.1 mcM and 5.1 ± 3.7 mcM, respectively), the investigators said. But when they tested the 1634R variant in human hepatoma cells, they observed a 3.4-fold increase in luminescence signaling, compared with cells transfected with capped replicon RNA from wild-type HEV (P = .04). Greater luminescence indicated that the 1634R mutation increased viral replication, they said.

In addition, an HEV replicon with the K1634 mutation showed 2.7 times more luminescence compared with cells transfected with wild-type viral RNA (P = .07), the researchers reported.

The investigators next studied the effects of the 1634 R/K mutations on the full-length HEV genome. They introduced HEV with the two variants into human hepatoma cells, measured the amounts of viral RNA released, and found that both variants replicated at higher levels than did wild-type virus. When they treated these cells with 10- or 25-mcM ribavirin, replication levels dropped for the 1634 R/K variants and for wild-type virus, but remained at least twice as high for the variants, they said.

“The increased replication capacity of the mutant may have contributed to the persistent disease courses despite [ribavirin] treatment, although other patient- and virus-related factors could have contributed as well,” the investigators said.

The research was supported by the Research Foundation–Flanders, KU Leuven University, the Robert Koch Institute, Geconcerteerde Onderzoeksactie, the German Federal Ministry for Education and Research, and EU FP7 project SILVER. The authors reported having no conflicts of interest.

A mutation in the hepatitis E virus might contribute to ribavirin treatment failure in transplant recipients with chronic HEV infection, according to a small study published in the November issue of Gastroenterology.

The study is the first to find in vitro evidence for a virulence mutation in HEV, said Dr. Yannick Debing at the University of Leuven in Belgium, Dr. Annett Gisa at the Hanover Medical School in Germany, and their associates.

Courtesy: American Gastroenterological Association

The researchers studied 15 solid-organ transplant recipients who received ribavirin monotherapy for chronic HEV infection. Thirteen patients were successfully treated, but two with genotype 3c infections failed therapy. Viral RNA levels in both of these patients initially dropped and then rose, suggesting emerging resistance to ribavirin therapy, the investigators said (Gastroenterology 2014 Aug. 30 [doi: 10.1053/j.gastro.2014.08.040]).

When the researchers sequenced HEV genomes from the nonresponders, they found a G1634R mutation in HEV viral polymerase that conferred greater replication capacity compared with wild-type HEV, even after in vitro ribavirin treatment, they reported. “It may be interesting to assess the possible use of position 1634 as a prognostic marker, and accordingly to adjust the dose and duration of ribavirin therapy based on the presence of the G1634R variant,” Dr. Debing and his associates said.

The mutation consisted of a G-to-A nucleotide substitution in the C-terminal region of viral polymerase, the investigators said. By comparing HEV sequences in GenBank (an open-access collection of publicly available nucleotide sequences and their proteins), they found that G1634 was the most common amino acid sequence in genotype 3 HEV, while the K1634 sequence predominated in genotypes 1 and 4.

A subgenomic replicon of genotype 3 HEV with the 1634R mutation showed no increase in ribavirin sensitivity, compared with the wild-type replicon (50% effective concentration [EC50] values, 5.1 ± 4.1 mcM and 5.1 ± 3.7 mcM, respectively), the investigators said. But when they tested the 1634R variant in human hepatoma cells, they observed a 3.4-fold increase in luminescence signaling, compared with cells transfected with capped replicon RNA from wild-type HEV (P = .04). Greater luminescence indicated that the 1634R mutation increased viral replication, they said.

In addition, an HEV replicon with the K1634 mutation showed 2.7 times more luminescence compared with cells transfected with wild-type viral RNA (P = .07), the researchers reported.

The investigators next studied the effects of the 1634 R/K mutations on the full-length HEV genome. They introduced HEV with the two variants into human hepatoma cells, measured the amounts of viral RNA released, and found that both variants replicated at higher levels than did wild-type virus. When they treated these cells with 10- or 25-mcM ribavirin, replication levels dropped for the 1634 R/K variants and for wild-type virus, but remained at least twice as high for the variants, they said.

“The increased replication capacity of the mutant may have contributed to the persistent disease courses despite [ribavirin] treatment, although other patient- and virus-related factors could have contributed as well,” the investigators said.

The research was supported by the Research Foundation–Flanders, KU Leuven University, the Robert Koch Institute, Geconcerteerde Onderzoeksactie, the German Federal Ministry for Education and Research, and EU FP7 project SILVER. The authors reported having no conflicts of interest.

A mutation in the hepatitis E virus might contribute to ribavirin treatment failure in transplant recipients with chronic HEV infection, according to a small study published in the November issue of Gastroenterology.

The study is the first to find in vitro evidence for a virulence mutation in HEV, said Dr. Yannick Debing at the University of Leuven in Belgium, Dr. Annett Gisa at the Hanover Medical School in Germany, and their associates.

Courtesy: American Gastroenterological Association

The researchers studied 15 solid-organ transplant recipients who received ribavirin monotherapy for chronic HEV infection. Thirteen patients were successfully treated, but two with genotype 3c infections failed therapy. Viral RNA levels in both of these patients initially dropped and then rose, suggesting emerging resistance to ribavirin therapy, the investigators said (Gastroenterology 2014 Aug. 30 [doi: 10.1053/j.gastro.2014.08.040]).

When the researchers sequenced HEV genomes from the nonresponders, they found a G1634R mutation in HEV viral polymerase that conferred greater replication capacity compared with wild-type HEV, even after in vitro ribavirin treatment, they reported. “It may be interesting to assess the possible use of position 1634 as a prognostic marker, and accordingly to adjust the dose and duration of ribavirin therapy based on the presence of the G1634R variant,” Dr. Debing and his associates said.

The mutation consisted of a G-to-A nucleotide substitution in the C-terminal region of viral polymerase, the investigators said. By comparing HEV sequences in GenBank (an open-access collection of publicly available nucleotide sequences and their proteins), they found that G1634 was the most common amino acid sequence in genotype 3 HEV, while the K1634 sequence predominated in genotypes 1 and 4.

A subgenomic replicon of genotype 3 HEV with the 1634R mutation showed no increase in ribavirin sensitivity, compared with the wild-type replicon (50% effective concentration [EC50] values, 5.1 ± 4.1 mcM and 5.1 ± 3.7 mcM, respectively), the investigators said. But when they tested the 1634R variant in human hepatoma cells, they observed a 3.4-fold increase in luminescence signaling, compared with cells transfected with capped replicon RNA from wild-type HEV (P = .04). Greater luminescence indicated that the 1634R mutation increased viral replication, they said.

In addition, an HEV replicon with the K1634 mutation showed 2.7 times more luminescence compared with cells transfected with wild-type viral RNA (P = .07), the researchers reported.

The investigators next studied the effects of the 1634 R/K mutations on the full-length HEV genome. They introduced HEV with the two variants into human hepatoma cells, measured the amounts of viral RNA released, and found that both variants replicated at higher levels than did wild-type virus. When they treated these cells with 10- or 25-mcM ribavirin, replication levels dropped for the 1634 R/K variants and for wild-type virus, but remained at least twice as high for the variants, they said.

“The increased replication capacity of the mutant may have contributed to the persistent disease courses despite [ribavirin] treatment, although other patient- and virus-related factors could have contributed as well,” the investigators said.

The research was supported by the Research Foundation–Flanders, KU Leuven University, the Robert Koch Institute, Geconcerteerde Onderzoeksactie, the German Federal Ministry for Education and Research, and EU FP7 project SILVER. The authors reported having no conflicts of interest.

A risk stratification model that determined whether patients with Crohn’s disease needed computed tomography cut scans of these patients in emergency departments by 43%, with a miss rate of only 0.8%, researchers reported online in Clinical Gastroenterology and Hepatology.

Computed tomography scans yield nonsignificant findings for almost one-third of patients with Crohn’s disease (CD) who present to emergency departments, said Dr. Shail Govani of the University of Michigan in Ann Arbor and his associates. By using their model to identify patients with serious gastrointestinal complications as opposed to straightforward intestinal inflammation, emergency departments could prevent more than 250 cancer cases and save more than $80 million per decade in the United States, the investigators added.

Source: American Gastroenterological Association

Patients with CD may be exposed to increasing cumulative radiation levels, and 30% of this exposure occurs in emergency departments, with 75% due to CT scans, the researchers said (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.036]).

For the study, the investigators retrospectively reviewed electronic medical records from the University of Michigan from 2000 through 2011, identifying 613 adults with CD who made 1,095 visits that included CT scans within 24 hours of presentation. The researchers then modeled associations between laboratory values and perforation, abscess, or other serious complications as opposed to intestinal inflammation.

Patients averaged 1.8 CT scans during the decade-long study period, and the overall rate of CT scans during that time rose from 63% to 87%, the investigators said. Only 16.8% of scans revealed a complication that would change clinical management, they reported.

Only C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly associated with complications (odds ratio for CRP, 1.10; 95% confidence interval, 1.05-1.15; P less than .001; odds ratio for ESR, 1.02; 95% CI, 1.01-1.03; P less than .001), the researchers said. Adding ESR to 5 x CRP and not scanning patients with a resulting value of 10 or less would avoid CT scans in 18.5% of patients, they reported. But by using the more complex logistic regression model instead of the simpler equation, scans could be avoided for 43.0% of patients, with a miss rate of 0.8%, they said.

Based on the study, patients assessed as likely to have complications should undergo a standard CT scan of the abdomen and pelvis with nonbarium contrast to avoid barium peritonitis, said Dr. Govani and associates. Other patients should forego CT scans, have a consult with a gastroenterologist prior to further imaging, or undergo lower-radiation CT enterography, depending on presenting signs and probability of inflammation, they added.

The researchers said they were unable to construct good models that included obstruction as an outcome. Patients with suspected obstructions should have abdominal x-rays and then CT if an obstruction remained likely, they said.

"These models are limited in that they are retrospective and represent data from one center," the investigators added. "Although our internal validation with 10-fold cross-validation shows that these models have good performance characteristics, further external validation studies are needed to determine whether these models are generalizable to CD patients elsewhere."

The authors are prospectively testing the algorithms and hope to continue to validate and study them in emergency departments, they said.

The Inflammatory Bowel Disease Working Group, the Department of Veterans Affairs, and UCB supported the research. The authors reported having no conflicts of interest.

A risk stratification model that determined whether patients with Crohn’s disease needed computed tomography cut scans of these patients in emergency departments by 43%, with a miss rate of only 0.8%, researchers reported online in Clinical Gastroenterology and Hepatology.

Computed tomography scans yield nonsignificant findings for almost one-third of patients with Crohn’s disease (CD) who present to emergency departments, said Dr. Shail Govani of the University of Michigan in Ann Arbor and his associates. By using their model to identify patients with serious gastrointestinal complications as opposed to straightforward intestinal inflammation, emergency departments could prevent more than 250 cancer cases and save more than $80 million per decade in the United States, the investigators added.

Source: American Gastroenterological Association

Patients with CD may be exposed to increasing cumulative radiation levels, and 30% of this exposure occurs in emergency departments, with 75% due to CT scans, the researchers said (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.036]).

For the study, the investigators retrospectively reviewed electronic medical records from the University of Michigan from 2000 through 2011, identifying 613 adults with CD who made 1,095 visits that included CT scans within 24 hours of presentation. The researchers then modeled associations between laboratory values and perforation, abscess, or other serious complications as opposed to intestinal inflammation.

Patients averaged 1.8 CT scans during the decade-long study period, and the overall rate of CT scans during that time rose from 63% to 87%, the investigators said. Only 16.8% of scans revealed a complication that would change clinical management, they reported.

Only C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly associated with complications (odds ratio for CRP, 1.10; 95% confidence interval, 1.05-1.15; P less than .001; odds ratio for ESR, 1.02; 95% CI, 1.01-1.03; P less than .001), the researchers said. Adding ESR to 5 x CRP and not scanning patients with a resulting value of 10 or less would avoid CT scans in 18.5% of patients, they reported. But by using the more complex logistic regression model instead of the simpler equation, scans could be avoided for 43.0% of patients, with a miss rate of 0.8%, they said.

Based on the study, patients assessed as likely to have complications should undergo a standard CT scan of the abdomen and pelvis with nonbarium contrast to avoid barium peritonitis, said Dr. Govani and associates. Other patients should forego CT scans, have a consult with a gastroenterologist prior to further imaging, or undergo lower-radiation CT enterography, depending on presenting signs and probability of inflammation, they added.

The researchers said they were unable to construct good models that included obstruction as an outcome. Patients with suspected obstructions should have abdominal x-rays and then CT if an obstruction remained likely, they said.

"These models are limited in that they are retrospective and represent data from one center," the investigators added. "Although our internal validation with 10-fold cross-validation shows that these models have good performance characteristics, further external validation studies are needed to determine whether these models are generalizable to CD patients elsewhere."

The authors are prospectively testing the algorithms and hope to continue to validate and study them in emergency departments, they said.

The Inflammatory Bowel Disease Working Group, the Department of Veterans Affairs, and UCB supported the research. The authors reported having no conflicts of interest.

A risk stratification model that determined whether patients with Crohn’s disease needed computed tomography cut scans of these patients in emergency departments by 43%, with a miss rate of only 0.8%, researchers reported online in Clinical Gastroenterology and Hepatology.

Computed tomography scans yield nonsignificant findings for almost one-third of patients with Crohn’s disease (CD) who present to emergency departments, said Dr. Shail Govani of the University of Michigan in Ann Arbor and his associates. By using their model to identify patients with serious gastrointestinal complications as opposed to straightforward intestinal inflammation, emergency departments could prevent more than 250 cancer cases and save more than $80 million per decade in the United States, the investigators added.

Source: American Gastroenterological Association

Patients with CD may be exposed to increasing cumulative radiation levels, and 30% of this exposure occurs in emergency departments, with 75% due to CT scans, the researchers said (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.036]).

For the study, the investigators retrospectively reviewed electronic medical records from the University of Michigan from 2000 through 2011, identifying 613 adults with CD who made 1,095 visits that included CT scans within 24 hours of presentation. The researchers then modeled associations between laboratory values and perforation, abscess, or other serious complications as opposed to intestinal inflammation.

Patients averaged 1.8 CT scans during the decade-long study period, and the overall rate of CT scans during that time rose from 63% to 87%, the investigators said. Only 16.8% of scans revealed a complication that would change clinical management, they reported.

Only C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly associated with complications (odds ratio for CRP, 1.10; 95% confidence interval, 1.05-1.15; P less than .001; odds ratio for ESR, 1.02; 95% CI, 1.01-1.03; P less than .001), the researchers said. Adding ESR to 5 x CRP and not scanning patients with a resulting value of 10 or less would avoid CT scans in 18.5% of patients, they reported. But by using the more complex logistic regression model instead of the simpler equation, scans could be avoided for 43.0% of patients, with a miss rate of 0.8%, they said.

Based on the study, patients assessed as likely to have complications should undergo a standard CT scan of the abdomen and pelvis with nonbarium contrast to avoid barium peritonitis, said Dr. Govani and associates. Other patients should forego CT scans, have a consult with a gastroenterologist prior to further imaging, or undergo lower-radiation CT enterography, depending on presenting signs and probability of inflammation, they added.

The researchers said they were unable to construct good models that included obstruction as an outcome. Patients with suspected obstructions should have abdominal x-rays and then CT if an obstruction remained likely, they said.

"These models are limited in that they are retrospective and represent data from one center," the investigators added. "Although our internal validation with 10-fold cross-validation shows that these models have good performance characteristics, further external validation studies are needed to determine whether these models are generalizable to CD patients elsewhere."

The authors are prospectively testing the algorithms and hope to continue to validate and study them in emergency departments, they said.

The Inflammatory Bowel Disease Working Group, the Department of Veterans Affairs, and UCB supported the research. The authors reported having no conflicts of interest.

Cytology and a microRNA-based test identified pancreatic cancer 91% of the time in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration – a substantial improvement, compared with cytology alone, researchers reported in the October issue of Clinical Gastroenterology and Hepatology.

The microRNA-based test could help reduce repeated fine-needle aspirations (FNAs) due to indeterminate cytologies, said Dr. Randall Brand of the University of Pittsburgh Medical Center and his associates. Correctly assessing pancreatic cancer before surgery also could help patients start neoadjuvant therapy sooner if appropriate, they noted.

© goa_novi / ThinkStockPhotos.com

Several microRNAs are expressed abnormally in patients with pancreatic ductal adenocarcinoma. The new test contains five of these sequences and is the first of its type for pancreatic cancer, the researchers said. To evaluate the assay, they assessed and compared relative quantitative polymerase chain reaction and cytology results from 95 formalin-fixed paraffin-embedded specimens and 228 endoscopic ultrasound-guided FNAs. Specimens were collected during routine visits by patients with solid pancreatic masses, the investigators said (Clin. Gastroenterol. Hepatol. 2014 October [doi:10.1016/j.cgh.2014.02.038]).

The test used together with cytology correctly identified pancreatic cancer in 91% of positive specimens (95% confidence interval, 85.6%-94.5%), while cytology alone had a sensitivity of 79% (95% CI, 72.2%-84.5%), the researchers reported. Cytology and the microRNA test each had positive predictive values greater than 99% (95% CI, 96%-100%), they added.

When used alone, the microRNA test had a diagnostic sensitivity of more than 82% and a specificity of 96% – better than cytology on the same specimens, the investigators said. And the test correctly found pancreatic cancer in 22 of 39 specimens previously assessed as benign, indeterminate, or nondiagnostic by cytology, they said.

The researchers separately assessed 46 specimens collected percutaneously instead of by endoscopic ultrasound-guided FNA and found much lower (58%) diagnostic sensitivity and a higher rate of technical failures, although specificity and predictive value still approached 90%, said the investigators. The percutaneous specimens all were collected from two study sites outside the United States, so further studies would need to validate whether a percutaneous approach could replace endoscopic ultrasound-guided FNA, they said.

Cytology and microRNA testing also had to be performed on different FNA specimens, a limitation that "could have contributed to some of the observed discrepancies between cytology and molecular results," the investigators said.

Pancreatic cancer remains notoriously difficult to treat, with overall 5-year survival rates of only about 6%. MicroRNA sequences are stable and can reliably be recovered from both formalin-fixed and FNA specimens, making them a "particularly promising" class of biomarkers for pancreatic and other cancers, the researchers said. Based on the study results, future studies should explore the test’s prognostic potential, such as for distinguishing patients with resectable tumors that are likely to progress early or to guide choice of therapies, they said.

The study was supported by Asuragen and by a grant from the German Federal Ministry of Education and Research. Dr. Brand and another author reported that they are on the clinical advisory board of Asuragen, and six of 27 coauthors reported being employees of the company. The rest reported no conflicts of interest.

Cytology and a microRNA-based test identified pancreatic cancer 91% of the time in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration – a substantial improvement, compared with cytology alone, researchers reported in the October issue of Clinical Gastroenterology and Hepatology.

The microRNA-based test could help reduce repeated fine-needle aspirations (FNAs) due to indeterminate cytologies, said Dr. Randall Brand of the University of Pittsburgh Medical Center and his associates. Correctly assessing pancreatic cancer before surgery also could help patients start neoadjuvant therapy sooner if appropriate, they noted.

© goa_novi / ThinkStockPhotos.com

Several microRNAs are expressed abnormally in patients with pancreatic ductal adenocarcinoma. The new test contains five of these sequences and is the first of its type for pancreatic cancer, the researchers said. To evaluate the assay, they assessed and compared relative quantitative polymerase chain reaction and cytology results from 95 formalin-fixed paraffin-embedded specimens and 228 endoscopic ultrasound-guided FNAs. Specimens were collected during routine visits by patients with solid pancreatic masses, the investigators said (Clin. Gastroenterol. Hepatol. 2014 October [doi:10.1016/j.cgh.2014.02.038]).

The test used together with cytology correctly identified pancreatic cancer in 91% of positive specimens (95% confidence interval, 85.6%-94.5%), while cytology alone had a sensitivity of 79% (95% CI, 72.2%-84.5%), the researchers reported. Cytology and the microRNA test each had positive predictive values greater than 99% (95% CI, 96%-100%), they added.

When used alone, the microRNA test had a diagnostic sensitivity of more than 82% and a specificity of 96% – better than cytology on the same specimens, the investigators said. And the test correctly found pancreatic cancer in 22 of 39 specimens previously assessed as benign, indeterminate, or nondiagnostic by cytology, they said.

The researchers separately assessed 46 specimens collected percutaneously instead of by endoscopic ultrasound-guided FNA and found much lower (58%) diagnostic sensitivity and a higher rate of technical failures, although specificity and predictive value still approached 90%, said the investigators. The percutaneous specimens all were collected from two study sites outside the United States, so further studies would need to validate whether a percutaneous approach could replace endoscopic ultrasound-guided FNA, they said.

Cytology and microRNA testing also had to be performed on different FNA specimens, a limitation that "could have contributed to some of the observed discrepancies between cytology and molecular results," the investigators said.

Pancreatic cancer remains notoriously difficult to treat, with overall 5-year survival rates of only about 6%. MicroRNA sequences are stable and can reliably be recovered from both formalin-fixed and FNA specimens, making them a "particularly promising" class of biomarkers for pancreatic and other cancers, the researchers said. Based on the study results, future studies should explore the test’s prognostic potential, such as for distinguishing patients with resectable tumors that are likely to progress early or to guide choice of therapies, they said.

The study was supported by Asuragen and by a grant from the German Federal Ministry of Education and Research. Dr. Brand and another author reported that they are on the clinical advisory board of Asuragen, and six of 27 coauthors reported being employees of the company. The rest reported no conflicts of interest.

Cytology and a microRNA-based test identified pancreatic cancer 91% of the time in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration – a substantial improvement, compared with cytology alone, researchers reported in the October issue of Clinical Gastroenterology and Hepatology.

The microRNA-based test could help reduce repeated fine-needle aspirations (FNAs) due to indeterminate cytologies, said Dr. Randall Brand of the University of Pittsburgh Medical Center and his associates. Correctly assessing pancreatic cancer before surgery also could help patients start neoadjuvant therapy sooner if appropriate, they noted.

© goa_novi / ThinkStockPhotos.com

Several microRNAs are expressed abnormally in patients with pancreatic ductal adenocarcinoma. The new test contains five of these sequences and is the first of its type for pancreatic cancer, the researchers said. To evaluate the assay, they assessed and compared relative quantitative polymerase chain reaction and cytology results from 95 formalin-fixed paraffin-embedded specimens and 228 endoscopic ultrasound-guided FNAs. Specimens were collected during routine visits by patients with solid pancreatic masses, the investigators said (Clin. Gastroenterol. Hepatol. 2014 October [doi:10.1016/j.cgh.2014.02.038]).

The test used together with cytology correctly identified pancreatic cancer in 91% of positive specimens (95% confidence interval, 85.6%-94.5%), while cytology alone had a sensitivity of 79% (95% CI, 72.2%-84.5%), the researchers reported. Cytology and the microRNA test each had positive predictive values greater than 99% (95% CI, 96%-100%), they added.

When used alone, the microRNA test had a diagnostic sensitivity of more than 82% and a specificity of 96% – better than cytology on the same specimens, the investigators said. And the test correctly found pancreatic cancer in 22 of 39 specimens previously assessed as benign, indeterminate, or nondiagnostic by cytology, they said.

The researchers separately assessed 46 specimens collected percutaneously instead of by endoscopic ultrasound-guided FNA and found much lower (58%) diagnostic sensitivity and a higher rate of technical failures, although specificity and predictive value still approached 90%, said the investigators. The percutaneous specimens all were collected from two study sites outside the United States, so further studies would need to validate whether a percutaneous approach could replace endoscopic ultrasound-guided FNA, they said.

Cytology and microRNA testing also had to be performed on different FNA specimens, a limitation that "could have contributed to some of the observed discrepancies between cytology and molecular results," the investigators said.

Pancreatic cancer remains notoriously difficult to treat, with overall 5-year survival rates of only about 6%. MicroRNA sequences are stable and can reliably be recovered from both formalin-fixed and FNA specimens, making them a "particularly promising" class of biomarkers for pancreatic and other cancers, the researchers said. Based on the study results, future studies should explore the test’s prognostic potential, such as for distinguishing patients with resectable tumors that are likely to progress early or to guide choice of therapies, they said.

The study was supported by Asuragen and by a grant from the German Federal Ministry of Education and Research. Dr. Brand and another author reported that they are on the clinical advisory board of Asuragen, and six of 27 coauthors reported being employees of the company. The rest reported no conflicts of interest.

A gluten-free diet benefited asymptomatic patients with serologic markers for celiac disease in a prospective randomized study.

The findings support active screening for celiac disease in patients at risk for the disease, even if symptoms aren’t present, according to Dr. Kalle Kurppa of the University of Tampere (Finland) and Tampere University Hospital.

The report is in the September issue of Gastroenterology (doi.org/10.1053/j.gastro.2014.05.003).

After 1 year, 20 adults with endomysial antibodies (EmA) who were randomized to a gluten-free diet (GFD) experienced significant increases in mean mucosal villous height:crypt depth values, significantly decreased levels of celiac-associated antibodies, and greater improvement in gastrointestinal symptoms, compared with 20 patients randomized to a gluten-containing diet. For example, mean small bowel mucosal villous height:crypt depth increased from 1.0 to about 2.8 in the GFD group, and from 0.8 to about 0.9 in the gluten-containing diet group, and total Gastrointestinal Symptoms Rating Scale scores improved significantly (–0.4 difference in mean change from baseline, favoring a GFD), as did individual scores for diarrhea, indigestion, and reflux in the GFD group, wrote Dr. Kurppa and colleagues.

The patients in the GFD group also experienced reduced indigestion, reflux, and anxiety, and better health as measured by Psychological, General Health, and Well-Being scores and most Short Form–36 scores, they noted.

Only social function scores on the Short Form–36 improved more in the gluten-containing diet group (–8.3 difference in mean change from baseline, favoring a gluten-containing diet).

The subjects in both groups had a median age of 42 years, and the groups were similar with respect to sex, medical history, and associated conditions.

No differences were seen between the two groups with respect to laboratory test results, bone mineral density, or body composition, and the subjects in the GFD group did not report any negative effects or reactions to the diet. After trial completion, 92% reported adherence to the gluten-free diet, and 85% said they expected to remain on the diet, the investigators noted.

Because celiac disease affects 1%-2% of the population, but is difficult to detect because of clinical heterogeneity, wide-scale screening with noninvasive serologic testing is frequently suggested.

"However, the only current treatment of the condition, a lifelong strict gluten-free diet, is restrictive and difficult to maintain and thus the positive effects of the screening are not straightforward," the investigators noted, adding that results of prior studies exploring the benefits of a gluten-free diet have been inconsistent – particularly for asymptomatic patients.

Another problem is that wide-scale screening often detects asymptomatic seropositive subjects with only mild enteropathy or even normal small-bowel mucosa, and it is unclear whether these individuals actually suffer from a true gluten-induced clinical disease, they said.

"The results of this randomized study showed that screen-detected and even apparently asymptomatic EmA-positive patients benefit from a gluten-free diet as measured by extensive clinical, serologic, and histologic parameters," the investigators said.

The fact that subjects who considered themselves asymptomatic experienced improvement in the current study suggests that "the patients may in fact have accepted mild symptoms as normal and recognized them as abnormal only later when on the diet," they said.

The findings support active screening for celiac disease in patients at risk, but the potential consequences of screening – particularly on social functioning, should be considered on an individual basis, they said, adding that prospective studies are needed "to unravel whether screen-detected seropositive subjects with completely normal small-bowel mucosal histology should be treated."

This study was supported by the Academy of Finland Research Council for Health, the Competitive Research Funding of the Pirkanmaa Hospital District, the Sigrid Juselius Foundation, the Finnish Foundation for Research, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, and the Finnish Celiac Society. The authors reported having no disclosures.

A gluten-free diet benefited asymptomatic patients with serologic markers for celiac disease in a prospective randomized study.

The findings support active screening for celiac disease in patients at risk for the disease, even if symptoms aren’t present, according to Dr. Kalle Kurppa of the University of Tampere (Finland) and Tampere University Hospital.

The report is in the September issue of Gastroenterology (doi.org/10.1053/j.gastro.2014.05.003).

After 1 year, 20 adults with endomysial antibodies (EmA) who were randomized to a gluten-free diet (GFD) experienced significant increases in mean mucosal villous height:crypt depth values, significantly decreased levels of celiac-associated antibodies, and greater improvement in gastrointestinal symptoms, compared with 20 patients randomized to a gluten-containing diet. For example, mean small bowel mucosal villous height:crypt depth increased from 1.0 to about 2.8 in the GFD group, and from 0.8 to about 0.9 in the gluten-containing diet group, and total Gastrointestinal Symptoms Rating Scale scores improved significantly (–0.4 difference in mean change from baseline, favoring a GFD), as did individual scores for diarrhea, indigestion, and reflux in the GFD group, wrote Dr. Kurppa and colleagues.

The patients in the GFD group also experienced reduced indigestion, reflux, and anxiety, and better health as measured by Psychological, General Health, and Well-Being scores and most Short Form–36 scores, they noted.

Only social function scores on the Short Form–36 improved more in the gluten-containing diet group (–8.3 difference in mean change from baseline, favoring a gluten-containing diet).

The subjects in both groups had a median age of 42 years, and the groups were similar with respect to sex, medical history, and associated conditions.

No differences were seen between the two groups with respect to laboratory test results, bone mineral density, or body composition, and the subjects in the GFD group did not report any negative effects or reactions to the diet. After trial completion, 92% reported adherence to the gluten-free diet, and 85% said they expected to remain on the diet, the investigators noted.

Because celiac disease affects 1%-2% of the population, but is difficult to detect because of clinical heterogeneity, wide-scale screening with noninvasive serologic testing is frequently suggested.

"However, the only current treatment of the condition, a lifelong strict gluten-free diet, is restrictive and difficult to maintain and thus the positive effects of the screening are not straightforward," the investigators noted, adding that results of prior studies exploring the benefits of a gluten-free diet have been inconsistent – particularly for asymptomatic patients.

Another problem is that wide-scale screening often detects asymptomatic seropositive subjects with only mild enteropathy or even normal small-bowel mucosa, and it is unclear whether these individuals actually suffer from a true gluten-induced clinical disease, they said.

"The results of this randomized study showed that screen-detected and even apparently asymptomatic EmA-positive patients benefit from a gluten-free diet as measured by extensive clinical, serologic, and histologic parameters," the investigators said.

The fact that subjects who considered themselves asymptomatic experienced improvement in the current study suggests that "the patients may in fact have accepted mild symptoms as normal and recognized them as abnormal only later when on the diet," they said.

The findings support active screening for celiac disease in patients at risk, but the potential consequences of screening – particularly on social functioning, should be considered on an individual basis, they said, adding that prospective studies are needed "to unravel whether screen-detected seropositive subjects with completely normal small-bowel mucosal histology should be treated."

This study was supported by the Academy of Finland Research Council for Health, the Competitive Research Funding of the Pirkanmaa Hospital District, the Sigrid Juselius Foundation, the Finnish Foundation for Research, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, and the Finnish Celiac Society. The authors reported having no disclosures.

A gluten-free diet benefited asymptomatic patients with serologic markers for celiac disease in a prospective randomized study.

The findings support active screening for celiac disease in patients at risk for the disease, even if symptoms aren’t present, according to Dr. Kalle Kurppa of the University of Tampere (Finland) and Tampere University Hospital.

The report is in the September issue of Gastroenterology (doi.org/10.1053/j.gastro.2014.05.003).

After 1 year, 20 adults with endomysial antibodies (EmA) who were randomized to a gluten-free diet (GFD) experienced significant increases in mean mucosal villous height:crypt depth values, significantly decreased levels of celiac-associated antibodies, and greater improvement in gastrointestinal symptoms, compared with 20 patients randomized to a gluten-containing diet. For example, mean small bowel mucosal villous height:crypt depth increased from 1.0 to about 2.8 in the GFD group, and from 0.8 to about 0.9 in the gluten-containing diet group, and total Gastrointestinal Symptoms Rating Scale scores improved significantly (–0.4 difference in mean change from baseline, favoring a GFD), as did individual scores for diarrhea, indigestion, and reflux in the GFD group, wrote Dr. Kurppa and colleagues.

The patients in the GFD group also experienced reduced indigestion, reflux, and anxiety, and better health as measured by Psychological, General Health, and Well-Being scores and most Short Form–36 scores, they noted.

Only social function scores on the Short Form–36 improved more in the gluten-containing diet group (–8.3 difference in mean change from baseline, favoring a gluten-containing diet).

The subjects in both groups had a median age of 42 years, and the groups were similar with respect to sex, medical history, and associated conditions.

No differences were seen between the two groups with respect to laboratory test results, bone mineral density, or body composition, and the subjects in the GFD group did not report any negative effects or reactions to the diet. After trial completion, 92% reported adherence to the gluten-free diet, and 85% said they expected to remain on the diet, the investigators noted.

Because celiac disease affects 1%-2% of the population, but is difficult to detect because of clinical heterogeneity, wide-scale screening with noninvasive serologic testing is frequently suggested.

"However, the only current treatment of the condition, a lifelong strict gluten-free diet, is restrictive and difficult to maintain and thus the positive effects of the screening are not straightforward," the investigators noted, adding that results of prior studies exploring the benefits of a gluten-free diet have been inconsistent – particularly for asymptomatic patients.

Another problem is that wide-scale screening often detects asymptomatic seropositive subjects with only mild enteropathy or even normal small-bowel mucosa, and it is unclear whether these individuals actually suffer from a true gluten-induced clinical disease, they said.

"The results of this randomized study showed that screen-detected and even apparently asymptomatic EmA-positive patients benefit from a gluten-free diet as measured by extensive clinical, serologic, and histologic parameters," the investigators said.

The fact that subjects who considered themselves asymptomatic experienced improvement in the current study suggests that "the patients may in fact have accepted mild symptoms as normal and recognized them as abnormal only later when on the diet," they said.

The findings support active screening for celiac disease in patients at risk, but the potential consequences of screening – particularly on social functioning, should be considered on an individual basis, they said, adding that prospective studies are needed "to unravel whether screen-detected seropositive subjects with completely normal small-bowel mucosal histology should be treated."

This study was supported by the Academy of Finland Research Council for Health, the Competitive Research Funding of the Pirkanmaa Hospital District, the Sigrid Juselius Foundation, the Finnish Foundation for Research, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, and the Finnish Celiac Society. The authors reported having no disclosures.

Vedolizumab was not superior to placebo for inducing remission at 6 weeks in patients with Crohn’s disease who failed to respond to anti–tumor necrosis factor therapy, according to findings from the double-blind, phase III GEMINI 3 trial.

However, therapeutic benefit from the humanized, anti–alpha-4 beta-7 integrin, immunoglobulin G1 monoclonal antibody did become apparent by week 10, Dr. Bruce E. Sands of the Icahn School of Medicine at Mount Sinai, New York, and his colleagues report in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2014.05.008).

Source: American Gastroenterological Association

The investigators randomized 315 patients with moderately to severely active Crohn’s disease who failed anti-TNF therapy to receive 300 mg of vedolizumab (158 patients) or placebo (157 patients) intravenously at weeks 0, 2, and 6. The results showed that 15.2% of the vedolizumab group was in remission at week 6, compared with 12.1% of the placebo group (relative risk, 1.2). At week 10, 26.6% of patients in the vedolizumab group, compared with 12.1% of those in the placebo group, were in remission (RR, 2.2), the investigators reported.

More patients in the vedolizumab group did, however, achieve at least a 100-point decrease in the Crohn’s Disease Activity Index (CDAI) score at both 6 weeks (39.2% vs. 22.3% of placebo patients; RR, 1.8) and 10 weeks (46.8% vs. 24.8%; RR, 1.4), they said.

The incidence and type of adverse events were similar in both groups.

GEMINI 3 was conducted between November 2010 and April 2012 at 107 sites in North America, Europe, Asia, Africa, and Australia. Participants were aged 18-80 years with moderately to severely active Crohn’s disease (defined in part by a CDAI score of 220-400 points), with known involvement of the ileum and/or colon at 3 or more months before enrollment.

Remission was defined by a CDAI score of 150 points or less.

Treatment with TNF antagonists has improved the care of patients with Crohn’s disease that is refractory to other treatments, but in controlled trials anti-TNF therapy failed in about two-thirds of patients. Treatment is also associated with an increased risk of serious infections in some patients. Natalizumab, another treatment used in Crohn’s disease, has been limited by its association with an increased risk of progressive multifocal leukoencephalopathy.

"Because of these limitations with TNF antagonists and natalizumab, therapies for patients with TNF antagonist failure are needed, and those that selectively inhibit lymphocyte trafficking to the gut may yield important safety benefits," the investigators said.

Vedolizumab was shown in the pivotal GEMINI 2 study to be safe and effective for induction and maintenance in patients with moderately to severely active Crohn’s disease who failed one or more prior therapies; GEMINI 3 specifically focuses on patients with prior TNF antagonist failure.

"The results of this short-term study support the safety of vedolizumab in patients with Crohn’s disease and are consistent with the drug’s postulated gut-selective mechanism of action," the investigators said.

Furthermore, several prespecified outcomes suggest that in addition to leading to clinical remission in the TNF antagonist–naive patients with Crohn’s disease, vedolizumab may lead to clinical remission at 10 weeks in those who failed TNF antagonist therapy.

"These clinically relevant response kinetics have potential implications for bridging induction therapy to vedolizumab maintenance therapy, which has established efficacy, in patients with this lifelong condition," they concluded.

This study was funded by Millennium Pharmaceuticals (doing business as Takeda Pharmaceuticals). Dr. Sands reported receiving consulting and advisory board fees, as well as clinical research/institutional grant support from AbbVie, Janssen, and Takeda. Detailed disclosures for all authors are available with the full text of the article.

Vedolizumab was not superior to placebo for inducing remission at 6 weeks in patients with Crohn’s disease who failed to respond to anti–tumor necrosis factor therapy, according to findings from the double-blind, phase III GEMINI 3 trial.

However, therapeutic benefit from the humanized, anti–alpha-4 beta-7 integrin, immunoglobulin G1 monoclonal antibody did become apparent by week 10, Dr. Bruce E. Sands of the Icahn School of Medicine at Mount Sinai, New York, and his colleagues report in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2014.05.008).

Source: American Gastroenterological Association

The investigators randomized 315 patients with moderately to severely active Crohn’s disease who failed anti-TNF therapy to receive 300 mg of vedolizumab (158 patients) or placebo (157 patients) intravenously at weeks 0, 2, and 6. The results showed that 15.2% of the vedolizumab group was in remission at week 6, compared with 12.1% of the placebo group (relative risk, 1.2). At week 10, 26.6% of patients in the vedolizumab group, compared with 12.1% of those in the placebo group, were in remission (RR, 2.2), the investigators reported.

More patients in the vedolizumab group did, however, achieve at least a 100-point decrease in the Crohn’s Disease Activity Index (CDAI) score at both 6 weeks (39.2% vs. 22.3% of placebo patients; RR, 1.8) and 10 weeks (46.8% vs. 24.8%; RR, 1.4), they said.

The incidence and type of adverse events were similar in both groups.

GEMINI 3 was conducted between November 2010 and April 2012 at 107 sites in North America, Europe, Asia, Africa, and Australia. Participants were aged 18-80 years with moderately to severely active Crohn’s disease (defined in part by a CDAI score of 220-400 points), with known involvement of the ileum and/or colon at 3 or more months before enrollment.

Remission was defined by a CDAI score of 150 points or less.

Treatment with TNF antagonists has improved the care of patients with Crohn’s disease that is refractory to other treatments, but in controlled trials anti-TNF therapy failed in about two-thirds of patients. Treatment is also associated with an increased risk of serious infections in some patients. Natalizumab, another treatment used in Crohn’s disease, has been limited by its association with an increased risk of progressive multifocal leukoencephalopathy.

"Because of these limitations with TNF antagonists and natalizumab, therapies for patients with TNF antagonist failure are needed, and those that selectively inhibit lymphocyte trafficking to the gut may yield important safety benefits," the investigators said.

Vedolizumab was shown in the pivotal GEMINI 2 study to be safe and effective for induction and maintenance in patients with moderately to severely active Crohn’s disease who failed one or more prior therapies; GEMINI 3 specifically focuses on patients with prior TNF antagonist failure.

"The results of this short-term study support the safety of vedolizumab in patients with Crohn’s disease and are consistent with the drug’s postulated gut-selective mechanism of action," the investigators said.

Furthermore, several prespecified outcomes suggest that in addition to leading to clinical remission in the TNF antagonist–naive patients with Crohn’s disease, vedolizumab may lead to clinical remission at 10 weeks in those who failed TNF antagonist therapy.

"These clinically relevant response kinetics have potential implications for bridging induction therapy to vedolizumab maintenance therapy, which has established efficacy, in patients with this lifelong condition," they concluded.

This study was funded by Millennium Pharmaceuticals (doing business as Takeda Pharmaceuticals). Dr. Sands reported receiving consulting and advisory board fees, as well as clinical research/institutional grant support from AbbVie, Janssen, and Takeda. Detailed disclosures for all authors are available with the full text of the article.

Vedolizumab was not superior to placebo for inducing remission at 6 weeks in patients with Crohn’s disease who failed to respond to anti–tumor necrosis factor therapy, according to findings from the double-blind, phase III GEMINI 3 trial.

However, therapeutic benefit from the humanized, anti–alpha-4 beta-7 integrin, immunoglobulin G1 monoclonal antibody did become apparent by week 10, Dr. Bruce E. Sands of the Icahn School of Medicine at Mount Sinai, New York, and his colleagues report in the September issue of Gastroenterology (doi: 10.1053/j.gastro.2014.05.008).

Source: American Gastroenterological Association

The investigators randomized 315 patients with moderately to severely active Crohn’s disease who failed anti-TNF therapy to receive 300 mg of vedolizumab (158 patients) or placebo (157 patients) intravenously at weeks 0, 2, and 6. The results showed that 15.2% of the vedolizumab group was in remission at week 6, compared with 12.1% of the placebo group (relative risk, 1.2). At week 10, 26.6% of patients in the vedolizumab group, compared with 12.1% of those in the placebo group, were in remission (RR, 2.2), the investigators reported.

More patients in the vedolizumab group did, however, achieve at least a 100-point decrease in the Crohn’s Disease Activity Index (CDAI) score at both 6 weeks (39.2% vs. 22.3% of placebo patients; RR, 1.8) and 10 weeks (46.8% vs. 24.8%; RR, 1.4), they said.

The incidence and type of adverse events were similar in both groups.

GEMINI 3 was conducted between November 2010 and April 2012 at 107 sites in North America, Europe, Asia, Africa, and Australia. Participants were aged 18-80 years with moderately to severely active Crohn’s disease (defined in part by a CDAI score of 220-400 points), with known involvement of the ileum and/or colon at 3 or more months before enrollment.

Remission was defined by a CDAI score of 150 points or less.

Treatment with TNF antagonists has improved the care of patients with Crohn’s disease that is refractory to other treatments, but in controlled trials anti-TNF therapy failed in about two-thirds of patients. Treatment is also associated with an increased risk of serious infections in some patients. Natalizumab, another treatment used in Crohn’s disease, has been limited by its association with an increased risk of progressive multifocal leukoencephalopathy.

"Because of these limitations with TNF antagonists and natalizumab, therapies for patients with TNF antagonist failure are needed, and those that selectively inhibit lymphocyte trafficking to the gut may yield important safety benefits," the investigators said.

Vedolizumab was shown in the pivotal GEMINI 2 study to be safe and effective for induction and maintenance in patients with moderately to severely active Crohn’s disease who failed one or more prior therapies; GEMINI 3 specifically focuses on patients with prior TNF antagonist failure.

"The results of this short-term study support the safety of vedolizumab in patients with Crohn’s disease and are consistent with the drug’s postulated gut-selective mechanism of action," the investigators said.

Furthermore, several prespecified outcomes suggest that in addition to leading to clinical remission in the TNF antagonist–naive patients with Crohn’s disease, vedolizumab may lead to clinical remission at 10 weeks in those who failed TNF antagonist therapy.

"These clinically relevant response kinetics have potential implications for bridging induction therapy to vedolizumab maintenance therapy, which has established efficacy, in patients with this lifelong condition," they concluded.

This study was funded by Millennium Pharmaceuticals (doing business as Takeda Pharmaceuticals). Dr. Sands reported receiving consulting and advisory board fees, as well as clinical research/institutional grant support from AbbVie, Janssen, and Takeda. Detailed disclosures for all authors are available with the full text of the article.

The risk of lymphoma is no greater in children with inflammatory bowel disease who are treated with anti–tumor necrosis factor therapy than in adults treated with anti-TNF therapies or in children treated with other therapies for IBD, according to findings from a systematic review.

The review, which included 65 studies involving a total of 5,528 patients with 9,516 patient-years of follow-up, also showed that the rate of serious infection was lower among children with IBD who were treated with anti-TNF agents than among those treated with steroids or among adults treated with anti-TNF agents, Dr. Parambir S. Dulai of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his colleagues reported in the September issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2014.01.021).

Source: American Gastroenterological Association

Two patients developed lymphoma, for a rate of 2.1/10,000 patient-years of follow-up (PYF), which did not differ significantly from the expected rate among children (5.8/100,000 PYF), the rate among pediatric patients receiving thiopurine monotherapy (4.5/10,000), or the rate among adults treated with anti-TNF agents (6.1/10,000), the investigators found.

The rate of serious infections was 352/10,000 PYF in pediatric patients treated with anti-TNF agents as part of prospective studies included in the review, which was similar to the expected rate in those treated with immunomodulator therapy (333/10,000 PYF), and significantly lower than the expected rate in those treated with glucocorticoids (730/10,000 PYF) and adults treated with anti-TNF agents (654/10,000 PYF).

Of seven deaths that occurred among the patients, five were considered related to treatment (four cases of sepsis, one case of arrhythmia), for a rate of 5.3/10,000 PYF.

Although anti-TNF therapy is an effective treatment option for pediatric IBD, many physicians are hesitant about prescribing anti-TNFs to children because of concerns about infection and lymphoma risk based on the adult literature and case reports of hepatosplenic T-cell lymphoma. However, the findings of this pooled analysis suggest that such concerns may be unfounded.

Older age, sex, and duration of IBD have been linked with increased risk of lymphoproliferative disorders and could help explain the observed differences between adults and pediatric IBD patients with respect to lymphoma rates after anti-TNF exposure, the investigators said.

"Overall, the risk of serious infection, lymphoma, and death with anti-TNF therapy in pediatric IBD is very low," they wrote.

However, they noted that the study is limited by a number of factors, including short duration of per-person follow-up, which means that while the data are promising, they are "not definitive in answering the question of whether anti-TNF therapy is associated with an increased risk of lymphoma, particularly with long-term use," the investigators said.

Long-term follow-up studies are needed in children to assess whether lymphoma risk is exposure dependent – as suggested by the existing literature – rather than a cumulative risk that is dependent on duration of therapy, they added.

Dr. Dulai reported having no disclosures. Coauthor Dr. Corey Siegel reported serving as an advisory board member or consultant for, and/or receiving grant support from Abbvie, Janssen, UCB, and the Agency for Healthcare Research and Quality. Dr. Marla Dubinsky serves as a consultant for Abbvie, Janssen, UCB, and Takeda.

The risk of lymphoma is no greater in children with inflammatory bowel disease who are treated with anti–tumor necrosis factor therapy than in adults treated with anti-TNF therapies or in children treated with other therapies for IBD, according to findings from a systematic review.

The review, which included 65 studies involving a total of 5,528 patients with 9,516 patient-years of follow-up, also showed that the rate of serious infection was lower among children with IBD who were treated with anti-TNF agents than among those treated with steroids or among adults treated with anti-TNF agents, Dr. Parambir S. Dulai of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his colleagues reported in the September issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2014.01.021).

Source: American Gastroenterological Association

Two patients developed lymphoma, for a rate of 2.1/10,000 patient-years of follow-up (PYF), which did not differ significantly from the expected rate among children (5.8/100,000 PYF), the rate among pediatric patients receiving thiopurine monotherapy (4.5/10,000), or the rate among adults treated with anti-TNF agents (6.1/10,000), the investigators found.

The rate of serious infections was 352/10,000 PYF in pediatric patients treated with anti-TNF agents as part of prospective studies included in the review, which was similar to the expected rate in those treated with immunomodulator therapy (333/10,000 PYF), and significantly lower than the expected rate in those treated with glucocorticoids (730/10,000 PYF) and adults treated with anti-TNF agents (654/10,000 PYF).

Of seven deaths that occurred among the patients, five were considered related to treatment (four cases of sepsis, one case of arrhythmia), for a rate of 5.3/10,000 PYF.

Although anti-TNF therapy is an effective treatment option for pediatric IBD, many physicians are hesitant about prescribing anti-TNFs to children because of concerns about infection and lymphoma risk based on the adult literature and case reports of hepatosplenic T-cell lymphoma. However, the findings of this pooled analysis suggest that such concerns may be unfounded.

Older age, sex, and duration of IBD have been linked with increased risk of lymphoproliferative disorders and could help explain the observed differences between adults and pediatric IBD patients with respect to lymphoma rates after anti-TNF exposure, the investigators said.

"Overall, the risk of serious infection, lymphoma, and death with anti-TNF therapy in pediatric IBD is very low," they wrote.

However, they noted that the study is limited by a number of factors, including short duration of per-person follow-up, which means that while the data are promising, they are "not definitive in answering the question of whether anti-TNF therapy is associated with an increased risk of lymphoma, particularly with long-term use," the investigators said.

Long-term follow-up studies are needed in children to assess whether lymphoma risk is exposure dependent – as suggested by the existing literature – rather than a cumulative risk that is dependent on duration of therapy, they added.

Dr. Dulai reported having no disclosures. Coauthor Dr. Corey Siegel reported serving as an advisory board member or consultant for, and/or receiving grant support from Abbvie, Janssen, UCB, and the Agency for Healthcare Research and Quality. Dr. Marla Dubinsky serves as a consultant for Abbvie, Janssen, UCB, and Takeda.

The risk of lymphoma is no greater in children with inflammatory bowel disease who are treated with anti–tumor necrosis factor therapy than in adults treated with anti-TNF therapies or in children treated with other therapies for IBD, according to findings from a systematic review.

The review, which included 65 studies involving a total of 5,528 patients with 9,516 patient-years of follow-up, also showed that the rate of serious infection was lower among children with IBD who were treated with anti-TNF agents than among those treated with steroids or among adults treated with anti-TNF agents, Dr. Parambir S. Dulai of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his colleagues reported in the September issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2014.01.021).

Source: American Gastroenterological Association

Two patients developed lymphoma, for a rate of 2.1/10,000 patient-years of follow-up (PYF), which did not differ significantly from the expected rate among children (5.8/100,000 PYF), the rate among pediatric patients receiving thiopurine monotherapy (4.5/10,000), or the rate among adults treated with anti-TNF agents (6.1/10,000), the investigators found.

The rate of serious infections was 352/10,000 PYF in pediatric patients treated with anti-TNF agents as part of prospective studies included in the review, which was similar to the expected rate in those treated with immunomodulator therapy (333/10,000 PYF), and significantly lower than the expected rate in those treated with glucocorticoids (730/10,000 PYF) and adults treated with anti-TNF agents (654/10,000 PYF).

Of seven deaths that occurred among the patients, five were considered related to treatment (four cases of sepsis, one case of arrhythmia), for a rate of 5.3/10,000 PYF.

Although anti-TNF therapy is an effective treatment option for pediatric IBD, many physicians are hesitant about prescribing anti-TNFs to children because of concerns about infection and lymphoma risk based on the adult literature and case reports of hepatosplenic T-cell lymphoma. However, the findings of this pooled analysis suggest that such concerns may be unfounded.

Older age, sex, and duration of IBD have been linked with increased risk of lymphoproliferative disorders and could help explain the observed differences between adults and pediatric IBD patients with respect to lymphoma rates after anti-TNF exposure, the investigators said.

"Overall, the risk of serious infection, lymphoma, and death with anti-TNF therapy in pediatric IBD is very low," they wrote.

However, they noted that the study is limited by a number of factors, including short duration of per-person follow-up, which means that while the data are promising, they are "not definitive in answering the question of whether anti-TNF therapy is associated with an increased risk of lymphoma, particularly with long-term use," the investigators said.

Long-term follow-up studies are needed in children to assess whether lymphoma risk is exposure dependent – as suggested by the existing literature – rather than a cumulative risk that is dependent on duration of therapy, they added.

Dr. Dulai reported having no disclosures. Coauthor Dr. Corey Siegel reported serving as an advisory board member or consultant for, and/or receiving grant support from Abbvie, Janssen, UCB, and the Agency for Healthcare Research and Quality. Dr. Marla Dubinsky serves as a consultant for Abbvie, Janssen, UCB, and Takeda.