DDW 2014

CHICAGO – A novel, externally worn device for the treatment of extraesophageal reflux proved effective, safe, and well tolerated in a multicenter clinical trial.

"Given the poor response to PPI [proton-pump inhibitors] therapy in many patients with extraesophageal reflux, this device may be an alternative form of treating this difficult disorder," Dr. Michael F. Vaezi said in a presentation of the study findings at the annual Digestive Disease Week.

Extraesophageal reflux (EER) affects more than 15 million Americans. The cost of care is estimated to be in excess of $50 billion annually, most of which goes for PPIs, which are overused and generally not effective in treating this common disorder, observed Dr. Vaezi, professor of medicine at Vanderbilt University, Nashville, Tenn.

EER is caused by reflux of gastroduodenal contents into the laryngopharynx, resulting in a range of symptoms including chronic cough, postnasal drip, throat clearing, hoarseness, and a sensation of a lump in the throat.

The investigational device, known as the Reza-Band, is an individually fitted upper esophageal sphincter assist device to be worn at bedtime. It is designed to apply slight pressure to the cricoid cartilage area sufficient to increase the intraluminal pressure of the upper esophageal sphincter to 20 mm Hg. In earlier studies, this modest increase in pressure eliminated pharyngeal reflux without affecting normal activities such as swallowing and belching.

Dr. Vaezi reported on 47 patients with EER treated with the upper esophageal assist device at four medical centers. Their mean age was 50 years, with an average body mass index of 26.1 kg/m². Three-quarters of patients were on PPI therapy, which they felt to be ineffective.

The primary study endpoint was the change in Reflux Symptom Index scores from baseline through week 4 of nighttime use of the assist device. The median score improved from 27 at baseline to 14 at week 2 and 12 at week 4. That translated to a mean 54% reduction. A total of 86% of subjects were deemed to have experienced treatment success as defined by at least a 25% improvement in their symptom score; 30% of participants showed a greater than 75% improvement.

Treatment side effects were few, mild, and brief, consisting chiefly of skin irritation from the device’s Velcro strap. No one withdrew from the study.

The Reza-Band device was developed by gastroenterologists at the Medical College of Wisconsin, Milwaukee. Dr. Vaezi said he and his coinvestigators decided to formally investigate the device because "we were intrigued and impressed by the fact that it has helped so many patients."

"For me, it’s a welcome development," Dr. Vaezi added. "Just anecdotally, many patients in the study wanted to know how they could purchase this device. It’s really welcome in an area [in which] we don’t have many therapeutic options."

Still, he noted, it’s probably a good idea for device users to continue to keep a couple of bricks under the head of the bed, in accord with standard medical advice.

Future plans include a sham-controlled study designed to assess the device’s true benefit over placebo therapy; this will be an important study because EER is known to have a substantial placebo response rate, he continued. Also, plans are afoot for a safety study assessing whether the device has any clinically meaningful impact upon intraocular pressure.

The study was supported by Somna Therapeutics, which is developing the device. Dr. Vaezi reported having no financial relationship with the company.

bjancin@frontlinemedcom.com

CHICAGO – A novel, externally worn device for the treatment of extraesophageal reflux proved effective, safe, and well tolerated in a multicenter clinical trial.

"Given the poor response to PPI [proton-pump inhibitors] therapy in many patients with extraesophageal reflux, this device may be an alternative form of treating this difficult disorder," Dr. Michael F. Vaezi said in a presentation of the study findings at the annual Digestive Disease Week.

Extraesophageal reflux (EER) affects more than 15 million Americans. The cost of care is estimated to be in excess of $50 billion annually, most of which goes for PPIs, which are overused and generally not effective in treating this common disorder, observed Dr. Vaezi, professor of medicine at Vanderbilt University, Nashville, Tenn.

EER is caused by reflux of gastroduodenal contents into the laryngopharynx, resulting in a range of symptoms including chronic cough, postnasal drip, throat clearing, hoarseness, and a sensation of a lump in the throat.

The investigational device, known as the Reza-Band, is an individually fitted upper esophageal sphincter assist device to be worn at bedtime. It is designed to apply slight pressure to the cricoid cartilage area sufficient to increase the intraluminal pressure of the upper esophageal sphincter to 20 mm Hg. In earlier studies, this modest increase in pressure eliminated pharyngeal reflux without affecting normal activities such as swallowing and belching.

Dr. Vaezi reported on 47 patients with EER treated with the upper esophageal assist device at four medical centers. Their mean age was 50 years, with an average body mass index of 26.1 kg/m². Three-quarters of patients were on PPI therapy, which they felt to be ineffective.

The primary study endpoint was the change in Reflux Symptom Index scores from baseline through week 4 of nighttime use of the assist device. The median score improved from 27 at baseline to 14 at week 2 and 12 at week 4. That translated to a mean 54% reduction. A total of 86% of subjects were deemed to have experienced treatment success as defined by at least a 25% improvement in their symptom score; 30% of participants showed a greater than 75% improvement.

Treatment side effects were few, mild, and brief, consisting chiefly of skin irritation from the device’s Velcro strap. No one withdrew from the study.

The Reza-Band device was developed by gastroenterologists at the Medical College of Wisconsin, Milwaukee. Dr. Vaezi said he and his coinvestigators decided to formally investigate the device because "we were intrigued and impressed by the fact that it has helped so many patients."

"For me, it’s a welcome development," Dr. Vaezi added. "Just anecdotally, many patients in the study wanted to know how they could purchase this device. It’s really welcome in an area [in which] we don’t have many therapeutic options."

Still, he noted, it’s probably a good idea for device users to continue to keep a couple of bricks under the head of the bed, in accord with standard medical advice.

Future plans include a sham-controlled study designed to assess the device’s true benefit over placebo therapy; this will be an important study because EER is known to have a substantial placebo response rate, he continued. Also, plans are afoot for a safety study assessing whether the device has any clinically meaningful impact upon intraocular pressure.

The study was supported by Somna Therapeutics, which is developing the device. Dr. Vaezi reported having no financial relationship with the company.

bjancin@frontlinemedcom.com

CHICAGO – A novel, externally worn device for the treatment of extraesophageal reflux proved effective, safe, and well tolerated in a multicenter clinical trial.

"Given the poor response to PPI [proton-pump inhibitors] therapy in many patients with extraesophageal reflux, this device may be an alternative form of treating this difficult disorder," Dr. Michael F. Vaezi said in a presentation of the study findings at the annual Digestive Disease Week.

Extraesophageal reflux (EER) affects more than 15 million Americans. The cost of care is estimated to be in excess of $50 billion annually, most of which goes for PPIs, which are overused and generally not effective in treating this common disorder, observed Dr. Vaezi, professor of medicine at Vanderbilt University, Nashville, Tenn.

EER is caused by reflux of gastroduodenal contents into the laryngopharynx, resulting in a range of symptoms including chronic cough, postnasal drip, throat clearing, hoarseness, and a sensation of a lump in the throat.

The investigational device, known as the Reza-Band, is an individually fitted upper esophageal sphincter assist device to be worn at bedtime. It is designed to apply slight pressure to the cricoid cartilage area sufficient to increase the intraluminal pressure of the upper esophageal sphincter to 20 mm Hg. In earlier studies, this modest increase in pressure eliminated pharyngeal reflux without affecting normal activities such as swallowing and belching.

Dr. Vaezi reported on 47 patients with EER treated with the upper esophageal assist device at four medical centers. Their mean age was 50 years, with an average body mass index of 26.1 kg/m². Three-quarters of patients were on PPI therapy, which they felt to be ineffective.

The primary study endpoint was the change in Reflux Symptom Index scores from baseline through week 4 of nighttime use of the assist device. The median score improved from 27 at baseline to 14 at week 2 and 12 at week 4. That translated to a mean 54% reduction. A total of 86% of subjects were deemed to have experienced treatment success as defined by at least a 25% improvement in their symptom score; 30% of participants showed a greater than 75% improvement.

Treatment side effects were few, mild, and brief, consisting chiefly of skin irritation from the device’s Velcro strap. No one withdrew from the study.

The Reza-Band device was developed by gastroenterologists at the Medical College of Wisconsin, Milwaukee. Dr. Vaezi said he and his coinvestigators decided to formally investigate the device because "we were intrigued and impressed by the fact that it has helped so many patients."

"For me, it’s a welcome development," Dr. Vaezi added. "Just anecdotally, many patients in the study wanted to know how they could purchase this device. It’s really welcome in an area [in which] we don’t have many therapeutic options."

Still, he noted, it’s probably a good idea for device users to continue to keep a couple of bricks under the head of the bed, in accord with standard medical advice.

Future plans include a sham-controlled study designed to assess the device’s true benefit over placebo therapy; this will be an important study because EER is known to have a substantial placebo response rate, he continued. Also, plans are afoot for a safety study assessing whether the device has any clinically meaningful impact upon intraocular pressure.

The study was supported by Somna Therapeutics, which is developing the device. Dr. Vaezi reported having no financial relationship with the company.

bjancin@frontlinemedcom.com

CHICAGO – Women with inflammatory bowel disease can safely continue monotherapy with azathioprine/6-mercaptopurine or antitumor necrosis–alpha agents during pregnancy to maintain remission, according to an analysis of 1,289 women and 1,039 live births.

Infants exposed to azathioprine/6 MP and anti-TNF-alpha agents achieve developmental milestone scores at rates similar to unexposed infants and do not have higher rates of congenital anomalies, lead author Dr. Uma Mahadevan said at the annual Digestive Disease Week.

Overall, there were 55 congenital anomalies, with 21 diagnosed at birth. Events were similar among infants with in utero exposure to azathioprine, anti-TNF agents, combination therapy, and those with no drug exposure (12 vs. 17 vs. 7 vs. 19 events).

Exposure was defined as any use of azathioprine/6 MP or the anti-TNF-alpha agents infliximab (Remicade), adalimumab (Humira), or certolizumab pegol (Cimzia) at any time from 3 months prior to conception to the end of the pregnancy. Nine women had exposure to the recombinant monoclonal antibody natalizumab (Tysabri) and were included in the anti-TNF agents group.

The analysis was based on the PIANO registry, a prospective cohort of pregnant women with IBD who were followed by telephone or in-person questionnaire at every trimester, at delivery, at 4, 9, and 12 months after delivery, and annually for the first 4 years of their child’s life. Seven women received their diagnosis of IBD during pregnancy, 59.4% had Crohn’s disease, 38.3% ulcerative colitis, and 2.3% were indeterminate.

Two-thirds of women reported breastfeeding, with unexposed women significantly more likely to breastfeed than women with exposure to azathioprine, anti-TNF agents, or combination therapy (85% vs. 65% vs. 71% vs. 61%; P less than .0001).

After controlling for drug exposure, breastfeeding was not associated with an increased risk of infant infection or reduced height or weight, reported Dr. Mahadevan, with the University of California San Francisco.

Infants exposed to combination therapy, however, had higher rates of preterm birth, after adjustment for none/mild vs. moderate/severe IBD activity (odds ratio, 2.6; P less than .05).

Infants exposed to combination therapy who were born to mothers with ulcerative colitis also had increased rates of preterm birth (odds ratio, 4.9), low birth weight (OR, 6.1), and NICU stay (OR, 3.9).

One possible reason for this signal is that women with ulcerative colitis in the PIANO registry, as well as two other studies, have more disease activity during pregnancy, Dr. Mahadevan suggested. Another possibility is that mothers with ulcerative colitis may have low levels of untreated inflammation.

With just 161 women available for analysis, the PIANO investigators previously reported a significant increase in infant infections at 12 months of age in those exposed to combination infliximab or adalimumab plus azathioprine. Most anti-TNF agents cross the placenta in the second and third trimester, which has raised concerns about immune system development and risk of subsequent infections.

In the current analysis, there was no increase in infant infections when the investigators looked at all anti-TNF drugs. "But when we removed certolizumab from the analysis, it was significant just as it was 2 years ago," Dr. Mahadevan said in an interview. "Certolizumab is not actively transported across the placenta. Fortunately, the majority of the infections were minor, including otitis media and upper respiratory infections."

Developmental milestones

Overall, infants exposed to azathioprine or anti-TNF agents were found to achieve developmental milestones at rates similar to unexposed infants of mothers with IBD based on Denver Childhood Developmental Test and Ages and Stages Questionnaire scores, she said.

After controlling for preterm birth, the mean developmental milestone score at 4 months was 0.92 for infants with no drug exposure, with a nonsignificant mean delta difference of 0.01, 0.01, 0.00 points for infants exposed to azathioprine, anti-TNF agents, and combination therapy, respectively.

In a surprising twist, infants exposed to anti-TNF agents alone actually had significantly better scores at 12 months than unexposed infants, bettering the average score of 0.81 in the unexposed group by a mean delta of 0.02 points (P = .01), Dr. Mahadevan said.

"I wouldn’t interpret this data [as indicating] that biologics make your baby smarter. I think the key thing is that it doesn’t make it worse," she remarked. "When you see the deltas, they are pretty small."

On the Ages and Stages Questionnaire, the biologic group had significantly better mean scores than the unexposed group for gross motor skills at 36 months (55.94 vs. 47.53; P = .01), gross motor skills at 48 months (60 vs. 51.20; P = .02), fine motor skills at 48 months (53.50 vs. 42.11; P = .01), and personal/social interaction at 48 months (58 vs. 51.93; P = .04).

The azathioprine-exposed group always had better scores than the unexposed group, Dr. Mahadevan said. Where it was statistically significant was for personal/social interaction at 24 months (50.75 vs. 47.34; P = .04), problem solving at 36 months (mean 52.04 vs. 48.66; P = .05), and problem solving at 48 months (mean 59.92 vs. 57.66; P = .02).

Dr. Mahadevan observed that the data may change because not all infants have reached each time point and may not reflect outcomes in lower socioeconomic groups since more than 90% of women were of similar socioeconomic and educational status.

Still, the findings are reassuring in the absence of any randomized controlled trials. A recent report found children born to mothers with IBD had higher rates of attention-deficit hyperactivity disorder and gross motor abnormalities (J. Crohns Colitis 2013;7:542-50), while a case series reported normal neuropsychological development in 25 consecutive children exposed in utero to TNF-alpha inhibitors (Inflamm. Bowel Dis. 2014;20:495-501), she noted.

A recent systematic review of 58 articles or abstracts also found no association between TNF-alpha inhibitor use during pregnancy with IBD and adverse pregnancy outcomes, congenital abnormalities, or infections in the first year of life (BMC Medicine 2013;11:174).

The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Mahadevan reported serving as an advisor for Janssen-Cilag, AbbVie, Takeda, and UCB Pharma, and receiving research grants from Prometheus Laboratories and GlaxoSmithKline.

pwendling@frontlinemedcom.com

CHICAGO – Women with inflammatory bowel disease can safely continue monotherapy with azathioprine/6-mercaptopurine or antitumor necrosis–alpha agents during pregnancy to maintain remission, according to an analysis of 1,289 women and 1,039 live births.

Infants exposed to azathioprine/6 MP and anti-TNF-alpha agents achieve developmental milestone scores at rates similar to unexposed infants and do not have higher rates of congenital anomalies, lead author Dr. Uma Mahadevan said at the annual Digestive Disease Week.

Overall, there were 55 congenital anomalies, with 21 diagnosed at birth. Events were similar among infants with in utero exposure to azathioprine, anti-TNF agents, combination therapy, and those with no drug exposure (12 vs. 17 vs. 7 vs. 19 events).

Exposure was defined as any use of azathioprine/6 MP or the anti-TNF-alpha agents infliximab (Remicade), adalimumab (Humira), or certolizumab pegol (Cimzia) at any time from 3 months prior to conception to the end of the pregnancy. Nine women had exposure to the recombinant monoclonal antibody natalizumab (Tysabri) and were included in the anti-TNF agents group.

The analysis was based on the PIANO registry, a prospective cohort of pregnant women with IBD who were followed by telephone or in-person questionnaire at every trimester, at delivery, at 4, 9, and 12 months after delivery, and annually for the first 4 years of their child’s life. Seven women received their diagnosis of IBD during pregnancy, 59.4% had Crohn’s disease, 38.3% ulcerative colitis, and 2.3% were indeterminate.

Two-thirds of women reported breastfeeding, with unexposed women significantly more likely to breastfeed than women with exposure to azathioprine, anti-TNF agents, or combination therapy (85% vs. 65% vs. 71% vs. 61%; P less than .0001).

After controlling for drug exposure, breastfeeding was not associated with an increased risk of infant infection or reduced height or weight, reported Dr. Mahadevan, with the University of California San Francisco.

Infants exposed to combination therapy, however, had higher rates of preterm birth, after adjustment for none/mild vs. moderate/severe IBD activity (odds ratio, 2.6; P less than .05).

Infants exposed to combination therapy who were born to mothers with ulcerative colitis also had increased rates of preterm birth (odds ratio, 4.9), low birth weight (OR, 6.1), and NICU stay (OR, 3.9).

One possible reason for this signal is that women with ulcerative colitis in the PIANO registry, as well as two other studies, have more disease activity during pregnancy, Dr. Mahadevan suggested. Another possibility is that mothers with ulcerative colitis may have low levels of untreated inflammation.

With just 161 women available for analysis, the PIANO investigators previously reported a significant increase in infant infections at 12 months of age in those exposed to combination infliximab or adalimumab plus azathioprine. Most anti-TNF agents cross the placenta in the second and third trimester, which has raised concerns about immune system development and risk of subsequent infections.

In the current analysis, there was no increase in infant infections when the investigators looked at all anti-TNF drugs. "But when we removed certolizumab from the analysis, it was significant just as it was 2 years ago," Dr. Mahadevan said in an interview. "Certolizumab is not actively transported across the placenta. Fortunately, the majority of the infections were minor, including otitis media and upper respiratory infections."

Developmental milestones

Overall, infants exposed to azathioprine or anti-TNF agents were found to achieve developmental milestones at rates similar to unexposed infants of mothers with IBD based on Denver Childhood Developmental Test and Ages and Stages Questionnaire scores, she said.

After controlling for preterm birth, the mean developmental milestone score at 4 months was 0.92 for infants with no drug exposure, with a nonsignificant mean delta difference of 0.01, 0.01, 0.00 points for infants exposed to azathioprine, anti-TNF agents, and combination therapy, respectively.

In a surprising twist, infants exposed to anti-TNF agents alone actually had significantly better scores at 12 months than unexposed infants, bettering the average score of 0.81 in the unexposed group by a mean delta of 0.02 points (P = .01), Dr. Mahadevan said.

"I wouldn’t interpret this data [as indicating] that biologics make your baby smarter. I think the key thing is that it doesn’t make it worse," she remarked. "When you see the deltas, they are pretty small."

On the Ages and Stages Questionnaire, the biologic group had significantly better mean scores than the unexposed group for gross motor skills at 36 months (55.94 vs. 47.53; P = .01), gross motor skills at 48 months (60 vs. 51.20; P = .02), fine motor skills at 48 months (53.50 vs. 42.11; P = .01), and personal/social interaction at 48 months (58 vs. 51.93; P = .04).

The azathioprine-exposed group always had better scores than the unexposed group, Dr. Mahadevan said. Where it was statistically significant was for personal/social interaction at 24 months (50.75 vs. 47.34; P = .04), problem solving at 36 months (mean 52.04 vs. 48.66; P = .05), and problem solving at 48 months (mean 59.92 vs. 57.66; P = .02).

Dr. Mahadevan observed that the data may change because not all infants have reached each time point and may not reflect outcomes in lower socioeconomic groups since more than 90% of women were of similar socioeconomic and educational status.

Still, the findings are reassuring in the absence of any randomized controlled trials. A recent report found children born to mothers with IBD had higher rates of attention-deficit hyperactivity disorder and gross motor abnormalities (J. Crohns Colitis 2013;7:542-50), while a case series reported normal neuropsychological development in 25 consecutive children exposed in utero to TNF-alpha inhibitors (Inflamm. Bowel Dis. 2014;20:495-501), she noted.

A recent systematic review of 58 articles or abstracts also found no association between TNF-alpha inhibitor use during pregnancy with IBD and adverse pregnancy outcomes, congenital abnormalities, or infections in the first year of life (BMC Medicine 2013;11:174).

The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Mahadevan reported serving as an advisor for Janssen-Cilag, AbbVie, Takeda, and UCB Pharma, and receiving research grants from Prometheus Laboratories and GlaxoSmithKline.

pwendling@frontlinemedcom.com

CHICAGO – Women with inflammatory bowel disease can safely continue monotherapy with azathioprine/6-mercaptopurine or antitumor necrosis–alpha agents during pregnancy to maintain remission, according to an analysis of 1,289 women and 1,039 live births.

Infants exposed to azathioprine/6 MP and anti-TNF-alpha agents achieve developmental milestone scores at rates similar to unexposed infants and do not have higher rates of congenital anomalies, lead author Dr. Uma Mahadevan said at the annual Digestive Disease Week.

Overall, there were 55 congenital anomalies, with 21 diagnosed at birth. Events were similar among infants with in utero exposure to azathioprine, anti-TNF agents, combination therapy, and those with no drug exposure (12 vs. 17 vs. 7 vs. 19 events).

Exposure was defined as any use of azathioprine/6 MP or the anti-TNF-alpha agents infliximab (Remicade), adalimumab (Humira), or certolizumab pegol (Cimzia) at any time from 3 months prior to conception to the end of the pregnancy. Nine women had exposure to the recombinant monoclonal antibody natalizumab (Tysabri) and were included in the anti-TNF agents group.

The analysis was based on the PIANO registry, a prospective cohort of pregnant women with IBD who were followed by telephone or in-person questionnaire at every trimester, at delivery, at 4, 9, and 12 months after delivery, and annually for the first 4 years of their child’s life. Seven women received their diagnosis of IBD during pregnancy, 59.4% had Crohn’s disease, 38.3% ulcerative colitis, and 2.3% were indeterminate.

Two-thirds of women reported breastfeeding, with unexposed women significantly more likely to breastfeed than women with exposure to azathioprine, anti-TNF agents, or combination therapy (85% vs. 65% vs. 71% vs. 61%; P less than .0001).

After controlling for drug exposure, breastfeeding was not associated with an increased risk of infant infection or reduced height or weight, reported Dr. Mahadevan, with the University of California San Francisco.

Infants exposed to combination therapy, however, had higher rates of preterm birth, after adjustment for none/mild vs. moderate/severe IBD activity (odds ratio, 2.6; P less than .05).

Infants exposed to combination therapy who were born to mothers with ulcerative colitis also had increased rates of preterm birth (odds ratio, 4.9), low birth weight (OR, 6.1), and NICU stay (OR, 3.9).

One possible reason for this signal is that women with ulcerative colitis in the PIANO registry, as well as two other studies, have more disease activity during pregnancy, Dr. Mahadevan suggested. Another possibility is that mothers with ulcerative colitis may have low levels of untreated inflammation.

With just 161 women available for analysis, the PIANO investigators previously reported a significant increase in infant infections at 12 months of age in those exposed to combination infliximab or adalimumab plus azathioprine. Most anti-TNF agents cross the placenta in the second and third trimester, which has raised concerns about immune system development and risk of subsequent infections.

In the current analysis, there was no increase in infant infections when the investigators looked at all anti-TNF drugs. "But when we removed certolizumab from the analysis, it was significant just as it was 2 years ago," Dr. Mahadevan said in an interview. "Certolizumab is not actively transported across the placenta. Fortunately, the majority of the infections were minor, including otitis media and upper respiratory infections."

Developmental milestones

Overall, infants exposed to azathioprine or anti-TNF agents were found to achieve developmental milestones at rates similar to unexposed infants of mothers with IBD based on Denver Childhood Developmental Test and Ages and Stages Questionnaire scores, she said.

After controlling for preterm birth, the mean developmental milestone score at 4 months was 0.92 for infants with no drug exposure, with a nonsignificant mean delta difference of 0.01, 0.01, 0.00 points for infants exposed to azathioprine, anti-TNF agents, and combination therapy, respectively.

In a surprising twist, infants exposed to anti-TNF agents alone actually had significantly better scores at 12 months than unexposed infants, bettering the average score of 0.81 in the unexposed group by a mean delta of 0.02 points (P = .01), Dr. Mahadevan said.

"I wouldn’t interpret this data [as indicating] that biologics make your baby smarter. I think the key thing is that it doesn’t make it worse," she remarked. "When you see the deltas, they are pretty small."

On the Ages and Stages Questionnaire, the biologic group had significantly better mean scores than the unexposed group for gross motor skills at 36 months (55.94 vs. 47.53; P = .01), gross motor skills at 48 months (60 vs. 51.20; P = .02), fine motor skills at 48 months (53.50 vs. 42.11; P = .01), and personal/social interaction at 48 months (58 vs. 51.93; P = .04).

The azathioprine-exposed group always had better scores than the unexposed group, Dr. Mahadevan said. Where it was statistically significant was for personal/social interaction at 24 months (50.75 vs. 47.34; P = .04), problem solving at 36 months (mean 52.04 vs. 48.66; P = .05), and problem solving at 48 months (mean 59.92 vs. 57.66; P = .02).

Dr. Mahadevan observed that the data may change because not all infants have reached each time point and may not reflect outcomes in lower socioeconomic groups since more than 90% of women were of similar socioeconomic and educational status.

Still, the findings are reassuring in the absence of any randomized controlled trials. A recent report found children born to mothers with IBD had higher rates of attention-deficit hyperactivity disorder and gross motor abnormalities (J. Crohns Colitis 2013;7:542-50), while a case series reported normal neuropsychological development in 25 consecutive children exposed in utero to TNF-alpha inhibitors (Inflamm. Bowel Dis. 2014;20:495-501), she noted.

A recent systematic review of 58 articles or abstracts also found no association between TNF-alpha inhibitor use during pregnancy with IBD and adverse pregnancy outcomes, congenital abnormalities, or infections in the first year of life (BMC Medicine 2013;11:174).

The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Mahadevan reported serving as an advisor for Janssen-Cilag, AbbVie, Takeda, and UCB Pharma, and receiving research grants from Prometheus Laboratories and GlaxoSmithKline.

pwendling@frontlinemedcom.com

CHICAGO – Women with inflammatory bowel disease can safely continue monotherapy with azathioprine/6-mercaptopurine or antitumor necrosis–alpha agents during pregnancy to maintain remission, according to an analysis of 1,289 women and 1,039 live births.

Infants exposed to azathioprine/6 MP and anti-TNF-alpha agents achieve developmental milestone scores at rates similar to unexposed infants and do not have higher rates of congenital anomalies, lead author Dr. Uma Mahadevan said at the annual Digestive Disease Week.

Overall, there were 55 congenital anomalies, with 21 diagnosed at birth. Events were similar among infants with in utero exposure to azathioprine, anti-TNF agents, combination therapy, and those with no drug exposure (12 vs. 17 vs. 7 vs. 19 events).

Exposure was defined as any use of azathioprine/6 MP or the anti-TNF-alpha agents infliximab (Remicade), adalimumab (Humira), or certolizumab pegol (Cimzia) at any time from 3 months prior to conception to the end of the pregnancy. Nine women had exposure to the recombinant monoclonal antibody natalizumab (Tysabri) and were included in the anti-TNF agents group.

The analysis was based on the PIANO registry, a prospective cohort of pregnant women with IBD who were followed by telephone or in-person questionnaire at every trimester, at delivery, at 4, 9, and 12 months after delivery, and annually for the first 4 years of their child’s life. Seven women received their diagnosis of IBD during pregnancy, 59.4% had Crohn’s disease, 38.3% ulcerative colitis, and 2.3% were indeterminate.

Two-thirds of women reported breastfeeding, with unexposed women significantly more likely to breastfeed than women with exposure to azathioprine, anti-TNF agents, or combination therapy (85% vs. 65% vs. 71% vs. 61%; P less than .0001).

After controlling for drug exposure, breastfeeding was not associated with an increased risk of infant infection or reduced height or weight, reported Dr. Mahadevan, with the University of California San Francisco.

Infants exposed to combination therapy, however, had higher rates of preterm birth, after adjustment for none/mild vs. moderate/severe IBD activity (odds ratio, 2.6; P less than .05).

Infants exposed to combination therapy who were born to mothers with ulcerative colitis also had increased rates of preterm birth (odds ratio, 4.9), low birth weight (OR, 6.1), and NICU stay (OR, 3.9).

One possible reason for this signal is that women with ulcerative colitis in the PIANO registry, as well as two other studies, have more disease activity during pregnancy, Dr. Mahadevan suggested. Another possibility is that mothers with ulcerative colitis may have low levels of untreated inflammation.

With just 161 women available for analysis, the PIANO investigators previously reported a significant increase in infant infections at 12 months of age in those exposed to combination infliximab or adalimumab plus azathioprine. Most anti-TNF agents cross the placenta in the second and third trimester, which has raised concerns about immune system development and risk of subsequent infections.

In the current analysis, there was no increase in infant infections when the investigators looked at all anti-TNF drugs. "But when we removed certolizumab from the analysis, it was significant just as it was 2 years ago," Dr. Mahadevan said in an interview. "Certolizumab is not actively transported across the placenta. Fortunately, the majority of the infections were minor, including otitis media and upper respiratory infections."

Developmental milestones

Overall, infants exposed to azathioprine or anti-TNF agents were found to achieve developmental milestones at rates similar to unexposed infants of mothers with IBD based on Denver Childhood Developmental Test and Ages and Stages Questionnaire scores, she said.

After controlling for preterm birth, the mean developmental milestone score at 4 months was 0.92 for infants with no drug exposure, with a nonsignificant mean delta difference of 0.01, 0.01, 0.00 points for infants exposed to azathioprine, anti-TNF agents, and combination therapy, respectively.

In a surprising twist, infants exposed to anti-TNF agents alone actually had significantly better scores at 12 months than unexposed infants, bettering the average score of 0.81 in the unexposed group by a mean delta of 0.02 points (P = .01), Dr. Mahadevan said.

"I wouldn’t interpret this data [as indicating] that biologics make your baby smarter. I think the key thing is that it doesn’t make it worse," she remarked. "When you see the deltas, they are pretty small."

On the Ages and Stages Questionnaire, the biologic group had significantly better mean scores than the unexposed group for gross motor skills at 36 months (55.94 vs. 47.53; P = .01), gross motor skills at 48 months (60 vs. 51.20; P = .02), fine motor skills at 48 months (53.50 vs. 42.11; P = .01), and personal/social interaction at 48 months (58 vs. 51.93; P = .04).

The azathioprine-exposed group always had better scores than the unexposed group, Dr. Mahadevan said. Where it was statistically significant was for personal/social interaction at 24 months (50.75 vs. 47.34; P = .04), problem solving at 36 months (mean 52.04 vs. 48.66; P = .05), and problem solving at 48 months (mean 59.92 vs. 57.66; P = .02).

Dr. Mahadevan observed that the data may change because not all infants have reached each time point and may not reflect outcomes in lower socioeconomic groups since more than 90% of women were of similar socioeconomic and educational status.

Still, the findings are reassuring in the absence of any randomized controlled trials. A recent report found children born to mothers with IBD had higher rates of attention-deficit hyperactivity disorder and gross motor abnormalities (J. Crohns Colitis 2013;7:542-50), while a case series reported normal neuropsychological development in 25 consecutive children exposed in utero to TNF-alpha inhibitors (Inflamm. Bowel Dis. 2014;20:495-501), she noted.

A recent systematic review of 58 articles or abstracts also found no association between TNF-alpha inhibitor use during pregnancy with IBD and adverse pregnancy outcomes, congenital abnormalities, or infections in the first year of life (BMC Medicine 2013;11:174).

The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Mahadevan reported serving as an advisor for Janssen-Cilag, AbbVie, Takeda, and UCB Pharma, and receiving research grants from Prometheus Laboratories and GlaxoSmithKline.

pwendling@frontlinemedcom.com

CHICAGO – Women with inflammatory bowel disease can safely continue monotherapy with azathioprine/6-mercaptopurine or antitumor necrosis–alpha agents during pregnancy to maintain remission, according to an analysis of 1,289 women and 1,039 live births.

Infants exposed to azathioprine/6 MP and anti-TNF-alpha agents achieve developmental milestone scores at rates similar to unexposed infants and do not have higher rates of congenital anomalies, lead author Dr. Uma Mahadevan said at the annual Digestive Disease Week.

Overall, there were 55 congenital anomalies, with 21 diagnosed at birth. Events were similar among infants with in utero exposure to azathioprine, anti-TNF agents, combination therapy, and those with no drug exposure (12 vs. 17 vs. 7 vs. 19 events).

Exposure was defined as any use of azathioprine/6 MP or the anti-TNF-alpha agents infliximab (Remicade), adalimumab (Humira), or certolizumab pegol (Cimzia) at any time from 3 months prior to conception to the end of the pregnancy. Nine women had exposure to the recombinant monoclonal antibody natalizumab (Tysabri) and were included in the anti-TNF agents group.

The analysis was based on the PIANO registry, a prospective cohort of pregnant women with IBD who were followed by telephone or in-person questionnaire at every trimester, at delivery, at 4, 9, and 12 months after delivery, and annually for the first 4 years of their child’s life. Seven women received their diagnosis of IBD during pregnancy, 59.4% had Crohn’s disease, 38.3% ulcerative colitis, and 2.3% were indeterminate.

Two-thirds of women reported breastfeeding, with unexposed women significantly more likely to breastfeed than women with exposure to azathioprine, anti-TNF agents, or combination therapy (85% vs. 65% vs. 71% vs. 61%; P less than .0001).

After controlling for drug exposure, breastfeeding was not associated with an increased risk of infant infection or reduced height or weight, reported Dr. Mahadevan, with the University of California San Francisco.

Infants exposed to combination therapy, however, had higher rates of preterm birth, after adjustment for none/mild vs. moderate/severe IBD activity (odds ratio, 2.6; P less than .05).

Infants exposed to combination therapy who were born to mothers with ulcerative colitis also had increased rates of preterm birth (odds ratio, 4.9), low birth weight (OR, 6.1), and NICU stay (OR, 3.9).

One possible reason for this signal is that women with ulcerative colitis in the PIANO registry, as well as two other studies, have more disease activity during pregnancy, Dr. Mahadevan suggested. Another possibility is that mothers with ulcerative colitis may have low levels of untreated inflammation.

With just 161 women available for analysis, the PIANO investigators previously reported a significant increase in infant infections at 12 months of age in those exposed to combination infliximab or adalimumab plus azathioprine. Most anti-TNF agents cross the placenta in the second and third trimester, which has raised concerns about immune system development and risk of subsequent infections.

In the current analysis, there was no increase in infant infections when the investigators looked at all anti-TNF drugs. "But when we removed certolizumab from the analysis, it was significant just as it was 2 years ago," Dr. Mahadevan said in an interview. "Certolizumab is not actively transported across the placenta. Fortunately, the majority of the infections were minor, including otitis media and upper respiratory infections."

Developmental milestones

Overall, infants exposed to azathioprine or anti-TNF agents were found to achieve developmental milestones at rates similar to unexposed infants of mothers with IBD based on Denver Childhood Developmental Test and Ages and Stages Questionnaire scores, she said.

After controlling for preterm birth, the mean developmental milestone score at 4 months was 0.92 for infants with no drug exposure, with a nonsignificant mean delta difference of 0.01, 0.01, 0.00 points for infants exposed to azathioprine, anti-TNF agents, and combination therapy, respectively.

In a surprising twist, infants exposed to anti-TNF agents alone actually had significantly better scores at 12 months than unexposed infants, bettering the average score of 0.81 in the unexposed group by a mean delta of 0.02 points (P = .01), Dr. Mahadevan said.

"I wouldn’t interpret this data [as indicating] that biologics make your baby smarter. I think the key thing is that it doesn’t make it worse," she remarked. "When you see the deltas, they are pretty small."

On the Ages and Stages Questionnaire, the biologic group had significantly better mean scores than the unexposed group for gross motor skills at 36 months (55.94 vs. 47.53; P = .01), gross motor skills at 48 months (60 vs. 51.20; P = .02), fine motor skills at 48 months (53.50 vs. 42.11; P = .01), and personal/social interaction at 48 months (58 vs. 51.93; P = .04).

The azathioprine-exposed group always had better scores than the unexposed group, Dr. Mahadevan said. Where it was statistically significant was for personal/social interaction at 24 months (50.75 vs. 47.34; P = .04), problem solving at 36 months (mean 52.04 vs. 48.66; P = .05), and problem solving at 48 months (mean 59.92 vs. 57.66; P = .02).

Dr. Mahadevan observed that the data may change because not all infants have reached each time point and may not reflect outcomes in lower socioeconomic groups since more than 90% of women were of similar socioeconomic and educational status.

Still, the findings are reassuring in the absence of any randomized controlled trials. A recent report found children born to mothers with IBD had higher rates of attention-deficit hyperactivity disorder and gross motor abnormalities (J. Crohns Colitis 2013;7:542-50), while a case series reported normal neuropsychological development in 25 consecutive children exposed in utero to TNF-alpha inhibitors (Inflamm. Bowel Dis. 2014;20:495-501), she noted.

A recent systematic review of 58 articles or abstracts also found no association between TNF-alpha inhibitor use during pregnancy with IBD and adverse pregnancy outcomes, congenital abnormalities, or infections in the first year of life (BMC Medicine 2013;11:174).

The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Mahadevan reported serving as an advisor for Janssen-Cilag, AbbVie, Takeda, and UCB Pharma, and receiving research grants from Prometheus Laboratories and GlaxoSmithKline.

pwendling@frontlinemedcom.com

CHICAGO – Women with inflammatory bowel disease can safely continue monotherapy with azathioprine/6-mercaptopurine or antitumor necrosis–alpha agents during pregnancy to maintain remission, according to an analysis of 1,289 women and 1,039 live births.

Infants exposed to azathioprine/6 MP and anti-TNF-alpha agents achieve developmental milestone scores at rates similar to unexposed infants and do not have higher rates of congenital anomalies, lead author Dr. Uma Mahadevan said at the annual Digestive Disease Week.

Overall, there were 55 congenital anomalies, with 21 diagnosed at birth. Events were similar among infants with in utero exposure to azathioprine, anti-TNF agents, combination therapy, and those with no drug exposure (12 vs. 17 vs. 7 vs. 19 events).

Exposure was defined as any use of azathioprine/6 MP or the anti-TNF-alpha agents infliximab (Remicade), adalimumab (Humira), or certolizumab pegol (Cimzia) at any time from 3 months prior to conception to the end of the pregnancy. Nine women had exposure to the recombinant monoclonal antibody natalizumab (Tysabri) and were included in the anti-TNF agents group.

The analysis was based on the PIANO registry, a prospective cohort of pregnant women with IBD who were followed by telephone or in-person questionnaire at every trimester, at delivery, at 4, 9, and 12 months after delivery, and annually for the first 4 years of their child’s life. Seven women received their diagnosis of IBD during pregnancy, 59.4% had Crohn’s disease, 38.3% ulcerative colitis, and 2.3% were indeterminate.

Two-thirds of women reported breastfeeding, with unexposed women significantly more likely to breastfeed than women with exposure to azathioprine, anti-TNF agents, or combination therapy (85% vs. 65% vs. 71% vs. 61%; P less than .0001).

After controlling for drug exposure, breastfeeding was not associated with an increased risk of infant infection or reduced height or weight, reported Dr. Mahadevan, with the University of California San Francisco.

Infants exposed to combination therapy, however, had higher rates of preterm birth, after adjustment for none/mild vs. moderate/severe IBD activity (odds ratio, 2.6; P less than .05).

Infants exposed to combination therapy who were born to mothers with ulcerative colitis also had increased rates of preterm birth (odds ratio, 4.9), low birth weight (OR, 6.1), and NICU stay (OR, 3.9).

One possible reason for this signal is that women with ulcerative colitis in the PIANO registry, as well as two other studies, have more disease activity during pregnancy, Dr. Mahadevan suggested. Another possibility is that mothers with ulcerative colitis may have low levels of untreated inflammation.

With just 161 women available for analysis, the PIANO investigators previously reported a significant increase in infant infections at 12 months of age in those exposed to combination infliximab or adalimumab plus azathioprine. Most anti-TNF agents cross the placenta in the second and third trimester, which has raised concerns about immune system development and risk of subsequent infections.

In the current analysis, there was no increase in infant infections when the investigators looked at all anti-TNF drugs. "But when we removed certolizumab from the analysis, it was significant just as it was 2 years ago," Dr. Mahadevan said in an interview. "Certolizumab is not actively transported across the placenta. Fortunately, the majority of the infections were minor, including otitis media and upper respiratory infections."

Developmental milestones

Overall, infants exposed to azathioprine or anti-TNF agents were found to achieve developmental milestones at rates similar to unexposed infants of mothers with IBD based on Denver Childhood Developmental Test and Ages and Stages Questionnaire scores, she said.

After controlling for preterm birth, the mean developmental milestone score at 4 months was 0.92 for infants with no drug exposure, with a nonsignificant mean delta difference of 0.01, 0.01, 0.00 points for infants exposed to azathioprine, anti-TNF agents, and combination therapy, respectively.

In a surprising twist, infants exposed to anti-TNF agents alone actually had significantly better scores at 12 months than unexposed infants, bettering the average score of 0.81 in the unexposed group by a mean delta of 0.02 points (P = .01), Dr. Mahadevan said.

"I wouldn’t interpret this data [as indicating] that biologics make your baby smarter. I think the key thing is that it doesn’t make it worse," she remarked. "When you see the deltas, they are pretty small."

On the Ages and Stages Questionnaire, the biologic group had significantly better mean scores than the unexposed group for gross motor skills at 36 months (55.94 vs. 47.53; P = .01), gross motor skills at 48 months (60 vs. 51.20; P = .02), fine motor skills at 48 months (53.50 vs. 42.11; P = .01), and personal/social interaction at 48 months (58 vs. 51.93; P = .04).

The azathioprine-exposed group always had better scores than the unexposed group, Dr. Mahadevan said. Where it was statistically significant was for personal/social interaction at 24 months (50.75 vs. 47.34; P = .04), problem solving at 36 months (mean 52.04 vs. 48.66; P = .05), and problem solving at 48 months (mean 59.92 vs. 57.66; P = .02).

Dr. Mahadevan observed that the data may change because not all infants have reached each time point and may not reflect outcomes in lower socioeconomic groups since more than 90% of women were of similar socioeconomic and educational status.

Still, the findings are reassuring in the absence of any randomized controlled trials. A recent report found children born to mothers with IBD had higher rates of attention-deficit hyperactivity disorder and gross motor abnormalities (J. Crohns Colitis 2013;7:542-50), while a case series reported normal neuropsychological development in 25 consecutive children exposed in utero to TNF-alpha inhibitors (Inflamm. Bowel Dis. 2014;20:495-501), she noted.

A recent systematic review of 58 articles or abstracts also found no association between TNF-alpha inhibitor use during pregnancy with IBD and adverse pregnancy outcomes, congenital abnormalities, or infections in the first year of life (BMC Medicine 2013;11:174).

The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Mahadevan reported serving as an advisor for Janssen-Cilag, AbbVie, Takeda, and UCB Pharma, and receiving research grants from Prometheus Laboratories and GlaxoSmithKline.

pwendling@frontlinemedcom.com

CHICAGO – Norfloxacin therapy relieved symptoms of irritable bowel syndrome better than placebo did in a prospective study of 80 patients, especially in patients with small intestinal bacterial overgrowth.*

The double-blind study randomized 15 patients with small intestinal bacterial overgrowth and 65 patients without overgrowth to treatment with either norfloxacin 400 mg b.i.d. or placebo for 10 days. Small intestinal bacterial overgrowth was diagnosed by a quantitative upper gut aspirate culture showing a total bacterial count of at least 10⁵/mL colony-forming units (CFU) of upper gut aspirate, or a glucose hydrogen breath test showing a rise in breath hydrogen of at least 12 ppm after glucose ingestion.

One month later, irritable bowel syndrome (IBS) symptoms resolved in 15 of 40 patients who received the fluoroquinolone antibiotic (38%) and in none of the 40 patients who got placebo, Dr. Uday C. Ghoshal and his associates reported at the annual Digestive Disease Week. Symptoms were assessed using the Rome III criteria.

Among the 15 patients with small intestinal bacterial overgrowth, symptoms resolved in 7 of 8 who received norfloxacin (88%) and in 0 of 7 who got placebo, reported Dr. Ghoshal of the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Among the 65 patients who tested negative for small intestinal bacterial overgrowth, symptoms resolved in 8 of 32 who got norfloxacin (25%) and in none of 33 patients on placebo. There was a trend for greater effectiveness with norfloxacin in the 19 patients with moderate colony counts (lower than 10⁵ CFO but at least 10³ CFU/mL), with symptoms resolving in 5 of 11 who got norfloxacin (46%) and in none of 8 patients on placebo, but the difference between treatment groups was not statistically significant. Among the 46 patients with the lowest colony counts (below 10³ CFU/mL), symptoms resolved in 3 of 21 who got norfloxacin (14%) and in none of 25 on placebo, which was statistically significant.

Mean symptoms scores before treatment in the norfloxacin group were 6 in those with small intestinal bacterial overgrowth, 10 in those without the overgrowth but with moderate colonization, and 8 in those with the least colonization, and decreased significantly in each subgroup 1 month after treatment to 2, 5, and 5, respectively. Among patients on placebo, mean symptom scores before treatment were 10 in those with small intestinal bacterial overgrowth, 6 in those with moderate colonization, and 9 in those with the least colonization and did not change significantly by 1 month after treatment, increasing to 11 in the overgrowth group and remaining at 6 and 9 in the other subgroups.

Repeat cultures and/or glucose hydrogen breath tests 1 month after treatment in 15 patients who consented to retesting suggested that norfloxacin was more effective than placebo was in eradicating small bacterial intestinal bacterial overgrowth, with eradication in 4 of 8 patients on the drug and none of 7 patients on placebo, Dr. Ghoshal said.

Patients were excluded from the study if they had taken antibiotics or probiotics within 8 weeks of the trial or if they had diabetes, thyroid disease, or previous abdominal surgery.

Dr. Ghoshal reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

Correction, 6/6/14: An earlier version of this article made multiple incorrect references to inflammatory bowel syndrome instead of irritable bowel syndrome.

CHICAGO – Norfloxacin therapy relieved symptoms of irritable bowel syndrome better than placebo did in a prospective study of 80 patients, especially in patients with small intestinal bacterial overgrowth.*

The double-blind study randomized 15 patients with small intestinal bacterial overgrowth and 65 patients without overgrowth to treatment with either norfloxacin 400 mg b.i.d. or placebo for 10 days. Small intestinal bacterial overgrowth was diagnosed by a quantitative upper gut aspirate culture showing a total bacterial count of at least 10⁵/mL colony-forming units (CFU) of upper gut aspirate, or a glucose hydrogen breath test showing a rise in breath hydrogen of at least 12 ppm after glucose ingestion.

One month later, irritable bowel syndrome (IBS) symptoms resolved in 15 of 40 patients who received the fluoroquinolone antibiotic (38%) and in none of the 40 patients who got placebo, Dr. Uday C. Ghoshal and his associates reported at the annual Digestive Disease Week. Symptoms were assessed using the Rome III criteria.

Among the 15 patients with small intestinal bacterial overgrowth, symptoms resolved in 7 of 8 who received norfloxacin (88%) and in 0 of 7 who got placebo, reported Dr. Ghoshal of the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Among the 65 patients who tested negative for small intestinal bacterial overgrowth, symptoms resolved in 8 of 32 who got norfloxacin (25%) and in none of 33 patients on placebo. There was a trend for greater effectiveness with norfloxacin in the 19 patients with moderate colony counts (lower than 10⁵ CFO but at least 10³ CFU/mL), with symptoms resolving in 5 of 11 who got norfloxacin (46%) and in none of 8 patients on placebo, but the difference between treatment groups was not statistically significant. Among the 46 patients with the lowest colony counts (below 10³ CFU/mL), symptoms resolved in 3 of 21 who got norfloxacin (14%) and in none of 25 on placebo, which was statistically significant.

Mean symptoms scores before treatment in the norfloxacin group were 6 in those with small intestinal bacterial overgrowth, 10 in those without the overgrowth but with moderate colonization, and 8 in those with the least colonization, and decreased significantly in each subgroup 1 month after treatment to 2, 5, and 5, respectively. Among patients on placebo, mean symptom scores before treatment were 10 in those with small intestinal bacterial overgrowth, 6 in those with moderate colonization, and 9 in those with the least colonization and did not change significantly by 1 month after treatment, increasing to 11 in the overgrowth group and remaining at 6 and 9 in the other subgroups.

Repeat cultures and/or glucose hydrogen breath tests 1 month after treatment in 15 patients who consented to retesting suggested that norfloxacin was more effective than placebo was in eradicating small bacterial intestinal bacterial overgrowth, with eradication in 4 of 8 patients on the drug and none of 7 patients on placebo, Dr. Ghoshal said.

Patients were excluded from the study if they had taken antibiotics or probiotics within 8 weeks of the trial or if they had diabetes, thyroid disease, or previous abdominal surgery.

Dr. Ghoshal reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

Correction, 6/6/14: An earlier version of this article made multiple incorrect references to inflammatory bowel syndrome instead of irritable bowel syndrome.

CHICAGO – Norfloxacin therapy relieved symptoms of irritable bowel syndrome better than placebo did in a prospective study of 80 patients, especially in patients with small intestinal bacterial overgrowth.*

The double-blind study randomized 15 patients with small intestinal bacterial overgrowth and 65 patients without overgrowth to treatment with either norfloxacin 400 mg b.i.d. or placebo for 10 days. Small intestinal bacterial overgrowth was diagnosed by a quantitative upper gut aspirate culture showing a total bacterial count of at least 10⁵/mL colony-forming units (CFU) of upper gut aspirate, or a glucose hydrogen breath test showing a rise in breath hydrogen of at least 12 ppm after glucose ingestion.

One month later, irritable bowel syndrome (IBS) symptoms resolved in 15 of 40 patients who received the fluoroquinolone antibiotic (38%) and in none of the 40 patients who got placebo, Dr. Uday C. Ghoshal and his associates reported at the annual Digestive Disease Week. Symptoms were assessed using the Rome III criteria.

Among the 15 patients with small intestinal bacterial overgrowth, symptoms resolved in 7 of 8 who received norfloxacin (88%) and in 0 of 7 who got placebo, reported Dr. Ghoshal of the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Among the 65 patients who tested negative for small intestinal bacterial overgrowth, symptoms resolved in 8 of 32 who got norfloxacin (25%) and in none of 33 patients on placebo. There was a trend for greater effectiveness with norfloxacin in the 19 patients with moderate colony counts (lower than 10⁵ CFO but at least 10³ CFU/mL), with symptoms resolving in 5 of 11 who got norfloxacin (46%) and in none of 8 patients on placebo, but the difference between treatment groups was not statistically significant. Among the 46 patients with the lowest colony counts (below 10³ CFU/mL), symptoms resolved in 3 of 21 who got norfloxacin (14%) and in none of 25 on placebo, which was statistically significant.

Mean symptoms scores before treatment in the norfloxacin group were 6 in those with small intestinal bacterial overgrowth, 10 in those without the overgrowth but with moderate colonization, and 8 in those with the least colonization, and decreased significantly in each subgroup 1 month after treatment to 2, 5, and 5, respectively. Among patients on placebo, mean symptom scores before treatment were 10 in those with small intestinal bacterial overgrowth, 6 in those with moderate colonization, and 9 in those with the least colonization and did not change significantly by 1 month after treatment, increasing to 11 in the overgrowth group and remaining at 6 and 9 in the other subgroups.

Repeat cultures and/or glucose hydrogen breath tests 1 month after treatment in 15 patients who consented to retesting suggested that norfloxacin was more effective than placebo was in eradicating small bacterial intestinal bacterial overgrowth, with eradication in 4 of 8 patients on the drug and none of 7 patients on placebo, Dr. Ghoshal said.

Patients were excluded from the study if they had taken antibiotics or probiotics within 8 weeks of the trial or if they had diabetes, thyroid disease, or previous abdominal surgery.

Dr. Ghoshal reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

Correction, 6/6/14: An earlier version of this article made multiple incorrect references to inflammatory bowel syndrome instead of irritable bowel syndrome.

CHICAGO – Patients with cirrhosis and medium to large esophageal varices were 81% less likely to develop a first esophageal variceal bleed within 5 years if they took rifaximin to manage hepatic encephalopathy, a retrospective study of 238 patients found.

Of the 97 patients who received rifaximin (a nonabsorbable antibiotic with broad-spectrum activity), 94% remained free of variceal hemorrhage at 3 years, 4 years, and 5 years after their sentinel endoscopy, the historic cohort study showed. Among the 141 patients who were not on rifaximin, 75% had not developed a variceal bleed within 3 years, and 58% had no variceal bleeds at years 4 and 5, Dr. Bradley Confer and his associates reported.

The cumulative incidence of esophageal variceal bleed was 11% in 5 years, or 4% for patients on rifaximin and 16% for those not on rifaximin, said Dr. Confer of the Cleveland Clinic.

Those statistically significant differences between groups suggest that rifaximin use decreases the risk of a first esophageal bleed and decreases the time to a first bleed in cirrhotic patients with medium to large varices, but a larger prospective randomized trial would be needed to confirm that, he said at the annual Digestive Disease Week.

All patients were treated with nonselective beta-blocker medications, esophageal band ligation, or a combination of both and were followed to the time of a first esophageal variceal bleed, liver transplant, last follow-up, or death. Beta-blockers were used by 63% of patients, and 87% underwent at least one banding procedure. Patients on rifaximin used the drug for a median of 9 months.

Although five factors were associated with the risk for a first variceal hemorrhage in a univariate analysis, only three remained significant after a multivariate analysis that adjusted for the use of beta-blockers and band ligation: rifaximin use (associated with an 81% decrease in risk), age (a 20% increase in risk with 5 additional years of age), and the patient’s International Normalized Ratio (which can be associated with more than a sixfold increase in bleed risk).

Previous data suggest that cirrhotic patients with medium to large esophageal varices still have a 10%-20% risk of developing a first esophageal variceal bleed even after treatment with either nonselective beta-blockers or band ligation. Many patients do not tolerate nonselective beta-blockers well, and the drugs may negatively affect a subgroup of patients with cirrhosis, he said. Repeating variceal ligation is a costly and invasive management strategy.

The investigators turned their attention to rifaximin after separate data showed that 4 weeks of use were associated with a significant decrease in hepatic venous pressure gradient in patients with alcoholic cirrhosis. They evaluated records on 1,121 patients with cirrhosis who underwent esophagogastroduodenoscopy in 2008-2011 and excluded any with no varices, small varices, a history of esophageal variceal bleeding, or noncirrhotic portal hypertension, or who received a transjugular intrahepatic portosystemic shunt.

The mean age at the time of esophagogastroduodenoscopy was 53 years, and 72% of patients were male. They had an average Model for End-Stage Liver Disease score of 14.3 and an average Child-Pugh score of 8.7. Compared with patients not on rifaximin, those who got the antibiotic were significantly less likely to use nonselective beta-blockers and were sicker, Dr. Confer said, with significantly higher serum creatinine levels, lower serum albumin, and a greater likelihood of hepatic encephalopathy at baseline.

Dr. Confer reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

This article was updated on June 26, 2014.

CHICAGO – Patients with cirrhosis and medium to large esophageal varices were 81% less likely to develop a first esophageal variceal bleed within 5 years if they took rifaximin to manage hepatic encephalopathy, a retrospective study of 238 patients found.

Of the 97 patients who received rifaximin (a nonabsorbable antibiotic with broad-spectrum activity), 94% remained free of variceal hemorrhage at 3 years, 4 years, and 5 years after their sentinel endoscopy, the historic cohort study showed. Among the 141 patients who were not on rifaximin, 75% had not developed a variceal bleed within 3 years, and 58% had no variceal bleeds at years 4 and 5, Dr. Bradley Confer and his associates reported.

The cumulative incidence of esophageal variceal bleed was 11% in 5 years, or 4% for patients on rifaximin and 16% for those not on rifaximin, said Dr. Confer of the Cleveland Clinic.

Those statistically significant differences between groups suggest that rifaximin use decreases the risk of a first esophageal bleed and decreases the time to a first bleed in cirrhotic patients with medium to large varices, but a larger prospective randomized trial would be needed to confirm that, he said at the annual Digestive Disease Week.

All patients were treated with nonselective beta-blocker medications, esophageal band ligation, or a combination of both and were followed to the time of a first esophageal variceal bleed, liver transplant, last follow-up, or death. Beta-blockers were used by 63% of patients, and 87% underwent at least one banding procedure. Patients on rifaximin used the drug for a median of 9 months.

Although five factors were associated with the risk for a first variceal hemorrhage in a univariate analysis, only three remained significant after a multivariate analysis that adjusted for the use of beta-blockers and band ligation: rifaximin use (associated with an 81% decrease in risk), age (a 20% increase in risk with 5 additional years of age), and the patient’s International Normalized Ratio (which can be associated with more than a sixfold increase in bleed risk).

Previous data suggest that cirrhotic patients with medium to large esophageal varices still have a 10%-20% risk of developing a first esophageal variceal bleed even after treatment with either nonselective beta-blockers or band ligation. Many patients do not tolerate nonselective beta-blockers well, and the drugs may negatively affect a subgroup of patients with cirrhosis, he said. Repeating variceal ligation is a costly and invasive management strategy.

The investigators turned their attention to rifaximin after separate data showed that 4 weeks of use were associated with a significant decrease in hepatic venous pressure gradient in patients with alcoholic cirrhosis. They evaluated records on 1,121 patients with cirrhosis who underwent esophagogastroduodenoscopy in 2008-2011 and excluded any with no varices, small varices, a history of esophageal variceal bleeding, or noncirrhotic portal hypertension, or who received a transjugular intrahepatic portosystemic shunt.

The mean age at the time of esophagogastroduodenoscopy was 53 years, and 72% of patients were male. They had an average Model for End-Stage Liver Disease score of 14.3 and an average Child-Pugh score of 8.7. Compared with patients not on rifaximin, those who got the antibiotic were significantly less likely to use nonselective beta-blockers and were sicker, Dr. Confer said, with significantly higher serum creatinine levels, lower serum albumin, and a greater likelihood of hepatic encephalopathy at baseline.

Dr. Confer reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

This article was updated on June 26, 2014.

CHICAGO – Patients with cirrhosis and medium to large esophageal varices were 81% less likely to develop a first esophageal variceal bleed within 5 years if they took rifaximin to manage hepatic encephalopathy, a retrospective study of 238 patients found.

Of the 97 patients who received rifaximin (a nonabsorbable antibiotic with broad-spectrum activity), 94% remained free of variceal hemorrhage at 3 years, 4 years, and 5 years after their sentinel endoscopy, the historic cohort study showed. Among the 141 patients who were not on rifaximin, 75% had not developed a variceal bleed within 3 years, and 58% had no variceal bleeds at years 4 and 5, Dr. Bradley Confer and his associates reported.

The cumulative incidence of esophageal variceal bleed was 11% in 5 years, or 4% for patients on rifaximin and 16% for those not on rifaximin, said Dr. Confer of the Cleveland Clinic.

Those statistically significant differences between groups suggest that rifaximin use decreases the risk of a first esophageal bleed and decreases the time to a first bleed in cirrhotic patients with medium to large varices, but a larger prospective randomized trial would be needed to confirm that, he said at the annual Digestive Disease Week.

All patients were treated with nonselective beta-blocker medications, esophageal band ligation, or a combination of both and were followed to the time of a first esophageal variceal bleed, liver transplant, last follow-up, or death. Beta-blockers were used by 63% of patients, and 87% underwent at least one banding procedure. Patients on rifaximin used the drug for a median of 9 months.

Although five factors were associated with the risk for a first variceal hemorrhage in a univariate analysis, only three remained significant after a multivariate analysis that adjusted for the use of beta-blockers and band ligation: rifaximin use (associated with an 81% decrease in risk), age (a 20% increase in risk with 5 additional years of age), and the patient’s International Normalized Ratio (which can be associated with more than a sixfold increase in bleed risk).

Previous data suggest that cirrhotic patients with medium to large esophageal varices still have a 10%-20% risk of developing a first esophageal variceal bleed even after treatment with either nonselective beta-blockers or band ligation. Many patients do not tolerate nonselective beta-blockers well, and the drugs may negatively affect a subgroup of patients with cirrhosis, he said. Repeating variceal ligation is a costly and invasive management strategy.

The investigators turned their attention to rifaximin after separate data showed that 4 weeks of use were associated with a significant decrease in hepatic venous pressure gradient in patients with alcoholic cirrhosis. They evaluated records on 1,121 patients with cirrhosis who underwent esophagogastroduodenoscopy in 2008-2011 and excluded any with no varices, small varices, a history of esophageal variceal bleeding, or noncirrhotic portal hypertension, or who received a transjugular intrahepatic portosystemic shunt.

The mean age at the time of esophagogastroduodenoscopy was 53 years, and 72% of patients were male. They had an average Model for End-Stage Liver Disease score of 14.3 and an average Child-Pugh score of 8.7. Compared with patients not on rifaximin, those who got the antibiotic were significantly less likely to use nonselective beta-blockers and were sicker, Dr. Confer said, with significantly higher serum creatinine levels, lower serum albumin, and a greater likelihood of hepatic encephalopathy at baseline.

Dr. Confer reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

This article was updated on June 26, 2014.

CHICAGO – A full 13% of patients diagnosed with hepatocellular carcinoma did not have underlying cirrhosis in a national sample of 1,500 veterans.

Although hepatocellular carcinoma (HCC) in patients with cirrhosis typically arises against a background of alcohol abuse or hepatitis C virus infection, this entity was strongly associated with nonalcoholic fatty liver disease (NAFLD) and idiopathic HCC.

"While this represents a small proportion, this poses a logistical problem for HCC surveillance, given the large population with NAFLD and no real identifying features of who is going to develop HCC," Dr. Sahil Mittal said at the annual Digestive Disease Week.

Patrice Wendling/Frontline Medical News

Despite a threefold increase in HCC in the United States over the last 3 decades and emerging evidence for NAFLD presenting in the absence of cirrhosis, this is the first study to assess the prevalence and risk factors for HCC without cirrhosis in a national sample of HCC patients, he said.

The investigators, led by Dr. Hashem B. El-Serag, section chief, gastroenterology and hepatology, Baylor College of Medicine, Houston, performed a chart review of 1,500 veterans with a confirmed diagnosis of HCC randomly selected between 2005 and 2011. Of these, cirrhosis was absent in 43 (3%), highly improbable in 151 (10%), and definite in 1,201 (80%), with the diagnosis unclear because of insufficient data in 105 (7%).

As expected, HCC patients with cirrhosis were significantly more likely than those with no or probable no cirrhosis to abuse alcohol (84% vs. 67.4% vs. 63.6%; P less than .01) and to have hepatitis C infection (72.2% vs. 42% vs. 44.4%; P less than .01), said Dr. Mittal, also with Baylor’s College of Medicine.

Hepatitis B infection was similar in all three groups (5% vs. 4.7% vs. 2%).

In contrast, NAFLD was more common in patients with no or probably no cirrhosis than in those with cirrhosis (14% vs. 20.5% vs. 5.8%; P less than .01), as was idiopathic HCC (18.6% vs. 27.8% vs. 8.2%; P less than .01), he said.

"NAFLD is associated with a significantly increased risk of HCC in the absence of cirrhosis, compared with hepatitis C or alcohol," he said.

With regard to clinical factors, sex and race did not differ between groups. However, the no and probably no cirrhosis patients were significantly older than were those with HCC accompanied by cirrhosis (65.5 years, vs. 69.7 years vs. 62.6 years) and significantly more likely to have comorbidities associated with metabolic syndrome, such as hypertension (88.4% vs. 86.8% vs. 72.6%), myocardial infarction (11.6% vs. 18.5% vs. 7.5%), and peripheral vascular disease (11.6% vs. 20% vs. 9.5%), Dr. Mittal reported. The differences among groups were statistically significant with P values of less than .01.

The investigators then performed logistic regression analysis to examine predictors of HCC without cirrhosis. After adjustment for confounders, they found NAFLD was more than threefold likely (odds ratio, 3.1) and idiopathic HCC more than twofold likely (OR, 2.8) in patients with HCC without cirrhosis, compared with patients with hepatitis C–related HCC.

This entity of HCC in the absence of cirrhosis was also associated with the metabolic syndrome–related comorbidities of hypertension (OR, 1.8) and myocardial infarction (OR, 1.8).

The findings suggest that the risk of HCC in patients with NAFLD is increased not only because of progression to cirrhosis, but possibly through other alternative noncirrhosis pathways, Dr. Mittal said in an interview. This has important implications for understanding the pathogenesis of HCC, as well as for HCC screening in NAFLD patients.

"Due to the high prevalence of NAFLD in the general population, conventional screening by ultrasonography may not be a feasible strategy, especially if one cannot rely on cirrhosis as the main predisposing lesion to HCC," he said. "Studies are needed to identify risk factors and biomarkers that can identify NAFLD patients at higher risk of developing HCC. Future research is also needed to investigate the role of chemoprevention."

Dr. Mittal reported no conflicting interests. Lead author Dr. El-Serag reported consulting fees and grant/research support from Gilead Sciences.

pwendling@frontlinemedcom.com

CHICAGO – A full 13% of patients diagnosed with hepatocellular carcinoma did not have underlying cirrhosis in a national sample of 1,500 veterans.

Although hepatocellular carcinoma (HCC) in patients with cirrhosis typically arises against a background of alcohol abuse or hepatitis C virus infection, this entity was strongly associated with nonalcoholic fatty liver disease (NAFLD) and idiopathic HCC.

"While this represents a small proportion, this poses a logistical problem for HCC surveillance, given the large population with NAFLD and no real identifying features of who is going to develop HCC," Dr. Sahil Mittal said at the annual Digestive Disease Week.

Patrice Wendling/Frontline Medical News

Despite a threefold increase in HCC in the United States over the last 3 decades and emerging evidence for NAFLD presenting in the absence of cirrhosis, this is the first study to assess the prevalence and risk factors for HCC without cirrhosis in a national sample of HCC patients, he said.

The investigators, led by Dr. Hashem B. El-Serag, section chief, gastroenterology and hepatology, Baylor College of Medicine, Houston, performed a chart review of 1,500 veterans with a confirmed diagnosis of HCC randomly selected between 2005 and 2011. Of these, cirrhosis was absent in 43 (3%), highly improbable in 151 (10%), and definite in 1,201 (80%), with the diagnosis unclear because of insufficient data in 105 (7%).

As expected, HCC patients with cirrhosis were significantly more likely than those with no or probable no cirrhosis to abuse alcohol (84% vs. 67.4% vs. 63.6%; P less than .01) and to have hepatitis C infection (72.2% vs. 42% vs. 44.4%; P less than .01), said Dr. Mittal, also with Baylor’s College of Medicine.

Hepatitis B infection was similar in all three groups (5% vs. 4.7% vs. 2%).

In contrast, NAFLD was more common in patients with no or probably no cirrhosis than in those with cirrhosis (14% vs. 20.5% vs. 5.8%; P less than .01), as was idiopathic HCC (18.6% vs. 27.8% vs. 8.2%; P less than .01), he said.

"NAFLD is associated with a significantly increased risk of HCC in the absence of cirrhosis, compared with hepatitis C or alcohol," he said.

With regard to clinical factors, sex and race did not differ between groups. However, the no and probably no cirrhosis patients were significantly older than were those with HCC accompanied by cirrhosis (65.5 years, vs. 69.7 years vs. 62.6 years) and significantly more likely to have comorbidities associated with metabolic syndrome, such as hypertension (88.4% vs. 86.8% vs. 72.6%), myocardial infarction (11.6% vs. 18.5% vs. 7.5%), and peripheral vascular disease (11.6% vs. 20% vs. 9.5%), Dr. Mittal reported. The differences among groups were statistically significant with P values of less than .01.

The investigators then performed logistic regression analysis to examine predictors of HCC without cirrhosis. After adjustment for confounders, they found NAFLD was more than threefold likely (odds ratio, 3.1) and idiopathic HCC more than twofold likely (OR, 2.8) in patients with HCC without cirrhosis, compared with patients with hepatitis C–related HCC.

This entity of HCC in the absence of cirrhosis was also associated with the metabolic syndrome–related comorbidities of hypertension (OR, 1.8) and myocardial infarction (OR, 1.8).

The findings suggest that the risk of HCC in patients with NAFLD is increased not only because of progression to cirrhosis, but possibly through other alternative noncirrhosis pathways, Dr. Mittal said in an interview. This has important implications for understanding the pathogenesis of HCC, as well as for HCC screening in NAFLD patients.

"Due to the high prevalence of NAFLD in the general population, conventional screening by ultrasonography may not be a feasible strategy, especially if one cannot rely on cirrhosis as the main predisposing lesion to HCC," he said. "Studies are needed to identify risk factors and biomarkers that can identify NAFLD patients at higher risk of developing HCC. Future research is also needed to investigate the role of chemoprevention."

Dr. Mittal reported no conflicting interests. Lead author Dr. El-Serag reported consulting fees and grant/research support from Gilead Sciences.

pwendling@frontlinemedcom.com

CHICAGO – A full 13% of patients diagnosed with hepatocellular carcinoma did not have underlying cirrhosis in a national sample of 1,500 veterans.

Although hepatocellular carcinoma (HCC) in patients with cirrhosis typically arises against a background of alcohol abuse or hepatitis C virus infection, this entity was strongly associated with nonalcoholic fatty liver disease (NAFLD) and idiopathic HCC.

"While this represents a small proportion, this poses a logistical problem for HCC surveillance, given the large population with NAFLD and no real identifying features of who is going to develop HCC," Dr. Sahil Mittal said at the annual Digestive Disease Week.

Patrice Wendling/Frontline Medical News

Despite a threefold increase in HCC in the United States over the last 3 decades and emerging evidence for NAFLD presenting in the absence of cirrhosis, this is the first study to assess the prevalence and risk factors for HCC without cirrhosis in a national sample of HCC patients, he said.

The investigators, led by Dr. Hashem B. El-Serag, section chief, gastroenterology and hepatology, Baylor College of Medicine, Houston, performed a chart review of 1,500 veterans with a confirmed diagnosis of HCC randomly selected between 2005 and 2011. Of these, cirrhosis was absent in 43 (3%), highly improbable in 151 (10%), and definite in 1,201 (80%), with the diagnosis unclear because of insufficient data in 105 (7%).

As expected, HCC patients with cirrhosis were significantly more likely than those with no or probable no cirrhosis to abuse alcohol (84% vs. 67.4% vs. 63.6%; P less than .01) and to have hepatitis C infection (72.2% vs. 42% vs. 44.4%; P less than .01), said Dr. Mittal, also with Baylor’s College of Medicine.

Hepatitis B infection was similar in all three groups (5% vs. 4.7% vs. 2%).

In contrast, NAFLD was more common in patients with no or probably no cirrhosis than in those with cirrhosis (14% vs. 20.5% vs. 5.8%; P less than .01), as was idiopathic HCC (18.6% vs. 27.8% vs. 8.2%; P less than .01), he said.

"NAFLD is associated with a significantly increased risk of HCC in the absence of cirrhosis, compared with hepatitis C or alcohol," he said.

With regard to clinical factors, sex and race did not differ between groups. However, the no and probably no cirrhosis patients were significantly older than were those with HCC accompanied by cirrhosis (65.5 years, vs. 69.7 years vs. 62.6 years) and significantly more likely to have comorbidities associated with metabolic syndrome, such as hypertension (88.4% vs. 86.8% vs. 72.6%), myocardial infarction (11.6% vs. 18.5% vs. 7.5%), and peripheral vascular disease (11.6% vs. 20% vs. 9.5%), Dr. Mittal reported. The differences among groups were statistically significant with P values of less than .01.

The investigators then performed logistic regression analysis to examine predictors of HCC without cirrhosis. After adjustment for confounders, they found NAFLD was more than threefold likely (odds ratio, 3.1) and idiopathic HCC more than twofold likely (OR, 2.8) in patients with HCC without cirrhosis, compared with patients with hepatitis C–related HCC.

This entity of HCC in the absence of cirrhosis was also associated with the metabolic syndrome–related comorbidities of hypertension (OR, 1.8) and myocardial infarction (OR, 1.8).

The findings suggest that the risk of HCC in patients with NAFLD is increased not only because of progression to cirrhosis, but possibly through other alternative noncirrhosis pathways, Dr. Mittal said in an interview. This has important implications for understanding the pathogenesis of HCC, as well as for HCC screening in NAFLD patients.

"Due to the high prevalence of NAFLD in the general population, conventional screening by ultrasonography may not be a feasible strategy, especially if one cannot rely on cirrhosis as the main predisposing lesion to HCC," he said. "Studies are needed to identify risk factors and biomarkers that can identify NAFLD patients at higher risk of developing HCC. Future research is also needed to investigate the role of chemoprevention."

Dr. Mittal reported no conflicting interests. Lead author Dr. El-Serag reported consulting fees and grant/research support from Gilead Sciences.

pwendling@frontlinemedcom.com

CHICAGO – Fluorescence in situ hybridization testing for aneuploidy and loss of the tumor suppressor gene P16 can be useful in predicting progression to high-grade dysplasia and adenocarcinoma in patients with nondysplastic Barrett’s esophagus.

Adding these genetic biomarkers to the clinical risk factors of age and Barrett’s esophagus (BE) segment length provides for an even more robust prediction tool, Dr. Margriet R. Timmer said at the annual Digestive Disease Week.

Patrice Wendling/Frontline Medical News

This conclusion is based on a prospective, multicenter cohort study involving 428 patients with nondysplastic BE. The average age of the patients was 59 years and maximum BE length 3 cm.

Fluorescence in situ hybridization (FISH) analysis was used to detect genetic abnormalities on endoscopic cytology brushes from all patients. The FISH panel included probes for six candidate biomarkers: the tumor suppressor genes P16 and P53, the oncogenes MYC, HER-2/neu, and 20q, as well as aneuploidy.

After a median follow-up of 45 months, 22 patients had histologic progression after review by two expert pathologists: 13 cases of high-grade dysplasia (HGD) and 9 cases of esophageal adenocarcinoma (EAC).

The rate of progression to HGD/EAC was 1.09% per patient-year and 0.65% per patient-year for EAC, said Dr. Timmer of the Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.

Univariable analysis revealed that P16 loss (hazard ratio, 2.56; P = .03) and aneuploidy (HR, 2.66; P = .04) significantly predicted progression, as did increasing age (HR, 1.06; P = .008) and longer BE length (HR, 1.15; P = .017).

None of the other biomarkers or clinical factors such as male sex, body mass index, tobacco use, family history of BE or EAC, or years of BE were significant.

A prediction model was then created using the significant predictors. The C statistic, which takes into account specificity and sensitivity, was 0.68 for the basic model that included only age and BE length, but this improved significantly to 0.73 when the biomarkers were added, she said.

Based on the prediction model, 236 patients were considered high risk and 192 patients were low risk.

Importantly, 5-year progression-free survival was significantly lower in the high-risk group than in the low-risk group (93.6% vs. 98.4%; P = .001), Dr. Timmer noted.

Session cochair Roy Wong of Walter Reed Army Medical Center, Washington, said in an interview that "intellectually, the concept is terrific," but that clinicians will need a specific risk cutoff to apply the findings to an individual patient in the community setting and that overall survival data would strengthen the results.

The study authors acknowledged that FISH testing is still costly and that they have yet to use it in the clinical setting. One major advantage of FISH, however, is that it can be applied to cytology specimens that can be easily obtained during upper endoscopy by brushing the entire Barrett’s segment, thereby overcoming the potential problem of biopsy sampling error, Dr. Timmer said.

The study was funded by grants from KWF Kanderbestrijding (the Dutch Cancer Society), NOW (De Nederlandse Organisatie voor Wetenschappelijk Onderzoek), Fonds NutsOhra, Gut Club, and Abbott Molecular. Dr. Timmer and her coauthors reported no financial disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Fluorescence in situ hybridization testing for aneuploidy and loss of the tumor suppressor gene P16 can be useful in predicting progression to high-grade dysplasia and adenocarcinoma in patients with nondysplastic Barrett’s esophagus.

Adding these genetic biomarkers to the clinical risk factors of age and Barrett’s esophagus (BE) segment length provides for an even more robust prediction tool, Dr. Margriet R. Timmer said at the annual Digestive Disease Week.

Patrice Wendling/Frontline Medical News

This conclusion is based on a prospective, multicenter cohort study involving 428 patients with nondysplastic BE. The average age of the patients was 59 years and maximum BE length 3 cm.

Fluorescence in situ hybridization (FISH) analysis was used to detect genetic abnormalities on endoscopic cytology brushes from all patients. The FISH panel included probes for six candidate biomarkers: the tumor suppressor genes P16 and P53, the oncogenes MYC, HER-2/neu, and 20q, as well as aneuploidy.

After a median follow-up of 45 months, 22 patients had histologic progression after review by two expert pathologists: 13 cases of high-grade dysplasia (HGD) and 9 cases of esophageal adenocarcinoma (EAC).

The rate of progression to HGD/EAC was 1.09% per patient-year and 0.65% per patient-year for EAC, said Dr. Timmer of the Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.

Univariable analysis revealed that P16 loss (hazard ratio, 2.56; P = .03) and aneuploidy (HR, 2.66; P = .04) significantly predicted progression, as did increasing age (HR, 1.06; P = .008) and longer BE length (HR, 1.15; P = .017).

None of the other biomarkers or clinical factors such as male sex, body mass index, tobacco use, family history of BE or EAC, or years of BE were significant.

A prediction model was then created using the significant predictors. The C statistic, which takes into account specificity and sensitivity, was 0.68 for the basic model that included only age and BE length, but this improved significantly to 0.73 when the biomarkers were added, she said.

Based on the prediction model, 236 patients were considered high risk and 192 patients were low risk.

Importantly, 5-year progression-free survival was significantly lower in the high-risk group than in the low-risk group (93.6% vs. 98.4%; P = .001), Dr. Timmer noted.

Session cochair Roy Wong of Walter Reed Army Medical Center, Washington, said in an interview that "intellectually, the concept is terrific," but that clinicians will need a specific risk cutoff to apply the findings to an individual patient in the community setting and that overall survival data would strengthen the results.

The study authors acknowledged that FISH testing is still costly and that they have yet to use it in the clinical setting. One major advantage of FISH, however, is that it can be applied to cytology specimens that can be easily obtained during upper endoscopy by brushing the entire Barrett’s segment, thereby overcoming the potential problem of biopsy sampling error, Dr. Timmer said.

The study was funded by grants from KWF Kanderbestrijding (the Dutch Cancer Society), NOW (De Nederlandse Organisatie voor Wetenschappelijk Onderzoek), Fonds NutsOhra, Gut Club, and Abbott Molecular. Dr. Timmer and her coauthors reported no financial disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Fluorescence in situ hybridization testing for aneuploidy and loss of the tumor suppressor gene P16 can be useful in predicting progression to high-grade dysplasia and adenocarcinoma in patients with nondysplastic Barrett’s esophagus.

Adding these genetic biomarkers to the clinical risk factors of age and Barrett’s esophagus (BE) segment length provides for an even more robust prediction tool, Dr. Margriet R. Timmer said at the annual Digestive Disease Week.

Patrice Wendling/Frontline Medical News

This conclusion is based on a prospective, multicenter cohort study involving 428 patients with nondysplastic BE. The average age of the patients was 59 years and maximum BE length 3 cm.

Fluorescence in situ hybridization (FISH) analysis was used to detect genetic abnormalities on endoscopic cytology brushes from all patients. The FISH panel included probes for six candidate biomarkers: the tumor suppressor genes P16 and P53, the oncogenes MYC, HER-2/neu, and 20q, as well as aneuploidy.

After a median follow-up of 45 months, 22 patients had histologic progression after review by two expert pathologists: 13 cases of high-grade dysplasia (HGD) and 9 cases of esophageal adenocarcinoma (EAC).

The rate of progression to HGD/EAC was 1.09% per patient-year and 0.65% per patient-year for EAC, said Dr. Timmer of the Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.

Univariable analysis revealed that P16 loss (hazard ratio, 2.56; P = .03) and aneuploidy (HR, 2.66; P = .04) significantly predicted progression, as did increasing age (HR, 1.06; P = .008) and longer BE length (HR, 1.15; P = .017).

None of the other biomarkers or clinical factors such as male sex, body mass index, tobacco use, family history of BE or EAC, or years of BE were significant.

A prediction model was then created using the significant predictors. The C statistic, which takes into account specificity and sensitivity, was 0.68 for the basic model that included only age and BE length, but this improved significantly to 0.73 when the biomarkers were added, she said.

Based on the prediction model, 236 patients were considered high risk and 192 patients were low risk.

Importantly, 5-year progression-free survival was significantly lower in the high-risk group than in the low-risk group (93.6% vs. 98.4%; P = .001), Dr. Timmer noted.

Session cochair Roy Wong of Walter Reed Army Medical Center, Washington, said in an interview that "intellectually, the concept is terrific," but that clinicians will need a specific risk cutoff to apply the findings to an individual patient in the community setting and that overall survival data would strengthen the results.

The study authors acknowledged that FISH testing is still costly and that they have yet to use it in the clinical setting. One major advantage of FISH, however, is that it can be applied to cytology specimens that can be easily obtained during upper endoscopy by brushing the entire Barrett’s segment, thereby overcoming the potential problem of biopsy sampling error, Dr. Timmer said.

The study was funded by grants from KWF Kanderbestrijding (the Dutch Cancer Society), NOW (De Nederlandse Organisatie voor Wetenschappelijk Onderzoek), Fonds NutsOhra, Gut Club, and Abbott Molecular. Dr. Timmer and her coauthors reported no financial disclosures.

pwendling@frontlinemedcom.com

CHICAGO – A genomewide association study has identified specific alleles that may pinpoint those at risk for thiopurine-induced pancreatitis in inflammatory bowel disease.

Patients heterozygous at rs2647087 are 2.5 times more likely to get pancreatitis if treated with thiopurine (Imuran), while those with homozygous risk alleles were 5 times more likely to do so, Dr. Graham Heap reported at the annual Digestive Disease Week.

Pancreatitis is a well-recognized, idiosyncratic complication of thiopurine that occurs in 4%-7% of patients, independent of dose, and usually stops treatment in its tracks. Thiopurines are a mainstay treatment in inflammatory bowel disease (IBD), particularly as an adjunct to anti–tumor necrosis factor–alpha drugs.

Patrice Wendling/Frontline Medical News

Dr. Heap and his associates at 168 research sites recruited 314 IBD patients with pancreatitis that developed within 3 months of starting a thiopurine for the genomewide linkage study and another 119 IBD patients for a case-control cohort. Thiopurine-induced pancreatitis was adjudicated by four independent experts, and determined to be definite in 61 patients, probable in 274, possible in 28, and unlikely in 70.

Among the definite and probable cases, pancreatitis developed within an average of 24 days after starting a thiopurine. Most cases were mild, but 70% of patients were hospitalized for an average of 5.7 days, noted Dr. Heap of Royal Devon and Exeter Hospital, Devon, England.

Analyses performed on three different genotyping platforms for 177 samples identified a significant single-nucleotide polymorphism (SNP) association in chromosome 6 within the class II HLA region. All four SNPs – rs7745656, rs2647087, rs6935723, and rs2647089 – had odds ratios of 2.6, with P values of 2.2 x 10^–16.

The investigators then looked in more detail at the HLA region, previously linked to celiac disease, and identified a strong association between thiopurine-induced pancreatitis and HLA-DRB1:07:01 (OR, 2.55; P = 1.17 x 10^–14) and HLA-DQA1:02:01 (OR, 2.54; P = 1.68 x 10^–14), he said.

The results were replicated in an independent cohort of 78 thiopurine-induced pancreatitis cases and 472 IBD controls who did not develop pancreatitis after at least a year of thiopurine therapy, and again there was a significant association with rs2647078 (OR, 2.21; P = 4 x 10^–6), Dr. Heap said.

Interestingly, there was no significant association between rs2647078 and known risk factors such as smoking status at the time of pancreatitis, thiopurine methyltransferase (TPMT) status, or inosine triphosphate pyrophosphatase genotype, he said.

What all this means for clinicians is that for every 1,000 patients tested, 77 risk allele homozygotes will be identified, and these individuals will have a 17% risk of pancreatitis, Dr. Heap said. If azathioprine and 6-mercaptopurine are avoided in these individuals, the number needed to treat is 76 patients to prevent one case of pancreatitis.

Session cochair and gastroenterologist Barrett Levesque of the University of California, San Diego,said in an interview that further testing is needed, but that the study approach was very robust, especially to show a number needed to treat of 76.

"Compared to what we use, TPMT activity levels, where there’s a few patients in a thousand who might not have the activity at all, this is very promising," he said. "I thought it was a great study."

In a separate interview, Dr. Heap said, "We do not currently feel this test has clinical utility on its own, but we will investigate its utility in combination with other pharmacogenetic tests in the future."

The study was funded by the International Serious Adverse Events Consortium. The authors reported no financial disclosures.

pwendling@frontlinemedcom.com

CHICAGO – A genomewide association study has identified specific alleles that may pinpoint those at risk for thiopurine-induced pancreatitis in inflammatory bowel disease.

Patients heterozygous at rs2647087 are 2.5 times more likely to get pancreatitis if treated with thiopurine (Imuran), while those with homozygous risk alleles were 5 times more likely to do so, Dr. Graham Heap reported at the annual Digestive Disease Week.

Pancreatitis is a well-recognized, idiosyncratic complication of thiopurine that occurs in 4%-7% of patients, independent of dose, and usually stops treatment in its tracks. Thiopurines are a mainstay treatment in inflammatory bowel disease (IBD), particularly as an adjunct to anti–tumor necrosis factor–alpha drugs.

Patrice Wendling/Frontline Medical News

Dr. Heap and his associates at 168 research sites recruited 314 IBD patients with pancreatitis that developed within 3 months of starting a thiopurine for the genomewide linkage study and another 119 IBD patients for a case-control cohort. Thiopurine-induced pancreatitis was adjudicated by four independent experts, and determined to be definite in 61 patients, probable in 274, possible in 28, and unlikely in 70.

Among the definite and probable cases, pancreatitis developed within an average of 24 days after starting a thiopurine. Most cases were mild, but 70% of patients were hospitalized for an average of 5.7 days, noted Dr. Heap of Royal Devon and Exeter Hospital, Devon, England.

Analyses performed on three different genotyping platforms for 177 samples identified a significant single-nucleotide polymorphism (SNP) association in chromosome 6 within the class II HLA region. All four SNPs – rs7745656, rs2647087, rs6935723, and rs2647089 – had odds ratios of 2.6, with P values of 2.2 x 10^–16.

The investigators then looked in more detail at the HLA region, previously linked to celiac disease, and identified a strong association between thiopurine-induced pancreatitis and HLA-DRB1:07:01 (OR, 2.55; P = 1.17 x 10^–14) and HLA-DQA1:02:01 (OR, 2.54; P = 1.68 x 10^–14), he said.

The results were replicated in an independent cohort of 78 thiopurine-induced pancreatitis cases and 472 IBD controls who did not develop pancreatitis after at least a year of thiopurine therapy, and again there was a significant association with rs2647078 (OR, 2.21; P = 4 x 10^–6), Dr. Heap said.

Interestingly, there was no significant association between rs2647078 and known risk factors such as smoking status at the time of pancreatitis, thiopurine methyltransferase (TPMT) status, or inosine triphosphate pyrophosphatase genotype, he said.

What all this means for clinicians is that for every 1,000 patients tested, 77 risk allele homozygotes will be identified, and these individuals will have a 17% risk of pancreatitis, Dr. Heap said. If azathioprine and 6-mercaptopurine are avoided in these individuals, the number needed to treat is 76 patients to prevent one case of pancreatitis.

Session cochair and gastroenterologist Barrett Levesque of the University of California, San Diego,said in an interview that further testing is needed, but that the study approach was very robust, especially to show a number needed to treat of 76.

"Compared to what we use, TPMT activity levels, where there’s a few patients in a thousand who might not have the activity at all, this is very promising," he said. "I thought it was a great study."

In a separate interview, Dr. Heap said, "We do not currently feel this test has clinical utility on its own, but we will investigate its utility in combination with other pharmacogenetic tests in the future."

The study was funded by the International Serious Adverse Events Consortium. The authors reported no financial disclosures.

pwendling@frontlinemedcom.com

CHICAGO – A genomewide association study has identified specific alleles that may pinpoint those at risk for thiopurine-induced pancreatitis in inflammatory bowel disease.

Patients heterozygous at rs2647087 are 2.5 times more likely to get pancreatitis if treated with thiopurine (Imuran), while those with homozygous risk alleles were 5 times more likely to do so, Dr. Graham Heap reported at the annual Digestive Disease Week.

Pancreatitis is a well-recognized, idiosyncratic complication of thiopurine that occurs in 4%-7% of patients, independent of dose, and usually stops treatment in its tracks. Thiopurines are a mainstay treatment in inflammatory bowel disease (IBD), particularly as an adjunct to anti–tumor necrosis factor–alpha drugs.

Patrice Wendling/Frontline Medical News

Dr. Heap and his associates at 168 research sites recruited 314 IBD patients with pancreatitis that developed within 3 months of starting a thiopurine for the genomewide linkage study and another 119 IBD patients for a case-control cohort. Thiopurine-induced pancreatitis was adjudicated by four independent experts, and determined to be definite in 61 patients, probable in 274, possible in 28, and unlikely in 70.

Among the definite and probable cases, pancreatitis developed within an average of 24 days after starting a thiopurine. Most cases were mild, but 70% of patients were hospitalized for an average of 5.7 days, noted Dr. Heap of Royal Devon and Exeter Hospital, Devon, England.

Analyses performed on three different genotyping platforms for 177 samples identified a significant single-nucleotide polymorphism (SNP) association in chromosome 6 within the class II HLA region. All four SNPs – rs7745656, rs2647087, rs6935723, and rs2647089 – had odds ratios of 2.6, with P values of 2.2 x 10^–16.

The investigators then looked in more detail at the HLA region, previously linked to celiac disease, and identified a strong association between thiopurine-induced pancreatitis and HLA-DRB1:07:01 (OR, 2.55; P = 1.17 x 10^–14) and HLA-DQA1:02:01 (OR, 2.54; P = 1.68 x 10^–14), he said.

The results were replicated in an independent cohort of 78 thiopurine-induced pancreatitis cases and 472 IBD controls who did not develop pancreatitis after at least a year of thiopurine therapy, and again there was a significant association with rs2647078 (OR, 2.21; P = 4 x 10^–6), Dr. Heap said.

Interestingly, there was no significant association between rs2647078 and known risk factors such as smoking status at the time of pancreatitis, thiopurine methyltransferase (TPMT) status, or inosine triphosphate pyrophosphatase genotype, he said.

What all this means for clinicians is that for every 1,000 patients tested, 77 risk allele homozygotes will be identified, and these individuals will have a 17% risk of pancreatitis, Dr. Heap said. If azathioprine and 6-mercaptopurine are avoided in these individuals, the number needed to treat is 76 patients to prevent one case of pancreatitis.

Session cochair and gastroenterologist Barrett Levesque of the University of California, San Diego,said in an interview that further testing is needed, but that the study approach was very robust, especially to show a number needed to treat of 76.

"Compared to what we use, TPMT activity levels, where there’s a few patients in a thousand who might not have the activity at all, this is very promising," he said. "I thought it was a great study."

In a separate interview, Dr. Heap said, "We do not currently feel this test has clinical utility on its own, but we will investigate its utility in combination with other pharmacogenetic tests in the future."

The study was funded by the International Serious Adverse Events Consortium. The authors reported no financial disclosures.

pwendling@frontlinemedcom.com