From the AGA Journals

Oxidized low-density lipoprotein prevented hepatitis C virus from entering liver cells and predicted interferon response among patients with chronic HCV infection, researchers reported online in the May issue of Cellular and Molecular Gastroenterology and Hepatology (2015 March 14 [doi:10.1016/j.jcmgh.2015.03.002]).

“Even as all-oral regimens begin to reach the market, interferon-based treatment will continue to be used in cost-restrained settings. Thus, there is a need for predictors of who is likely to respond to interferon and who will require a more expensive direct-acting antiviral combination regimen,” said Dr. Philipp Solbach of Medizinische Hochschule Hannover and the German Center for Infection Research and his associates. Combinations of interferon and viral entry inhibitors might benefit patients with chronic HCV infection (CHC), the investigators added.

Hepatitis C virus spreads between hepatocytes with the help of several cell surface receptors, including scavenger receptor class B type 1 (SR-BI). Research has shown that oxidized low-density lipoprotein (oxLDL) noncompetitively inhibits the interaction between SR-B1 and HCV. To further study the role of oxLDL in CHC pathology, the investigators used a commercial enzyme-linked immunosorbent assay test to measure serum levels in 379 patients with genotype 1 CHC from the INDIV-2 study. Patients in that study received a pegylated interferon-ribavirin combination for 24-72 weeks, depending on baseline viral load. Dr. Solbach and his associates also studied the effects of oxLDL on HCV replication in hepatoma cells.

Average serum oxLDL levels were significantly higher among patients who achieved SVR on peg-IFN/RBV than in those who did not (7.1 mU/L [standard deviation, 3.2] vs. 5.9 mU/L [SD, 2.6]; P < .001), the researchers reported. In the multivariate analysis, oxLDL levels independently predicted SVR, but were not associated with increased ALT or ferritin levels, both of which point to liver inflammation. Increased serum oxLDL also was linked to decreased infected cell loss rate, further supporting the idea that oxLDL helps inhibit cell-to-cell spread of HCV in chronically infected patients, they said.

Area under the receiver operative curve (AUROC) values were similar for LDL and oxLDL, indicating that one value was a good clinical indicator of the other, the investigators said. The optimal cutoff points to predict SVR in their model were 8.85 mU/L for oxLDL and 3.6 mmol/L for LDL.

In the in vitro study, oxLDL did not affect the sensitivity of HCV replication to interferon, but strongly inhibited the spread of HCV between adjacent hepatocytes, the investigators reported. “We found that oxLDL but not LDL potently inhibits cell-to-cell spread between neighboring cells,” they noted. “Cell-to-cell spread is thought to be the dominant route of new cell infection within the chronically infected liver.”

Taken together, the findings suggest that HCV needs to interact with SR-BI in order to spread between hepatocytes, that oxLDL can impede that interaction and thereby limit infection of naive cells, and that oxLDL is neither an inflammatory marker nor a modulator of interferon response, Dr. Solback and his associates said. “The slower second-phase decline of viral load during interferon-based therapy is thought to reflect a declining pool of infected hepatocytes, and the slope of second-phase decline and even more the estimated viral kinetic parameter describing the infected cell loss rate is predictive of eventual SVR,” they added. “The presence of an agent reducing the rate at which naive cells get infected might thus be beneficial.”

The Germany Center for Infection Research partially funded the study. Five coauthors reported having served as clinical researchers, consultants, or speakers for MSD/Merck and Roche. The other authors declared no conflicts of interest.

Oxidized low-density lipoprotein prevented hepatitis C virus from entering liver cells and predicted interferon response among patients with chronic HCV infection, researchers reported online in the May issue of Cellular and Molecular Gastroenterology and Hepatology (2015 March 14 [doi:10.1016/j.jcmgh.2015.03.002]).

“Even as all-oral regimens begin to reach the market, interferon-based treatment will continue to be used in cost-restrained settings. Thus, there is a need for predictors of who is likely to respond to interferon and who will require a more expensive direct-acting antiviral combination regimen,” said Dr. Philipp Solbach of Medizinische Hochschule Hannover and the German Center for Infection Research and his associates. Combinations of interferon and viral entry inhibitors might benefit patients with chronic HCV infection (CHC), the investigators added.

Hepatitis C virus spreads between hepatocytes with the help of several cell surface receptors, including scavenger receptor class B type 1 (SR-BI). Research has shown that oxidized low-density lipoprotein (oxLDL) noncompetitively inhibits the interaction between SR-B1 and HCV. To further study the role of oxLDL in CHC pathology, the investigators used a commercial enzyme-linked immunosorbent assay test to measure serum levels in 379 patients with genotype 1 CHC from the INDIV-2 study. Patients in that study received a pegylated interferon-ribavirin combination for 24-72 weeks, depending on baseline viral load. Dr. Solbach and his associates also studied the effects of oxLDL on HCV replication in hepatoma cells.

Average serum oxLDL levels were significantly higher among patients who achieved SVR on peg-IFN/RBV than in those who did not (7.1 mU/L [standard deviation, 3.2] vs. 5.9 mU/L [SD, 2.6]; P < .001), the researchers reported. In the multivariate analysis, oxLDL levels independently predicted SVR, but were not associated with increased ALT or ferritin levels, both of which point to liver inflammation. Increased serum oxLDL also was linked to decreased infected cell loss rate, further supporting the idea that oxLDL helps inhibit cell-to-cell spread of HCV in chronically infected patients, they said.

Area under the receiver operative curve (AUROC) values were similar for LDL and oxLDL, indicating that one value was a good clinical indicator of the other, the investigators said. The optimal cutoff points to predict SVR in their model were 8.85 mU/L for oxLDL and 3.6 mmol/L for LDL.

In the in vitro study, oxLDL did not affect the sensitivity of HCV replication to interferon, but strongly inhibited the spread of HCV between adjacent hepatocytes, the investigators reported. “We found that oxLDL but not LDL potently inhibits cell-to-cell spread between neighboring cells,” they noted. “Cell-to-cell spread is thought to be the dominant route of new cell infection within the chronically infected liver.”

Taken together, the findings suggest that HCV needs to interact with SR-BI in order to spread between hepatocytes, that oxLDL can impede that interaction and thereby limit infection of naive cells, and that oxLDL is neither an inflammatory marker nor a modulator of interferon response, Dr. Solback and his associates said. “The slower second-phase decline of viral load during interferon-based therapy is thought to reflect a declining pool of infected hepatocytes, and the slope of second-phase decline and even more the estimated viral kinetic parameter describing the infected cell loss rate is predictive of eventual SVR,” they added. “The presence of an agent reducing the rate at which naive cells get infected might thus be beneficial.”

The Germany Center for Infection Research partially funded the study. Five coauthors reported having served as clinical researchers, consultants, or speakers for MSD/Merck and Roche. The other authors declared no conflicts of interest.

Oxidized low-density lipoprotein prevented hepatitis C virus from entering liver cells and predicted interferon response among patients with chronic HCV infection, researchers reported online in the May issue of Cellular and Molecular Gastroenterology and Hepatology (2015 March 14 [doi:10.1016/j.jcmgh.2015.03.002]).

“Even as all-oral regimens begin to reach the market, interferon-based treatment will continue to be used in cost-restrained settings. Thus, there is a need for predictors of who is likely to respond to interferon and who will require a more expensive direct-acting antiviral combination regimen,” said Dr. Philipp Solbach of Medizinische Hochschule Hannover and the German Center for Infection Research and his associates. Combinations of interferon and viral entry inhibitors might benefit patients with chronic HCV infection (CHC), the investigators added.

Hepatitis C virus spreads between hepatocytes with the help of several cell surface receptors, including scavenger receptor class B type 1 (SR-BI). Research has shown that oxidized low-density lipoprotein (oxLDL) noncompetitively inhibits the interaction between SR-B1 and HCV. To further study the role of oxLDL in CHC pathology, the investigators used a commercial enzyme-linked immunosorbent assay test to measure serum levels in 379 patients with genotype 1 CHC from the INDIV-2 study. Patients in that study received a pegylated interferon-ribavirin combination for 24-72 weeks, depending on baseline viral load. Dr. Solbach and his associates also studied the effects of oxLDL on HCV replication in hepatoma cells.

Average serum oxLDL levels were significantly higher among patients who achieved SVR on peg-IFN/RBV than in those who did not (7.1 mU/L [standard deviation, 3.2] vs. 5.9 mU/L [SD, 2.6]; P < .001), the researchers reported. In the multivariate analysis, oxLDL levels independently predicted SVR, but were not associated with increased ALT or ferritin levels, both of which point to liver inflammation. Increased serum oxLDL also was linked to decreased infected cell loss rate, further supporting the idea that oxLDL helps inhibit cell-to-cell spread of HCV in chronically infected patients, they said.

Area under the receiver operative curve (AUROC) values were similar for LDL and oxLDL, indicating that one value was a good clinical indicator of the other, the investigators said. The optimal cutoff points to predict SVR in their model were 8.85 mU/L for oxLDL and 3.6 mmol/L for LDL.

In the in vitro study, oxLDL did not affect the sensitivity of HCV replication to interferon, but strongly inhibited the spread of HCV between adjacent hepatocytes, the investigators reported. “We found that oxLDL but not LDL potently inhibits cell-to-cell spread between neighboring cells,” they noted. “Cell-to-cell spread is thought to be the dominant route of new cell infection within the chronically infected liver.”

Taken together, the findings suggest that HCV needs to interact with SR-BI in order to spread between hepatocytes, that oxLDL can impede that interaction and thereby limit infection of naive cells, and that oxLDL is neither an inflammatory marker nor a modulator of interferon response, Dr. Solback and his associates said. “The slower second-phase decline of viral load during interferon-based therapy is thought to reflect a declining pool of infected hepatocytes, and the slope of second-phase decline and even more the estimated viral kinetic parameter describing the infected cell loss rate is predictive of eventual SVR,” they added. “The presence of an agent reducing the rate at which naive cells get infected might thus be beneficial.”

The Germany Center for Infection Research partially funded the study. Five coauthors reported having served as clinical researchers, consultants, or speakers for MSD/Merck and Roche. The other authors declared no conflicts of interest.

Hospital mortality among patients with cirrhosis fell by 41% in the United States between 2002 and 2010, far outpacing improvements in survival among inpatients who did not have cirrhosis, researchers reported in the May issue of Gastroenterology (2015 [doi:10.1053/j.gastro.2015.01.032]).

The drop occurred even though cirrhosis inpatients were older and had more comorbidities by the end, compared with the beginning of the study, said Monica Schmidtat the University of North Carolina Liver Center and the Gillings School of Global Public Health in Chapel Hill, N.C., and her associates. The finding was “remarkably consistent across several cirrhosis complications, and [suggested] improving cirrhosis care that may extend beyond general improvements in inpatient care,” the researchers added. “On the other hand, sepsis had an increasing mortality risk, suggesting that cirrhotic patients may need a more tailored approach to sepsis,” they said.

©Sebastian Kaulitzki/thinkstockphotos.com

Source: American Gastroenterological Association

New treatments have emerged in the past 10-15 years for several complications of cirrhosis, including hepatorenal syndrome, variceal bleeding, spontaneous bacterial peritonitis, ascites, and hepatocellular carcinoma, Ms. Schmidt and her associates noted. To study the extent to which these advances and updated guidelines have entered hospital practice, they examined 781,515 hospitalizations with a diagnosis of cirrhosis, and equal numbers of hospitalizations without cirrhosis or with congestive heart failure. Data were from the National Inpatient Sample of the Healthcare Cost and Utilization Project, which includes 46 states and is the single largest all-payer inpatient database in the country. Cohorts were matched by age, sex, and year of hospital discharge from 2002 through 2010.

Hospital mortality among cirrhosis patients dropped by 41% (from 9.1% to 5.4%) during the 8 years of the study, compared with declines of 44% for inpatients with congestive heart failure and 19% for inpatients without cirrhosis, the investigators said. Furthermore, the independent risk of dying in the hospital among cirrhosis patients declined steadily to 0.50 by the end of the study (95% confidence interval, 0.48-0.52), despite the population’s increasing age and medical complexity. Hospital mortality rates were higher for subgroups of cirrhosis patients with hepatorenal syndrome, hepatocellular carcinoma, variceal bleeding, and spontaneous bacterial peritonitis, but independent mortality risks for each of these conditions fell progressively over time, the investigators noted.

In contrast, cirrhosis inpatients with sepsis were 22% more likely to die in the hospital in 2010 than in 2002 (relative risk in 2002, 3.6; 95% CI, 3.3-3.95; RR in 2010, 4.6; 95% CI, 4.4-4.8), the researchers found. The increase was so marked that the mortality risk related to sepsis in 2010 exceeded even that for hepatorenal syndrome, they said. The unexpected finding contradicted a report of declining overall sepsis-related mortality, which was based on the same data source and a similar time period, the investigators noted.

“Cirrhosis patients have particularly poor hemodynamic reserve, with wider perturbations in immune inflammatory and compensatory responses that could hinder survival,” they commented. “Therefore, it is possible that cirrhosis patients are doing much worse with sepsis, compared with other patients. The surviving sepsis campaign may need guidelines that specifically target cirrhosis patients.”

The National Institutes of Health partly funded the study. The authors reported having no relevant conflicts of interest.

Hospital mortality among patients with cirrhosis fell by 41% in the United States between 2002 and 2010, far outpacing improvements in survival among inpatients who did not have cirrhosis, researchers reported in the May issue of Gastroenterology (2015 [doi:10.1053/j.gastro.2015.01.032]).

The drop occurred even though cirrhosis inpatients were older and had more comorbidities by the end, compared with the beginning of the study, said Monica Schmidtat the University of North Carolina Liver Center and the Gillings School of Global Public Health in Chapel Hill, N.C., and her associates. The finding was “remarkably consistent across several cirrhosis complications, and [suggested] improving cirrhosis care that may extend beyond general improvements in inpatient care,” the researchers added. “On the other hand, sepsis had an increasing mortality risk, suggesting that cirrhotic patients may need a more tailored approach to sepsis,” they said.

©Sebastian Kaulitzki/thinkstockphotos.com

Source: American Gastroenterological Association

New treatments have emerged in the past 10-15 years for several complications of cirrhosis, including hepatorenal syndrome, variceal bleeding, spontaneous bacterial peritonitis, ascites, and hepatocellular carcinoma, Ms. Schmidt and her associates noted. To study the extent to which these advances and updated guidelines have entered hospital practice, they examined 781,515 hospitalizations with a diagnosis of cirrhosis, and equal numbers of hospitalizations without cirrhosis or with congestive heart failure. Data were from the National Inpatient Sample of the Healthcare Cost and Utilization Project, which includes 46 states and is the single largest all-payer inpatient database in the country. Cohorts were matched by age, sex, and year of hospital discharge from 2002 through 2010.

Hospital mortality among cirrhosis patients dropped by 41% (from 9.1% to 5.4%) during the 8 years of the study, compared with declines of 44% for inpatients with congestive heart failure and 19% for inpatients without cirrhosis, the investigators said. Furthermore, the independent risk of dying in the hospital among cirrhosis patients declined steadily to 0.50 by the end of the study (95% confidence interval, 0.48-0.52), despite the population’s increasing age and medical complexity. Hospital mortality rates were higher for subgroups of cirrhosis patients with hepatorenal syndrome, hepatocellular carcinoma, variceal bleeding, and spontaneous bacterial peritonitis, but independent mortality risks for each of these conditions fell progressively over time, the investigators noted.

In contrast, cirrhosis inpatients with sepsis were 22% more likely to die in the hospital in 2010 than in 2002 (relative risk in 2002, 3.6; 95% CI, 3.3-3.95; RR in 2010, 4.6; 95% CI, 4.4-4.8), the researchers found. The increase was so marked that the mortality risk related to sepsis in 2010 exceeded even that for hepatorenal syndrome, they said. The unexpected finding contradicted a report of declining overall sepsis-related mortality, which was based on the same data source and a similar time period, the investigators noted.

“Cirrhosis patients have particularly poor hemodynamic reserve, with wider perturbations in immune inflammatory and compensatory responses that could hinder survival,” they commented. “Therefore, it is possible that cirrhosis patients are doing much worse with sepsis, compared with other patients. The surviving sepsis campaign may need guidelines that specifically target cirrhosis patients.”

The National Institutes of Health partly funded the study. The authors reported having no relevant conflicts of interest.

Hospital mortality among patients with cirrhosis fell by 41% in the United States between 2002 and 2010, far outpacing improvements in survival among inpatients who did not have cirrhosis, researchers reported in the May issue of Gastroenterology (2015 [doi:10.1053/j.gastro.2015.01.032]).

The drop occurred even though cirrhosis inpatients were older and had more comorbidities by the end, compared with the beginning of the study, said Monica Schmidtat the University of North Carolina Liver Center and the Gillings School of Global Public Health in Chapel Hill, N.C., and her associates. The finding was “remarkably consistent across several cirrhosis complications, and [suggested] improving cirrhosis care that may extend beyond general improvements in inpatient care,” the researchers added. “On the other hand, sepsis had an increasing mortality risk, suggesting that cirrhotic patients may need a more tailored approach to sepsis,” they said.

©Sebastian Kaulitzki/thinkstockphotos.com

Source: American Gastroenterological Association

New treatments have emerged in the past 10-15 years for several complications of cirrhosis, including hepatorenal syndrome, variceal bleeding, spontaneous bacterial peritonitis, ascites, and hepatocellular carcinoma, Ms. Schmidt and her associates noted. To study the extent to which these advances and updated guidelines have entered hospital practice, they examined 781,515 hospitalizations with a diagnosis of cirrhosis, and equal numbers of hospitalizations without cirrhosis or with congestive heart failure. Data were from the National Inpatient Sample of the Healthcare Cost and Utilization Project, which includes 46 states and is the single largest all-payer inpatient database in the country. Cohorts were matched by age, sex, and year of hospital discharge from 2002 through 2010.

Hospital mortality among cirrhosis patients dropped by 41% (from 9.1% to 5.4%) during the 8 years of the study, compared with declines of 44% for inpatients with congestive heart failure and 19% for inpatients without cirrhosis, the investigators said. Furthermore, the independent risk of dying in the hospital among cirrhosis patients declined steadily to 0.50 by the end of the study (95% confidence interval, 0.48-0.52), despite the population’s increasing age and medical complexity. Hospital mortality rates were higher for subgroups of cirrhosis patients with hepatorenal syndrome, hepatocellular carcinoma, variceal bleeding, and spontaneous bacterial peritonitis, but independent mortality risks for each of these conditions fell progressively over time, the investigators noted.

In contrast, cirrhosis inpatients with sepsis were 22% more likely to die in the hospital in 2010 than in 2002 (relative risk in 2002, 3.6; 95% CI, 3.3-3.95; RR in 2010, 4.6; 95% CI, 4.4-4.8), the researchers found. The increase was so marked that the mortality risk related to sepsis in 2010 exceeded even that for hepatorenal syndrome, they said. The unexpected finding contradicted a report of declining overall sepsis-related mortality, which was based on the same data source and a similar time period, the investigators noted.

“Cirrhosis patients have particularly poor hemodynamic reserve, with wider perturbations in immune inflammatory and compensatory responses that could hinder survival,” they commented. “Therefore, it is possible that cirrhosis patients are doing much worse with sepsis, compared with other patients. The surviving sepsis campaign may need guidelines that specifically target cirrhosis patients.”

The National Institutes of Health partly funded the study. The authors reported having no relevant conflicts of interest.

Patients with compensated cirrhosis and chronic genotype 1 hepatitis C virus infections were significantly more likely to clear their infections and had fewer adverse effects when treated with simeprevir and sofosbuvir instead of peginterferon, ribavirin, and sofosbuvir, investigators reported in the April issue of Gastroenterology. “Patients given the interferon-containing regimen had a significantly greater rate of virologic relapse than patients given simeprevir and sofosbuvir ... and reported worse outcomes and more side effects,” said Dr. Brian L. Pearlman and his associates of Atlanta Medical Center and Emory University, Atlanta.

Liver disease associated with chronic hepatitis C virus (HCV) infection causes at least 350,000 deaths per year worldwide. Genotype 1 (GT-1) HCV is the most common HCV strain and the hardest to treat, especially when patients have cirrhosis. Treatments for chronic GT-1 HCV infections historically included interferon, but achieved only moderate rates of sustained virologic response (SVR) and caused adverse somatic and psychiatric effects. All-oral, interferon-free regimens are now in widespread use, but many of the pivotal trials were industry sponsored and had strict enrollment criteria, potentially limiting their generalizability in community settings, the researchers reported (Gastroenterology 2015 April [doi:10.1053/j.gastro.2014.12.027]).Their open-label trial included 82 patients with HCV GT-1a infection and Child’s grade A cirrhosis recruited from two clinical practices in Atlanta. Thirty-two of the patients were treatment naive, while 50 had previously not responded to peginterferon and ribavirin treatment. Patients were randomized to either 12 weeks of all-oral simeprevir (150 mg/day) and sofosbuvir (400 mg/day), or peginterferon alfa 2b (1.5 mcg/kg per week), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day).Fully 54 of 58 (93%) patients given the simeprevir-sofosbuvir regimen had undetectable levels of HCV RNA at 12 weeks (SVR12), compared with 18 of 24 (75%) patients who received the interferon-containing regimen (P = .02), the researchers reported. Rates of SVR12 among prior nonresponders were 92% and 64%, and were 95% and 80% for treatment-naive patients, although P-values did not reach statistical significance. The interferon group also had a higher rate of virologic relapse than did patients given simeprevir and sofosbuvir (P = .009), and had worse self-reported outcomes and more side effects, the researchers said. Patients in both groups who achieved SVR12 had higher quality-of-life scores than those who did not. Notably, almost half of patients were African American, a group that has historically had lower cure rates compared with other racial groups, said the investigators.

“Given that several new regimens for genotype 1 infection, including the sofosbuvir-ledipasvir combination pill, already have been approved, we believe that this study is very timely,” Dr. Pearlman and his associates said. “Although these are not head-to-head comparisons, the 12-week simeprevir and sofosbuvir regimen in this trial may compare favorably with the SVR rates for 12 weeks of sofosbuvir/ledipasvir and 12 weeks of the regimen, paritaprevir/ritonavir, ombitasvir and dasabuvir plus ribavirin for patients with cirrhosis, particularly for prior nonresponders to older therapies, with the caveat that many more patients were studied in the registration trials.”While industry-sponsored trials have had psychiatric exclusion criteria, several patients in the open-label trial had serious psychiatric conditions, said the researchers. A patient with stable bipolar disorder received the interferon-containing regimen, and two patients with stable schizophrenia received the all-oral regimen. None reported worsening psychiatric symptoms on treatment.

Dr. Pearlman reported having contracted research for Johnson & Johnson, Gilead, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, and Merck; and having served on speaker and advisory boards for Johnson & Johnson, Gilead, and Abbvie. He also was an investigator and author in the COSMOS trial of simeprevir and sofosbuvir in patients with HCV/HIV coinfection. The other authors reported no conflicts of interest.

Patients with compensated cirrhosis and chronic genotype 1 hepatitis C virus infections were significantly more likely to clear their infections and had fewer adverse effects when treated with simeprevir and sofosbuvir instead of peginterferon, ribavirin, and sofosbuvir, investigators reported in the April issue of Gastroenterology. “Patients given the interferon-containing regimen had a significantly greater rate of virologic relapse than patients given simeprevir and sofosbuvir ... and reported worse outcomes and more side effects,” said Dr. Brian L. Pearlman and his associates of Atlanta Medical Center and Emory University, Atlanta.

Liver disease associated with chronic hepatitis C virus (HCV) infection causes at least 350,000 deaths per year worldwide. Genotype 1 (GT-1) HCV is the most common HCV strain and the hardest to treat, especially when patients have cirrhosis. Treatments for chronic GT-1 HCV infections historically included interferon, but achieved only moderate rates of sustained virologic response (SVR) and caused adverse somatic and psychiatric effects. All-oral, interferon-free regimens are now in widespread use, but many of the pivotal trials were industry sponsored and had strict enrollment criteria, potentially limiting their generalizability in community settings, the researchers reported (Gastroenterology 2015 April [doi:10.1053/j.gastro.2014.12.027]).Their open-label trial included 82 patients with HCV GT-1a infection and Child’s grade A cirrhosis recruited from two clinical practices in Atlanta. Thirty-two of the patients were treatment naive, while 50 had previously not responded to peginterferon and ribavirin treatment. Patients were randomized to either 12 weeks of all-oral simeprevir (150 mg/day) and sofosbuvir (400 mg/day), or peginterferon alfa 2b (1.5 mcg/kg per week), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day).Fully 54 of 58 (93%) patients given the simeprevir-sofosbuvir regimen had undetectable levels of HCV RNA at 12 weeks (SVR12), compared with 18 of 24 (75%) patients who received the interferon-containing regimen (P = .02), the researchers reported. Rates of SVR12 among prior nonresponders were 92% and 64%, and were 95% and 80% for treatment-naive patients, although P-values did not reach statistical significance. The interferon group also had a higher rate of virologic relapse than did patients given simeprevir and sofosbuvir (P = .009), and had worse self-reported outcomes and more side effects, the researchers said. Patients in both groups who achieved SVR12 had higher quality-of-life scores than those who did not. Notably, almost half of patients were African American, a group that has historically had lower cure rates compared with other racial groups, said the investigators.

“Given that several new regimens for genotype 1 infection, including the sofosbuvir-ledipasvir combination pill, already have been approved, we believe that this study is very timely,” Dr. Pearlman and his associates said. “Although these are not head-to-head comparisons, the 12-week simeprevir and sofosbuvir regimen in this trial may compare favorably with the SVR rates for 12 weeks of sofosbuvir/ledipasvir and 12 weeks of the regimen, paritaprevir/ritonavir, ombitasvir and dasabuvir plus ribavirin for patients with cirrhosis, particularly for prior nonresponders to older therapies, with the caveat that many more patients were studied in the registration trials.”While industry-sponsored trials have had psychiatric exclusion criteria, several patients in the open-label trial had serious psychiatric conditions, said the researchers. A patient with stable bipolar disorder received the interferon-containing regimen, and two patients with stable schizophrenia received the all-oral regimen. None reported worsening psychiatric symptoms on treatment.

Dr. Pearlman reported having contracted research for Johnson & Johnson, Gilead, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, and Merck; and having served on speaker and advisory boards for Johnson & Johnson, Gilead, and Abbvie. He also was an investigator and author in the COSMOS trial of simeprevir and sofosbuvir in patients with HCV/HIV coinfection. The other authors reported no conflicts of interest.

Patients with compensated cirrhosis and chronic genotype 1 hepatitis C virus infections were significantly more likely to clear their infections and had fewer adverse effects when treated with simeprevir and sofosbuvir instead of peginterferon, ribavirin, and sofosbuvir, investigators reported in the April issue of Gastroenterology. “Patients given the interferon-containing regimen had a significantly greater rate of virologic relapse than patients given simeprevir and sofosbuvir ... and reported worse outcomes and more side effects,” said Dr. Brian L. Pearlman and his associates of Atlanta Medical Center and Emory University, Atlanta.

Liver disease associated with chronic hepatitis C virus (HCV) infection causes at least 350,000 deaths per year worldwide. Genotype 1 (GT-1) HCV is the most common HCV strain and the hardest to treat, especially when patients have cirrhosis. Treatments for chronic GT-1 HCV infections historically included interferon, but achieved only moderate rates of sustained virologic response (SVR) and caused adverse somatic and psychiatric effects. All-oral, interferon-free regimens are now in widespread use, but many of the pivotal trials were industry sponsored and had strict enrollment criteria, potentially limiting their generalizability in community settings, the researchers reported (Gastroenterology 2015 April [doi:10.1053/j.gastro.2014.12.027]).Their open-label trial included 82 patients with HCV GT-1a infection and Child’s grade A cirrhosis recruited from two clinical practices in Atlanta. Thirty-two of the patients were treatment naive, while 50 had previously not responded to peginterferon and ribavirin treatment. Patients were randomized to either 12 weeks of all-oral simeprevir (150 mg/day) and sofosbuvir (400 mg/day), or peginterferon alfa 2b (1.5 mcg/kg per week), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day).Fully 54 of 58 (93%) patients given the simeprevir-sofosbuvir regimen had undetectable levels of HCV RNA at 12 weeks (SVR12), compared with 18 of 24 (75%) patients who received the interferon-containing regimen (P = .02), the researchers reported. Rates of SVR12 among prior nonresponders were 92% and 64%, and were 95% and 80% for treatment-naive patients, although P-values did not reach statistical significance. The interferon group also had a higher rate of virologic relapse than did patients given simeprevir and sofosbuvir (P = .009), and had worse self-reported outcomes and more side effects, the researchers said. Patients in both groups who achieved SVR12 had higher quality-of-life scores than those who did not. Notably, almost half of patients were African American, a group that has historically had lower cure rates compared with other racial groups, said the investigators.

“Given that several new regimens for genotype 1 infection, including the sofosbuvir-ledipasvir combination pill, already have been approved, we believe that this study is very timely,” Dr. Pearlman and his associates said. “Although these are not head-to-head comparisons, the 12-week simeprevir and sofosbuvir regimen in this trial may compare favorably with the SVR rates for 12 weeks of sofosbuvir/ledipasvir and 12 weeks of the regimen, paritaprevir/ritonavir, ombitasvir and dasabuvir plus ribavirin for patients with cirrhosis, particularly for prior nonresponders to older therapies, with the caveat that many more patients were studied in the registration trials.”While industry-sponsored trials have had psychiatric exclusion criteria, several patients in the open-label trial had serious psychiatric conditions, said the researchers. A patient with stable bipolar disorder received the interferon-containing regimen, and two patients with stable schizophrenia received the all-oral regimen. None reported worsening psychiatric symptoms on treatment.

Dr. Pearlman reported having contracted research for Johnson & Johnson, Gilead, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, and Merck; and having served on speaker and advisory boards for Johnson & Johnson, Gilead, and Abbvie. He also was an investigator and author in the COSMOS trial of simeprevir and sofosbuvir in patients with HCV/HIV coinfection. The other authors reported no conflicts of interest.

Four gene loci in patients with Crohn’s disease were significantly linked with phenotypic traits such as erythema nodosum or having a complicated or mild course of disease, researchers reported in the April issue of Gastroenterology (doi:10.1053/j.gastro.2014.12.030).

The work is the first genome-wide study to link specific genetic loci with clinically relevant traits in patients with Crohn’s disease (CD), said Dr. Arnald Alonso at the Vall d’Hebron Research Institute and the University of Catalonia in Barcelona and his associates. “Importantly, these new loci have not been previously described as risk factors for CD,” the researchers said. “Our results therefore demonstrate the existence of a genetic component for disease heterogeneity that is independent of the genetic variation associated with the susceptibility to Crohn’s disease.”

Crohn’s disease varies greatly in terms of severity, location of pathology, complications, and other factors. Genome-wide association studies have linked 140 genetic “risk loci” with susceptibility to CD, but past work has only found one gene locus (NOD2) that is definitively linked a single clinical trait of CD (ileal pathology), the investigators noted. For their genome-wide association study, they genotyped 576,818 single nucleotide polymorphisms in a discovery cohort of 1,090 CD patients of European ancestry who presented at university hospitals in Spain between 2007 and 2010, as well as 1,493 healthy controls. They examined associations between these genetic markers and 17 characteristics (or phenotypes) of CD related to disease location, disease behavior and course, age at onset, and extra-intestinal manifestations of CD. Next, the investigators studied a separate “replication” cohort of 1,296 CD patients in order to assess the 57 markers that had been most strongly associated (P < .0002) with CD phenotypes among the discovery cohort (Gastroenterology, http://www.gastrojournal.org/article/S0016-5085(14)01582-0/abstract).

These combined analyses showed that clinical phenotypes in CD were most significantly linked with four markers, including MAGI1, CLCA2, 2q24.1, and LY75, reported the investigators. The MAGI1 gene was found to predict complicated structuring disease course and stricturing behavior in CD, although it did not appear to speed its onset, they said. The gene encodes proteins that have been found to play an important role in the tight junctions between epithelial cells, and consequently in intestinal barrier function, they noted, adding that disruption of that mucosal integrity contributes to the pathogenesis of ulcerative colitis and CD. “Importantly, an increased intestinal permeability has been described in patients with active CD as well as in their first-degree relatives,” they added. “This evidence strongly suggests that increased intestinal permeability is not only a consequence of intestinal inflammation occurring in CD patients, but it is rather a risk factor for CD.”

The other three loci that were significantly associated with CD traits predicted ileal involvement (CLCA2), erythema nodosum (LY75), and having a mild disease course (2q24.1), the researchers reported. Taken together, the findings “indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease,” concluded Dr. Alonso and his associates. “Further functional studies of these new loci will provide a better understanding of the biological mechanisms that are involved in the development of these relevant clinical phenotypes.”

The Spanish Ministry of Economy and Competitiveness funded the study. The investigators reported having no relevant financial disclosures.

Four gene loci in patients with Crohn’s disease were significantly linked with phenotypic traits such as erythema nodosum or having a complicated or mild course of disease, researchers reported in the April issue of Gastroenterology (doi:10.1053/j.gastro.2014.12.030).

The work is the first genome-wide study to link specific genetic loci with clinically relevant traits in patients with Crohn’s disease (CD), said Dr. Arnald Alonso at the Vall d’Hebron Research Institute and the University of Catalonia in Barcelona and his associates. “Importantly, these new loci have not been previously described as risk factors for CD,” the researchers said. “Our results therefore demonstrate the existence of a genetic component for disease heterogeneity that is independent of the genetic variation associated with the susceptibility to Crohn’s disease.”

Crohn’s disease varies greatly in terms of severity, location of pathology, complications, and other factors. Genome-wide association studies have linked 140 genetic “risk loci” with susceptibility to CD, but past work has only found one gene locus (NOD2) that is definitively linked a single clinical trait of CD (ileal pathology), the investigators noted. For their genome-wide association study, they genotyped 576,818 single nucleotide polymorphisms in a discovery cohort of 1,090 CD patients of European ancestry who presented at university hospitals in Spain between 2007 and 2010, as well as 1,493 healthy controls. They examined associations between these genetic markers and 17 characteristics (or phenotypes) of CD related to disease location, disease behavior and course, age at onset, and extra-intestinal manifestations of CD. Next, the investigators studied a separate “replication” cohort of 1,296 CD patients in order to assess the 57 markers that had been most strongly associated (P < .0002) with CD phenotypes among the discovery cohort (Gastroenterology, http://www.gastrojournal.org/article/S0016-5085(14)01582-0/abstract).

These combined analyses showed that clinical phenotypes in CD were most significantly linked with four markers, including MAGI1, CLCA2, 2q24.1, and LY75, reported the investigators. The MAGI1 gene was found to predict complicated structuring disease course and stricturing behavior in CD, although it did not appear to speed its onset, they said. The gene encodes proteins that have been found to play an important role in the tight junctions between epithelial cells, and consequently in intestinal barrier function, they noted, adding that disruption of that mucosal integrity contributes to the pathogenesis of ulcerative colitis and CD. “Importantly, an increased intestinal permeability has been described in patients with active CD as well as in their first-degree relatives,” they added. “This evidence strongly suggests that increased intestinal permeability is not only a consequence of intestinal inflammation occurring in CD patients, but it is rather a risk factor for CD.”

The other three loci that were significantly associated with CD traits predicted ileal involvement (CLCA2), erythema nodosum (LY75), and having a mild disease course (2q24.1), the researchers reported. Taken together, the findings “indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease,” concluded Dr. Alonso and his associates. “Further functional studies of these new loci will provide a better understanding of the biological mechanisms that are involved in the development of these relevant clinical phenotypes.”

The Spanish Ministry of Economy and Competitiveness funded the study. The investigators reported having no relevant financial disclosures.

Four gene loci in patients with Crohn’s disease were significantly linked with phenotypic traits such as erythema nodosum or having a complicated or mild course of disease, researchers reported in the April issue of Gastroenterology (doi:10.1053/j.gastro.2014.12.030).

The work is the first genome-wide study to link specific genetic loci with clinically relevant traits in patients with Crohn’s disease (CD), said Dr. Arnald Alonso at the Vall d’Hebron Research Institute and the University of Catalonia in Barcelona and his associates. “Importantly, these new loci have not been previously described as risk factors for CD,” the researchers said. “Our results therefore demonstrate the existence of a genetic component for disease heterogeneity that is independent of the genetic variation associated with the susceptibility to Crohn’s disease.”

Crohn’s disease varies greatly in terms of severity, location of pathology, complications, and other factors. Genome-wide association studies have linked 140 genetic “risk loci” with susceptibility to CD, but past work has only found one gene locus (NOD2) that is definitively linked a single clinical trait of CD (ileal pathology), the investigators noted. For their genome-wide association study, they genotyped 576,818 single nucleotide polymorphisms in a discovery cohort of 1,090 CD patients of European ancestry who presented at university hospitals in Spain between 2007 and 2010, as well as 1,493 healthy controls. They examined associations between these genetic markers and 17 characteristics (or phenotypes) of CD related to disease location, disease behavior and course, age at onset, and extra-intestinal manifestations of CD. Next, the investigators studied a separate “replication” cohort of 1,296 CD patients in order to assess the 57 markers that had been most strongly associated (P < .0002) with CD phenotypes among the discovery cohort (Gastroenterology, http://www.gastrojournal.org/article/S0016-5085(14)01582-0/abstract).

These combined analyses showed that clinical phenotypes in CD were most significantly linked with four markers, including MAGI1, CLCA2, 2q24.1, and LY75, reported the investigators. The MAGI1 gene was found to predict complicated structuring disease course and stricturing behavior in CD, although it did not appear to speed its onset, they said. The gene encodes proteins that have been found to play an important role in the tight junctions between epithelial cells, and consequently in intestinal barrier function, they noted, adding that disruption of that mucosal integrity contributes to the pathogenesis of ulcerative colitis and CD. “Importantly, an increased intestinal permeability has been described in patients with active CD as well as in their first-degree relatives,” they added. “This evidence strongly suggests that increased intestinal permeability is not only a consequence of intestinal inflammation occurring in CD patients, but it is rather a risk factor for CD.”

The other three loci that were significantly associated with CD traits predicted ileal involvement (CLCA2), erythema nodosum (LY75), and having a mild disease course (2q24.1), the researchers reported. Taken together, the findings “indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease,” concluded Dr. Alonso and his associates. “Further functional studies of these new loci will provide a better understanding of the biological mechanisms that are involved in the development of these relevant clinical phenotypes.”

The Spanish Ministry of Economy and Competitiveness funded the study. The investigators reported having no relevant financial disclosures.

Two-thirds of endoscopists met national quality benchmarks for detecting colonic adenomas, but detection rates varied eightfold among male patients and 27-fold among female patients, according to a retrospective community-based cohort study.

These ranges narrowed somewhat when researchers controlled for patient-specific factors, such as age and sex, said Dr. Christopher Jensen and his associates at Kaiser Permanente Division of Research in Oakland, Calif. But researchers found that adjusting for those variables had little effect on how endoscopists ranked in terms of adenoma detection rates (ADRs) compared with their peers. Based on those findings, evaluators probably only need to account for patient demographics when comparing ADRs for endoscopists who tend to see very distinct types of patients, the investigators wrote in the April issue of Clinical Gastroenterology and Hepatology 2014 Oct 25. (doi:10.1016/j.cgh.2014.10.020).

Colorectal cancer remains the second leading cause of cancer mortality in the United States, and prevention hinges on detecting and removing precancerous adenomatous polyps of the colon. For this reason, organizations such as the U.S. Multi-Society Task Force on Colorectal Cancer and the U.S. Centers for Medicaid and Medicare Services have recommended benchmark ADRs of at least 25% for male patients and 15% for female patients. Although some studies have examined how characteristics of physicians and their practices affect ADRs, none have previously assessed effects of patient-specific variables, Dr. Jensen and his associates said (Clin. Gastroenterol. Hepatol. http://www.ncbi.nlm.nih.gov/pubmed/25445767.

The investigators retrospectively studied 108,662 colonoscopies and 20,792 screening colonoscopies carried out by 102 endoscopists at Kaiser Permanente Northern California between 2006 and 2008. They calculated ADRs for each physician before and after they adjusted for the patients’ age, sex, race/ethnicity, and family history of colorectal cancer.

In all, 67% of examiners met the gastrointestinal society guidelines for ADRs in male patients, and 68% met guidelines for female patients, the researchers found. But ADRs among the examiners ranged widely – from 7.7% to 61.5% for male patients and from 1.7% to 45.6% for females, the investigators said. Adjustments for patient demographics and family history of colorectal cancer cut the variation from 8-fold down to 3-fold for male patients, and from 27-fold to 5-fold for females. However, physicians’ absolute rankings among their peers remained similar before and after controlling for patient case mix. “Moderate differences in patient demographics between physicians are unlikely to substantially change rates of adenoma detection,” concluded Dr. Jensen and his associates. “The findings raise the question of whether adenoma detection rates should routinely be adjusted for case mix,” they added. “The need for adjustment will likely depend on the degree of variation between physicians in patient case mix, and how rates are used as a performance metric. Adjusted rates would likely only be needed in settings where physicians had very different patient demographics relative to sex and age.”

The study was funded by the Kaiser Permanente Community Benefits program, the National Cancer Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases. The investigators reported having no relevant financial disclosures.

Two-thirds of endoscopists met national quality benchmarks for detecting colonic adenomas, but detection rates varied eightfold among male patients and 27-fold among female patients, according to a retrospective community-based cohort study.

These ranges narrowed somewhat when researchers controlled for patient-specific factors, such as age and sex, said Dr. Christopher Jensen and his associates at Kaiser Permanente Division of Research in Oakland, Calif. But researchers found that adjusting for those variables had little effect on how endoscopists ranked in terms of adenoma detection rates (ADRs) compared with their peers. Based on those findings, evaluators probably only need to account for patient demographics when comparing ADRs for endoscopists who tend to see very distinct types of patients, the investigators wrote in the April issue of Clinical Gastroenterology and Hepatology 2014 Oct 25. (doi:10.1016/j.cgh.2014.10.020).

Colorectal cancer remains the second leading cause of cancer mortality in the United States, and prevention hinges on detecting and removing precancerous adenomatous polyps of the colon. For this reason, organizations such as the U.S. Multi-Society Task Force on Colorectal Cancer and the U.S. Centers for Medicaid and Medicare Services have recommended benchmark ADRs of at least 25% for male patients and 15% for female patients. Although some studies have examined how characteristics of physicians and their practices affect ADRs, none have previously assessed effects of patient-specific variables, Dr. Jensen and his associates said (Clin. Gastroenterol. Hepatol. http://www.ncbi.nlm.nih.gov/pubmed/25445767.

The investigators retrospectively studied 108,662 colonoscopies and 20,792 screening colonoscopies carried out by 102 endoscopists at Kaiser Permanente Northern California between 2006 and 2008. They calculated ADRs for each physician before and after they adjusted for the patients’ age, sex, race/ethnicity, and family history of colorectal cancer.

In all, 67% of examiners met the gastrointestinal society guidelines for ADRs in male patients, and 68% met guidelines for female patients, the researchers found. But ADRs among the examiners ranged widely – from 7.7% to 61.5% for male patients and from 1.7% to 45.6% for females, the investigators said. Adjustments for patient demographics and family history of colorectal cancer cut the variation from 8-fold down to 3-fold for male patients, and from 27-fold to 5-fold for females. However, physicians’ absolute rankings among their peers remained similar before and after controlling for patient case mix. “Moderate differences in patient demographics between physicians are unlikely to substantially change rates of adenoma detection,” concluded Dr. Jensen and his associates. “The findings raise the question of whether adenoma detection rates should routinely be adjusted for case mix,” they added. “The need for adjustment will likely depend on the degree of variation between physicians in patient case mix, and how rates are used as a performance metric. Adjusted rates would likely only be needed in settings where physicians had very different patient demographics relative to sex and age.”

The study was funded by the Kaiser Permanente Community Benefits program, the National Cancer Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases. The investigators reported having no relevant financial disclosures.

Two-thirds of endoscopists met national quality benchmarks for detecting colonic adenomas, but detection rates varied eightfold among male patients and 27-fold among female patients, according to a retrospective community-based cohort study.

These ranges narrowed somewhat when researchers controlled for patient-specific factors, such as age and sex, said Dr. Christopher Jensen and his associates at Kaiser Permanente Division of Research in Oakland, Calif. But researchers found that adjusting for those variables had little effect on how endoscopists ranked in terms of adenoma detection rates (ADRs) compared with their peers. Based on those findings, evaluators probably only need to account for patient demographics when comparing ADRs for endoscopists who tend to see very distinct types of patients, the investigators wrote in the April issue of Clinical Gastroenterology and Hepatology 2014 Oct 25. (doi:10.1016/j.cgh.2014.10.020).

Colorectal cancer remains the second leading cause of cancer mortality in the United States, and prevention hinges on detecting and removing precancerous adenomatous polyps of the colon. For this reason, organizations such as the U.S. Multi-Society Task Force on Colorectal Cancer and the U.S. Centers for Medicaid and Medicare Services have recommended benchmark ADRs of at least 25% for male patients and 15% for female patients. Although some studies have examined how characteristics of physicians and their practices affect ADRs, none have previously assessed effects of patient-specific variables, Dr. Jensen and his associates said (Clin. Gastroenterol. Hepatol. http://www.ncbi.nlm.nih.gov/pubmed/25445767.

The investigators retrospectively studied 108,662 colonoscopies and 20,792 screening colonoscopies carried out by 102 endoscopists at Kaiser Permanente Northern California between 2006 and 2008. They calculated ADRs for each physician before and after they adjusted for the patients’ age, sex, race/ethnicity, and family history of colorectal cancer.

In all, 67% of examiners met the gastrointestinal society guidelines for ADRs in male patients, and 68% met guidelines for female patients, the researchers found. But ADRs among the examiners ranged widely – from 7.7% to 61.5% for male patients and from 1.7% to 45.6% for females, the investigators said. Adjustments for patient demographics and family history of colorectal cancer cut the variation from 8-fold down to 3-fold for male patients, and from 27-fold to 5-fold for females. However, physicians’ absolute rankings among their peers remained similar before and after controlling for patient case mix. “Moderate differences in patient demographics between physicians are unlikely to substantially change rates of adenoma detection,” concluded Dr. Jensen and his associates. “The findings raise the question of whether adenoma detection rates should routinely be adjusted for case mix,” they added. “The need for adjustment will likely depend on the degree of variation between physicians in patient case mix, and how rates are used as a performance metric. Adjusted rates would likely only be needed in settings where physicians had very different patient demographics relative to sex and age.”

The study was funded by the Kaiser Permanente Community Benefits program, the National Cancer Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases. The investigators reported having no relevant financial disclosures.

Women with Crohn’s disease had about a 53% greater risk of developing cervical cancer compared with controls, and women with inflammatory bowel disease had a significantly greater risk of having had cervical neoplasia years earlier, according to a large population-based study reported in the April issue of Clinical Gastroenterology and Hepatology (http://dx.doi.org/10.1016/j.cgh.2014.07.036).

“We found a two-way association between inflammatory bowel disease, notably Crohn’s disease, and neoplastic lesions of the uterine cervix. This observation is not explained by differences in screening activity,” said Dr. Christine Rungoe at Statens Serum Institut in Copenhagen and her associates. “Patients with IBD should be encouraged to follow the screening program for cervical neoplasia, and clinicians should be aware of the slightly increased risk of HPV-related cervical lesions in IBD patients.”

Studies of IBD and cervical neoplasia have yielded mixed results as to a possible association. Some experts have postulated that underlying immunologic changes or the use of immunosuppressive drugs in IBD could thwart patients’ ability to clear HPV infections, thereby increasing their risk of developing cervical neoplasia. To explore that possibility, Dr. Rungoe and her associates compared rates of cervical dysplasia or cervical cancer among 27,408 women newly diagnosed with ulcerative colitis or Crohn’s disease and 1,508,334 controls without IBD. They identified cases and controls from a national patient registry of about 4 million women living in Denmark during 1979-2011. They also calculated the likelihood of a cervical neoplasia diagnosis preceding IBD.

Women with Crohn’s disease had a 26% higher rate of low-grade intraepithelial lesions of the cervix, a 28% greater incidence of high-grade lesions, and a 53% greater risk of cervical cancer compared with controls, the researchers reported (incidence rate ratios and 95% confidence intervals, respectively: 1.26, 1.07-1.48; 1.28, 1.13-1.45; and 1.53, 1.04-2.27). Women with ulcerative colitis also had about a 12%-15% increase in risk of developing cervical dysplasia, compared with controls (IRR for low-grade lesions, 1.15; 95% CI, 1.00-1.32; IRR for high-grade lesions, 1.12; 95% CI, 1.01-1.25), but no significant increase in cervical cancer risk.

Notably, women newly diagnosed with IBD had a “markedly elevated” odds of having been diagnosed with cervical neoplasia up to 10 years beforehand, the investigators reported. “This is a novel finding that may suggest a yet unexplored common susceptibility to IBD and cervical neoplasia, rather than an etiologic role of IBD or its treatment in development of cervical neoplasia,” they said.

Treatment with common IBD therapies such as azathioprine, mesalamine, and corticosteroids did not affect rates of cervical neoplasia, but women with Crohn’s disease who had used tumor necrosis factor–alpha antagonists had an 85% increase in high-grade intraepithelial cervical lesions. They also had a 2% increase in risk of these lesions for each filled prescription for hormonal contraceptives.

The frequency of cervical screening was slightly higher among women with ulcerative colitis, compared with controls, but was similar between controls and women with Crohn’s disease, the investigators noted.

The study was funded in part by the Danish Council of Independent Research. The investigators reported having no relevant financial disclosures.

Women with Crohn’s disease had about a 53% greater risk of developing cervical cancer compared with controls, and women with inflammatory bowel disease had a significantly greater risk of having had cervical neoplasia years earlier, according to a large population-based study reported in the April issue of Clinical Gastroenterology and Hepatology (http://dx.doi.org/10.1016/j.cgh.2014.07.036).

“We found a two-way association between inflammatory bowel disease, notably Crohn’s disease, and neoplastic lesions of the uterine cervix. This observation is not explained by differences in screening activity,” said Dr. Christine Rungoe at Statens Serum Institut in Copenhagen and her associates. “Patients with IBD should be encouraged to follow the screening program for cervical neoplasia, and clinicians should be aware of the slightly increased risk of HPV-related cervical lesions in IBD patients.”

Studies of IBD and cervical neoplasia have yielded mixed results as to a possible association. Some experts have postulated that underlying immunologic changes or the use of immunosuppressive drugs in IBD could thwart patients’ ability to clear HPV infections, thereby increasing their risk of developing cervical neoplasia. To explore that possibility, Dr. Rungoe and her associates compared rates of cervical dysplasia or cervical cancer among 27,408 women newly diagnosed with ulcerative colitis or Crohn’s disease and 1,508,334 controls without IBD. They identified cases and controls from a national patient registry of about 4 million women living in Denmark during 1979-2011. They also calculated the likelihood of a cervical neoplasia diagnosis preceding IBD.

Women with Crohn’s disease had a 26% higher rate of low-grade intraepithelial lesions of the cervix, a 28% greater incidence of high-grade lesions, and a 53% greater risk of cervical cancer compared with controls, the researchers reported (incidence rate ratios and 95% confidence intervals, respectively: 1.26, 1.07-1.48; 1.28, 1.13-1.45; and 1.53, 1.04-2.27). Women with ulcerative colitis also had about a 12%-15% increase in risk of developing cervical dysplasia, compared with controls (IRR for low-grade lesions, 1.15; 95% CI, 1.00-1.32; IRR for high-grade lesions, 1.12; 95% CI, 1.01-1.25), but no significant increase in cervical cancer risk.

Notably, women newly diagnosed with IBD had a “markedly elevated” odds of having been diagnosed with cervical neoplasia up to 10 years beforehand, the investigators reported. “This is a novel finding that may suggest a yet unexplored common susceptibility to IBD and cervical neoplasia, rather than an etiologic role of IBD or its treatment in development of cervical neoplasia,” they said.

Treatment with common IBD therapies such as azathioprine, mesalamine, and corticosteroids did not affect rates of cervical neoplasia, but women with Crohn’s disease who had used tumor necrosis factor–alpha antagonists had an 85% increase in high-grade intraepithelial cervical lesions. They also had a 2% increase in risk of these lesions for each filled prescription for hormonal contraceptives.

The frequency of cervical screening was slightly higher among women with ulcerative colitis, compared with controls, but was similar between controls and women with Crohn’s disease, the investigators noted.

The study was funded in part by the Danish Council of Independent Research. The investigators reported having no relevant financial disclosures.

Women with Crohn’s disease had about a 53% greater risk of developing cervical cancer compared with controls, and women with inflammatory bowel disease had a significantly greater risk of having had cervical neoplasia years earlier, according to a large population-based study reported in the April issue of Clinical Gastroenterology and Hepatology (http://dx.doi.org/10.1016/j.cgh.2014.07.036).

“We found a two-way association between inflammatory bowel disease, notably Crohn’s disease, and neoplastic lesions of the uterine cervix. This observation is not explained by differences in screening activity,” said Dr. Christine Rungoe at Statens Serum Institut in Copenhagen and her associates. “Patients with IBD should be encouraged to follow the screening program for cervical neoplasia, and clinicians should be aware of the slightly increased risk of HPV-related cervical lesions in IBD patients.”

Studies of IBD and cervical neoplasia have yielded mixed results as to a possible association. Some experts have postulated that underlying immunologic changes or the use of immunosuppressive drugs in IBD could thwart patients’ ability to clear HPV infections, thereby increasing their risk of developing cervical neoplasia. To explore that possibility, Dr. Rungoe and her associates compared rates of cervical dysplasia or cervical cancer among 27,408 women newly diagnosed with ulcerative colitis or Crohn’s disease and 1,508,334 controls without IBD. They identified cases and controls from a national patient registry of about 4 million women living in Denmark during 1979-2011. They also calculated the likelihood of a cervical neoplasia diagnosis preceding IBD.

Women with Crohn’s disease had a 26% higher rate of low-grade intraepithelial lesions of the cervix, a 28% greater incidence of high-grade lesions, and a 53% greater risk of cervical cancer compared with controls, the researchers reported (incidence rate ratios and 95% confidence intervals, respectively: 1.26, 1.07-1.48; 1.28, 1.13-1.45; and 1.53, 1.04-2.27). Women with ulcerative colitis also had about a 12%-15% increase in risk of developing cervical dysplasia, compared with controls (IRR for low-grade lesions, 1.15; 95% CI, 1.00-1.32; IRR for high-grade lesions, 1.12; 95% CI, 1.01-1.25), but no significant increase in cervical cancer risk.

Notably, women newly diagnosed with IBD had a “markedly elevated” odds of having been diagnosed with cervical neoplasia up to 10 years beforehand, the investigators reported. “This is a novel finding that may suggest a yet unexplored common susceptibility to IBD and cervical neoplasia, rather than an etiologic role of IBD or its treatment in development of cervical neoplasia,” they said.

Treatment with common IBD therapies such as azathioprine, mesalamine, and corticosteroids did not affect rates of cervical neoplasia, but women with Crohn’s disease who had used tumor necrosis factor–alpha antagonists had an 85% increase in high-grade intraepithelial cervical lesions. They also had a 2% increase in risk of these lesions for each filled prescription for hormonal contraceptives.

The frequency of cervical screening was slightly higher among women with ulcerative colitis, compared with controls, but was similar between controls and women with Crohn’s disease, the investigators noted.

The study was funded in part by the Danish Council of Independent Research. The investigators reported having no relevant financial disclosures.

A mixture of eight probiotic bacterial strains only somewhat outperformed placebo for preventing endoscopic recurrence after ileal resection in Crohn’s disease patients, according to a multicenter, randomized trial.

After 90 days of treatment, 9.3% of patients who received the probiotic mixture (VSL#3) had developed severe endoscopic recurrence, compared with 15.7% of the placebo group (P = .19), reported Dr. Richard Fedorak of the University of Alberta, Edmonton, and his associates.

The recurrence rate for the placebo group was about two-thirds lower than what the researchers had expected based on the sample size calculation, they noted. But the probiotic blend was linked to significantly significant decreases in colonic mucosal levels of proinflammatory cytokines, they reported (Clin. Gastroenterol. Hepatol. 2014 Nov. 6 [doi:10.1016/j.cgh.2014.10.031]).

Investigators have tested probiotics as a preventive therapy for Crohn’s disease because patients with active disease have less diverse intestinal microbiota, compared with those with quiescent disease or healthy controls. Past studies of single-strain probiotics have shown them to be no better than placebo for preventing endoscopic recurrence.

But in one small study, rifampin followed by VSL#3 outperformed mesalamine at 1 year (Gastroenterology 2000;118:A781), the researchers noted. “This mixture could confer protective effects where single-strain or lactobacillus-only formulations had failed,” they hypothesized.

To test that theory, the investigators randomized 120 patients with Crohn’s disease who had undergone ileal resection and ileocolonic anastomosis to twice-daily VSL#3 or placebo. Treatment began within 30 days after surgery and continued for 90 days, after which all patients received open-label VSL#3 for another 9 months.

Among patients who had nonsevere endoscopic lesions at day 90, 1-year rates of severe endoscopic recurrence were 10% for the early VSL#3 group, compared with 26.7% for the late VSL#3 group (P = .09), said the researchers. Likewise, combined rates of severe recurrence on days 90 and 365 were not statistically different, they reported. However, the early VSL#3 group had lower mucosal levels of 13 pro-inflammatory cytokines, compared with patients who received placebo until day 90 (P < .05). Measures of Crohn’s disease activity and disease-related quality of life scores were similar for both groups.

“Early treatment with VSL#3 had a larger effect than late treatment,” concluded the investigators. “Future larger studies will be needed to confirm the effect of VSL#3 in prevention of postoperative recurrence.”

The study was funded by VSL Pharmaceuticals, the Canadian Institutes of Health Research, and Crohn’s and Colitis Foundation of Canada. Dr. Fedorak reported having served on a speakers bureau for VSL Pharmaceuticals. The other authors declared no relevant conflicts of interest.

A mixture of eight probiotic bacterial strains only somewhat outperformed placebo for preventing endoscopic recurrence after ileal resection in Crohn’s disease patients, according to a multicenter, randomized trial.

After 90 days of treatment, 9.3% of patients who received the probiotic mixture (VSL#3) had developed severe endoscopic recurrence, compared with 15.7% of the placebo group (P = .19), reported Dr. Richard Fedorak of the University of Alberta, Edmonton, and his associates.

The recurrence rate for the placebo group was about two-thirds lower than what the researchers had expected based on the sample size calculation, they noted. But the probiotic blend was linked to significantly significant decreases in colonic mucosal levels of proinflammatory cytokines, they reported (Clin. Gastroenterol. Hepatol. 2014 Nov. 6 [doi:10.1016/j.cgh.2014.10.031]).

Investigators have tested probiotics as a preventive therapy for Crohn’s disease because patients with active disease have less diverse intestinal microbiota, compared with those with quiescent disease or healthy controls. Past studies of single-strain probiotics have shown them to be no better than placebo for preventing endoscopic recurrence.

But in one small study, rifampin followed by VSL#3 outperformed mesalamine at 1 year (Gastroenterology 2000;118:A781), the researchers noted. “This mixture could confer protective effects where single-strain or lactobacillus-only formulations had failed,” they hypothesized.

To test that theory, the investigators randomized 120 patients with Crohn’s disease who had undergone ileal resection and ileocolonic anastomosis to twice-daily VSL#3 or placebo. Treatment began within 30 days after surgery and continued for 90 days, after which all patients received open-label VSL#3 for another 9 months.

Among patients who had nonsevere endoscopic lesions at day 90, 1-year rates of severe endoscopic recurrence were 10% for the early VSL#3 group, compared with 26.7% for the late VSL#3 group (P = .09), said the researchers. Likewise, combined rates of severe recurrence on days 90 and 365 were not statistically different, they reported. However, the early VSL#3 group had lower mucosal levels of 13 pro-inflammatory cytokines, compared with patients who received placebo until day 90 (P < .05). Measures of Crohn’s disease activity and disease-related quality of life scores were similar for both groups.

“Early treatment with VSL#3 had a larger effect than late treatment,” concluded the investigators. “Future larger studies will be needed to confirm the effect of VSL#3 in prevention of postoperative recurrence.”

The study was funded by VSL Pharmaceuticals, the Canadian Institutes of Health Research, and Crohn’s and Colitis Foundation of Canada. Dr. Fedorak reported having served on a speakers bureau for VSL Pharmaceuticals. The other authors declared no relevant conflicts of interest.

A mixture of eight probiotic bacterial strains only somewhat outperformed placebo for preventing endoscopic recurrence after ileal resection in Crohn’s disease patients, according to a multicenter, randomized trial.

After 90 days of treatment, 9.3% of patients who received the probiotic mixture (VSL#3) had developed severe endoscopic recurrence, compared with 15.7% of the placebo group (P = .19), reported Dr. Richard Fedorak of the University of Alberta, Edmonton, and his associates.

The recurrence rate for the placebo group was about two-thirds lower than what the researchers had expected based on the sample size calculation, they noted. But the probiotic blend was linked to significantly significant decreases in colonic mucosal levels of proinflammatory cytokines, they reported (Clin. Gastroenterol. Hepatol. 2014 Nov. 6 [doi:10.1016/j.cgh.2014.10.031]).

Investigators have tested probiotics as a preventive therapy for Crohn’s disease because patients with active disease have less diverse intestinal microbiota, compared with those with quiescent disease or healthy controls. Past studies of single-strain probiotics have shown them to be no better than placebo for preventing endoscopic recurrence.

But in one small study, rifampin followed by VSL#3 outperformed mesalamine at 1 year (Gastroenterology 2000;118:A781), the researchers noted. “This mixture could confer protective effects where single-strain or lactobacillus-only formulations had failed,” they hypothesized.

To test that theory, the investigators randomized 120 patients with Crohn’s disease who had undergone ileal resection and ileocolonic anastomosis to twice-daily VSL#3 or placebo. Treatment began within 30 days after surgery and continued for 90 days, after which all patients received open-label VSL#3 for another 9 months.

Among patients who had nonsevere endoscopic lesions at day 90, 1-year rates of severe endoscopic recurrence were 10% for the early VSL#3 group, compared with 26.7% for the late VSL#3 group (P = .09), said the researchers. Likewise, combined rates of severe recurrence on days 90 and 365 were not statistically different, they reported. However, the early VSL#3 group had lower mucosal levels of 13 pro-inflammatory cytokines, compared with patients who received placebo until day 90 (P < .05). Measures of Crohn’s disease activity and disease-related quality of life scores were similar for both groups.

“Early treatment with VSL#3 had a larger effect than late treatment,” concluded the investigators. “Future larger studies will be needed to confirm the effect of VSL#3 in prevention of postoperative recurrence.”

The study was funded by VSL Pharmaceuticals, the Canadian Institutes of Health Research, and Crohn’s and Colitis Foundation of Canada. Dr. Fedorak reported having served on a speakers bureau for VSL Pharmaceuticals. The other authors declared no relevant conflicts of interest.

Infliximab caused liver injury in 8.3% of treated patients in a prospective study, exceeding rates for other tumor necrosis factor-alpha antagonists, investigators reported online in Clinical Gastroenterology and Hepatology.

The findings show that “liver injury associated with the use of TNF-alpha antagonists is more common than previously reported, occurring in 1 in 120 of those exposed to infliximab,” said Dr. Einar S. Björnsson at the University of Iceland in Reykjavik and his associates. Furthermore, neither anti-TNF treatment dose nor baseline antinuclear acid antibody (ANA) status predicted which patients would develop drug-induced liver injury (DILI), the researchers said.

Since emerging in the 1990s, anti-TNF agents have dramatically altered the treatment landscape for autoimmune diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Although they are known to cause liver damage in some patients, data on the topic mainly come from single case reports, the researchers said (Clin. Gastroenterol. Hepatol. 2014 [doi: http://dx.doi.org/10.1016/j.cgh.2014.07.062]) To better understand the association, the researchers prospectively studied patients who received anti-TNF agents between 2009 and 2013 at the University Hospital in Iceland. They defined liver injury as aspartate aminotransferase or alanine aminotransferase (ALT) levels that were at least triple the normal upper limit, or alkaline phosphatase levels of at least double the upper limit.

A total of 1,776 patients were treated with anti-TNF agents during the 5-year study period, the researchers reported. In all, 11 developed drug-induced liver injury (DILI), of which nine cases were caused by infliximab, they said. Liver injury developed in 8.3% of patients treated with infliximab, compared with only 3.7% of those who received adalimumab and 2.3% of those given etanercept, they added. In a past analysis, the researchers calculated that one in every 148 patients would develop DILI during 2 years of treatment with infliximab (Gastroenterology 2014;144:1419-25). Patients who developed DILI on one anti-TNF agent were able to switch therapies without DILI recurring, the investigators said. Seven patients were switched from infliximab to adalimumab, etanercept, or both, and one was switched to infliximab after developing DILI on adalimumab, they added.

The researchers also compared the 11 cases to 22 randomized controls matched by age, sex, underlying condition, and treatment. Notably, among the 11 patients diagnosed with DILI, just 1 (9%) was receiving methotrexate at the time of diagnosis, compared with 59% of the controls (P = .009), they reported. “The reason for this is not clear,” they added. “Methotrexate has been shown to lead to a decrease in circulating autoantibodies in cutaneous lupus erythematosus, but the influence of methotrexate could not be confirmed during infliximab treatment.”

Five of the 11 patients with DILI had liver biopsies, of which three showed severe acute hepatitis, two indicated mild unspecified chronic hepatitis, and one showed pure canalicular cholestasis, the researchers reported. About half the patients needed steroids acutely, but “the vast majority” did not need long-term steroid treatment, they said. Exactly how anti-TNF agents cause liver injury remains unclear, they added. Future studies might evaluate whether these drugs trigger CD4 T cells to react against liver cells, as is the case in classic autoimmune hepatitis, they said.

The researchers reported no funding sources and declared having no conflicts of interest.

Infliximab caused liver injury in 8.3% of treated patients in a prospective study, exceeding rates for other tumor necrosis factor-alpha antagonists, investigators reported online in Clinical Gastroenterology and Hepatology.

The findings show that “liver injury associated with the use of TNF-alpha antagonists is more common than previously reported, occurring in 1 in 120 of those exposed to infliximab,” said Dr. Einar S. Björnsson at the University of Iceland in Reykjavik and his associates. Furthermore, neither anti-TNF treatment dose nor baseline antinuclear acid antibody (ANA) status predicted which patients would develop drug-induced liver injury (DILI), the researchers said.

Since emerging in the 1990s, anti-TNF agents have dramatically altered the treatment landscape for autoimmune diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Although they are known to cause liver damage in some patients, data on the topic mainly come from single case reports, the researchers said (Clin. Gastroenterol. Hepatol. 2014 [doi: http://dx.doi.org/10.1016/j.cgh.2014.07.062]) To better understand the association, the researchers prospectively studied patients who received anti-TNF agents between 2009 and 2013 at the University Hospital in Iceland. They defined liver injury as aspartate aminotransferase or alanine aminotransferase (ALT) levels that were at least triple the normal upper limit, or alkaline phosphatase levels of at least double the upper limit.

A total of 1,776 patients were treated with anti-TNF agents during the 5-year study period, the researchers reported. In all, 11 developed drug-induced liver injury (DILI), of which nine cases were caused by infliximab, they said. Liver injury developed in 8.3% of patients treated with infliximab, compared with only 3.7% of those who received adalimumab and 2.3% of those given etanercept, they added. In a past analysis, the researchers calculated that one in every 148 patients would develop DILI during 2 years of treatment with infliximab (Gastroenterology 2014;144:1419-25). Patients who developed DILI on one anti-TNF agent were able to switch therapies without DILI recurring, the investigators said. Seven patients were switched from infliximab to adalimumab, etanercept, or both, and one was switched to infliximab after developing DILI on adalimumab, they added.

The researchers also compared the 11 cases to 22 randomized controls matched by age, sex, underlying condition, and treatment. Notably, among the 11 patients diagnosed with DILI, just 1 (9%) was receiving methotrexate at the time of diagnosis, compared with 59% of the controls (P = .009), they reported. “The reason for this is not clear,” they added. “Methotrexate has been shown to lead to a decrease in circulating autoantibodies in cutaneous lupus erythematosus, but the influence of methotrexate could not be confirmed during infliximab treatment.”

Five of the 11 patients with DILI had liver biopsies, of which three showed severe acute hepatitis, two indicated mild unspecified chronic hepatitis, and one showed pure canalicular cholestasis, the researchers reported. About half the patients needed steroids acutely, but “the vast majority” did not need long-term steroid treatment, they said. Exactly how anti-TNF agents cause liver injury remains unclear, they added. Future studies might evaluate whether these drugs trigger CD4 T cells to react against liver cells, as is the case in classic autoimmune hepatitis, they said.

The researchers reported no funding sources and declared having no conflicts of interest.

Infliximab caused liver injury in 8.3% of treated patients in a prospective study, exceeding rates for other tumor necrosis factor-alpha antagonists, investigators reported online in Clinical Gastroenterology and Hepatology.

The findings show that “liver injury associated with the use of TNF-alpha antagonists is more common than previously reported, occurring in 1 in 120 of those exposed to infliximab,” said Dr. Einar S. Björnsson at the University of Iceland in Reykjavik and his associates. Furthermore, neither anti-TNF treatment dose nor baseline antinuclear acid antibody (ANA) status predicted which patients would develop drug-induced liver injury (DILI), the researchers said.

Since emerging in the 1990s, anti-TNF agents have dramatically altered the treatment landscape for autoimmune diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Although they are known to cause liver damage in some patients, data on the topic mainly come from single case reports, the researchers said (Clin. Gastroenterol. Hepatol. 2014 [doi: http://dx.doi.org/10.1016/j.cgh.2014.07.062]) To better understand the association, the researchers prospectively studied patients who received anti-TNF agents between 2009 and 2013 at the University Hospital in Iceland. They defined liver injury as aspartate aminotransferase or alanine aminotransferase (ALT) levels that were at least triple the normal upper limit, or alkaline phosphatase levels of at least double the upper limit.

A total of 1,776 patients were treated with anti-TNF agents during the 5-year study period, the researchers reported. In all, 11 developed drug-induced liver injury (DILI), of which nine cases were caused by infliximab, they said. Liver injury developed in 8.3% of patients treated with infliximab, compared with only 3.7% of those who received adalimumab and 2.3% of those given etanercept, they added. In a past analysis, the researchers calculated that one in every 148 patients would develop DILI during 2 years of treatment with infliximab (Gastroenterology 2014;144:1419-25). Patients who developed DILI on one anti-TNF agent were able to switch therapies without DILI recurring, the investigators said. Seven patients were switched from infliximab to adalimumab, etanercept, or both, and one was switched to infliximab after developing DILI on adalimumab, they added.

The researchers also compared the 11 cases to 22 randomized controls matched by age, sex, underlying condition, and treatment. Notably, among the 11 patients diagnosed with DILI, just 1 (9%) was receiving methotrexate at the time of diagnosis, compared with 59% of the controls (P = .009), they reported. “The reason for this is not clear,” they added. “Methotrexate has been shown to lead to a decrease in circulating autoantibodies in cutaneous lupus erythematosus, but the influence of methotrexate could not be confirmed during infliximab treatment.”

Five of the 11 patients with DILI had liver biopsies, of which three showed severe acute hepatitis, two indicated mild unspecified chronic hepatitis, and one showed pure canalicular cholestasis, the researchers reported. About half the patients needed steroids acutely, but “the vast majority” did not need long-term steroid treatment, they said. Exactly how anti-TNF agents cause liver injury remains unclear, they added. Future studies might evaluate whether these drugs trigger CD4 T cells to react against liver cells, as is the case in classic autoimmune hepatitis, they said.

The researchers reported no funding sources and declared having no conflicts of interest.

Chronic Helicobacter pylori infection suppresses interleukin-33 cytokine in the stomach, which inhibits the CD4+ T helper cell 2 (or Th2) response and may set the stage for gastric carcinoma, investigators reported online in Cellular and Molecular Gastroenterology and Hepatology.

But long-term rises in IL-33 also can trigger precancerous changes in the stomach by causing the immune system to skew excessively toward Th2 instead of Th1 immunity, said Jon Buzzelli and his associates at the University of Melbourne in Parkville, Australia.

“Despite the immune response being vastly different ... the outcome appears to be similar, as preneoplastic changes occur in both settings,” the researchers added. “In keeping with recent findings, these data suggest that H. pylori may be a beneficial organism that under certain circumstances may help to ensure that gastric immunity is tightly regulated.” (Cellular and Molecular Gastroenterology and Hepatology 2015 [http://dx.doi.org/10.1016/j.jcmgh.2014.12.003 5])

©NDDIC.NIH.gov

IL-33 is a member of a diverse group of cytokines called alarmins, which quickly trigger an immune response to injury or infection when released by dying cells. Fasted mice in the study that were given oral aspirin to induce gastric injury had elevated IL-33 expression, compared with controls 4 hours later, the investigators reported. “This demonstrates that IL-33 responds immediately to gastric insult through relocalization and transcriptional changes, and may be involved in gastric wound healing,” they added.

The researchers also found that gastric IL-33 levels in mice rose fourfold just 1 day after they were infected with H. pylori. But 2 months later, the mice’s IL-33 levels had fallen below those of controls, resembling the researchers’ comparison of H. pylori–positive and uninfected human stomach specimens, they said.

Furthermore, the drop in IL-33 caused a tilt away from Th2 toward Th1 immunity, which appeared to trigger precancerous changes to the gastric mucosa, the researchers added. “The inhibition of gastric IL-33 in response to chronic H. pylori infection may be a key event in gastric cancer progression,” they concluded.

But eliminating H. pylori might also cause problems in some cases, the findings suggested. The declining prevalence of helicobacteriosis in humans has accompanied a rise in Barrett’s esophagus, which precedes esophageal cancer, they noted. When the researchers administered extra IL-33 to mice – mimicking the absence of H. pylori – the cardia of their stomachs expanded and became markedly metaplastic, which precedes Barrett’s esophagus in humans, they noted. H. pylori might help prevent Barrett’s esophagus by suppressing IL-33 and thereby regulating Th2 immunity, they concluded.

The researchers also found that mice born and reared in a pathogen-free environment had lower IL-33 levels, compared with those in conventional housing, they said. Gastric IL-33 expression appeared to rise as bacterial load and diversity increased, supporting the idea that IL-33 functions in this setting as an alarmin, they added.

The investigators also examined whether the TFF2 gene – which helps regulate homeostasis in mucus cells – promoted IL-33 expression in the stomach, as it does in the lungs. Indeed, TFF2 knockout mice had about 40% less gastric IL-33, compared with wild-type mice, they said. Humans with chronic helicobacteriosis also have low TFF2 expression, which continues to fall as gastric cancer grows, they noted.

The study was funded by the Victorian Government’s Operational Infrastructure Support Program and National Health & Medical Research Council, Australia. The researchers reported no conflicts of interest.

Chronic Helicobacter pylori infection suppresses interleukin-33 cytokine in the stomach, which inhibits the CD4+ T helper cell 2 (or Th2) response and may set the stage for gastric carcinoma, investigators reported online in Cellular and Molecular Gastroenterology and Hepatology.

But long-term rises in IL-33 also can trigger precancerous changes in the stomach by causing the immune system to skew excessively toward Th2 instead of Th1 immunity, said Jon Buzzelli and his associates at the University of Melbourne in Parkville, Australia.

“Despite the immune response being vastly different ... the outcome appears to be similar, as preneoplastic changes occur in both settings,” the researchers added. “In keeping with recent findings, these data suggest that H. pylori may be a beneficial organism that under certain circumstances may help to ensure that gastric immunity is tightly regulated.” (Cellular and Molecular Gastroenterology and Hepatology 2015 [http://dx.doi.org/10.1016/j.jcmgh.2014.12.003 5])

©NDDIC.NIH.gov

IL-33 is a member of a diverse group of cytokines called alarmins, which quickly trigger an immune response to injury or infection when released by dying cells. Fasted mice in the study that were given oral aspirin to induce gastric injury had elevated IL-33 expression, compared with controls 4 hours later, the investigators reported. “This demonstrates that IL-33 responds immediately to gastric insult through relocalization and transcriptional changes, and may be involved in gastric wound healing,” they added.

The researchers also found that gastric IL-33 levels in mice rose fourfold just 1 day after they were infected with H. pylori. But 2 months later, the mice’s IL-33 levels had fallen below those of controls, resembling the researchers’ comparison of H. pylori–positive and uninfected human stomach specimens, they said.

Furthermore, the drop in IL-33 caused a tilt away from Th2 toward Th1 immunity, which appeared to trigger precancerous changes to the gastric mucosa, the researchers added. “The inhibition of gastric IL-33 in response to chronic H. pylori infection may be a key event in gastric cancer progression,” they concluded.

But eliminating H. pylori might also cause problems in some cases, the findings suggested. The declining prevalence of helicobacteriosis in humans has accompanied a rise in Barrett’s esophagus, which precedes esophageal cancer, they noted. When the researchers administered extra IL-33 to mice – mimicking the absence of H. pylori – the cardia of their stomachs expanded and became markedly metaplastic, which precedes Barrett’s esophagus in humans, they noted. H. pylori might help prevent Barrett’s esophagus by suppressing IL-33 and thereby regulating Th2 immunity, they concluded.

The researchers also found that mice born and reared in a pathogen-free environment had lower IL-33 levels, compared with those in conventional housing, they said. Gastric IL-33 expression appeared to rise as bacterial load and diversity increased, supporting the idea that IL-33 functions in this setting as an alarmin, they added.

The investigators also examined whether the TFF2 gene – which helps regulate homeostasis in mucus cells – promoted IL-33 expression in the stomach, as it does in the lungs. Indeed, TFF2 knockout mice had about 40% less gastric IL-33, compared with wild-type mice, they said. Humans with chronic helicobacteriosis also have low TFF2 expression, which continues to fall as gastric cancer grows, they noted.

The study was funded by the Victorian Government’s Operational Infrastructure Support Program and National Health & Medical Research Council, Australia. The researchers reported no conflicts of interest.

Chronic Helicobacter pylori infection suppresses interleukin-33 cytokine in the stomach, which inhibits the CD4+ T helper cell 2 (or Th2) response and may set the stage for gastric carcinoma, investigators reported online in Cellular and Molecular Gastroenterology and Hepatology.

But long-term rises in IL-33 also can trigger precancerous changes in the stomach by causing the immune system to skew excessively toward Th2 instead of Th1 immunity, said Jon Buzzelli and his associates at the University of Melbourne in Parkville, Australia.

“Despite the immune response being vastly different ... the outcome appears to be similar, as preneoplastic changes occur in both settings,” the researchers added. “In keeping with recent findings, these data suggest that H. pylori may be a beneficial organism that under certain circumstances may help to ensure that gastric immunity is tightly regulated.” (Cellular and Molecular Gastroenterology and Hepatology 2015 [http://dx.doi.org/10.1016/j.jcmgh.2014.12.003 5])

©NDDIC.NIH.gov

IL-33 is a member of a diverse group of cytokines called alarmins, which quickly trigger an immune response to injury or infection when released by dying cells. Fasted mice in the study that were given oral aspirin to induce gastric injury had elevated IL-33 expression, compared with controls 4 hours later, the investigators reported. “This demonstrates that IL-33 responds immediately to gastric insult through relocalization and transcriptional changes, and may be involved in gastric wound healing,” they added.

The researchers also found that gastric IL-33 levels in mice rose fourfold just 1 day after they were infected with H. pylori. But 2 months later, the mice’s IL-33 levels had fallen below those of controls, resembling the researchers’ comparison of H. pylori–positive and uninfected human stomach specimens, they said.

Furthermore, the drop in IL-33 caused a tilt away from Th2 toward Th1 immunity, which appeared to trigger precancerous changes to the gastric mucosa, the researchers added. “The inhibition of gastric IL-33 in response to chronic H. pylori infection may be a key event in gastric cancer progression,” they concluded.

But eliminating H. pylori might also cause problems in some cases, the findings suggested. The declining prevalence of helicobacteriosis in humans has accompanied a rise in Barrett’s esophagus, which precedes esophageal cancer, they noted. When the researchers administered extra IL-33 to mice – mimicking the absence of H. pylori – the cardia of their stomachs expanded and became markedly metaplastic, which precedes Barrett’s esophagus in humans, they noted. H. pylori might help prevent Barrett’s esophagus by suppressing IL-33 and thereby regulating Th2 immunity, they concluded.

The researchers also found that mice born and reared in a pathogen-free environment had lower IL-33 levels, compared with those in conventional housing, they said. Gastric IL-33 expression appeared to rise as bacterial load and diversity increased, supporting the idea that IL-33 functions in this setting as an alarmin, they added.

The investigators also examined whether the TFF2 gene – which helps regulate homeostasis in mucus cells – promoted IL-33 expression in the stomach, as it does in the lungs. Indeed, TFF2 knockout mice had about 40% less gastric IL-33, compared with wild-type mice, they said. Humans with chronic helicobacteriosis also have low TFF2 expression, which continues to fall as gastric cancer grows, they noted.

The study was funded by the Victorian Government’s Operational Infrastructure Support Program and National Health & Medical Research Council, Australia. The researchers reported no conflicts of interest.