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Sacral nerve stimulation reduced irritable bowel symptoms
Permanent sacral nerve stimulation looked promising in a prospective, randomized controlled study to reduce symptoms in a select group of 21 adults with diarrhea-predominant or mixed irritable bowel syndrome.
In this crossover trial, all patients had sacral nerve stimulators implanted. One group had the stimulator turned on for 1 month and off the next month, while the other group had the opposite – the stimulator was off and then on during those same time periods. Active stimulation improved symptom scores as measured by the Gastrointestinal Symptom Rating Scale – Irritable Bowel Syndrome (GSRS-IBS).
The median change in symptom scores between months 1 and 2 differed significantly between the two groups. In the group that had the stimulator on and then off, symptom scores increased by a median of 12 points. In the group that had the stimulator off and then on, scores decreased by a median of 18 points, Janne L. Fassov, Ph.D., and associates reported.
One year later, with sacral nerve stimulation continuing and data available from 19 patients, the median GSRS-IBS score of 25 was significantly lower than the median symptom score of 62 at baseline, reported Dr. Fassov of Aarhus (Denmark) University Hospital.
The Annals of Surgery published the findings online ahead of print (2014 Feb. 6 [doi:10.1097/SLA.000000000000559]).
The investigators recruited 43 patients from their tertiary care institution who had failed standard treatments for diarrhea-predominant or mixed irritable bowel syndrome. After undergoing a percutaneous nerve evaluation under general anesthesia, they underwent 3 weeks of stimulation using a test electrode connected to an external neurostimulator. Thirty-one patients who had at least a 30% reduction in GSRS-IBS symptom scores during the 3-week test period were offered permanent implantation of the neurostimulator. Patients worked with a nurse specialist for 1-20 months after implantation to individually optimize the stimulator settings for best symptom control before being randomized in the current study.
Two patients who became pregnant and three who withdrew consent did not get stimulators. Five of 26 patients with permanent implantation were excluded from the results, two because of gastric bypass procedures before the crossover month, one who was mentally unstable, and two who refused to have the stimulator turned off because of its excellent effects.
Although patients and investigators were not told when the stimulators were on or off, patients usually could sense when they were on, so the study was not truly blinded.
One of the 21 remaining patients withdrew from the study before finishing it after needing morphine to relieve abdominal pain during the month that the neurostimulator was off.
In the 20 patients who completed the study, quality of life scores on the Irritable Bowel Syndrome Impact Scale (IBS-IS) improved during the month with stimulation. When stimulation went from on to off, IBS-IS scores increased by a median of 16 points. When stimulation went from off to on, IBS-IS scores decreased by a median of 42 points. The difference in median changes between the two groups was statistically significant.
Scores improved significantly with stimulation in all five domains of the symptom scale (pain, bloating, constipation, diarrhea, and satiety) and in all five domains of the quality of life scale (fatigue, daily impaired activities, sleep, emotional distress, and eating habits).
Ten device-related adverse events in seven patients included elective revision of the lead for suspected migration in two patients, persistent postoperative pain at the implantation site requiring relocation of the pacemaker in three patients, recurrent cystitis in one patient that resolved with triple voiding, and spontaneously resolving postoperative pain at the implantation site in four patients.
Sacral nerve stimulation is a well-established, cost-effective treatment for fecal incontinence, and the effects of stimulation for inflammatory bowel disease in this study were similar to those that have been reported for fecal incontinence, the investigators noted. Because minor complications are common with sacral nerve stimulation, this treatment should be reserved for patients with inflammatory bowel disease who do not respond to pharmacotherapy, they suggested.
Medtronic provided its neurostimulators for the study free of charge. Some of Dr. Fassov’s associates in the study have been speakers and/or advisers for Medtronic. The Danish Council for Strategic Research funded the study.
On Twitter @sherryboschert
Permanent sacral nerve stimulation looked promising in a prospective, randomized controlled study to reduce symptoms in a select group of 21 adults with diarrhea-predominant or mixed irritable bowel syndrome.
In this crossover trial, all patients had sacral nerve stimulators implanted. One group had the stimulator turned on for 1 month and off the next month, while the other group had the opposite – the stimulator was off and then on during those same time periods. Active stimulation improved symptom scores as measured by the Gastrointestinal Symptom Rating Scale – Irritable Bowel Syndrome (GSRS-IBS).
The median change in symptom scores between months 1 and 2 differed significantly between the two groups. In the group that had the stimulator on and then off, symptom scores increased by a median of 12 points. In the group that had the stimulator off and then on, scores decreased by a median of 18 points, Janne L. Fassov, Ph.D., and associates reported.
One year later, with sacral nerve stimulation continuing and data available from 19 patients, the median GSRS-IBS score of 25 was significantly lower than the median symptom score of 62 at baseline, reported Dr. Fassov of Aarhus (Denmark) University Hospital.
The Annals of Surgery published the findings online ahead of print (2014 Feb. 6 [doi:10.1097/SLA.000000000000559]).
The investigators recruited 43 patients from their tertiary care institution who had failed standard treatments for diarrhea-predominant or mixed irritable bowel syndrome. After undergoing a percutaneous nerve evaluation under general anesthesia, they underwent 3 weeks of stimulation using a test electrode connected to an external neurostimulator. Thirty-one patients who had at least a 30% reduction in GSRS-IBS symptom scores during the 3-week test period were offered permanent implantation of the neurostimulator. Patients worked with a nurse specialist for 1-20 months after implantation to individually optimize the stimulator settings for best symptom control before being randomized in the current study.
Two patients who became pregnant and three who withdrew consent did not get stimulators. Five of 26 patients with permanent implantation were excluded from the results, two because of gastric bypass procedures before the crossover month, one who was mentally unstable, and two who refused to have the stimulator turned off because of its excellent effects.
Although patients and investigators were not told when the stimulators were on or off, patients usually could sense when they were on, so the study was not truly blinded.
One of the 21 remaining patients withdrew from the study before finishing it after needing morphine to relieve abdominal pain during the month that the neurostimulator was off.
In the 20 patients who completed the study, quality of life scores on the Irritable Bowel Syndrome Impact Scale (IBS-IS) improved during the month with stimulation. When stimulation went from on to off, IBS-IS scores increased by a median of 16 points. When stimulation went from off to on, IBS-IS scores decreased by a median of 42 points. The difference in median changes between the two groups was statistically significant.
Scores improved significantly with stimulation in all five domains of the symptom scale (pain, bloating, constipation, diarrhea, and satiety) and in all five domains of the quality of life scale (fatigue, daily impaired activities, sleep, emotional distress, and eating habits).
Ten device-related adverse events in seven patients included elective revision of the lead for suspected migration in two patients, persistent postoperative pain at the implantation site requiring relocation of the pacemaker in three patients, recurrent cystitis in one patient that resolved with triple voiding, and spontaneously resolving postoperative pain at the implantation site in four patients.
Sacral nerve stimulation is a well-established, cost-effective treatment for fecal incontinence, and the effects of stimulation for inflammatory bowel disease in this study were similar to those that have been reported for fecal incontinence, the investigators noted. Because minor complications are common with sacral nerve stimulation, this treatment should be reserved for patients with inflammatory bowel disease who do not respond to pharmacotherapy, they suggested.
Medtronic provided its neurostimulators for the study free of charge. Some of Dr. Fassov’s associates in the study have been speakers and/or advisers for Medtronic. The Danish Council for Strategic Research funded the study.
On Twitter @sherryboschert
Permanent sacral nerve stimulation looked promising in a prospective, randomized controlled study to reduce symptoms in a select group of 21 adults with diarrhea-predominant or mixed irritable bowel syndrome.
In this crossover trial, all patients had sacral nerve stimulators implanted. One group had the stimulator turned on for 1 month and off the next month, while the other group had the opposite – the stimulator was off and then on during those same time periods. Active stimulation improved symptom scores as measured by the Gastrointestinal Symptom Rating Scale – Irritable Bowel Syndrome (GSRS-IBS).
The median change in symptom scores between months 1 and 2 differed significantly between the two groups. In the group that had the stimulator on and then off, symptom scores increased by a median of 12 points. In the group that had the stimulator off and then on, scores decreased by a median of 18 points, Janne L. Fassov, Ph.D., and associates reported.
One year later, with sacral nerve stimulation continuing and data available from 19 patients, the median GSRS-IBS score of 25 was significantly lower than the median symptom score of 62 at baseline, reported Dr. Fassov of Aarhus (Denmark) University Hospital.
The Annals of Surgery published the findings online ahead of print (2014 Feb. 6 [doi:10.1097/SLA.000000000000559]).
The investigators recruited 43 patients from their tertiary care institution who had failed standard treatments for diarrhea-predominant or mixed irritable bowel syndrome. After undergoing a percutaneous nerve evaluation under general anesthesia, they underwent 3 weeks of stimulation using a test electrode connected to an external neurostimulator. Thirty-one patients who had at least a 30% reduction in GSRS-IBS symptom scores during the 3-week test period were offered permanent implantation of the neurostimulator. Patients worked with a nurse specialist for 1-20 months after implantation to individually optimize the stimulator settings for best symptom control before being randomized in the current study.
Two patients who became pregnant and three who withdrew consent did not get stimulators. Five of 26 patients with permanent implantation were excluded from the results, two because of gastric bypass procedures before the crossover month, one who was mentally unstable, and two who refused to have the stimulator turned off because of its excellent effects.
Although patients and investigators were not told when the stimulators were on or off, patients usually could sense when they were on, so the study was not truly blinded.
One of the 21 remaining patients withdrew from the study before finishing it after needing morphine to relieve abdominal pain during the month that the neurostimulator was off.
In the 20 patients who completed the study, quality of life scores on the Irritable Bowel Syndrome Impact Scale (IBS-IS) improved during the month with stimulation. When stimulation went from on to off, IBS-IS scores increased by a median of 16 points. When stimulation went from off to on, IBS-IS scores decreased by a median of 42 points. The difference in median changes between the two groups was statistically significant.
Scores improved significantly with stimulation in all five domains of the symptom scale (pain, bloating, constipation, diarrhea, and satiety) and in all five domains of the quality of life scale (fatigue, daily impaired activities, sleep, emotional distress, and eating habits).
Ten device-related adverse events in seven patients included elective revision of the lead for suspected migration in two patients, persistent postoperative pain at the implantation site requiring relocation of the pacemaker in three patients, recurrent cystitis in one patient that resolved with triple voiding, and spontaneously resolving postoperative pain at the implantation site in four patients.
Sacral nerve stimulation is a well-established, cost-effective treatment for fecal incontinence, and the effects of stimulation for inflammatory bowel disease in this study were similar to those that have been reported for fecal incontinence, the investigators noted. Because minor complications are common with sacral nerve stimulation, this treatment should be reserved for patients with inflammatory bowel disease who do not respond to pharmacotherapy, they suggested.
Medtronic provided its neurostimulators for the study free of charge. Some of Dr. Fassov’s associates in the study have been speakers and/or advisers for Medtronic. The Danish Council for Strategic Research funded the study.
On Twitter @sherryboschert
FROM ANNALS OF SURGERY
Major finding: Median symptom scores worsened by 12 points between months when the stimulator was on and then off and improved by 18 points between months when the stimulator was off and then on, a significant difference.
Data source: A prospective, randomized, controlled crossover study of 21 patients with diarrhea-predominant or mixed irritable bowel syndrome at a single institution.
Disclosures: Medtronic provided the neurostimulators for the study free of charge and some of Dr. Fassov’s associates in the study have been speakers and/or advisers for Medtronic. The Danish Council for Strategic Research funded the study.
Linaclotide effective even in severe IBS
Linaclotide is safe and effective, even in severe cases of irritable bowel syndrome with constipation, according to a post-hoc analysis of phase III trial data.
Indeed, more acute patients "responded ... just as well as, if not better than, the intent-to-treat population, which included patients with milder abdominal symptoms," wrote Dr. Satish S. C. Rao and colleagues in the April issue of Clinical Gastroenterology and Hepatology (doi:10.1053/j.gastro.2014.01.0130).
According to Dr. Rao of Georgia Regents University, Augusta, although the guanylate cyclase-C agonist is already Food and Drug Administration approved for irritable bowel syndrome–constipation (IBS-C) subtype in 2012, it has not been explicitly tested in patients with more severe disease.
In the current study, Dr. Rao and his fellow investigators looked specifically at several symptoms common to this population: pain, cramping, bloating, fullness, and discomfort.
Patients who ranked at least one of these as being greater than or equal to 7 at baseline were scored as severe, where 0 represents no symptoms and 10 represents the worst possible symptoms.
Overall, out of a total intent-to-treat population of 1,602 patients, 376 reported severe pain, 507 reported severe discomfort, 702 reported severe bloating, 708 reported severe fullness, and 359 reported severe cramping.
Given the overlap between the pain/cramping and bloating/fullness cohorts, the investigators organized the severe IBS group into four subgroups: patients reporting severe pain as their primary complaint (including cramping), severe bloating (including fullness), severe discomfort, and those patients who reported severe symptoms in all three realms.
Demographics were similar between each subgroup and in the overall study population, "although the subpopulations tended to be younger, more female, and more non-white than the intent-to-treat population," the investigators wrote.
Patients were randomized to receive placebo or linaclotide 290 mcg once daily; primary endpoints for this study were assessed at 12 weeks.
The investigators found that, among all severe IBS patients in all subgroups, the mean changes from baseline were significantly greater for linaclotide-treated patients compared with placebo patients for pain, discomfort, bloating, fullness, and cramping (P less than .0001 for all).
Looking at the whole severe IBS cohort, the authors found that 59%-61% of linaclotide patients reported adequate relief of IBS symptoms at week 12, compared with 28%-32% of placebo patients (P less than .0001).
Of those with severe IBS, 70%-77% of linaclotide-treated patients reported being "moderately, quite, or very satisfied" with treatment at week 12, but only 41%-43% of placebo-treated patients said the same (P less than .0001).
Finally, looking specifically at severe versus more mild IBS cases, the investigators found that, overall, the severe IBS cohort reported significantly greater improvements with the drug, compared with their less severe, drug-treated counterparts in the intent-to-treat population.
The most common side effect – diarrhea – occurred in almost one-fifth of linaclotide-treated patients with severe IBS, versus an occurrence rate of 1.6%-2.1% among placebo-treated patients.
In addition to the finding that linaclotide is effective in severe IBS-C, the investigators also wrote that their finding of severe bloating and fullness in many of these patients should give clinicians pause.
"Pain or discomfort is considered a clinical hallmark of IBS," they wrote, but "the presence of bloating and fullness in patients with IBS-C may warrant greater attention in clinical practice as well as in clinical trial design."
Several of the investigators are employees of Ironwood Pharmaceuticals, maker of linaclotide. Additionally, Dr. Rao and another investigator disclosed financial relationships with the pharmaceutical company, which also funded the study.
Irritable bowel syndrome with constipation is a heterogeneous disorder. Heterogeneity exists both with regard to the predominant symptom (constipation vs. pain vs. bloating) and the severity of those symptoms.
|
|
The severity of IBS-C symptoms is unique to each patient and is influenced by multiple factors, including the duration, intensity, frequency, and unpredictability of symptoms; quality of life; fears and concerns about the disease state; coping skills; sex, ethnicity, and culture; and the presence of coexisting functional gastrointestinal disorders, psychological disorders, and medical disorders.
Understanding the level of severity in an IBS-C patient is important as it may influence both diagnostic tests and treatment options. However, despite the prevalence of IBS and its impact on the health care system, few research studies have attempted to categorize IBS-C patients by level of severity to determine their responsiveness to therapy.
In the study by Dr. Rao and his colleagues, a post-hoc analysis of two previously published phase III clinical trials of linaclotide in patients with IBS-C was performed to assess the prevalence of severe abdominal symptoms and the efficacy of linaclotide on these severe symptoms. Abdominal symptoms were evaluated prospectively in each trial using an 11-point numerical rating scale (0 = none; 10 = very severe).
In this post-hoc analysis, the effects of linaclotide were measured for patients with scores greater than 7.0 at baseline. Interestingly, 44% of patients (n = 1,602) reported severe bloating and abdominal fullness. Abdominal discomfort (32%), pain (23%), and cramping (22%) were less common. Not surprisingly, there was considerable overlap with these symptoms, and 21% reported that three symptoms were severe (bloating, pain, and discomfort). Linaclotide improved all five severe symptoms to a greater degree than did placebo, but, more importantly, improved symptoms to a greater degree in these severe patients compared with the study population as a whole.
This study sets the stage for future prospective therapeutic trials. Regardless of IBS subtype (constipation vs. diarrhea vs. mixed) we need to better understand the severity of symptoms of IBS patients enrolled in research studies.
It is likely that critical information is being lost by grouping all IBS patients together with regard to the efficacy of a particular therapeutic agent. This could explain the low therapeutic gain seen in some IBS drug trials. It is likely that differential effects will be observed based on symptom severity. Thus, a patient with moderate to severe IBS symptoms (and thus a reduced quality of life and greater impact on the health care system) may respond better to a particular medication than someone with very mild symptoms (usually with a better quality of life and less impact on the health care system).
One could envision a future practice strategy based on symptom severity with less risky/less expensive treatments (education, reassurance, diet, and exercise) recommended to those with mild symptoms and more aggressive, multimodal therapy (behavioral therapy, psychological therapy, and overlapping medications for visceral/somatic/psychological distress) recommended to those with more severe symptoms. This study provides a framework for future IBS studies to better categorize symptom severity.
Dr. Brian Lacy is section chief of gastroenterology and hepatology and associate professor of medicine at the Geisel School of Medicine, Dartmouth University, Lebanon, N.H. He has received research funding from the National Institutes of Health and is on the advisory boards of Takeda, Prometheus, and Ironwood.
Irritable bowel syndrome with constipation is a heterogeneous disorder. Heterogeneity exists both with regard to the predominant symptom (constipation vs. pain vs. bloating) and the severity of those symptoms.
|
|
|
The severity of IBS-C symptoms is unique to each patient and is influenced by multiple factors, including the duration, intensity, frequency, and unpredictability of symptoms; quality of life; fears and concerns about the disease state; coping skills; sex, ethnicity, and culture; and the presence of coexisting functional gastrointestinal disorders, psychological disorders, and medical disorders.
Understanding the level of severity in an IBS-C patient is important as it may influence both diagnostic tests and treatment options. However, despite the prevalence of IBS and its impact on the health care system, few research studies have attempted to categorize IBS-C patients by level of severity to determine their responsiveness to therapy.
In the study by Dr. Rao and his colleagues, a post-hoc analysis of two previously published phase III clinical trials of linaclotide in patients with IBS-C was performed to assess the prevalence of severe abdominal symptoms and the efficacy of linaclotide on these severe symptoms. Abdominal symptoms were evaluated prospectively in each trial using an 11-point numerical rating scale (0 = none; 10 = very severe).
In this post-hoc analysis, the effects of linaclotide were measured for patients with scores greater than 7.0 at baseline. Interestingly, 44% of patients (n = 1,602) reported severe bloating and abdominal fullness. Abdominal discomfort (32%), pain (23%), and cramping (22%) were less common. Not surprisingly, there was considerable overlap with these symptoms, and 21% reported that three symptoms were severe (bloating, pain, and discomfort). Linaclotide improved all five severe symptoms to a greater degree than did placebo, but, more importantly, improved symptoms to a greater degree in these severe patients compared with the study population as a whole.
This study sets the stage for future prospective therapeutic trials. Regardless of IBS subtype (constipation vs. diarrhea vs. mixed) we need to better understand the severity of symptoms of IBS patients enrolled in research studies.
It is likely that critical information is being lost by grouping all IBS patients together with regard to the efficacy of a particular therapeutic agent. This could explain the low therapeutic gain seen in some IBS drug trials. It is likely that differential effects will be observed based on symptom severity. Thus, a patient with moderate to severe IBS symptoms (and thus a reduced quality of life and greater impact on the health care system) may respond better to a particular medication than someone with very mild symptoms (usually with a better quality of life and less impact on the health care system).
One could envision a future practice strategy based on symptom severity with less risky/less expensive treatments (education, reassurance, diet, and exercise) recommended to those with mild symptoms and more aggressive, multimodal therapy (behavioral therapy, psychological therapy, and overlapping medications for visceral/somatic/psychological distress) recommended to those with more severe symptoms. This study provides a framework for future IBS studies to better categorize symptom severity.
Dr. Brian Lacy is section chief of gastroenterology and hepatology and associate professor of medicine at the Geisel School of Medicine, Dartmouth University, Lebanon, N.H. He has received research funding from the National Institutes of Health and is on the advisory boards of Takeda, Prometheus, and Ironwood.
Irritable bowel syndrome with constipation is a heterogeneous disorder. Heterogeneity exists both with regard to the predominant symptom (constipation vs. pain vs. bloating) and the severity of those symptoms.
|
|
|
The severity of IBS-C symptoms is unique to each patient and is influenced by multiple factors, including the duration, intensity, frequency, and unpredictability of symptoms; quality of life; fears and concerns about the disease state; coping skills; sex, ethnicity, and culture; and the presence of coexisting functional gastrointestinal disorders, psychological disorders, and medical disorders.
Understanding the level of severity in an IBS-C patient is important as it may influence both diagnostic tests and treatment options. However, despite the prevalence of IBS and its impact on the health care system, few research studies have attempted to categorize IBS-C patients by level of severity to determine their responsiveness to therapy.
In the study by Dr. Rao and his colleagues, a post-hoc analysis of two previously published phase III clinical trials of linaclotide in patients with IBS-C was performed to assess the prevalence of severe abdominal symptoms and the efficacy of linaclotide on these severe symptoms. Abdominal symptoms were evaluated prospectively in each trial using an 11-point numerical rating scale (0 = none; 10 = very severe).
In this post-hoc analysis, the effects of linaclotide were measured for patients with scores greater than 7.0 at baseline. Interestingly, 44% of patients (n = 1,602) reported severe bloating and abdominal fullness. Abdominal discomfort (32%), pain (23%), and cramping (22%) were less common. Not surprisingly, there was considerable overlap with these symptoms, and 21% reported that three symptoms were severe (bloating, pain, and discomfort). Linaclotide improved all five severe symptoms to a greater degree than did placebo, but, more importantly, improved symptoms to a greater degree in these severe patients compared with the study population as a whole.
This study sets the stage for future prospective therapeutic trials. Regardless of IBS subtype (constipation vs. diarrhea vs. mixed) we need to better understand the severity of symptoms of IBS patients enrolled in research studies.
It is likely that critical information is being lost by grouping all IBS patients together with regard to the efficacy of a particular therapeutic agent. This could explain the low therapeutic gain seen in some IBS drug trials. It is likely that differential effects will be observed based on symptom severity. Thus, a patient with moderate to severe IBS symptoms (and thus a reduced quality of life and greater impact on the health care system) may respond better to a particular medication than someone with very mild symptoms (usually with a better quality of life and less impact on the health care system).
One could envision a future practice strategy based on symptom severity with less risky/less expensive treatments (education, reassurance, diet, and exercise) recommended to those with mild symptoms and more aggressive, multimodal therapy (behavioral therapy, psychological therapy, and overlapping medications for visceral/somatic/psychological distress) recommended to those with more severe symptoms. This study provides a framework for future IBS studies to better categorize symptom severity.
Dr. Brian Lacy is section chief of gastroenterology and hepatology and associate professor of medicine at the Geisel School of Medicine, Dartmouth University, Lebanon, N.H. He has received research funding from the National Institutes of Health and is on the advisory boards of Takeda, Prometheus, and Ironwood.
Linaclotide is safe and effective, even in severe cases of irritable bowel syndrome with constipation, according to a post-hoc analysis of phase III trial data.
Indeed, more acute patients "responded ... just as well as, if not better than, the intent-to-treat population, which included patients with milder abdominal symptoms," wrote Dr. Satish S. C. Rao and colleagues in the April issue of Clinical Gastroenterology and Hepatology (doi:10.1053/j.gastro.2014.01.0130).
According to Dr. Rao of Georgia Regents University, Augusta, although the guanylate cyclase-C agonist is already Food and Drug Administration approved for irritable bowel syndrome–constipation (IBS-C) subtype in 2012, it has not been explicitly tested in patients with more severe disease.
In the current study, Dr. Rao and his fellow investigators looked specifically at several symptoms common to this population: pain, cramping, bloating, fullness, and discomfort.
Patients who ranked at least one of these as being greater than or equal to 7 at baseline were scored as severe, where 0 represents no symptoms and 10 represents the worst possible symptoms.
Overall, out of a total intent-to-treat population of 1,602 patients, 376 reported severe pain, 507 reported severe discomfort, 702 reported severe bloating, 708 reported severe fullness, and 359 reported severe cramping.
Given the overlap between the pain/cramping and bloating/fullness cohorts, the investigators organized the severe IBS group into four subgroups: patients reporting severe pain as their primary complaint (including cramping), severe bloating (including fullness), severe discomfort, and those patients who reported severe symptoms in all three realms.
Demographics were similar between each subgroup and in the overall study population, "although the subpopulations tended to be younger, more female, and more non-white than the intent-to-treat population," the investigators wrote.
Patients were randomized to receive placebo or linaclotide 290 mcg once daily; primary endpoints for this study were assessed at 12 weeks.
The investigators found that, among all severe IBS patients in all subgroups, the mean changes from baseline were significantly greater for linaclotide-treated patients compared with placebo patients for pain, discomfort, bloating, fullness, and cramping (P less than .0001 for all).
Looking at the whole severe IBS cohort, the authors found that 59%-61% of linaclotide patients reported adequate relief of IBS symptoms at week 12, compared with 28%-32% of placebo patients (P less than .0001).
Of those with severe IBS, 70%-77% of linaclotide-treated patients reported being "moderately, quite, or very satisfied" with treatment at week 12, but only 41%-43% of placebo-treated patients said the same (P less than .0001).
Finally, looking specifically at severe versus more mild IBS cases, the investigators found that, overall, the severe IBS cohort reported significantly greater improvements with the drug, compared with their less severe, drug-treated counterparts in the intent-to-treat population.
The most common side effect – diarrhea – occurred in almost one-fifth of linaclotide-treated patients with severe IBS, versus an occurrence rate of 1.6%-2.1% among placebo-treated patients.
In addition to the finding that linaclotide is effective in severe IBS-C, the investigators also wrote that their finding of severe bloating and fullness in many of these patients should give clinicians pause.
"Pain or discomfort is considered a clinical hallmark of IBS," they wrote, but "the presence of bloating and fullness in patients with IBS-C may warrant greater attention in clinical practice as well as in clinical trial design."
Several of the investigators are employees of Ironwood Pharmaceuticals, maker of linaclotide. Additionally, Dr. Rao and another investigator disclosed financial relationships with the pharmaceutical company, which also funded the study.
Linaclotide is safe and effective, even in severe cases of irritable bowel syndrome with constipation, according to a post-hoc analysis of phase III trial data.
Indeed, more acute patients "responded ... just as well as, if not better than, the intent-to-treat population, which included patients with milder abdominal symptoms," wrote Dr. Satish S. C. Rao and colleagues in the April issue of Clinical Gastroenterology and Hepatology (doi:10.1053/j.gastro.2014.01.0130).
According to Dr. Rao of Georgia Regents University, Augusta, although the guanylate cyclase-C agonist is already Food and Drug Administration approved for irritable bowel syndrome–constipation (IBS-C) subtype in 2012, it has not been explicitly tested in patients with more severe disease.
In the current study, Dr. Rao and his fellow investigators looked specifically at several symptoms common to this population: pain, cramping, bloating, fullness, and discomfort.
Patients who ranked at least one of these as being greater than or equal to 7 at baseline were scored as severe, where 0 represents no symptoms and 10 represents the worst possible symptoms.
Overall, out of a total intent-to-treat population of 1,602 patients, 376 reported severe pain, 507 reported severe discomfort, 702 reported severe bloating, 708 reported severe fullness, and 359 reported severe cramping.
Given the overlap between the pain/cramping and bloating/fullness cohorts, the investigators organized the severe IBS group into four subgroups: patients reporting severe pain as their primary complaint (including cramping), severe bloating (including fullness), severe discomfort, and those patients who reported severe symptoms in all three realms.
Demographics were similar between each subgroup and in the overall study population, "although the subpopulations tended to be younger, more female, and more non-white than the intent-to-treat population," the investigators wrote.
Patients were randomized to receive placebo or linaclotide 290 mcg once daily; primary endpoints for this study were assessed at 12 weeks.
The investigators found that, among all severe IBS patients in all subgroups, the mean changes from baseline were significantly greater for linaclotide-treated patients compared with placebo patients for pain, discomfort, bloating, fullness, and cramping (P less than .0001 for all).
Looking at the whole severe IBS cohort, the authors found that 59%-61% of linaclotide patients reported adequate relief of IBS symptoms at week 12, compared with 28%-32% of placebo patients (P less than .0001).
Of those with severe IBS, 70%-77% of linaclotide-treated patients reported being "moderately, quite, or very satisfied" with treatment at week 12, but only 41%-43% of placebo-treated patients said the same (P less than .0001).
Finally, looking specifically at severe versus more mild IBS cases, the investigators found that, overall, the severe IBS cohort reported significantly greater improvements with the drug, compared with their less severe, drug-treated counterparts in the intent-to-treat population.
The most common side effect – diarrhea – occurred in almost one-fifth of linaclotide-treated patients with severe IBS, versus an occurrence rate of 1.6%-2.1% among placebo-treated patients.
In addition to the finding that linaclotide is effective in severe IBS-C, the investigators also wrote that their finding of severe bloating and fullness in many of these patients should give clinicians pause.
"Pain or discomfort is considered a clinical hallmark of IBS," they wrote, but "the presence of bloating and fullness in patients with IBS-C may warrant greater attention in clinical practice as well as in clinical trial design."
Several of the investigators are employees of Ironwood Pharmaceuticals, maker of linaclotide. Additionally, Dr. Rao and another investigator disclosed financial relationships with the pharmaceutical company, which also funded the study.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major finding: Up to 61% of linaclotide-treated patients with severe irritable bowel symptoms had adequate relief by 12 weeks, compared with 32% of placebo patients (P less than .0001).
Data source: A post hoc analysis of 1,602 patients in a phase III study.
Disclosures: Several investigators are employees of Ironwood Pharmaceuticals, maker of linaclotide. Additionally, Dr. Rao and another investigator disclosed financial relationships with the pharmaceutical company, which also funded the study.
Most health care–associated infections aren’t device associated
An estimated 4% of inpatients at U.S. acute care hospitals have at least one health care–associated infection on any given day, according to a report published online March 26 in the New England Journal of Medicine.
Moreover, in a prevalence survey involving 183 acute care hospitals across 10 geographically diverse states, device-associated infections, "which have been a major focus of infection prevention in recent decades," accounted for only 25.6% of all health care–associated infections, said Dr. Shelley S. Magill of the division of health care quality promotion, Centers for Disease Control and Prevention, and her associates (N. Engl. J. Med. 2014;370:1198-1208).
In contrast, Clostridium difficile and other gastrointestinal infections, as well as non–ventilator-associated pneumonia, accounted for approximately half of all health care–associated infections in the survey. Surgical site infections also are still very common, accounting for 21.8%.
Because it appears that ventilator-associated pneumonia, catheter-associated UTIs, and central catheter–associated bloodstream infections are no longer the primary threat that they used to be, the study findings should prompt experts to "expand the public health focus to include these other types of infections, identifying patients at risk and developing effective countermeasures," the report’s authors noted.
The report shows that as a nation, we’re moving in the right direction; but there’s a great deal of work still to be done," Dr. Michael Bell said in a media briefing. "On any given day, 1 out of 25 hospitalized patients has an infection. And of those people, as many as one out of nine go on to die. This is not a minor issue," said Dr. Bell, deputy director of the CDC’s division of health care quality promotion.
The investigators developed and conducted the survey in 2011 to address a serious knowledge gap: No single surveillance system can provide estimates of "the burden of all types of such infections across acute care patient populations." So, Dr. Magill and her colleagues studied health care–associated infections among inpatients of all ages at 93 small, 68 medium-sized, and 22 large hospitals.
They found 504 such infections in 452 patients out of 11,282 patients covered in the survey, for an overall incidence of 4%. Using a statistical modeling process that accounted for predictors of infection prevalence and then applying those results to a nationally representative sample of U.S. community hospital stays, the investigators estimated that 648,000 inpatients nationwide had approximately 721,800 health care–associated infections in 2011.
Those estimates are lower than previous ones, such as those derived from the Study on the Efficacy of Nosocomial Infection Control in the 1970s , which postulated 2.1 million health care–associated infections each year, and those derived from National Nosocomial Infections Surveillance system data from 1990 to 2002, which estimated 1.7 million each year.
However, "it is difficult to draw conclusions from these comparisons because of the differences in patient populations, surveillance definitions of health care–associated infections, and data collection and analytical methods among these CDC methods," Dr. Magill and her associates said.
The current survey showed that 42.9% of health care–associated infections developed during a stay in a critical care unit or within 48 hours after; another 42.4% developed after a stay in a nonnursery ward.
Most of the surgical site infections were related to colon surgeries (14.5%), hip arthroplasty (10.0%), and small-bowel procedures (6.4%).
The median length of time between hospital admission and the onset of infection symptoms was 6 days.
C. difficile was the most frequently identified pathogen, accounting for 70.9% of all nosocomial GI infections and 12.1% of all health care–associated infections. Other common pathogens included Staphylococcus aureus (10.7% of all health care–associated infections), Klebsiella pneumoniae and Klebsiella oxytoca (9.9%), and Escherichia coli (9.3%).
The report’s investigators noted that their estimates "are remarkably similar to estimates from other data sources," such as the National Healthcare Safety Network and the Emerging Infections Program. That "bolsters our confidence in the overall estimates of health care–associated infections that we have generated," they said.
Sounding the alarm
The report "sounds the alarm" about infectious threats to hospitalized patients that need addressing, especially lung and gut infections and infections related to surgery or urinary catheters, Dr. Bell said. It also sheds light on several important pathogens, especially C. difficile, Staphylococci, and the family of Enterobacter organisms.
Those pathogens are at the center of President Barack Obama’s request for $30 million as part of his proposed $6.6 billion budget for 2015 for a new initiative to halve infections by those organisms within 5 years, Dr. Bell said.
The $30 million would be used to improve tracking of infections, the nation’s capacity for lab testing to determine which pathogens are most problematic, and "boots on the ground" to help hospitals implement best practices, Dr. Bell said.
The CDC would like to see every hospital in the country develop a strong antibiotic stewardship program, because "the challenge with antibiotic resistance can’t be overstated," he cautioned.
A patient advocate echoed that concern at the media briefing.
"While inwardly I breathe a small sigh of relief that annual infections and mortalities are diminishing, I remain extremely cautious regarding the growing threat of antibiotic resistance and the dire impact of this potential danger to American health care," said Victoria Nahum, executive director of the Safe Care Campaign. Ms. Nahum and her husband, Armando Nahum, founded the nonprofit organization after their son died of a health care–associated infection and two other family members developed complications from health care–associated infections.
Health care providers "have the power to prevent health care–associated infections" through compulsive hand hygiene and other best practices, Ms. Nahum said. Patients need to be more assertive, she added. "You just don’t flop down and say, ‘Take care of me.’ You have to kind of navigate what’s going to happen to you. In doing so, that can save your own life."
Dr. Bell suggested that hospitalized patients have a friend or family member be the "bad cop" and repeatedly ask caregivers if they have washed their hands, when urinary catheters can come out, and whether testing is being done to ensure that the right antibiotic is being used.
He said he knows that can be difficult for patients who may feel intimidated. "When my own mother was in the intensive care unit, I found it hard to pipe up," Dr. Bell said. "If I find it hard, I can’t imagine what it’s like for everybody else."
Dr. Magill reported no potential financial conflicts of interest; two of her associates reported ties to the Infectious Disease Consulting Corp. and Parexel.
An estimated 4% of inpatients at U.S. acute care hospitals have at least one health care–associated infection on any given day, according to a report published online March 26 in the New England Journal of Medicine.
Moreover, in a prevalence survey involving 183 acute care hospitals across 10 geographically diverse states, device-associated infections, "which have been a major focus of infection prevention in recent decades," accounted for only 25.6% of all health care–associated infections, said Dr. Shelley S. Magill of the division of health care quality promotion, Centers for Disease Control and Prevention, and her associates (N. Engl. J. Med. 2014;370:1198-1208).
In contrast, Clostridium difficile and other gastrointestinal infections, as well as non–ventilator-associated pneumonia, accounted for approximately half of all health care–associated infections in the survey. Surgical site infections also are still very common, accounting for 21.8%.
Because it appears that ventilator-associated pneumonia, catheter-associated UTIs, and central catheter–associated bloodstream infections are no longer the primary threat that they used to be, the study findings should prompt experts to "expand the public health focus to include these other types of infections, identifying patients at risk and developing effective countermeasures," the report’s authors noted.
The report shows that as a nation, we’re moving in the right direction; but there’s a great deal of work still to be done," Dr. Michael Bell said in a media briefing. "On any given day, 1 out of 25 hospitalized patients has an infection. And of those people, as many as one out of nine go on to die. This is not a minor issue," said Dr. Bell, deputy director of the CDC’s division of health care quality promotion.
The investigators developed and conducted the survey in 2011 to address a serious knowledge gap: No single surveillance system can provide estimates of "the burden of all types of such infections across acute care patient populations." So, Dr. Magill and her colleagues studied health care–associated infections among inpatients of all ages at 93 small, 68 medium-sized, and 22 large hospitals.
They found 504 such infections in 452 patients out of 11,282 patients covered in the survey, for an overall incidence of 4%. Using a statistical modeling process that accounted for predictors of infection prevalence and then applying those results to a nationally representative sample of U.S. community hospital stays, the investigators estimated that 648,000 inpatients nationwide had approximately 721,800 health care–associated infections in 2011.
Those estimates are lower than previous ones, such as those derived from the Study on the Efficacy of Nosocomial Infection Control in the 1970s , which postulated 2.1 million health care–associated infections each year, and those derived from National Nosocomial Infections Surveillance system data from 1990 to 2002, which estimated 1.7 million each year.
However, "it is difficult to draw conclusions from these comparisons because of the differences in patient populations, surveillance definitions of health care–associated infections, and data collection and analytical methods among these CDC methods," Dr. Magill and her associates said.
The current survey showed that 42.9% of health care–associated infections developed during a stay in a critical care unit or within 48 hours after; another 42.4% developed after a stay in a nonnursery ward.
Most of the surgical site infections were related to colon surgeries (14.5%), hip arthroplasty (10.0%), and small-bowel procedures (6.4%).
The median length of time between hospital admission and the onset of infection symptoms was 6 days.
C. difficile was the most frequently identified pathogen, accounting for 70.9% of all nosocomial GI infections and 12.1% of all health care–associated infections. Other common pathogens included Staphylococcus aureus (10.7% of all health care–associated infections), Klebsiella pneumoniae and Klebsiella oxytoca (9.9%), and Escherichia coli (9.3%).
The report’s investigators noted that their estimates "are remarkably similar to estimates from other data sources," such as the National Healthcare Safety Network and the Emerging Infections Program. That "bolsters our confidence in the overall estimates of health care–associated infections that we have generated," they said.
Sounding the alarm
The report "sounds the alarm" about infectious threats to hospitalized patients that need addressing, especially lung and gut infections and infections related to surgery or urinary catheters, Dr. Bell said. It also sheds light on several important pathogens, especially C. difficile, Staphylococci, and the family of Enterobacter organisms.
Those pathogens are at the center of President Barack Obama’s request for $30 million as part of his proposed $6.6 billion budget for 2015 for a new initiative to halve infections by those organisms within 5 years, Dr. Bell said.
The $30 million would be used to improve tracking of infections, the nation’s capacity for lab testing to determine which pathogens are most problematic, and "boots on the ground" to help hospitals implement best practices, Dr. Bell said.
The CDC would like to see every hospital in the country develop a strong antibiotic stewardship program, because "the challenge with antibiotic resistance can’t be overstated," he cautioned.
A patient advocate echoed that concern at the media briefing.
"While inwardly I breathe a small sigh of relief that annual infections and mortalities are diminishing, I remain extremely cautious regarding the growing threat of antibiotic resistance and the dire impact of this potential danger to American health care," said Victoria Nahum, executive director of the Safe Care Campaign. Ms. Nahum and her husband, Armando Nahum, founded the nonprofit organization after their son died of a health care–associated infection and two other family members developed complications from health care–associated infections.
Health care providers "have the power to prevent health care–associated infections" through compulsive hand hygiene and other best practices, Ms. Nahum said. Patients need to be more assertive, she added. "You just don’t flop down and say, ‘Take care of me.’ You have to kind of navigate what’s going to happen to you. In doing so, that can save your own life."
Dr. Bell suggested that hospitalized patients have a friend or family member be the "bad cop" and repeatedly ask caregivers if they have washed their hands, when urinary catheters can come out, and whether testing is being done to ensure that the right antibiotic is being used.
He said he knows that can be difficult for patients who may feel intimidated. "When my own mother was in the intensive care unit, I found it hard to pipe up," Dr. Bell said. "If I find it hard, I can’t imagine what it’s like for everybody else."
Dr. Magill reported no potential financial conflicts of interest; two of her associates reported ties to the Infectious Disease Consulting Corp. and Parexel.
An estimated 4% of inpatients at U.S. acute care hospitals have at least one health care–associated infection on any given day, according to a report published online March 26 in the New England Journal of Medicine.
Moreover, in a prevalence survey involving 183 acute care hospitals across 10 geographically diverse states, device-associated infections, "which have been a major focus of infection prevention in recent decades," accounted for only 25.6% of all health care–associated infections, said Dr. Shelley S. Magill of the division of health care quality promotion, Centers for Disease Control and Prevention, and her associates (N. Engl. J. Med. 2014;370:1198-1208).
In contrast, Clostridium difficile and other gastrointestinal infections, as well as non–ventilator-associated pneumonia, accounted for approximately half of all health care–associated infections in the survey. Surgical site infections also are still very common, accounting for 21.8%.
Because it appears that ventilator-associated pneumonia, catheter-associated UTIs, and central catheter–associated bloodstream infections are no longer the primary threat that they used to be, the study findings should prompt experts to "expand the public health focus to include these other types of infections, identifying patients at risk and developing effective countermeasures," the report’s authors noted.
The report shows that as a nation, we’re moving in the right direction; but there’s a great deal of work still to be done," Dr. Michael Bell said in a media briefing. "On any given day, 1 out of 25 hospitalized patients has an infection. And of those people, as many as one out of nine go on to die. This is not a minor issue," said Dr. Bell, deputy director of the CDC’s division of health care quality promotion.
The investigators developed and conducted the survey in 2011 to address a serious knowledge gap: No single surveillance system can provide estimates of "the burden of all types of such infections across acute care patient populations." So, Dr. Magill and her colleagues studied health care–associated infections among inpatients of all ages at 93 small, 68 medium-sized, and 22 large hospitals.
They found 504 such infections in 452 patients out of 11,282 patients covered in the survey, for an overall incidence of 4%. Using a statistical modeling process that accounted for predictors of infection prevalence and then applying those results to a nationally representative sample of U.S. community hospital stays, the investigators estimated that 648,000 inpatients nationwide had approximately 721,800 health care–associated infections in 2011.
Those estimates are lower than previous ones, such as those derived from the Study on the Efficacy of Nosocomial Infection Control in the 1970s , which postulated 2.1 million health care–associated infections each year, and those derived from National Nosocomial Infections Surveillance system data from 1990 to 2002, which estimated 1.7 million each year.
However, "it is difficult to draw conclusions from these comparisons because of the differences in patient populations, surveillance definitions of health care–associated infections, and data collection and analytical methods among these CDC methods," Dr. Magill and her associates said.
The current survey showed that 42.9% of health care–associated infections developed during a stay in a critical care unit or within 48 hours after; another 42.4% developed after a stay in a nonnursery ward.
Most of the surgical site infections were related to colon surgeries (14.5%), hip arthroplasty (10.0%), and small-bowel procedures (6.4%).
The median length of time between hospital admission and the onset of infection symptoms was 6 days.
C. difficile was the most frequently identified pathogen, accounting for 70.9% of all nosocomial GI infections and 12.1% of all health care–associated infections. Other common pathogens included Staphylococcus aureus (10.7% of all health care–associated infections), Klebsiella pneumoniae and Klebsiella oxytoca (9.9%), and Escherichia coli (9.3%).
The report’s investigators noted that their estimates "are remarkably similar to estimates from other data sources," such as the National Healthcare Safety Network and the Emerging Infections Program. That "bolsters our confidence in the overall estimates of health care–associated infections that we have generated," they said.
Sounding the alarm
The report "sounds the alarm" about infectious threats to hospitalized patients that need addressing, especially lung and gut infections and infections related to surgery or urinary catheters, Dr. Bell said. It also sheds light on several important pathogens, especially C. difficile, Staphylococci, and the family of Enterobacter organisms.
Those pathogens are at the center of President Barack Obama’s request for $30 million as part of his proposed $6.6 billion budget for 2015 for a new initiative to halve infections by those organisms within 5 years, Dr. Bell said.
The $30 million would be used to improve tracking of infections, the nation’s capacity for lab testing to determine which pathogens are most problematic, and "boots on the ground" to help hospitals implement best practices, Dr. Bell said.
The CDC would like to see every hospital in the country develop a strong antibiotic stewardship program, because "the challenge with antibiotic resistance can’t be overstated," he cautioned.
A patient advocate echoed that concern at the media briefing.
"While inwardly I breathe a small sigh of relief that annual infections and mortalities are diminishing, I remain extremely cautious regarding the growing threat of antibiotic resistance and the dire impact of this potential danger to American health care," said Victoria Nahum, executive director of the Safe Care Campaign. Ms. Nahum and her husband, Armando Nahum, founded the nonprofit organization after their son died of a health care–associated infection and two other family members developed complications from health care–associated infections.
Health care providers "have the power to prevent health care–associated infections" through compulsive hand hygiene and other best practices, Ms. Nahum said. Patients need to be more assertive, she added. "You just don’t flop down and say, ‘Take care of me.’ You have to kind of navigate what’s going to happen to you. In doing so, that can save your own life."
Dr. Bell suggested that hospitalized patients have a friend or family member be the "bad cop" and repeatedly ask caregivers if they have washed their hands, when urinary catheters can come out, and whether testing is being done to ensure that the right antibiotic is being used.
He said he knows that can be difficult for patients who may feel intimidated. "When my own mother was in the intensive care unit, I found it hard to pipe up," Dr. Bell said. "If I find it hard, I can’t imagine what it’s like for everybody else."
Dr. Magill reported no potential financial conflicts of interest; two of her associates reported ties to the Infectious Disease Consulting Corp. and Parexel.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major finding: An estimated 648,000 inpatients at U.S. acute care hospitals had approximately 721,800 health care–associated infections in 2011, but only 25% of these infections were related to devices such as ventilators, catheters, or central lines. Most health care–associated infections were non–ventilator-associated pneumonias, surgical site infections, or GI infections.
Data source: A prevalence survey of health care–associated infections among inpatients of all ages at 183 acute care hospitals in 10 geographically diverse states, plus an application of the results to a nationally representative sample of community hospital stays.
Disclosures: Dr. Magill reported no potential financial conflicts of interest; two of her associates reported ties to the Infectious Disease Consulting Corp. and Parexel.
Antibiotics may contribute to high pediatric C. difficile infection rate
Nearly three-quarters of Clostridium difficile infections in children and teens were community associated, with the highest incidence among 1-year-olds, according to a study published March 3 in Pediatrics.
The 944 pediatric cases analyzed for the study involved 885 children identified in select counties throughout eight states in 2010 and 10 states in 2011 as part of the Centers for Disease Control and Prevention’s Emerging Infections Program. Among those cases, 71% were community associated, 17% were community onset health care facility–associated and 12% were health care facility–onset (Pediatrics 2014 March 3 [doi:10.1542/peds.2013-3049]).
The highest incidence of 66.3 children/100,000 occurred among those aged 12-23 months old, followed by an incidence of 35.7 in children aged 2-3 years, 15.6 for those aged 4-9 years, and 16.6 for children aged 10-17 years.
"The high C. difficile infection incidence we observed among the youngest age group may be related to the finding that children 0-2 years of age have the highest outpatient antibiotic prescribing rate," reported Dr. Joyanna Wendt, a medical officer at the CDC, and her colleagues. Antibiotic use increases risk of C. difficile infection because the medication can change or kill beneficial bacteria that protect against infection.
Among a smaller sample of 84 cases interviewed in the study and reporting diarrhea on the first day of stool collection, 73% (61 cases) reported taking antibiotics within 12 weeks before the diarrhea began. Ear, sinus, and upper respiratory tract infections comprised the most common reasons for antibiotic use.
"Improved antibiotic prescribing is critical to protect the health of our nation’s children," Dr. Tom Frieden, CDC director, said in a prepared statement. "When antibiotics are prescribed incorrectly, our children are needlessly put at risk for health problems, including C. difficile infection and dangerous antibiotic-resistant infections."
Incidence did not differ by sex, but white children had a higher incidence, with 23.9 cases/100,000 children, compared with 17.4 for nonwhite children, "likely reflecting, in part, differences in health care access," the researchers wrote.
This study was supported by the CDC. Coauthor Dr. Dennis N. Gerding is a board member at Merck, Rebiotix, Summit, and Actelion and consults for Roche, Novartis, Sanofi Pasteur, and Cubist; he consults for and holds patents licensed to ViroPharma, which manufactures vancomycin to treat C difficile. No other authors reported disclosures.
Nearly three-quarters of Clostridium difficile infections in children and teens were community associated, with the highest incidence among 1-year-olds, according to a study published March 3 in Pediatrics.
The 944 pediatric cases analyzed for the study involved 885 children identified in select counties throughout eight states in 2010 and 10 states in 2011 as part of the Centers for Disease Control and Prevention’s Emerging Infections Program. Among those cases, 71% were community associated, 17% were community onset health care facility–associated and 12% were health care facility–onset (Pediatrics 2014 March 3 [doi:10.1542/peds.2013-3049]).
The highest incidence of 66.3 children/100,000 occurred among those aged 12-23 months old, followed by an incidence of 35.7 in children aged 2-3 years, 15.6 for those aged 4-9 years, and 16.6 for children aged 10-17 years.
"The high C. difficile infection incidence we observed among the youngest age group may be related to the finding that children 0-2 years of age have the highest outpatient antibiotic prescribing rate," reported Dr. Joyanna Wendt, a medical officer at the CDC, and her colleagues. Antibiotic use increases risk of C. difficile infection because the medication can change or kill beneficial bacteria that protect against infection.
Among a smaller sample of 84 cases interviewed in the study and reporting diarrhea on the first day of stool collection, 73% (61 cases) reported taking antibiotics within 12 weeks before the diarrhea began. Ear, sinus, and upper respiratory tract infections comprised the most common reasons for antibiotic use.
"Improved antibiotic prescribing is critical to protect the health of our nation’s children," Dr. Tom Frieden, CDC director, said in a prepared statement. "When antibiotics are prescribed incorrectly, our children are needlessly put at risk for health problems, including C. difficile infection and dangerous antibiotic-resistant infections."
Incidence did not differ by sex, but white children had a higher incidence, with 23.9 cases/100,000 children, compared with 17.4 for nonwhite children, "likely reflecting, in part, differences in health care access," the researchers wrote.
This study was supported by the CDC. Coauthor Dr. Dennis N. Gerding is a board member at Merck, Rebiotix, Summit, and Actelion and consults for Roche, Novartis, Sanofi Pasteur, and Cubist; he consults for and holds patents licensed to ViroPharma, which manufactures vancomycin to treat C difficile. No other authors reported disclosures.
Nearly three-quarters of Clostridium difficile infections in children and teens were community associated, with the highest incidence among 1-year-olds, according to a study published March 3 in Pediatrics.
The 944 pediatric cases analyzed for the study involved 885 children identified in select counties throughout eight states in 2010 and 10 states in 2011 as part of the Centers for Disease Control and Prevention’s Emerging Infections Program. Among those cases, 71% were community associated, 17% were community onset health care facility–associated and 12% were health care facility–onset (Pediatrics 2014 March 3 [doi:10.1542/peds.2013-3049]).
The highest incidence of 66.3 children/100,000 occurred among those aged 12-23 months old, followed by an incidence of 35.7 in children aged 2-3 years, 15.6 for those aged 4-9 years, and 16.6 for children aged 10-17 years.
"The high C. difficile infection incidence we observed among the youngest age group may be related to the finding that children 0-2 years of age have the highest outpatient antibiotic prescribing rate," reported Dr. Joyanna Wendt, a medical officer at the CDC, and her colleagues. Antibiotic use increases risk of C. difficile infection because the medication can change or kill beneficial bacteria that protect against infection.
Among a smaller sample of 84 cases interviewed in the study and reporting diarrhea on the first day of stool collection, 73% (61 cases) reported taking antibiotics within 12 weeks before the diarrhea began. Ear, sinus, and upper respiratory tract infections comprised the most common reasons for antibiotic use.
"Improved antibiotic prescribing is critical to protect the health of our nation’s children," Dr. Tom Frieden, CDC director, said in a prepared statement. "When antibiotics are prescribed incorrectly, our children are needlessly put at risk for health problems, including C. difficile infection and dangerous antibiotic-resistant infections."
Incidence did not differ by sex, but white children had a higher incidence, with 23.9 cases/100,000 children, compared with 17.4 for nonwhite children, "likely reflecting, in part, differences in health care access," the researchers wrote.
This study was supported by the CDC. Coauthor Dr. Dennis N. Gerding is a board member at Merck, Rebiotix, Summit, and Actelion and consults for Roche, Novartis, Sanofi Pasteur, and Cubist; he consults for and holds patents licensed to ViroPharma, which manufactures vancomycin to treat C difficile. No other authors reported disclosures.
FROM PEDIATRICS
Major Finding: Seventy-one percent of 944 pediatric C. difficile infections were community associated with the highest incidence among 1-year-old (66.3/100,000) and white children (23.9/100,000).
Data Source: A CDC Emerging Infections Program surveillance of pediatric (ages 1-17) C. difficile cases across eight states in 2010 and 10 states in 2011.
Disclosures: This study was supported by the CDC. Dr. Gerding is a board member at Merck, Rebiotix, Summit, and Actelion and consults for Roche, Novartis, Sanofi Pasteur, and Cubist; he consults for and holds patents licensed to Viropharma, which manufactures vancomycin to treat C. difficile. No other authors reported disclosures.
Aim for deep remission, high troughs in Crohn’s
"Deep remission" of Crohn’s disease is associated with better quality of life, physical function, and cost savings.
Moreover, this composite clinical and endoscopic endpoint may be best accomplished through monitoring of the tumor necrosis factor antagonists’ plasma concentration, meaning that the pharmacokinetics of these therapies must be accounted for when optimizing drug treatment.
Those are the findings from two new analyses in the March issue of Clinical Gastroenterology and Hepatology, both by Dr. Jean-Frédéric Colombel of the Mount Sinai Hospital School of Medicine in New York.
In the first study, Dr. Colombel and his colleagues looked at 135 adults with moderate to severe ileocolonic Crohn’s enrolled in the EXTEND trial, a 52-week, randomized, double-blind placebo-controlled trial of adalimumab (doi:10.1016/j.cgh.2013.06.019).
The goal of EXTEND was to assess the effect of induction plus maintenance dosing of adalimumab, versus induction only. All patients received open-label adalimumab (160 mg and 80 mg at weeks 0 and 2, respectively) during the 4-week induction phase and were randomized at week 4 to receive adalimumab 40 mg every other week or placebo.
Overall, 19% of patients who received both adalimumab induction and maintenance therapy achieved so-called deep remission, defined as the absence of mucosal ulceration plus clinical remission (Crohn’s Disease Activity Index [CDAI], less than 150). Of the remaining responders, 8 had an absence of mucosal ulceration without clinical remission, and 19 had clinical remission with persistent mucosal ulceration.
Dr. Colombel and his coinvestigators found that patients in deep remission registered significantly fewer days absent from work, less work productivity impairment, greater work productivity, and less daily nonwork activity impairment, compared with patients who did not achieve deep remission (P less than .05 for all).
Moreover, at 1 year after therapy induction, significantly more patients in the deep remission group achieved remission according to the Inflammatory Bowel Disease Questionnaire (64% vs. 26%; P less than .05) and normal Short Form–36 Health Survey status (55% vs. 19%; P less than .05), compared with patients who were not in deep remission.
Finally, during the 40 weeks after early deep remission achievement, estimated savings among deep remission patients were $6,117 for direct medical costs and $4,243 for indirect costs related to productivity, compared with the costs for patients not in deep remission.
"This treatment target in CD [of deep remission], which combines symptom control with an objective indicator of inflammatory disease activity, still is evolving," wrote the investigators.
However, "current analysis provides preliminary evidence that early [deep remission] is achievable and may be a useful treatment target," they added.
The second analysis, also by Dr. Colombel, looked at the optimization of TNF antagonists in Crohn’s disease – specifically, at certolizumab pegol (doi:10.1016/j.cgh.2013.10.025).
In this post hoc analysis, Dr. Colombel looked at patients enrolled in the MUSIC trial, a 54-week, multicenter, single-arm open-label study assessing endoscopic improvement in patients with moderate to severe Crohn’s disease.
All patients received loading doses of certolizumab pegol 400 mg at 0, 2, and 4 weeks, followed by a maintenance dose of 400 mg every 4 weeks.
The authors found that at week 10, patients who achieved a clinical and an endoscopic response had "nominally higher" trough plasma certolizumab pegol concentrations at week 8 than those with no response or remission (16.5 mcg/mL for patients with a clinical response and 19.8 mcg/mL for patients with an endoscopic response, vs. 13.7 mcg/mL and 11.5 mcg/mL in the clinical and endoscopic nonresponders).
Similarly, patients who achieved clinical and endoscopic remission at week 10 also had nominally higher trough plasma concentrations at week 8, with clinical remission patients registering 17.6 mcg/mL (vs. 11.1 mcg/mL in patients without clinical remission) and endoscopic remission patients measuring 19.2 mcg/mL (vs. 12.6 mcg/mL in patients who did not achieve that endpoint).
"Plasma certolizumab pegol concentration is not readily measured in standard clinical practice at this time," wrote the authors.
However, "additional studies are needed to understand the relationships among clinical response, body weight, and plasma concentration of the TNF antagonist," they added.
Dr. Colombel and his colleagues disclosed numerous financial relationships with pharmaceutical companies, including the makers of adalimumab and certolizumab pegol; the EXTEND trial was funded by AbbieVie, the maker of adalimumab, and the MUSIC trial was funded by UCB Pharma, maker of certolizumab pegol.
This month's issue of Clinical Gastroenterology and Hepatology contains two articles that explore important, novel concepts in the management of patients with Crohn's disease - that of mucosal healing as a potential therapeutic endpoint and that of therapeutic drug monitoring of tumor necrosis factor antagonists.
New endpoints are required because the currently accepted endpoint of a Crohn's Disease Activity Index score of less than 150 points does not optimally track with endoscopic healing, which appears to correlate with favorable longer-term outcomes such as reduced need for corticosteroids, hospitalizations, and major abdominal surgeries.
In a secondary analysis of the EXTEND trial (a study of endoscopic healing of Crohn's disease with adalimumab), the authors were able to show that patients who had achieved the endpoint of "deep remission" (that is, clinical remission and absence of ulcerations on endoscopy) by week 12 had fewer hospitalizations and surgeries than those who had not achieved deep remission.
Interestingly, those patients achieving deep remission had better outcomes than those who achieved endoscopic but not clinical remission, whereas there didn't appear to be an incremental benefit of achieving deep remission over clinical remission alone.
One should consider this a proof of concept study of the potential utility of deep remission as an endpoint, and we need to see prospective trials before concluding that deep remission is an endpoint to strive for in all of our patients.
The second article was a secondary analysis of the MUSIC trial (a study of endoscopic improvement of Crohn's disease with certolizumab pegol) and attempted to correlate certolizumab pegol concentrations with endoscopic response or remission.
The authors found that levels at week 8 were significantly associated with rates of endoscopic response and remission at week 10. They also found that higher body weight and serum C-reactive protein levels were associated with lower certolizumab levels.
This study corroborates evidence from other studies that concentrations of infliximab and adalimumab can be correlated to clinical outcomes.
Furthermore, the relationship between certolizumab plasma levels and other factors such as body weight and C-reactive protein levels highlights the complex pharmacokinetics of these biologic agents and underscores the potential need for therapeutic drug monitoring.
Dr. Edward V. Loftus Jr., AGAF, is professor of medicine and director, inflammatory bowel disease clinic, division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. He is a consultant for AbbVie, UCB, Janssen, Takeda-Millennium, and Immune Pharmaceuticals and receives research support from AbbVie, UCB, Janssen, Takeda-Millennium, Pfizer, Amgen, Santarus, Robarts Clinical Trials, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Shire, and Braintree Labs.
This month's issue of Clinical Gastroenterology and Hepatology contains two articles that explore important, novel concepts in the management of patients with Crohn's disease - that of mucosal healing as a potential therapeutic endpoint and that of therapeutic drug monitoring of tumor necrosis factor antagonists.
New endpoints are required because the currently accepted endpoint of a Crohn's Disease Activity Index score of less than 150 points does not optimally track with endoscopic healing, which appears to correlate with favorable longer-term outcomes such as reduced need for corticosteroids, hospitalizations, and major abdominal surgeries.
In a secondary analysis of the EXTEND trial (a study of endoscopic healing of Crohn's disease with adalimumab), the authors were able to show that patients who had achieved the endpoint of "deep remission" (that is, clinical remission and absence of ulcerations on endoscopy) by week 12 had fewer hospitalizations and surgeries than those who had not achieved deep remission.
Interestingly, those patients achieving deep remission had better outcomes than those who achieved endoscopic but not clinical remission, whereas there didn't appear to be an incremental benefit of achieving deep remission over clinical remission alone.
One should consider this a proof of concept study of the potential utility of deep remission as an endpoint, and we need to see prospective trials before concluding that deep remission is an endpoint to strive for in all of our patients.
The second article was a secondary analysis of the MUSIC trial (a study of endoscopic improvement of Crohn's disease with certolizumab pegol) and attempted to correlate certolizumab pegol concentrations with endoscopic response or remission.
The authors found that levels at week 8 were significantly associated with rates of endoscopic response and remission at week 10. They also found that higher body weight and serum C-reactive protein levels were associated with lower certolizumab levels.
This study corroborates evidence from other studies that concentrations of infliximab and adalimumab can be correlated to clinical outcomes.
Furthermore, the relationship between certolizumab plasma levels and other factors such as body weight and C-reactive protein levels highlights the complex pharmacokinetics of these biologic agents and underscores the potential need for therapeutic drug monitoring.
Dr. Edward V. Loftus Jr., AGAF, is professor of medicine and director, inflammatory bowel disease clinic, division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. He is a consultant for AbbVie, UCB, Janssen, Takeda-Millennium, and Immune Pharmaceuticals and receives research support from AbbVie, UCB, Janssen, Takeda-Millennium, Pfizer, Amgen, Santarus, Robarts Clinical Trials, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Shire, and Braintree Labs.
This month's issue of Clinical Gastroenterology and Hepatology contains two articles that explore important, novel concepts in the management of patients with Crohn's disease - that of mucosal healing as a potential therapeutic endpoint and that of therapeutic drug monitoring of tumor necrosis factor antagonists.
New endpoints are required because the currently accepted endpoint of a Crohn's Disease Activity Index score of less than 150 points does not optimally track with endoscopic healing, which appears to correlate with favorable longer-term outcomes such as reduced need for corticosteroids, hospitalizations, and major abdominal surgeries.
In a secondary analysis of the EXTEND trial (a study of endoscopic healing of Crohn's disease with adalimumab), the authors were able to show that patients who had achieved the endpoint of "deep remission" (that is, clinical remission and absence of ulcerations on endoscopy) by week 12 had fewer hospitalizations and surgeries than those who had not achieved deep remission.
Interestingly, those patients achieving deep remission had better outcomes than those who achieved endoscopic but not clinical remission, whereas there didn't appear to be an incremental benefit of achieving deep remission over clinical remission alone.
One should consider this a proof of concept study of the potential utility of deep remission as an endpoint, and we need to see prospective trials before concluding that deep remission is an endpoint to strive for in all of our patients.
The second article was a secondary analysis of the MUSIC trial (a study of endoscopic improvement of Crohn's disease with certolizumab pegol) and attempted to correlate certolizumab pegol concentrations with endoscopic response or remission.
The authors found that levels at week 8 were significantly associated with rates of endoscopic response and remission at week 10. They also found that higher body weight and serum C-reactive protein levels were associated with lower certolizumab levels.
This study corroborates evidence from other studies that concentrations of infliximab and adalimumab can be correlated to clinical outcomes.
Furthermore, the relationship between certolizumab plasma levels and other factors such as body weight and C-reactive protein levels highlights the complex pharmacokinetics of these biologic agents and underscores the potential need for therapeutic drug monitoring.
Dr. Edward V. Loftus Jr., AGAF, is professor of medicine and director, inflammatory bowel disease clinic, division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. He is a consultant for AbbVie, UCB, Janssen, Takeda-Millennium, and Immune Pharmaceuticals and receives research support from AbbVie, UCB, Janssen, Takeda-Millennium, Pfizer, Amgen, Santarus, Robarts Clinical Trials, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Shire, and Braintree Labs.
"Deep remission" of Crohn’s disease is associated with better quality of life, physical function, and cost savings.
Moreover, this composite clinical and endoscopic endpoint may be best accomplished through monitoring of the tumor necrosis factor antagonists’ plasma concentration, meaning that the pharmacokinetics of these therapies must be accounted for when optimizing drug treatment.
Those are the findings from two new analyses in the March issue of Clinical Gastroenterology and Hepatology, both by Dr. Jean-Frédéric Colombel of the Mount Sinai Hospital School of Medicine in New York.
In the first study, Dr. Colombel and his colleagues looked at 135 adults with moderate to severe ileocolonic Crohn’s enrolled in the EXTEND trial, a 52-week, randomized, double-blind placebo-controlled trial of adalimumab (doi:10.1016/j.cgh.2013.06.019).
The goal of EXTEND was to assess the effect of induction plus maintenance dosing of adalimumab, versus induction only. All patients received open-label adalimumab (160 mg and 80 mg at weeks 0 and 2, respectively) during the 4-week induction phase and were randomized at week 4 to receive adalimumab 40 mg every other week or placebo.
Overall, 19% of patients who received both adalimumab induction and maintenance therapy achieved so-called deep remission, defined as the absence of mucosal ulceration plus clinical remission (Crohn’s Disease Activity Index [CDAI], less than 150). Of the remaining responders, 8 had an absence of mucosal ulceration without clinical remission, and 19 had clinical remission with persistent mucosal ulceration.
Dr. Colombel and his coinvestigators found that patients in deep remission registered significantly fewer days absent from work, less work productivity impairment, greater work productivity, and less daily nonwork activity impairment, compared with patients who did not achieve deep remission (P less than .05 for all).
Moreover, at 1 year after therapy induction, significantly more patients in the deep remission group achieved remission according to the Inflammatory Bowel Disease Questionnaire (64% vs. 26%; P less than .05) and normal Short Form–36 Health Survey status (55% vs. 19%; P less than .05), compared with patients who were not in deep remission.
Finally, during the 40 weeks after early deep remission achievement, estimated savings among deep remission patients were $6,117 for direct medical costs and $4,243 for indirect costs related to productivity, compared with the costs for patients not in deep remission.
"This treatment target in CD [of deep remission], which combines symptom control with an objective indicator of inflammatory disease activity, still is evolving," wrote the investigators.
However, "current analysis provides preliminary evidence that early [deep remission] is achievable and may be a useful treatment target," they added.
The second analysis, also by Dr. Colombel, looked at the optimization of TNF antagonists in Crohn’s disease – specifically, at certolizumab pegol (doi:10.1016/j.cgh.2013.10.025).
In this post hoc analysis, Dr. Colombel looked at patients enrolled in the MUSIC trial, a 54-week, multicenter, single-arm open-label study assessing endoscopic improvement in patients with moderate to severe Crohn’s disease.
All patients received loading doses of certolizumab pegol 400 mg at 0, 2, and 4 weeks, followed by a maintenance dose of 400 mg every 4 weeks.
The authors found that at week 10, patients who achieved a clinical and an endoscopic response had "nominally higher" trough plasma certolizumab pegol concentrations at week 8 than those with no response or remission (16.5 mcg/mL for patients with a clinical response and 19.8 mcg/mL for patients with an endoscopic response, vs. 13.7 mcg/mL and 11.5 mcg/mL in the clinical and endoscopic nonresponders).
Similarly, patients who achieved clinical and endoscopic remission at week 10 also had nominally higher trough plasma concentrations at week 8, with clinical remission patients registering 17.6 mcg/mL (vs. 11.1 mcg/mL in patients without clinical remission) and endoscopic remission patients measuring 19.2 mcg/mL (vs. 12.6 mcg/mL in patients who did not achieve that endpoint).
"Plasma certolizumab pegol concentration is not readily measured in standard clinical practice at this time," wrote the authors.
However, "additional studies are needed to understand the relationships among clinical response, body weight, and plasma concentration of the TNF antagonist," they added.
Dr. Colombel and his colleagues disclosed numerous financial relationships with pharmaceutical companies, including the makers of adalimumab and certolizumab pegol; the EXTEND trial was funded by AbbieVie, the maker of adalimumab, and the MUSIC trial was funded by UCB Pharma, maker of certolizumab pegol.
"Deep remission" of Crohn’s disease is associated with better quality of life, physical function, and cost savings.
Moreover, this composite clinical and endoscopic endpoint may be best accomplished through monitoring of the tumor necrosis factor antagonists’ plasma concentration, meaning that the pharmacokinetics of these therapies must be accounted for when optimizing drug treatment.
Those are the findings from two new analyses in the March issue of Clinical Gastroenterology and Hepatology, both by Dr. Jean-Frédéric Colombel of the Mount Sinai Hospital School of Medicine in New York.
In the first study, Dr. Colombel and his colleagues looked at 135 adults with moderate to severe ileocolonic Crohn’s enrolled in the EXTEND trial, a 52-week, randomized, double-blind placebo-controlled trial of adalimumab (doi:10.1016/j.cgh.2013.06.019).
The goal of EXTEND was to assess the effect of induction plus maintenance dosing of adalimumab, versus induction only. All patients received open-label adalimumab (160 mg and 80 mg at weeks 0 and 2, respectively) during the 4-week induction phase and were randomized at week 4 to receive adalimumab 40 mg every other week or placebo.
Overall, 19% of patients who received both adalimumab induction and maintenance therapy achieved so-called deep remission, defined as the absence of mucosal ulceration plus clinical remission (Crohn’s Disease Activity Index [CDAI], less than 150). Of the remaining responders, 8 had an absence of mucosal ulceration without clinical remission, and 19 had clinical remission with persistent mucosal ulceration.
Dr. Colombel and his coinvestigators found that patients in deep remission registered significantly fewer days absent from work, less work productivity impairment, greater work productivity, and less daily nonwork activity impairment, compared with patients who did not achieve deep remission (P less than .05 for all).
Moreover, at 1 year after therapy induction, significantly more patients in the deep remission group achieved remission according to the Inflammatory Bowel Disease Questionnaire (64% vs. 26%; P less than .05) and normal Short Form–36 Health Survey status (55% vs. 19%; P less than .05), compared with patients who were not in deep remission.
Finally, during the 40 weeks after early deep remission achievement, estimated savings among deep remission patients were $6,117 for direct medical costs and $4,243 for indirect costs related to productivity, compared with the costs for patients not in deep remission.
"This treatment target in CD [of deep remission], which combines symptom control with an objective indicator of inflammatory disease activity, still is evolving," wrote the investigators.
However, "current analysis provides preliminary evidence that early [deep remission] is achievable and may be a useful treatment target," they added.
The second analysis, also by Dr. Colombel, looked at the optimization of TNF antagonists in Crohn’s disease – specifically, at certolizumab pegol (doi:10.1016/j.cgh.2013.10.025).
In this post hoc analysis, Dr. Colombel looked at patients enrolled in the MUSIC trial, a 54-week, multicenter, single-arm open-label study assessing endoscopic improvement in patients with moderate to severe Crohn’s disease.
All patients received loading doses of certolizumab pegol 400 mg at 0, 2, and 4 weeks, followed by a maintenance dose of 400 mg every 4 weeks.
The authors found that at week 10, patients who achieved a clinical and an endoscopic response had "nominally higher" trough plasma certolizumab pegol concentrations at week 8 than those with no response or remission (16.5 mcg/mL for patients with a clinical response and 19.8 mcg/mL for patients with an endoscopic response, vs. 13.7 mcg/mL and 11.5 mcg/mL in the clinical and endoscopic nonresponders).
Similarly, patients who achieved clinical and endoscopic remission at week 10 also had nominally higher trough plasma concentrations at week 8, with clinical remission patients registering 17.6 mcg/mL (vs. 11.1 mcg/mL in patients without clinical remission) and endoscopic remission patients measuring 19.2 mcg/mL (vs. 12.6 mcg/mL in patients who did not achieve that endpoint).
"Plasma certolizumab pegol concentration is not readily measured in standard clinical practice at this time," wrote the authors.
However, "additional studies are needed to understand the relationships among clinical response, body weight, and plasma concentration of the TNF antagonist," they added.
Dr. Colombel and his colleagues disclosed numerous financial relationships with pharmaceutical companies, including the makers of adalimumab and certolizumab pegol; the EXTEND trial was funded by AbbieVie, the maker of adalimumab, and the MUSIC trial was funded by UCB Pharma, maker of certolizumab pegol.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Major finding: Deep remission in Crohn’s disease is a novel and useful treatment target; reaching it may depend on monitoring blood levels of the drugs used to treat the disease.
Data source: Analyses of the EXTEND and MUSIC trials.
Disclosures: Dr. Colombel and his colleagues disclosed numerous financial relationships with pharmaceutical companies, including the makers of adalimumab and certolizumab pegol; the EXTEND trial was funded by AbbieVie, the maker of adalimumab, and the MUSIC trial was funded by UCB Pharma, maker of certolizumab pegol.
Gut-joint connection promising in psoriatic arthritis
SNOWMASS, COLO. – Mounting circumstantial evidence points to perturbation of bacterial communities in the gut and skin as important environmental triggers for psoriasis and psoriatic arthritis.
A distinctive pattern of alterations in the skin microbiota, termed bacterial "cutaneotypes," has recently been documented in lesional and uninvolved skin of psoriasis patients. Similarly, psoriatic arthritis patients show decreased diversity of their intestinal bacterial community in a pattern similar to patients with inflammatory bowel disease, Dr. Jose U. Scher said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
The current working hypothesis of disease pathogenesis is that, in individuals genetically predisposed to psoriasis or psoriatic arthritis, this microbial dysbiosis at the cutaneous and gut levels provides an environmental trigger for overt expression of clinical disease.
"This dysbiosis is potentially relevant as a diagnostic and/or therapeutic target in psoriasis and psoriatic arthritis. For example, it may eventually become possible to assess the gut microbiota to predict which psoriasis patients will later develop psoriatic arthritis. And reconstituting the gut flora may turn out to have therapeutic benefit. But much more work is needed," explained Dr. Scher, director of the Microbiome Center for Rheumatology and Autoimmunity at New York University.
About 25%-30% of psoriasis patients develop inflammatory psoriatic arthritis, most often roughly 7 years after onset of their skin disease. Genetics clearly plays a role, as shown in a classic Danish twin registry study with more than 21,000 subjects. Fifty-five percent of the siblings of monozygotic twins with psoriatic arthritis had skin psoriasis, but only 10% of the siblings had psoriatic arthritis, as did 3.8% of siblings of dizygotic twins with psoriatic arthritis. The lesser concordance rate seen for psoriatic arthritis hinted at the importance of environmental factors in disease genesis (Ann. Rheum. Dis. 2008;67:1417-21).
Subclinical gut inflammation is common in psoriatic arthritis. In one early study, histologic evidence of mild or moderate gut mucosal inflammation was detected in 45% of a group of psoriatic arthritis patients, compared with 15% of patients with rheumatoid arthritis and 0% of controls (Scand. J. Rheumatol. 1997;26:92-8).
Also, psoriasis patients are at a roughly 3.5-fold increased risk of developing Crohn’s disease. Among patients with established psoriatic arthritis, this risk climbs to 6.5-fold greater than in nonpsoriatic controls (Ann. Rheum. Dis. 2013;72:1200-5).
In a soon-to-be-published study, Dr. Scher and his coworkers have taken the field a step further, employing high-throughput gene sequencing to analyze the gut bacterial communities of psoriatic arthritis patients and controls. These were all new-onset psoriatic arthritis patients who had never been exposed to systemic corticosteroids, biologic agents, or conventional disease-modifying antirheumatic drugs.
Compared with the stool samples of healthy controls, several major bacterial species were underrepresented or absent in the gut microbiota of psoriatic arthritis patients. These included Akkermansia, the most common mucolytic bacterium in healthy subjects. Intriguingly, Akkermansia counts are decreased 15-fold in Crohn’s disease and 92-fold in ulcerative colitis, according to the rheumatologist.
Other bacterial species markedly less abundant in the psoriatic arthritis patients’ gut flora were Ruminoccocus, Alistipes, and Roseburia. Like Akkermansia, these are mucin-degrading bacteria that promote a healthy gut environment, and they, too, are reduced in inflammatory bowel disease, Dr. Scher said.
He theorized that these disruptions of the bacterial ecosystem might arise from a course of antibiotics, a change in diet, or other insults. The result is activation of dendritic cells to produce interleukin-23, which triggers a proinflammatory cascade including tumor necrosis factor-alpha, interleukin-22, and antimicrobial peptides.
As shown by other investigators (Mucosal Immunol. 2013;6:666-77), these proinflammatory cytokines inhibit RANK ligand, which is the critical factor for differentiation of microfold cells in the gut. These microfold cells, or M cells, are specialized epithelial cells that transport antigens across the gut epithelium and play an important role in maintenance of an efficient immune response. It’s plausible that, when these M cells are defective, the resultant loss of tolerance and chronic inflammatory state can result in psoriatic arthritis, he explained.
Dr. Scher’s colleagues at New York University have used high-throughput gene sequencing to analyze the cutaneous microbiota of lesional and nonlesional skin in psoriasis patients, as well as skin samples from the same sites in healthy controls. The impetus for this study was a hypothesis that psoriasis might represent an inappropriate cutaneous immune response directed against offending bacteria in the skin microbiota.
Sure enough, the bacterial community present in psoriatic lesions displayed a markedly decreased diversity, compared with controls. This decreased diversity also was present, albeit to a lesser extent, in the psoriasis patients’ nonlesional skin. Both the lesional and nonlesional skin of psoriasis patients contained an increased abundance of Corynebacterium, Staphylococcus, and Streptococcus, compared with controls.
In addition, the skin microbiota could be classified into one of two characteristic patterns, which the investigators termed "cutaneotypes." Cutaneotype 1, which predominated in the skin of normal controls, contained an abundance of Proteobacteria. In contrast, cutaneotype 2, which was 3.5-fold more prevalent in psoriatic lesions than in controls, was enriched in Firmicutes and Actinobacteria. The psoriatic patients’ nonlesional skin contained a balance of cutaneotypes 1 and 2 (Microbiome 2013 Dec. 23 [doi:10.1186/2049-2618-1-31]).
Dr. Scher said that the next step in his own research is to learn whether the gut microbiota of psoriasis patients differs from that of psoriatic arthritis patients.
"That’s to me the most important piece of data. I think there’s a lot of work to do, and we’re doing it now, in prospective fashion. We’re following patients with psoriasis, and for those who later convert to psoriatic arthritis we’ll want to know if there’s alteration of their bacterial immunity, both in the gut and the skin," he explained.
Dr. Scher reported having no financial conflicts.
SNOWMASS, COLO. – Mounting circumstantial evidence points to perturbation of bacterial communities in the gut and skin as important environmental triggers for psoriasis and psoriatic arthritis.
A distinctive pattern of alterations in the skin microbiota, termed bacterial "cutaneotypes," has recently been documented in lesional and uninvolved skin of psoriasis patients. Similarly, psoriatic arthritis patients show decreased diversity of their intestinal bacterial community in a pattern similar to patients with inflammatory bowel disease, Dr. Jose U. Scher said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
The current working hypothesis of disease pathogenesis is that, in individuals genetically predisposed to psoriasis or psoriatic arthritis, this microbial dysbiosis at the cutaneous and gut levels provides an environmental trigger for overt expression of clinical disease.
"This dysbiosis is potentially relevant as a diagnostic and/or therapeutic target in psoriasis and psoriatic arthritis. For example, it may eventually become possible to assess the gut microbiota to predict which psoriasis patients will later develop psoriatic arthritis. And reconstituting the gut flora may turn out to have therapeutic benefit. But much more work is needed," explained Dr. Scher, director of the Microbiome Center for Rheumatology and Autoimmunity at New York University.
About 25%-30% of psoriasis patients develop inflammatory psoriatic arthritis, most often roughly 7 years after onset of their skin disease. Genetics clearly plays a role, as shown in a classic Danish twin registry study with more than 21,000 subjects. Fifty-five percent of the siblings of monozygotic twins with psoriatic arthritis had skin psoriasis, but only 10% of the siblings had psoriatic arthritis, as did 3.8% of siblings of dizygotic twins with psoriatic arthritis. The lesser concordance rate seen for psoriatic arthritis hinted at the importance of environmental factors in disease genesis (Ann. Rheum. Dis. 2008;67:1417-21).
Subclinical gut inflammation is common in psoriatic arthritis. In one early study, histologic evidence of mild or moderate gut mucosal inflammation was detected in 45% of a group of psoriatic arthritis patients, compared with 15% of patients with rheumatoid arthritis and 0% of controls (Scand. J. Rheumatol. 1997;26:92-8).
Also, psoriasis patients are at a roughly 3.5-fold increased risk of developing Crohn’s disease. Among patients with established psoriatic arthritis, this risk climbs to 6.5-fold greater than in nonpsoriatic controls (Ann. Rheum. Dis. 2013;72:1200-5).
In a soon-to-be-published study, Dr. Scher and his coworkers have taken the field a step further, employing high-throughput gene sequencing to analyze the gut bacterial communities of psoriatic arthritis patients and controls. These were all new-onset psoriatic arthritis patients who had never been exposed to systemic corticosteroids, biologic agents, or conventional disease-modifying antirheumatic drugs.
Compared with the stool samples of healthy controls, several major bacterial species were underrepresented or absent in the gut microbiota of psoriatic arthritis patients. These included Akkermansia, the most common mucolytic bacterium in healthy subjects. Intriguingly, Akkermansia counts are decreased 15-fold in Crohn’s disease and 92-fold in ulcerative colitis, according to the rheumatologist.
Other bacterial species markedly less abundant in the psoriatic arthritis patients’ gut flora were Ruminoccocus, Alistipes, and Roseburia. Like Akkermansia, these are mucin-degrading bacteria that promote a healthy gut environment, and they, too, are reduced in inflammatory bowel disease, Dr. Scher said.
He theorized that these disruptions of the bacterial ecosystem might arise from a course of antibiotics, a change in diet, or other insults. The result is activation of dendritic cells to produce interleukin-23, which triggers a proinflammatory cascade including tumor necrosis factor-alpha, interleukin-22, and antimicrobial peptides.
As shown by other investigators (Mucosal Immunol. 2013;6:666-77), these proinflammatory cytokines inhibit RANK ligand, which is the critical factor for differentiation of microfold cells in the gut. These microfold cells, or M cells, are specialized epithelial cells that transport antigens across the gut epithelium and play an important role in maintenance of an efficient immune response. It’s plausible that, when these M cells are defective, the resultant loss of tolerance and chronic inflammatory state can result in psoriatic arthritis, he explained.
Dr. Scher’s colleagues at New York University have used high-throughput gene sequencing to analyze the cutaneous microbiota of lesional and nonlesional skin in psoriasis patients, as well as skin samples from the same sites in healthy controls. The impetus for this study was a hypothesis that psoriasis might represent an inappropriate cutaneous immune response directed against offending bacteria in the skin microbiota.
Sure enough, the bacterial community present in psoriatic lesions displayed a markedly decreased diversity, compared with controls. This decreased diversity also was present, albeit to a lesser extent, in the psoriasis patients’ nonlesional skin. Both the lesional and nonlesional skin of psoriasis patients contained an increased abundance of Corynebacterium, Staphylococcus, and Streptococcus, compared with controls.
In addition, the skin microbiota could be classified into one of two characteristic patterns, which the investigators termed "cutaneotypes." Cutaneotype 1, which predominated in the skin of normal controls, contained an abundance of Proteobacteria. In contrast, cutaneotype 2, which was 3.5-fold more prevalent in psoriatic lesions than in controls, was enriched in Firmicutes and Actinobacteria. The psoriatic patients’ nonlesional skin contained a balance of cutaneotypes 1 and 2 (Microbiome 2013 Dec. 23 [doi:10.1186/2049-2618-1-31]).
Dr. Scher said that the next step in his own research is to learn whether the gut microbiota of psoriasis patients differs from that of psoriatic arthritis patients.
"That’s to me the most important piece of data. I think there’s a lot of work to do, and we’re doing it now, in prospective fashion. We’re following patients with psoriasis, and for those who later convert to psoriatic arthritis we’ll want to know if there’s alteration of their bacterial immunity, both in the gut and the skin," he explained.
Dr. Scher reported having no financial conflicts.
SNOWMASS, COLO. – Mounting circumstantial evidence points to perturbation of bacterial communities in the gut and skin as important environmental triggers for psoriasis and psoriatic arthritis.
A distinctive pattern of alterations in the skin microbiota, termed bacterial "cutaneotypes," has recently been documented in lesional and uninvolved skin of psoriasis patients. Similarly, psoriatic arthritis patients show decreased diversity of their intestinal bacterial community in a pattern similar to patients with inflammatory bowel disease, Dr. Jose U. Scher said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
The current working hypothesis of disease pathogenesis is that, in individuals genetically predisposed to psoriasis or psoriatic arthritis, this microbial dysbiosis at the cutaneous and gut levels provides an environmental trigger for overt expression of clinical disease.
"This dysbiosis is potentially relevant as a diagnostic and/or therapeutic target in psoriasis and psoriatic arthritis. For example, it may eventually become possible to assess the gut microbiota to predict which psoriasis patients will later develop psoriatic arthritis. And reconstituting the gut flora may turn out to have therapeutic benefit. But much more work is needed," explained Dr. Scher, director of the Microbiome Center for Rheumatology and Autoimmunity at New York University.
About 25%-30% of psoriasis patients develop inflammatory psoriatic arthritis, most often roughly 7 years after onset of their skin disease. Genetics clearly plays a role, as shown in a classic Danish twin registry study with more than 21,000 subjects. Fifty-five percent of the siblings of monozygotic twins with psoriatic arthritis had skin psoriasis, but only 10% of the siblings had psoriatic arthritis, as did 3.8% of siblings of dizygotic twins with psoriatic arthritis. The lesser concordance rate seen for psoriatic arthritis hinted at the importance of environmental factors in disease genesis (Ann. Rheum. Dis. 2008;67:1417-21).
Subclinical gut inflammation is common in psoriatic arthritis. In one early study, histologic evidence of mild or moderate gut mucosal inflammation was detected in 45% of a group of psoriatic arthritis patients, compared with 15% of patients with rheumatoid arthritis and 0% of controls (Scand. J. Rheumatol. 1997;26:92-8).
Also, psoriasis patients are at a roughly 3.5-fold increased risk of developing Crohn’s disease. Among patients with established psoriatic arthritis, this risk climbs to 6.5-fold greater than in nonpsoriatic controls (Ann. Rheum. Dis. 2013;72:1200-5).
In a soon-to-be-published study, Dr. Scher and his coworkers have taken the field a step further, employing high-throughput gene sequencing to analyze the gut bacterial communities of psoriatic arthritis patients and controls. These were all new-onset psoriatic arthritis patients who had never been exposed to systemic corticosteroids, biologic agents, or conventional disease-modifying antirheumatic drugs.
Compared with the stool samples of healthy controls, several major bacterial species were underrepresented or absent in the gut microbiota of psoriatic arthritis patients. These included Akkermansia, the most common mucolytic bacterium in healthy subjects. Intriguingly, Akkermansia counts are decreased 15-fold in Crohn’s disease and 92-fold in ulcerative colitis, according to the rheumatologist.
Other bacterial species markedly less abundant in the psoriatic arthritis patients’ gut flora were Ruminoccocus, Alistipes, and Roseburia. Like Akkermansia, these are mucin-degrading bacteria that promote a healthy gut environment, and they, too, are reduced in inflammatory bowel disease, Dr. Scher said.
He theorized that these disruptions of the bacterial ecosystem might arise from a course of antibiotics, a change in diet, or other insults. The result is activation of dendritic cells to produce interleukin-23, which triggers a proinflammatory cascade including tumor necrosis factor-alpha, interleukin-22, and antimicrobial peptides.
As shown by other investigators (Mucosal Immunol. 2013;6:666-77), these proinflammatory cytokines inhibit RANK ligand, which is the critical factor for differentiation of microfold cells in the gut. These microfold cells, or M cells, are specialized epithelial cells that transport antigens across the gut epithelium and play an important role in maintenance of an efficient immune response. It’s plausible that, when these M cells are defective, the resultant loss of tolerance and chronic inflammatory state can result in psoriatic arthritis, he explained.
Dr. Scher’s colleagues at New York University have used high-throughput gene sequencing to analyze the cutaneous microbiota of lesional and nonlesional skin in psoriasis patients, as well as skin samples from the same sites in healthy controls. The impetus for this study was a hypothesis that psoriasis might represent an inappropriate cutaneous immune response directed against offending bacteria in the skin microbiota.
Sure enough, the bacterial community present in psoriatic lesions displayed a markedly decreased diversity, compared with controls. This decreased diversity also was present, albeit to a lesser extent, in the psoriasis patients’ nonlesional skin. Both the lesional and nonlesional skin of psoriasis patients contained an increased abundance of Corynebacterium, Staphylococcus, and Streptococcus, compared with controls.
In addition, the skin microbiota could be classified into one of two characteristic patterns, which the investigators termed "cutaneotypes." Cutaneotype 1, which predominated in the skin of normal controls, contained an abundance of Proteobacteria. In contrast, cutaneotype 2, which was 3.5-fold more prevalent in psoriatic lesions than in controls, was enriched in Firmicutes and Actinobacteria. The psoriatic patients’ nonlesional skin contained a balance of cutaneotypes 1 and 2 (Microbiome 2013 Dec. 23 [doi:10.1186/2049-2618-1-31]).
Dr. Scher said that the next step in his own research is to learn whether the gut microbiota of psoriasis patients differs from that of psoriatic arthritis patients.
"That’s to me the most important piece of data. I think there’s a lot of work to do, and we’re doing it now, in prospective fashion. We’re following patients with psoriasis, and for those who later convert to psoriatic arthritis we’ll want to know if there’s alteration of their bacterial immunity, both in the gut and the skin," he explained.
Dr. Scher reported having no financial conflicts.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Keep mesenteric ischemia on your radar in young patients
CHICAGO – Early recognition of mesenteric ischemia in young adults and children is essential to prevent bowel loss and other serious consequences associated with this rare condition, Dr. Michael Dalsing said at a vascular surgery symposium.
Mesenteric ischemia is generally seen in the elderly as the result of atherosclerotic and embolic occlusive diseases. Because young adults and children typically don’t have any of the telltale associated comorbidities such as cardiac arrhythmia or coronary artery disease to point physicians in this direction, the diagnosis of mesenteric ischemia is often delayed or misinterpreted as appendicitis, cholecystitis, or intra-abdominal abscess, he said.
Among 26 young adults under age 40 years who presented with acute mesenteric ischemia, only 6 were properly diagnosed preoperatively (Wien. Med. Wochenschr. 2012;162:349-53). The postoperative complication and mortality rates reached 61.5% and 27%, which is typical in this population, despite their otherwise good health, said Dr. Dalsing, director of vascular surgery at Indiana University, Indianapolis.
The hallmarks of acute mesenteric ischemia are standard in both young and old patients and include abdominal pain out of proportion to the physical exam, nausea, vomiting, and/or diarrhea. Acidosis, acute renal failure, and septic shock/sepsis can develop in roughly half of patients with more extensive liver or bowel ischemia or necrosis. The signs and symptoms of chronic ischemia are weight loss, food fear, and postprandial abdominal pain.
"For chronic mesenteric ischemia, what’s the important message? Consider the diagnosis," Dr. Dalsing said. "Do the imaging, find out what you have, and then you can worry about ancillary testing because, in general, these aren’t going to be your typical etiologies. In fact, they’re not standard fare at all."
The broad and atypical list of etiologies to consider in those under age 40 years include congenital aortic anomalies, hypercoagulable states, inflammatory conditions, collagen vascular disorders, and environmental agents such as cocaine use, smoking, or trauma. While MI is often suspected in those using cocaine, the vasoconstrictive effects of the drug can also cause vasospasm of the smaller branches of the mesenteric vessels, leading to nonocclusive mesenteric ischemia, he explained.
Once a diagnosis of chronic mesenteric ischemia is made in a young patient, management consists of fluid resuscitation, broad spectrum antibiotics, bowel rest, and imaging, often with a CT angiogram. The need for additional work-up, including hypercoagulable and inflammatory marker panels, varies based on initial clinical symptoms.
If vascular compromise is identified, the overall management goals should be to remove frankly necrotic bowel, reperfuse ischemic bowel, limit the resection length when possible to prevent short-gut syndrome, and treat the underlying etiology, Dr. Dalsing advised. Anticoagulation is also integral to prevent thrombus propagation.
Just six cases of mesenteric ischemia have been diagnosed at Indiana University in young adults over the last 16 years, with Takayasu’s arteritis the most common etiology, he noted. This includes a 20-year-old woman with a 5-year history of Takayasu’s, who presented with worsening abdominal pain despite remission of her Takayasu’s, as indicated by a normal sedimentation rate.
Repeat CT imaging revealed more than 70% celiac artery stenosis and more than 50% stenosis of the superior mesenteric artery (SMA). A median arcuate ligament division and celiac and SMA bypass graft, both with reverse saphenous vein originating from bilateral iliac arteries, was performed. "She’s had dramatic improvement" in her symptoms and remains on clopidogrel (Plavix) and low-dose steroids, Dr. Dalsing said.
A second patient with Takayasu’s presented with a 4-month history of abdominal pain, a 50-pound weight loss, stenosis of all major mesenteric arteries, and bowel pneumatosis. Despite this, her sedimentation rate was only slightly elevated at 33 mm/hour, and all other coagulation and inflammatory tests were normal. She remains symptom free at 2 years on daily aspirin after undergoing an emergent right common iliac-to-SMA bypass graft with reversed saphenous vein and bowel resection.
In cases in which bypass grafting is necessary, the internal iliac artery is the preferred conduit in children since the saphenous vein is very thin walled and thus, more prone to aneurysmal degeneration, Dr. Dalsing observed. In grown patients, the saphenous vein may be the best conduit in terms of ease of harvest and adequate length for even bifurcated grafts or C-loop alignment.
During postoperative follow-up, special effort should be taken because of the young age of these patients to reduce the detrimental effects of radiation from recurrent CT angiograms, he said. Patients with symptomatic improvement are followed at 1 month postoperatively with a physical exam that includes their weight and a mesenteric duplex to evaluate graft or stent patency. This is repeated every 6 months for 1-2 years, and decreased to yearly visits, if no disease progression is detected. More aggressive imaging with CT angiography is reserved for patients with recurrent symptoms or if duplex ultrasound is insufficient or shows progressive disease, he said at the meeting, sponsored by Northwestern University.
Dr. Dalsing reported having no financial disclosures.
No longer is gastrointestinal ischemia a disease that only gerontologists need know about. Ischemic diseases present in a very wide disease spectrum that may be acute, subacute, or chronic; may involve the mesenteric veins, venules, arterioles, or arteries; small and or large intestine; short segments of bowel or long areas. Moreover, even in young adults, the list of predisposing factors is immense and includes inflammatory diseases, vasculitides, thrombophilic states, surgery, colonoscopy, and medications such as triptans , estrogens, and those that cause constipation; as well as recreational activities such as long-distance running and illicit cocaine use.
To complicate diagnostic matters, the GI tract can evidence disease only in a limited number of ways and so, regardless of etiology, manifestations can mimic those of more common diseases, including abdominal pain, diarrhea, rectal bleeding, and abdominal distention, among others. The CT scan has become a prominent substitute for complete history and physical examination today, but a CT scan does not allow appreciation of the fearful look on a patient's face when a physical exam reveals little and the patient still has severe pain. It is this discrepancy that is still fundamental in recognizing acute mesenteric ischemia early on when the injury is still reversible and the injured bowel can be salvaged by the combined use of intra-arterial papaverine and prompt surgery. Early findings on CT, however, are nonspecific, and findings that are specific - for example, gangrene of the bowel, pneumatosis linearis, and portal mesenteric venous gas - occur too late in the game to help save bowel.
For chronic mesenteric ischemia or intestinal angina, it is important to recognize the classic history of food-associated abdominal pain that tends over time to occur earlier in the meal; lasts longer after the meal; and ultimately, preinfarction, become persistent. Fear of eating, avoidance of meals, and weight loss are characteristic. In such circumstances, splanchnic vascular imaging usually shows two of the three mesenteric vessels to be occluded. Such occlusion does not make the diagnosis, however, as angiography merely shows anatomy that supports or refutes the clinician's diagnosis. A typical clinical history and supportive anatomy prompts either percutaneous or surgical revascularization - probably the latter in a young patient - an otherwise good operative risk.
This was once sure death but can now be treated if diagnosed in time.
Dr. Lawrence J. Brandt, MACG, AGA-F, FASGE, professor of medicine and surgery at Albert Einstein College of Medicine, N.Y., emeritus chief of gastroenterology at Montefiore Medical Center, N.Y. He has no disclosures.
No longer is gastrointestinal ischemia a disease that only gerontologists need know about. Ischemic diseases present in a very wide disease spectrum that may be acute, subacute, or chronic; may involve the mesenteric veins, venules, arterioles, or arteries; small and or large intestine; short segments of bowel or long areas. Moreover, even in young adults, the list of predisposing factors is immense and includes inflammatory diseases, vasculitides, thrombophilic states, surgery, colonoscopy, and medications such as triptans , estrogens, and those that cause constipation; as well as recreational activities such as long-distance running and illicit cocaine use.
To complicate diagnostic matters, the GI tract can evidence disease only in a limited number of ways and so, regardless of etiology, manifestations can mimic those of more common diseases, including abdominal pain, diarrhea, rectal bleeding, and abdominal distention, among others. The CT scan has become a prominent substitute for complete history and physical examination today, but a CT scan does not allow appreciation of the fearful look on a patient's face when a physical exam reveals little and the patient still has severe pain. It is this discrepancy that is still fundamental in recognizing acute mesenteric ischemia early on when the injury is still reversible and the injured bowel can be salvaged by the combined use of intra-arterial papaverine and prompt surgery. Early findings on CT, however, are nonspecific, and findings that are specific - for example, gangrene of the bowel, pneumatosis linearis, and portal mesenteric venous gas - occur too late in the game to help save bowel.
For chronic mesenteric ischemia or intestinal angina, it is important to recognize the classic history of food-associated abdominal pain that tends over time to occur earlier in the meal; lasts longer after the meal; and ultimately, preinfarction, become persistent. Fear of eating, avoidance of meals, and weight loss are characteristic. In such circumstances, splanchnic vascular imaging usually shows two of the three mesenteric vessels to be occluded. Such occlusion does not make the diagnosis, however, as angiography merely shows anatomy that supports or refutes the clinician's diagnosis. A typical clinical history and supportive anatomy prompts either percutaneous or surgical revascularization - probably the latter in a young patient - an otherwise good operative risk.
This was once sure death but can now be treated if diagnosed in time.
Dr. Lawrence J. Brandt, MACG, AGA-F, FASGE, professor of medicine and surgery at Albert Einstein College of Medicine, N.Y., emeritus chief of gastroenterology at Montefiore Medical Center, N.Y. He has no disclosures.
No longer is gastrointestinal ischemia a disease that only gerontologists need know about. Ischemic diseases present in a very wide disease spectrum that may be acute, subacute, or chronic; may involve the mesenteric veins, venules, arterioles, or arteries; small and or large intestine; short segments of bowel or long areas. Moreover, even in young adults, the list of predisposing factors is immense and includes inflammatory diseases, vasculitides, thrombophilic states, surgery, colonoscopy, and medications such as triptans , estrogens, and those that cause constipation; as well as recreational activities such as long-distance running and illicit cocaine use.
To complicate diagnostic matters, the GI tract can evidence disease only in a limited number of ways and so, regardless of etiology, manifestations can mimic those of more common diseases, including abdominal pain, diarrhea, rectal bleeding, and abdominal distention, among others. The CT scan has become a prominent substitute for complete history and physical examination today, but a CT scan does not allow appreciation of the fearful look on a patient's face when a physical exam reveals little and the patient still has severe pain. It is this discrepancy that is still fundamental in recognizing acute mesenteric ischemia early on when the injury is still reversible and the injured bowel can be salvaged by the combined use of intra-arterial papaverine and prompt surgery. Early findings on CT, however, are nonspecific, and findings that are specific - for example, gangrene of the bowel, pneumatosis linearis, and portal mesenteric venous gas - occur too late in the game to help save bowel.
For chronic mesenteric ischemia or intestinal angina, it is important to recognize the classic history of food-associated abdominal pain that tends over time to occur earlier in the meal; lasts longer after the meal; and ultimately, preinfarction, become persistent. Fear of eating, avoidance of meals, and weight loss are characteristic. In such circumstances, splanchnic vascular imaging usually shows two of the three mesenteric vessels to be occluded. Such occlusion does not make the diagnosis, however, as angiography merely shows anatomy that supports or refutes the clinician's diagnosis. A typical clinical history and supportive anatomy prompts either percutaneous or surgical revascularization - probably the latter in a young patient - an otherwise good operative risk.
This was once sure death but can now be treated if diagnosed in time.
Dr. Lawrence J. Brandt, MACG, AGA-F, FASGE, professor of medicine and surgery at Albert Einstein College of Medicine, N.Y., emeritus chief of gastroenterology at Montefiore Medical Center, N.Y. He has no disclosures.
CHICAGO – Early recognition of mesenteric ischemia in young adults and children is essential to prevent bowel loss and other serious consequences associated with this rare condition, Dr. Michael Dalsing said at a vascular surgery symposium.
Mesenteric ischemia is generally seen in the elderly as the result of atherosclerotic and embolic occlusive diseases. Because young adults and children typically don’t have any of the telltale associated comorbidities such as cardiac arrhythmia or coronary artery disease to point physicians in this direction, the diagnosis of mesenteric ischemia is often delayed or misinterpreted as appendicitis, cholecystitis, or intra-abdominal abscess, he said.
Among 26 young adults under age 40 years who presented with acute mesenteric ischemia, only 6 were properly diagnosed preoperatively (Wien. Med. Wochenschr. 2012;162:349-53). The postoperative complication and mortality rates reached 61.5% and 27%, which is typical in this population, despite their otherwise good health, said Dr. Dalsing, director of vascular surgery at Indiana University, Indianapolis.
The hallmarks of acute mesenteric ischemia are standard in both young and old patients and include abdominal pain out of proportion to the physical exam, nausea, vomiting, and/or diarrhea. Acidosis, acute renal failure, and septic shock/sepsis can develop in roughly half of patients with more extensive liver or bowel ischemia or necrosis. The signs and symptoms of chronic ischemia are weight loss, food fear, and postprandial abdominal pain.
"For chronic mesenteric ischemia, what’s the important message? Consider the diagnosis," Dr. Dalsing said. "Do the imaging, find out what you have, and then you can worry about ancillary testing because, in general, these aren’t going to be your typical etiologies. In fact, they’re not standard fare at all."
The broad and atypical list of etiologies to consider in those under age 40 years include congenital aortic anomalies, hypercoagulable states, inflammatory conditions, collagen vascular disorders, and environmental agents such as cocaine use, smoking, or trauma. While MI is often suspected in those using cocaine, the vasoconstrictive effects of the drug can also cause vasospasm of the smaller branches of the mesenteric vessels, leading to nonocclusive mesenteric ischemia, he explained.
Once a diagnosis of chronic mesenteric ischemia is made in a young patient, management consists of fluid resuscitation, broad spectrum antibiotics, bowel rest, and imaging, often with a CT angiogram. The need for additional work-up, including hypercoagulable and inflammatory marker panels, varies based on initial clinical symptoms.
If vascular compromise is identified, the overall management goals should be to remove frankly necrotic bowel, reperfuse ischemic bowel, limit the resection length when possible to prevent short-gut syndrome, and treat the underlying etiology, Dr. Dalsing advised. Anticoagulation is also integral to prevent thrombus propagation.
Just six cases of mesenteric ischemia have been diagnosed at Indiana University in young adults over the last 16 years, with Takayasu’s arteritis the most common etiology, he noted. This includes a 20-year-old woman with a 5-year history of Takayasu’s, who presented with worsening abdominal pain despite remission of her Takayasu’s, as indicated by a normal sedimentation rate.
Repeat CT imaging revealed more than 70% celiac artery stenosis and more than 50% stenosis of the superior mesenteric artery (SMA). A median arcuate ligament division and celiac and SMA bypass graft, both with reverse saphenous vein originating from bilateral iliac arteries, was performed. "She’s had dramatic improvement" in her symptoms and remains on clopidogrel (Plavix) and low-dose steroids, Dr. Dalsing said.
A second patient with Takayasu’s presented with a 4-month history of abdominal pain, a 50-pound weight loss, stenosis of all major mesenteric arteries, and bowel pneumatosis. Despite this, her sedimentation rate was only slightly elevated at 33 mm/hour, and all other coagulation and inflammatory tests were normal. She remains symptom free at 2 years on daily aspirin after undergoing an emergent right common iliac-to-SMA bypass graft with reversed saphenous vein and bowel resection.
In cases in which bypass grafting is necessary, the internal iliac artery is the preferred conduit in children since the saphenous vein is very thin walled and thus, more prone to aneurysmal degeneration, Dr. Dalsing observed. In grown patients, the saphenous vein may be the best conduit in terms of ease of harvest and adequate length for even bifurcated grafts or C-loop alignment.
During postoperative follow-up, special effort should be taken because of the young age of these patients to reduce the detrimental effects of radiation from recurrent CT angiograms, he said. Patients with symptomatic improvement are followed at 1 month postoperatively with a physical exam that includes their weight and a mesenteric duplex to evaluate graft or stent patency. This is repeated every 6 months for 1-2 years, and decreased to yearly visits, if no disease progression is detected. More aggressive imaging with CT angiography is reserved for patients with recurrent symptoms or if duplex ultrasound is insufficient or shows progressive disease, he said at the meeting, sponsored by Northwestern University.
Dr. Dalsing reported having no financial disclosures.
CHICAGO – Early recognition of mesenteric ischemia in young adults and children is essential to prevent bowel loss and other serious consequences associated with this rare condition, Dr. Michael Dalsing said at a vascular surgery symposium.
Mesenteric ischemia is generally seen in the elderly as the result of atherosclerotic and embolic occlusive diseases. Because young adults and children typically don’t have any of the telltale associated comorbidities such as cardiac arrhythmia or coronary artery disease to point physicians in this direction, the diagnosis of mesenteric ischemia is often delayed or misinterpreted as appendicitis, cholecystitis, or intra-abdominal abscess, he said.
Among 26 young adults under age 40 years who presented with acute mesenteric ischemia, only 6 were properly diagnosed preoperatively (Wien. Med. Wochenschr. 2012;162:349-53). The postoperative complication and mortality rates reached 61.5% and 27%, which is typical in this population, despite their otherwise good health, said Dr. Dalsing, director of vascular surgery at Indiana University, Indianapolis.
The hallmarks of acute mesenteric ischemia are standard in both young and old patients and include abdominal pain out of proportion to the physical exam, nausea, vomiting, and/or diarrhea. Acidosis, acute renal failure, and septic shock/sepsis can develop in roughly half of patients with more extensive liver or bowel ischemia or necrosis. The signs and symptoms of chronic ischemia are weight loss, food fear, and postprandial abdominal pain.
"For chronic mesenteric ischemia, what’s the important message? Consider the diagnosis," Dr. Dalsing said. "Do the imaging, find out what you have, and then you can worry about ancillary testing because, in general, these aren’t going to be your typical etiologies. In fact, they’re not standard fare at all."
The broad and atypical list of etiologies to consider in those under age 40 years include congenital aortic anomalies, hypercoagulable states, inflammatory conditions, collagen vascular disorders, and environmental agents such as cocaine use, smoking, or trauma. While MI is often suspected in those using cocaine, the vasoconstrictive effects of the drug can also cause vasospasm of the smaller branches of the mesenteric vessels, leading to nonocclusive mesenteric ischemia, he explained.
Once a diagnosis of chronic mesenteric ischemia is made in a young patient, management consists of fluid resuscitation, broad spectrum antibiotics, bowel rest, and imaging, often with a CT angiogram. The need for additional work-up, including hypercoagulable and inflammatory marker panels, varies based on initial clinical symptoms.
If vascular compromise is identified, the overall management goals should be to remove frankly necrotic bowel, reperfuse ischemic bowel, limit the resection length when possible to prevent short-gut syndrome, and treat the underlying etiology, Dr. Dalsing advised. Anticoagulation is also integral to prevent thrombus propagation.
Just six cases of mesenteric ischemia have been diagnosed at Indiana University in young adults over the last 16 years, with Takayasu’s arteritis the most common etiology, he noted. This includes a 20-year-old woman with a 5-year history of Takayasu’s, who presented with worsening abdominal pain despite remission of her Takayasu’s, as indicated by a normal sedimentation rate.
Repeat CT imaging revealed more than 70% celiac artery stenosis and more than 50% stenosis of the superior mesenteric artery (SMA). A median arcuate ligament division and celiac and SMA bypass graft, both with reverse saphenous vein originating from bilateral iliac arteries, was performed. "She’s had dramatic improvement" in her symptoms and remains on clopidogrel (Plavix) and low-dose steroids, Dr. Dalsing said.
A second patient with Takayasu’s presented with a 4-month history of abdominal pain, a 50-pound weight loss, stenosis of all major mesenteric arteries, and bowel pneumatosis. Despite this, her sedimentation rate was only slightly elevated at 33 mm/hour, and all other coagulation and inflammatory tests were normal. She remains symptom free at 2 years on daily aspirin after undergoing an emergent right common iliac-to-SMA bypass graft with reversed saphenous vein and bowel resection.
In cases in which bypass grafting is necessary, the internal iliac artery is the preferred conduit in children since the saphenous vein is very thin walled and thus, more prone to aneurysmal degeneration, Dr. Dalsing observed. In grown patients, the saphenous vein may be the best conduit in terms of ease of harvest and adequate length for even bifurcated grafts or C-loop alignment.
During postoperative follow-up, special effort should be taken because of the young age of these patients to reduce the detrimental effects of radiation from recurrent CT angiograms, he said. Patients with symptomatic improvement are followed at 1 month postoperatively with a physical exam that includes their weight and a mesenteric duplex to evaluate graft or stent patency. This is repeated every 6 months for 1-2 years, and decreased to yearly visits, if no disease progression is detected. More aggressive imaging with CT angiography is reserved for patients with recurrent symptoms or if duplex ultrasound is insufficient or shows progressive disease, he said at the meeting, sponsored by Northwestern University.
Dr. Dalsing reported having no financial disclosures.
AT A VASCULAR SURGERY SYMPOSIUM
Tips on preparing an IND application for fecal microbiota transplantation studies
As the practice of fecal microbiota transplantation to treat recurrent Clostridium difficile infection continues to evolve, a growing number of researchers have expressed interest in studying the procedure for other conditions, according to an article published in the February issue of Clinical Gastroenterology and Hepatology.
Even though the mechanism of action behind fecal microbiota transplantation (FMT) remains unclear, "the procedure results in restoration of normal microbial gut ecology," wrote Dr. Colleen Kelly, a gastroenterologist at the Women’s Medicine Collaborative, Providence, R.I., and her coinvestigators. "Therefore, it is possible that FMT may become applicable to other conditions associated with intestinal dysbiosis, including inflammatory bowel disease, irritable bowel syndrome, antibiotic-associated diarrhea, and components of metabolic syndrome such as obesity and diabetes."
Source: American Gastroenterological Association
With this in mind and noting that FMT is considered an investigational agent by the Food and Drug Administration, Dr. Kelly and her associates set out to provide guidance to other investigators and clinicians on how to prepare an investigational new drug application (IND) for the Center for Biologics Evaluation and Research to study FMT for recurrent C. difficile infection (R-CDI). "Because of the complexity of IND applications and their burden on a physician, the FDA announced its intention to exercise enforcement discretion regarding IND applications for use of FMT to treat R-CDI," the authors explained (doi:10.1016/j.cgh.2013.09.060). "In these cases, an IND is encouraged but not required. At this time, this decision decreases the need for INDs to treat individual patients with R-CDI. However, an IND for the use of FMT is still required for indications other than CDI for research purposes."
The IND application can have only one sponsor: the investigator or clinician who applies for it. After that is secured, 10 basic elements are required to complete the IND application, according to the authors. These include product name/chemical structure, proposed indications, dosage and route of administration, background about the therapy, and information regarding chemistry, manufacturing, and controls. "The contents of this section vary depending on the source/form of donor material," wrote the authors, who indicated that they hold approved INDs to use FMT in patients with CDI and inflammatory bowel disease. For example, "if the sponsor decides to seek an IND for frozen material, they will need to provide detail about how donor stool will be processed and stored."
Other basic elements of an IND application, according to the article, include a clinical data summary, an FMT treatment protocol that includes plans for clinical follow-up of treated patients and adverse event reporting, an explanation of the risks associated with FMT, and a safety-monitoring protocol that "may consist of symptom diaries maintained by patients/subjects and follow-up telephone contacts and clinic visits."
Dr. Kelly and her associates emphasized that their recommendations are "only a guide to all the elements necessary to put together a protocol and an FDA application and a starting point for the new IND sponsor." They added that minimal requirements for donor testing "are likely to change over time. Some testing that is currently merely recommended may become absolute requirements or may be found unnecessary."
The National Institutes of Health provided funding support for the article. One of the authors, Dr. Alexander Khoruts, has received research funding from CIPAC LLC. The other authors said they had no relevant financial conflicts to disclose.
The use of human feces for curing recurrent Clostridium difficile infection, or for any other medical use, makes it a biologic product. Since the efficacy and safety profiles of human fecal microbiota have not been assessed in controlled clinical trials, fecal microbiota transplantation falls under the jurisdiction of the Food and Drug Administration. The enforcement discretion policy regarding the use of FMT for recurrent CDI is temporary.
The IND application process may well be foreign to many practitioners whose everyday goal and focus is to simply treat their patients, and many practitioners may not have time to pursue the details of such an application. Some may then opt to abandon this treatment option rather than take the time to explore, educate themselves, and apply for an IND.
Fortunately, Dr. Kelly and her colleagues have simplified this task by breaking it down into its component parts and providing guidance for completing each. Dr. Kelly and her team are well versed in the IND application requirements and anyone considering the use of this procedure will undoubtedly appreciate the advice and guidance offered in their article.
The IND application process can be frustrating, but the importance of FDA regulation must be underscored. We are merely beginning to realize the metabolic potential of the gut microbiome, only recognizing that certain compositions are associated with disease phenotypes. When FMT is performed, not only bacteria, but also fungi and viruses, are transplanted, and our investigation into the potential role of these microbes in human health and disease has not even begun. Therefore, when the gut microbiome of an individual is altered through FMT, we must realize the possibility that the stage is being set for the development of chronic diseases that may not become apparent until several years later. Therefore, FDA oversight is justified and INDs are warranted.
Dr. Gail Hecht, AGAF, is professor of medicine, microbiology/immunology, director of the division of gastroenterology and nutrition, and assistant dean for medical students at Loyola University, Chicago. She said she has no financial conflicts of interest.
The use of human feces for curing recurrent Clostridium difficile infection, or for any other medical use, makes it a biologic product. Since the efficacy and safety profiles of human fecal microbiota have not been assessed in controlled clinical trials, fecal microbiota transplantation falls under the jurisdiction of the Food and Drug Administration. The enforcement discretion policy regarding the use of FMT for recurrent CDI is temporary.
The IND application process may well be foreign to many practitioners whose everyday goal and focus is to simply treat their patients, and many practitioners may not have time to pursue the details of such an application. Some may then opt to abandon this treatment option rather than take the time to explore, educate themselves, and apply for an IND.
Fortunately, Dr. Kelly and her colleagues have simplified this task by breaking it down into its component parts and providing guidance for completing each. Dr. Kelly and her team are well versed in the IND application requirements and anyone considering the use of this procedure will undoubtedly appreciate the advice and guidance offered in their article.
The IND application process can be frustrating, but the importance of FDA regulation must be underscored. We are merely beginning to realize the metabolic potential of the gut microbiome, only recognizing that certain compositions are associated with disease phenotypes. When FMT is performed, not only bacteria, but also fungi and viruses, are transplanted, and our investigation into the potential role of these microbes in human health and disease has not even begun. Therefore, when the gut microbiome of an individual is altered through FMT, we must realize the possibility that the stage is being set for the development of chronic diseases that may not become apparent until several years later. Therefore, FDA oversight is justified and INDs are warranted.
Dr. Gail Hecht, AGAF, is professor of medicine, microbiology/immunology, director of the division of gastroenterology and nutrition, and assistant dean for medical students at Loyola University, Chicago. She said she has no financial conflicts of interest.
The use of human feces for curing recurrent Clostridium difficile infection, or for any other medical use, makes it a biologic product. Since the efficacy and safety profiles of human fecal microbiota have not been assessed in controlled clinical trials, fecal microbiota transplantation falls under the jurisdiction of the Food and Drug Administration. The enforcement discretion policy regarding the use of FMT for recurrent CDI is temporary.
The IND application process may well be foreign to many practitioners whose everyday goal and focus is to simply treat their patients, and many practitioners may not have time to pursue the details of such an application. Some may then opt to abandon this treatment option rather than take the time to explore, educate themselves, and apply for an IND.
Fortunately, Dr. Kelly and her colleagues have simplified this task by breaking it down into its component parts and providing guidance for completing each. Dr. Kelly and her team are well versed in the IND application requirements and anyone considering the use of this procedure will undoubtedly appreciate the advice and guidance offered in their article.
The IND application process can be frustrating, but the importance of FDA regulation must be underscored. We are merely beginning to realize the metabolic potential of the gut microbiome, only recognizing that certain compositions are associated with disease phenotypes. When FMT is performed, not only bacteria, but also fungi and viruses, are transplanted, and our investigation into the potential role of these microbes in human health and disease has not even begun. Therefore, when the gut microbiome of an individual is altered through FMT, we must realize the possibility that the stage is being set for the development of chronic diseases that may not become apparent until several years later. Therefore, FDA oversight is justified and INDs are warranted.
Dr. Gail Hecht, AGAF, is professor of medicine, microbiology/immunology, director of the division of gastroenterology and nutrition, and assistant dean for medical students at Loyola University, Chicago. She said she has no financial conflicts of interest.
As the practice of fecal microbiota transplantation to treat recurrent Clostridium difficile infection continues to evolve, a growing number of researchers have expressed interest in studying the procedure for other conditions, according to an article published in the February issue of Clinical Gastroenterology and Hepatology.
Even though the mechanism of action behind fecal microbiota transplantation (FMT) remains unclear, "the procedure results in restoration of normal microbial gut ecology," wrote Dr. Colleen Kelly, a gastroenterologist at the Women’s Medicine Collaborative, Providence, R.I., and her coinvestigators. "Therefore, it is possible that FMT may become applicable to other conditions associated with intestinal dysbiosis, including inflammatory bowel disease, irritable bowel syndrome, antibiotic-associated diarrhea, and components of metabolic syndrome such as obesity and diabetes."
Source: American Gastroenterological Association
With this in mind and noting that FMT is considered an investigational agent by the Food and Drug Administration, Dr. Kelly and her associates set out to provide guidance to other investigators and clinicians on how to prepare an investigational new drug application (IND) for the Center for Biologics Evaluation and Research to study FMT for recurrent C. difficile infection (R-CDI). "Because of the complexity of IND applications and their burden on a physician, the FDA announced its intention to exercise enforcement discretion regarding IND applications for use of FMT to treat R-CDI," the authors explained (doi:10.1016/j.cgh.2013.09.060). "In these cases, an IND is encouraged but not required. At this time, this decision decreases the need for INDs to treat individual patients with R-CDI. However, an IND for the use of FMT is still required for indications other than CDI for research purposes."
The IND application can have only one sponsor: the investigator or clinician who applies for it. After that is secured, 10 basic elements are required to complete the IND application, according to the authors. These include product name/chemical structure, proposed indications, dosage and route of administration, background about the therapy, and information regarding chemistry, manufacturing, and controls. "The contents of this section vary depending on the source/form of donor material," wrote the authors, who indicated that they hold approved INDs to use FMT in patients with CDI and inflammatory bowel disease. For example, "if the sponsor decides to seek an IND for frozen material, they will need to provide detail about how donor stool will be processed and stored."
Other basic elements of an IND application, according to the article, include a clinical data summary, an FMT treatment protocol that includes plans for clinical follow-up of treated patients and adverse event reporting, an explanation of the risks associated with FMT, and a safety-monitoring protocol that "may consist of symptom diaries maintained by patients/subjects and follow-up telephone contacts and clinic visits."
Dr. Kelly and her associates emphasized that their recommendations are "only a guide to all the elements necessary to put together a protocol and an FDA application and a starting point for the new IND sponsor." They added that minimal requirements for donor testing "are likely to change over time. Some testing that is currently merely recommended may become absolute requirements or may be found unnecessary."
The National Institutes of Health provided funding support for the article. One of the authors, Dr. Alexander Khoruts, has received research funding from CIPAC LLC. The other authors said they had no relevant financial conflicts to disclose.
As the practice of fecal microbiota transplantation to treat recurrent Clostridium difficile infection continues to evolve, a growing number of researchers have expressed interest in studying the procedure for other conditions, according to an article published in the February issue of Clinical Gastroenterology and Hepatology.
Even though the mechanism of action behind fecal microbiota transplantation (FMT) remains unclear, "the procedure results in restoration of normal microbial gut ecology," wrote Dr. Colleen Kelly, a gastroenterologist at the Women’s Medicine Collaborative, Providence, R.I., and her coinvestigators. "Therefore, it is possible that FMT may become applicable to other conditions associated with intestinal dysbiosis, including inflammatory bowel disease, irritable bowel syndrome, antibiotic-associated diarrhea, and components of metabolic syndrome such as obesity and diabetes."
Source: American Gastroenterological Association
With this in mind and noting that FMT is considered an investigational agent by the Food and Drug Administration, Dr. Kelly and her associates set out to provide guidance to other investigators and clinicians on how to prepare an investigational new drug application (IND) for the Center for Biologics Evaluation and Research to study FMT for recurrent C. difficile infection (R-CDI). "Because of the complexity of IND applications and their burden on a physician, the FDA announced its intention to exercise enforcement discretion regarding IND applications for use of FMT to treat R-CDI," the authors explained (doi:10.1016/j.cgh.2013.09.060). "In these cases, an IND is encouraged but not required. At this time, this decision decreases the need for INDs to treat individual patients with R-CDI. However, an IND for the use of FMT is still required for indications other than CDI for research purposes."
The IND application can have only one sponsor: the investigator or clinician who applies for it. After that is secured, 10 basic elements are required to complete the IND application, according to the authors. These include product name/chemical structure, proposed indications, dosage and route of administration, background about the therapy, and information regarding chemistry, manufacturing, and controls. "The contents of this section vary depending on the source/form of donor material," wrote the authors, who indicated that they hold approved INDs to use FMT in patients with CDI and inflammatory bowel disease. For example, "if the sponsor decides to seek an IND for frozen material, they will need to provide detail about how donor stool will be processed and stored."
Other basic elements of an IND application, according to the article, include a clinical data summary, an FMT treatment protocol that includes plans for clinical follow-up of treated patients and adverse event reporting, an explanation of the risks associated with FMT, and a safety-monitoring protocol that "may consist of symptom diaries maintained by patients/subjects and follow-up telephone contacts and clinic visits."
Dr. Kelly and her associates emphasized that their recommendations are "only a guide to all the elements necessary to put together a protocol and an FDA application and a starting point for the new IND sponsor." They added that minimal requirements for donor testing "are likely to change over time. Some testing that is currently merely recommended may become absolute requirements or may be found unnecessary."
The National Institutes of Health provided funding support for the article. One of the authors, Dr. Alexander Khoruts, has received research funding from CIPAC LLC. The other authors said they had no relevant financial conflicts to disclose.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Early anti-TNF-alpha treatment found effective in children with Crohn’s
Children with Crohn’s disease who received antitumor necrosis factor-alpha within 3 months of diagnosis experienced better overall clinical and growth outcomes at 1 year, compared with their counterparts who received an immunomodulator or those who received no immunomodulator therapy, results from an observational study demonstrated.
Although the current standard of practice for children recently diagnosed with Crohn’s disease (CD) involves early administration of immunomodulators after initial treatment with corticosteroids, some pediatric gastroenterologists, inspired by data from adult trials, "are adopting earlier introduction of anti-TNF-alpha therapy (without a trial of immunomodulators alone) in patients with inflammatory luminal CD judged to be at risk of serious chronically active disease," researchers led by Dr. Thomas D. Walters wrote in the February issue of Gastroenterology.
Source: American Gastroenterological Association
Dr. Walters of the Hospital for Sick Children in Toronto and his associates went on to note that while the efficacy of anti-TNF-alpha therapy is well established, "it has yet to be shown that the early use of this therapy in a specific group of pediatric patients (those with inflammatory luminal disease) is any more effective at improving patient outcomes than the classic step-up approach." In an effort to answer this question, the researchers analyzed data from the ongoing Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children With Crohn’s Disease (RS) trial, which was launched in 2008 at 28 pediatric gastroenterology centers in North America. The purpose of the current study was to determine whether anti-TNF-alpha monotherapy started within 3 months of diagnosis improves 1-year outcomes, compared with clinically similar patients who were treated with immunomodulator monotherapy started within 3 months of diagnosis or those who were treated with no immunotherapy during that time frame.
The researchers evaluated data from 552 patients who participated in the trial RISK between 2008 and 2012. They used propensity score matching "to avoid the usual problem of confounding by indication when using observational cohort data to explore differences in treatment response." More than half of the patients (61%) were male, their mean age was 11.8 years, and 63% had a Pediatric Crohn’s Disease Activity Index (PCDAI) score of greater than 30. The primary outcome of interest was corticosteroid-free clinical remission (defined as a PCDAI of 10 or less) at 1 year after diagnosis without luminal resection (Gastroenterology 2013 [doi: 10.1053/j.gastro.2013.10.027]).
Of the 552 patients, 68 received early anti-TNF-alpha monotherapy, 248 received early immunomodulator therapy, and 236 received no early immunotherapy. After propensity score matching, 85% of patients treated with early anti-TNF-alpha monotherapy achieved remission at 1 year, compared with 60% of those who were treated with early immunomodulator monotherapy and 54% of those who received no early immunotherapy, a difference that reached statistical significance (P =.0003). When the researchers factored in therapy after 3 months as a covariate, the results did not change; treatment with anti-TNF-alpha monotherapy remained significantly superior to early immunomodulator monotherapy (risk ratio, 1.51; P =.0004), while early immunomodulator monotherapy was no different from no early immunotherapy (RR, 1.00; P =.99).
Dr. Walters and his associates also observed that while weight and body mass index scores improved in all three groups, the height z score only showed improvement in the early anti-TNF-alpha group.
"Although our data clearly have added to the evidence base guiding treatment decisions after a diagnosis of Crohn’s disease in children, they should not be taken as an endorsement of one early therapeutic regimen over another," the authors concluded. "We were not able to identify any common clinical or laboratory characteristic that predicted response or failure with a particular approach. Further genetic, serologic, and microbiome analysis of our study cohort in conjunction with comparative efficacy results will better elucidate the value of different treatment decisions."
The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Walters and many of his coauthors disclosed having received research support, consulting fees, or being on the speakers bureau for numerous pharmaceutical companies.
Children with Crohn’s disease who received antitumor necrosis factor-alpha within 3 months of diagnosis experienced better overall clinical and growth outcomes at 1 year, compared with their counterparts who received an immunomodulator or those who received no immunomodulator therapy, results from an observational study demonstrated.
Although the current standard of practice for children recently diagnosed with Crohn’s disease (CD) involves early administration of immunomodulators after initial treatment with corticosteroids, some pediatric gastroenterologists, inspired by data from adult trials, "are adopting earlier introduction of anti-TNF-alpha therapy (without a trial of immunomodulators alone) in patients with inflammatory luminal CD judged to be at risk of serious chronically active disease," researchers led by Dr. Thomas D. Walters wrote in the February issue of Gastroenterology.
Source: American Gastroenterological Association
Dr. Walters of the Hospital for Sick Children in Toronto and his associates went on to note that while the efficacy of anti-TNF-alpha therapy is well established, "it has yet to be shown that the early use of this therapy in a specific group of pediatric patients (those with inflammatory luminal disease) is any more effective at improving patient outcomes than the classic step-up approach." In an effort to answer this question, the researchers analyzed data from the ongoing Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children With Crohn’s Disease (RS) trial, which was launched in 2008 at 28 pediatric gastroenterology centers in North America. The purpose of the current study was to determine whether anti-TNF-alpha monotherapy started within 3 months of diagnosis improves 1-year outcomes, compared with clinically similar patients who were treated with immunomodulator monotherapy started within 3 months of diagnosis or those who were treated with no immunotherapy during that time frame.
The researchers evaluated data from 552 patients who participated in the trial RISK between 2008 and 2012. They used propensity score matching "to avoid the usual problem of confounding by indication when using observational cohort data to explore differences in treatment response." More than half of the patients (61%) were male, their mean age was 11.8 years, and 63% had a Pediatric Crohn’s Disease Activity Index (PCDAI) score of greater than 30. The primary outcome of interest was corticosteroid-free clinical remission (defined as a PCDAI of 10 or less) at 1 year after diagnosis without luminal resection (Gastroenterology 2013 [doi: 10.1053/j.gastro.2013.10.027]).
Of the 552 patients, 68 received early anti-TNF-alpha monotherapy, 248 received early immunomodulator therapy, and 236 received no early immunotherapy. After propensity score matching, 85% of patients treated with early anti-TNF-alpha monotherapy achieved remission at 1 year, compared with 60% of those who were treated with early immunomodulator monotherapy and 54% of those who received no early immunotherapy, a difference that reached statistical significance (P =.0003). When the researchers factored in therapy after 3 months as a covariate, the results did not change; treatment with anti-TNF-alpha monotherapy remained significantly superior to early immunomodulator monotherapy (risk ratio, 1.51; P =.0004), while early immunomodulator monotherapy was no different from no early immunotherapy (RR, 1.00; P =.99).
Dr. Walters and his associates also observed that while weight and body mass index scores improved in all three groups, the height z score only showed improvement in the early anti-TNF-alpha group.
"Although our data clearly have added to the evidence base guiding treatment decisions after a diagnosis of Crohn’s disease in children, they should not be taken as an endorsement of one early therapeutic regimen over another," the authors concluded. "We were not able to identify any common clinical or laboratory characteristic that predicted response or failure with a particular approach. Further genetic, serologic, and microbiome analysis of our study cohort in conjunction with comparative efficacy results will better elucidate the value of different treatment decisions."
The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Walters and many of his coauthors disclosed having received research support, consulting fees, or being on the speakers bureau for numerous pharmaceutical companies.
Children with Crohn’s disease who received antitumor necrosis factor-alpha within 3 months of diagnosis experienced better overall clinical and growth outcomes at 1 year, compared with their counterparts who received an immunomodulator or those who received no immunomodulator therapy, results from an observational study demonstrated.
Although the current standard of practice for children recently diagnosed with Crohn’s disease (CD) involves early administration of immunomodulators after initial treatment with corticosteroids, some pediatric gastroenterologists, inspired by data from adult trials, "are adopting earlier introduction of anti-TNF-alpha therapy (without a trial of immunomodulators alone) in patients with inflammatory luminal CD judged to be at risk of serious chronically active disease," researchers led by Dr. Thomas D. Walters wrote in the February issue of Gastroenterology.
Source: American Gastroenterological Association
Dr. Walters of the Hospital for Sick Children in Toronto and his associates went on to note that while the efficacy of anti-TNF-alpha therapy is well established, "it has yet to be shown that the early use of this therapy in a specific group of pediatric patients (those with inflammatory luminal disease) is any more effective at improving patient outcomes than the classic step-up approach." In an effort to answer this question, the researchers analyzed data from the ongoing Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children With Crohn’s Disease (RS) trial, which was launched in 2008 at 28 pediatric gastroenterology centers in North America. The purpose of the current study was to determine whether anti-TNF-alpha monotherapy started within 3 months of diagnosis improves 1-year outcomes, compared with clinically similar patients who were treated with immunomodulator monotherapy started within 3 months of diagnosis or those who were treated with no immunotherapy during that time frame.
The researchers evaluated data from 552 patients who participated in the trial RISK between 2008 and 2012. They used propensity score matching "to avoid the usual problem of confounding by indication when using observational cohort data to explore differences in treatment response." More than half of the patients (61%) were male, their mean age was 11.8 years, and 63% had a Pediatric Crohn’s Disease Activity Index (PCDAI) score of greater than 30. The primary outcome of interest was corticosteroid-free clinical remission (defined as a PCDAI of 10 or less) at 1 year after diagnosis without luminal resection (Gastroenterology 2013 [doi: 10.1053/j.gastro.2013.10.027]).
Of the 552 patients, 68 received early anti-TNF-alpha monotherapy, 248 received early immunomodulator therapy, and 236 received no early immunotherapy. After propensity score matching, 85% of patients treated with early anti-TNF-alpha monotherapy achieved remission at 1 year, compared with 60% of those who were treated with early immunomodulator monotherapy and 54% of those who received no early immunotherapy, a difference that reached statistical significance (P =.0003). When the researchers factored in therapy after 3 months as a covariate, the results did not change; treatment with anti-TNF-alpha monotherapy remained significantly superior to early immunomodulator monotherapy (risk ratio, 1.51; P =.0004), while early immunomodulator monotherapy was no different from no early immunotherapy (RR, 1.00; P =.99).
Dr. Walters and his associates also observed that while weight and body mass index scores improved in all three groups, the height z score only showed improvement in the early anti-TNF-alpha group.
"Although our data clearly have added to the evidence base guiding treatment decisions after a diagnosis of Crohn’s disease in children, they should not be taken as an endorsement of one early therapeutic regimen over another," the authors concluded. "We were not able to identify any common clinical or laboratory characteristic that predicted response or failure with a particular approach. Further genetic, serologic, and microbiome analysis of our study cohort in conjunction with comparative efficacy results will better elucidate the value of different treatment decisions."
The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Walters and many of his coauthors disclosed having received research support, consulting fees, or being on the speakers bureau for numerous pharmaceutical companies.
FROM GASTROENTEROLOGY
Major finding: After propensity score matching, 85% of children with Crohn’s disease who were treated with early anti-TNF-alpha monotherapy achieved remission at 1 year, compared with 60% of those who were treated with early immunomodulator monotherapy and 54% of those who received no early immunotherapy, a difference that reached statistical significance (P =.0003).
Data source: An observational cohort study of 552 patients enrolled in the ongoing Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children With Crohn’s Disease trial.
Disclosures: The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Walters and many of his coauthors disclosed having received research support, consulting fees, or being on the speakers bureau for numerous pharmaceutical companies.
IBD linked to increased risk of certain cancers
Immunosuppressive therapies for inflammatory bowel disease do not appear to be implicated in the increased risk for melanomas and hematologic malignancies seen in these patients, based on the results of a large database analysis and a separate meta-analysis published in the February edition of Clinical Gastroenterology and Hepatology.
The first study, based on a nationwide population-based cohort analysis conducted in Denmark, found that patients with inflammatory bowel disease (IBD) are at increased risk for cancer, in particular hematologic malignancies and melanoma at standardized incidence ratios of 1.9 and 1.4, respectively.
The second study, based on a systematic review and meta-analysis of the medical literature, found a diagnosis of Crohn’s disease or ulcerative colitis was associated with a 37% increase in the risk of developing melanoma. Melanoma risk was higher in studies performed before the introduction of biologic therapies in 1998, but not in those studies performed after 1998.
For the first study, researchers led by Dr. Michael D. Kappelman of the division of pediatric gastroenterology at the University of North Carolina at Chapel Hill used health care databases to identify patients in Denmark with a diagnosis of Crohn’s disease or ulcerative colitis from 1978 through 2010 (doi: 10.1016/j.cgh.2013.03.034). They followed the patients until the first occurrence of cancer, death, or emigration and used standardized incidence ratios (SIRs) to compare cancer incidence in patients with IBD with that expected in the general population.
"If immunosuppressive medications reduce the risk of gastrointestinal malignancy by suppressing intestinal inflammation but increase the risk of extraintestinal malignancies, IBD patients may be trading off one set of risks for another," the researchers wrote. "We therefore sought to evaluate both intestinal and extraintestinal malignancies comprehensively, as well as the occurrence of any invasive cancer, in a nationwide cohort of patients with IBD in Denmark."
The analysis included 13,756 patients with Crohn’s disease and 35,152 patients with ulcerative colitis who were followed up for a mean of nearly 8 years. After the exclusion of cancers diagnosed within 1 year of IBD diagnosis, 772 cases of invasive cancer occurred among patients with Crohn’s disease (SIR 1.3) and 2,331 occurred among patients with ulcerative colitis (SIR 1.1). Diagnosis of Crohn’s disease was weakly associated with gastrointestinal cancers (SIR 1.2) and extraintestinal cancers (SIR 1.3), with the strongest associations for hematologic malignancies (SIR 1.9), smoking-related cancers (SIR 1.5), and melanoma (SIR 1.4). Associations between ulcerative colitis and gastrointestinal and extraintestinal cancers were weaker (SIR of 1.1 for both).
The excess risk of cancer in patients with Crohn’s disease "largely is owing to extraintestinal cancers, particularly hematologic malignancies and melanoma, both of which may be related to immune suppression, and smoking-related cancers," the researchers concluded. They added that their study "provides reassuring data that the decreasing risk for gastrointestinal malignancy observed here ... has not been offset by a concomitant increase in the risk of extraintestinal or hematologic malignancies. These findings suggest that changes in the medical and surgical treatment of IBD and/or other secular trends have not substantially impacted cancer relative risk on a population basis."
The study was supported in part by grants from the National Institute for Diabetes and Digestive and Kidney Diseases, the Karen Elise Jensen Foundation, and the Clinical Epidemiological Research Foundation.
In the second study from the journal, researchers led by Dr. Suddharth Singh of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn., conducted a systematic literature search through March 2013 for cohort studies showing incident melanoma after IBD diagnosis and an estimate of incident rate ratio or standardized incidence rate. Case reports or case series were excluded (doi: 10.1016/j.cgh.2013.04.033).
Of the 838 studies identified, 12 that comprised 172,837 patients with IBD were included in the final analysis. The pooled crude incidence rate of melanoma among patients in the 12 studies was 27.7/100,000 person-years. This translated into a 37% increase in the risk of melanoma (risk ratio of 1.37). The increase was observed independently in the patients with Crohn’s disease (RR 1.51) and in those with ulcerative colitis (RR 1.23). In addition, the risk of melanoma was higher in studies conducted prior to 1998, when biologic therapies were introduced (RR 1.52), but not in those conducted after 1998 (RR 1.08).
"The risk of melanoma has been shown to be increased in immunosuppressed patients, including patients with a prior solid organ transplant, lymphoma, and patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. It is possible that the increased risk of melanoma observed in patients with IBD may be related to underlying immune dysfunction in these patients, resulting in altered tumor surveillance" the researchers wrote.
They hypothesized that immunosuppressive medications may increase the risk of melanoma by "down-regulation of the tumor surveillance mechanisms, increased susceptibility to infection with oncogenic viruses such as melanoma-associated retroviruses, or through direct pharmacologic effects of medications on DNA metabolism. Although thiopurine analogs have been associated with an increased risk of nonmelanoma skin cancers, our pooled analysis did not suggest an increased risk of melanoma, albeit there were a limited number of studies."
Dr. Singh and his associates acknowledged certain limitations of the analysis, including the potential for misclassification bias in the included studies and the fact that studies "did not adjust for known risk factors for melanoma, including personal history of nonmelanoma skin cancers, family history of melanoma, or sun exposure."
For the meta-analysis, one author, Dr. Edward V. Loftus, disclosed that he has consulted for and has received research support from Janssen Biotech, Abbott Laboratories, and UCB Pharma. The others had no relevant conflicts to disclose.
Immunosuppressive therapies for inflammatory bowel disease do not appear to be implicated in the increased risk for melanomas and hematologic malignancies seen in these patients, based on the results of a large database analysis and a separate meta-analysis published in the February edition of Clinical Gastroenterology and Hepatology.
The first study, based on a nationwide population-based cohort analysis conducted in Denmark, found that patients with inflammatory bowel disease (IBD) are at increased risk for cancer, in particular hematologic malignancies and melanoma at standardized incidence ratios of 1.9 and 1.4, respectively.
The second study, based on a systematic review and meta-analysis of the medical literature, found a diagnosis of Crohn’s disease or ulcerative colitis was associated with a 37% increase in the risk of developing melanoma. Melanoma risk was higher in studies performed before the introduction of biologic therapies in 1998, but not in those studies performed after 1998.
For the first study, researchers led by Dr. Michael D. Kappelman of the division of pediatric gastroenterology at the University of North Carolina at Chapel Hill used health care databases to identify patients in Denmark with a diagnosis of Crohn’s disease or ulcerative colitis from 1978 through 2010 (doi: 10.1016/j.cgh.2013.03.034). They followed the patients until the first occurrence of cancer, death, or emigration and used standardized incidence ratios (SIRs) to compare cancer incidence in patients with IBD with that expected in the general population.
"If immunosuppressive medications reduce the risk of gastrointestinal malignancy by suppressing intestinal inflammation but increase the risk of extraintestinal malignancies, IBD patients may be trading off one set of risks for another," the researchers wrote. "We therefore sought to evaluate both intestinal and extraintestinal malignancies comprehensively, as well as the occurrence of any invasive cancer, in a nationwide cohort of patients with IBD in Denmark."
The analysis included 13,756 patients with Crohn’s disease and 35,152 patients with ulcerative colitis who were followed up for a mean of nearly 8 years. After the exclusion of cancers diagnosed within 1 year of IBD diagnosis, 772 cases of invasive cancer occurred among patients with Crohn’s disease (SIR 1.3) and 2,331 occurred among patients with ulcerative colitis (SIR 1.1). Diagnosis of Crohn’s disease was weakly associated with gastrointestinal cancers (SIR 1.2) and extraintestinal cancers (SIR 1.3), with the strongest associations for hematologic malignancies (SIR 1.9), smoking-related cancers (SIR 1.5), and melanoma (SIR 1.4). Associations between ulcerative colitis and gastrointestinal and extraintestinal cancers were weaker (SIR of 1.1 for both).
The excess risk of cancer in patients with Crohn’s disease "largely is owing to extraintestinal cancers, particularly hematologic malignancies and melanoma, both of which may be related to immune suppression, and smoking-related cancers," the researchers concluded. They added that their study "provides reassuring data that the decreasing risk for gastrointestinal malignancy observed here ... has not been offset by a concomitant increase in the risk of extraintestinal or hematologic malignancies. These findings suggest that changes in the medical and surgical treatment of IBD and/or other secular trends have not substantially impacted cancer relative risk on a population basis."
The study was supported in part by grants from the National Institute for Diabetes and Digestive and Kidney Diseases, the Karen Elise Jensen Foundation, and the Clinical Epidemiological Research Foundation.
In the second study from the journal, researchers led by Dr. Suddharth Singh of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn., conducted a systematic literature search through March 2013 for cohort studies showing incident melanoma after IBD diagnosis and an estimate of incident rate ratio or standardized incidence rate. Case reports or case series were excluded (doi: 10.1016/j.cgh.2013.04.033).
Of the 838 studies identified, 12 that comprised 172,837 patients with IBD were included in the final analysis. The pooled crude incidence rate of melanoma among patients in the 12 studies was 27.7/100,000 person-years. This translated into a 37% increase in the risk of melanoma (risk ratio of 1.37). The increase was observed independently in the patients with Crohn’s disease (RR 1.51) and in those with ulcerative colitis (RR 1.23). In addition, the risk of melanoma was higher in studies conducted prior to 1998, when biologic therapies were introduced (RR 1.52), but not in those conducted after 1998 (RR 1.08).
"The risk of melanoma has been shown to be increased in immunosuppressed patients, including patients with a prior solid organ transplant, lymphoma, and patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. It is possible that the increased risk of melanoma observed in patients with IBD may be related to underlying immune dysfunction in these patients, resulting in altered tumor surveillance" the researchers wrote.
They hypothesized that immunosuppressive medications may increase the risk of melanoma by "down-regulation of the tumor surveillance mechanisms, increased susceptibility to infection with oncogenic viruses such as melanoma-associated retroviruses, or through direct pharmacologic effects of medications on DNA metabolism. Although thiopurine analogs have been associated with an increased risk of nonmelanoma skin cancers, our pooled analysis did not suggest an increased risk of melanoma, albeit there were a limited number of studies."
Dr. Singh and his associates acknowledged certain limitations of the analysis, including the potential for misclassification bias in the included studies and the fact that studies "did not adjust for known risk factors for melanoma, including personal history of nonmelanoma skin cancers, family history of melanoma, or sun exposure."
For the meta-analysis, one author, Dr. Edward V. Loftus, disclosed that he has consulted for and has received research support from Janssen Biotech, Abbott Laboratories, and UCB Pharma. The others had no relevant conflicts to disclose.
Immunosuppressive therapies for inflammatory bowel disease do not appear to be implicated in the increased risk for melanomas and hematologic malignancies seen in these patients, based on the results of a large database analysis and a separate meta-analysis published in the February edition of Clinical Gastroenterology and Hepatology.
The first study, based on a nationwide population-based cohort analysis conducted in Denmark, found that patients with inflammatory bowel disease (IBD) are at increased risk for cancer, in particular hematologic malignancies and melanoma at standardized incidence ratios of 1.9 and 1.4, respectively.
The second study, based on a systematic review and meta-analysis of the medical literature, found a diagnosis of Crohn’s disease or ulcerative colitis was associated with a 37% increase in the risk of developing melanoma. Melanoma risk was higher in studies performed before the introduction of biologic therapies in 1998, but not in those studies performed after 1998.
For the first study, researchers led by Dr. Michael D. Kappelman of the division of pediatric gastroenterology at the University of North Carolina at Chapel Hill used health care databases to identify patients in Denmark with a diagnosis of Crohn’s disease or ulcerative colitis from 1978 through 2010 (doi: 10.1016/j.cgh.2013.03.034). They followed the patients until the first occurrence of cancer, death, or emigration and used standardized incidence ratios (SIRs) to compare cancer incidence in patients with IBD with that expected in the general population.
"If immunosuppressive medications reduce the risk of gastrointestinal malignancy by suppressing intestinal inflammation but increase the risk of extraintestinal malignancies, IBD patients may be trading off one set of risks for another," the researchers wrote. "We therefore sought to evaluate both intestinal and extraintestinal malignancies comprehensively, as well as the occurrence of any invasive cancer, in a nationwide cohort of patients with IBD in Denmark."
The analysis included 13,756 patients with Crohn’s disease and 35,152 patients with ulcerative colitis who were followed up for a mean of nearly 8 years. After the exclusion of cancers diagnosed within 1 year of IBD diagnosis, 772 cases of invasive cancer occurred among patients with Crohn’s disease (SIR 1.3) and 2,331 occurred among patients with ulcerative colitis (SIR 1.1). Diagnosis of Crohn’s disease was weakly associated with gastrointestinal cancers (SIR 1.2) and extraintestinal cancers (SIR 1.3), with the strongest associations for hematologic malignancies (SIR 1.9), smoking-related cancers (SIR 1.5), and melanoma (SIR 1.4). Associations between ulcerative colitis and gastrointestinal and extraintestinal cancers were weaker (SIR of 1.1 for both).
The excess risk of cancer in patients with Crohn’s disease "largely is owing to extraintestinal cancers, particularly hematologic malignancies and melanoma, both of which may be related to immune suppression, and smoking-related cancers," the researchers concluded. They added that their study "provides reassuring data that the decreasing risk for gastrointestinal malignancy observed here ... has not been offset by a concomitant increase in the risk of extraintestinal or hematologic malignancies. These findings suggest that changes in the medical and surgical treatment of IBD and/or other secular trends have not substantially impacted cancer relative risk on a population basis."
The study was supported in part by grants from the National Institute for Diabetes and Digestive and Kidney Diseases, the Karen Elise Jensen Foundation, and the Clinical Epidemiological Research Foundation.
In the second study from the journal, researchers led by Dr. Suddharth Singh of the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn., conducted a systematic literature search through March 2013 for cohort studies showing incident melanoma after IBD diagnosis and an estimate of incident rate ratio or standardized incidence rate. Case reports or case series were excluded (doi: 10.1016/j.cgh.2013.04.033).
Of the 838 studies identified, 12 that comprised 172,837 patients with IBD were included in the final analysis. The pooled crude incidence rate of melanoma among patients in the 12 studies was 27.7/100,000 person-years. This translated into a 37% increase in the risk of melanoma (risk ratio of 1.37). The increase was observed independently in the patients with Crohn’s disease (RR 1.51) and in those with ulcerative colitis (RR 1.23). In addition, the risk of melanoma was higher in studies conducted prior to 1998, when biologic therapies were introduced (RR 1.52), but not in those conducted after 1998 (RR 1.08).
"The risk of melanoma has been shown to be increased in immunosuppressed patients, including patients with a prior solid organ transplant, lymphoma, and patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. It is possible that the increased risk of melanoma observed in patients with IBD may be related to underlying immune dysfunction in these patients, resulting in altered tumor surveillance" the researchers wrote.
They hypothesized that immunosuppressive medications may increase the risk of melanoma by "down-regulation of the tumor surveillance mechanisms, increased susceptibility to infection with oncogenic viruses such as melanoma-associated retroviruses, or through direct pharmacologic effects of medications on DNA metabolism. Although thiopurine analogs have been associated with an increased risk of nonmelanoma skin cancers, our pooled analysis did not suggest an increased risk of melanoma, albeit there were a limited number of studies."
Dr. Singh and his associates acknowledged certain limitations of the analysis, including the potential for misclassification bias in the included studies and the fact that studies "did not adjust for known risk factors for melanoma, including personal history of nonmelanoma skin cancers, family history of melanoma, or sun exposure."
For the meta-analysis, one author, Dr. Edward V. Loftus, disclosed that he has consulted for and has received research support from Janssen Biotech, Abbott Laboratories, and UCB Pharma. The others had no relevant conflicts to disclose.
FROM CLINICAL GASTROENTEROLOGY AND hEPATOLOGY
Major finding: In a population-based cohort study, patients with inflammatory bowel disease (IBD) were found to be at increased risk for gastrointestinal and extraintestinal cancer, particularly hematologic malignancies and melanoma (standardized incidence ratios of 1.9 and 1.4, respectively). In a separate meta-analysis, patients with IBD were found to be at 37% increased risk of developing melanoma.
Data source: A population-based study from Denmark involving 48,908 patients with IBD and a meta-analysis involving 172,837 patients with IBD.
Disclosures: The population-based study was supported in part by grants from the National Institute for Diabetes and Digestive and Kidney Diseases, the Karen Elise Jensen Foundation, and the Clinical Epidemiological Research Foundation. For the meta-analysis, one author, Dr. Edward V. Loftus, disclosed that he has consulted for and has received research support from Janssen Biotech, Abbott Laboratories, and UCB Pharma. The others had no relevant conflicts to disclose.
